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Sacral Insufficiency Fracture After Partial Sacrectomy
Chordomas persist as one of the rarer malignancies, accounting for approximately 1% to 4% of primary bone cancers.1 When chordomas occur, these tumors localize predominantly in the sacrococcygeal region.2 In addition to the urgency for addressing a relatively fast-growing tumor, the anatomical complexity of this area complicates the potential treatments. Furthermore, because of the lack of definitive symptoms, diagnosis is often difficult and typically occurs later in the disease progression.3 An aggressive treatment approach is often warranted because of the biologically aggressive nature of this disease. Full or partial sacrectomy is often the only option that offers the possibility of a long-term cure.4 A sacrectomy is a destructive procedure that can lead to mechanical instability depending on the extent of the surgical resection. When the entire sacrum is removed, there is an obvious need for lumbar-pelvic fixation; however, traditionally, partial sacrectomy procedures have been successfully performed without the need for instrumentation.3,4
This report describes the case of a patient with a noninstrumented sacrectomy procedure distal to the S2 foramen that resulted in an insufficiency fracture. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 66-year-old woman presented with severe lower back pain of a month’s duration. Her pain was localized to the coccyx area and did not radiate to the lower legs. Although the pain could not be elicited by palpation, pain occurred when sitting and increased when standing for prolonged periods. Three weeks prior to the patient’s initial office visit, she noticed transient constipation and urinary retention. She denied any fever, chills, nausea, vomiting, unexplained weight loss, weight gain, and abdominal pain. There were no motor deficits in the lower limbs. Sensation was intact in the lower limbs except for the posterior aspect of the left leg down to the popliteal fossa, where light touch perception was absent. She recalled the loss of sensation in this area 20 years earlier, and it had neither progressed nor abated since then. She had a history of osteoarthritis and had been diagnosed with degenerative disc disease 20 years ago.
A radiographic review of her lumbar spine showed significant spinal stenosis and degenerative disease of the lumbar spine on non–contrast-enhanced magnetic resonance imaging (MRI). The MRI also revealed a large, soft-tissue mass at the S3-S4 level, eroding most of the S3 vertebral body and extending into the S4 vertebral body. The MRI images used for this analysis were insufficient in providing a complete portrayal of the entire mass. Because of these uncertainties, contrast-enhanced and non–contrast-enhanced pelvic MRIs were taken. The MRI analyses identified a mass density replacing the lower sacrum and upper coccyx that was bright in intensity on T2 and dim on T1 sequences. Sagittal imaging measurements were 5.9×2.5 cm and 4.4 cm right-to-left on coronal imaging. The mass extended beyond the involved sacrococcygeal segments and dorsally beyond the normal cortical margin of the sacrum and coccyx (Figures 1A, 1B). Next, a computer tomographic–guided needle biopsy through a posterior paraspinal approach was obtained. The biopsy consisted of fragments of a malignant neoplasm consistent with physaliferous cells. The specimen was positive for pankeratin, keratin AE1/AE3, epithelial membrane antigen, and S100 protein. This supported a diagnosis of a sacral chordoma. An en bloc sacrectomy at S2; lumbar laminectomy at L5, S1, and S2; and thecal sac transection at the S3 nerve roots were planned.
Surgical Procedure
The patient was placed in the prone position after a colostomy and harvesting of a rectus flap in the supine position. A midline incision was made from the spinous process of L5 down through the tip of the coccyx, and soft tissues were elevated while maintaining hemostasis. The most distal part of the coccyx was transected, and using a combination of electrocautery and paraspinal elevators, rectal and peritoneal tissues were elevated off the ventral component of the coccyx until a hand could easily reach the bifurcation of the iliac vessels. Electrocautery transected paraspinal muscles at the S1 and S2 levels while the more cranial paraspinal musculature was elevated to allow for a laminectomy. The spinous processes were removed from L5 and the sacrum with a Leksell rongeur. A high-speed burr thinned the dorsal lamina components of L5, S1, and the leading edge of S2. The L5, S1, and S2 nerve roots were identified. The gluteal muscles were elevated and the sacral coccygeal ligaments were transected. After identifying the sciatic notches, the S2 nerves exiting the foramen were identified, followed out through the sciatic notch, and a wire was passed through this region. Three 2-0 silk ties were applied to the exposed portion of the S3 and S4 nerve roots, and the nerves were transected because they were integrally involved with the tumor. Using a series of high-speed burrs and osteotomes, lateral cuts were made through the sciatic notch. The sacrum was osteotomized at the S2 sacral foramen through the anterior component with an osteotome, while a hand protected the ventral structures. The remaining parts of the S3 and S4 dorsal nerve roots were transected. An incision through the peritoneum was made to access the rectus flap, and a plastic surgeon closed the wounds and secured the flap.
Postoperative Course
The patient’s final pathology confirmed a chordoma with negative margins. Postoperatively, the rectus flap became ischemic and a wound infection developed. It was irrigated, débrided, and treated with vacuum-assisted closure (VAC), in addition to perioperative antibiotic administration. An abdominal computed tomography (CT) scan did not show any fistula, and her wound remained healthy, pink, and viable as her VAC was changed every 3 days. Because the patient’s nutritional status was compromised, she started nutritional supplements in addition to a regular diet. Physical therapy was prescribed and the patient began bladder training with self-catheterization after a failed voiding trial attempt. After 2 months of convalescence, the patient had mobilized well and had progressed to walking without an ambulatory aide.
At her third postoperative month, the patient noted new onset of extreme pain in the groin and left thigh regions. The patient was examined and appeared to have a stable neurological exam. She had reproducible pain with a FABER (Flexion, Abduction, External Rotation, and Extension) test. MRI showed increased signal on short tau inversion recovery (STIR) sequences and T2-weighted images that was consistent with a left sacral ala stress fracture with a vertically oriented fracture line (Figures 2A, 2B). The patient was asked to begin utilizing a walker for ambulatory assistance, but her weight-bearing status was not changed. Over the course of 3 months, the patient noted a resolution of her pain. All postoperative MRI images confirmed the patient to be disease-free; and in addition, all of her follow-up radiographs showed a stable pelvic ring (Figures 3A, 3B). At her 2-year follow-up, the patient remained disease- and pain-free.
Discussion
Full discussions of the mechanical considerations of a partial sacrectomy have been described previously5-8; however, surgeons typically consider the need for lumbar-pelvic stabilization when the surgical resection requires a violation of the S1 body. Approximately two-thirds of sacral tumors occur at or below the level of the S2 body.8 These lesions of the caudal sacrum can sometimes be effectively resected with transverse partial sacrectomy. Great care is taken to resect only the portion of the sacrum necessary for local disease control, sparing as much of the sacroiliac joint and as many of the lumbosacral nerve roots as possible.
Under normal conditions, the sacroiliac articulation is stabilized by both its geometric interface and its extraordinarily strong ligaments. This spatial arrangement conveys stability primarily against caudal migration of the sacrum. The sacroiliac, sacrotuberous, sacrospinous, and lumbosacral ligaments, which are among the strongest ligaments in the body, primarily act to provide stability to the pelvic ring by preventing diastasis. The combination of these factors renders the spinopelvic segment especially stable. Previously, 2 biomechanical studies that specifically looked at extreme loading patterns to better understand the need for lumbar-pelvic instrumentation predicted a fracture pattern when there was an inability of the base of the sacral ala to resist shear.8,9 This is precisely where our patient’s insufficiency fracture occurred.
To our knowledge, this is the first reported in vivo evidence of this fracture pattern. While this patient’s potential history of osteoporosis may have elevated or contributed to her risk for fracture, her preoperative bone densitometry, with T scores of -1.0 on the left and right femur necks and 0.8 on her L1-L4 anteroposterior spine, would argue against this risk factor. None of these values represent a truly osteoporotic patient. It would appear that our patient sustained the fracture pattern predicted by Hugate and colleagues.8
The edema seen on the MRI most likely represents a fracture; however, sacroiliitis and infection are also potential diagnoses. Because there was no tumor in this region on the preoperative scans, we thought that a residual tumor was unlikely. The signal changes seen on T2 MRI sequences represent edema. The use of a bone scan that detects healing bone may have been a useful additional study to confirm this fracture as opposed to sacroiliitis. A CT scan would have been a potentially useful study to provide detail of fracture displacement and the overall fracture pattern. Standing plain radiographs are best for viewing fracture displacement with weight-bearing.
Surgeons contemplating performing partial sacrectomies should bear in mind that, even with preservation of the S1 body, a potential for fracture exists as evidenced by our patient. In our opinion, this patient did not require instrumentation but a more gradual rehabilitation program.
1. Varga PP, Lazary A. Chordoma of the sacrum: “en bloc” total sacrectomy and lumbopelvic reconstruction. Eur Spine. 2010;19(6):1039-1040.
2. Heffelfinger MJ, Dahlin DC, MacCarty CS, Beabout JW. Chordomas and cartilaginous tumors at the skull base. Cancer. 1973; 32(2):410-420.
3. Varga PP, Bors I, Lazary A. Sacral tumors and management. Orthop Clin North Am. 2009;40(1):105-123.
4. Puri A, Agarwal MG, Shah M, et al. Decision making in primary sacral tumors. Spine J. 2009;9(5):396-403.
5. Cheng L, Yu Y, Zhu R, et al. Structural stability of different reconstruction techniques following total sacrectomy: a biomechanical study. Clin Biomech (Bristol, Avon). 2011;26 (10):977-981.
6. Yu BS, Zhuang XM, Li ZM, et al. Biomechanical effects of the extent of sacrectomy on the stability of lumbo-iliac reconstruction using iliac screw techniques: What level of sacrectomy requires the bilateral dual iliac screw technique? Clin Biomech (Bristol, Avon). 2010;25(9):867-872.
7. Yu B, Zheng Z, Zhuang X, et al. Biomechanical effects of transverse partial sacrectomy on the sacroiliac joints: an in vitro human cadaveric investigation of the borderline of sacroiliac joint instability. Spine (Phila Pa 1976). 2009;34(13):1370-1375.
8. Hugate RR Jr, Dickey ID, Phimolsarnti R, Yaszemski MJ, Sim FH. Mechanical effects of partial sacrectomy: when is reconstruction necessary? Clin Orthop. 2006;450:82-88.
9. Gunterberg B, Romanus B, Stener B. Pelvic strength after major amputation of the sacrum. An experimental study. Acta Orthop Scand. 1976; 47(6):635-642.
Chordomas persist as one of the rarer malignancies, accounting for approximately 1% to 4% of primary bone cancers.1 When chordomas occur, these tumors localize predominantly in the sacrococcygeal region.2 In addition to the urgency for addressing a relatively fast-growing tumor, the anatomical complexity of this area complicates the potential treatments. Furthermore, because of the lack of definitive symptoms, diagnosis is often difficult and typically occurs later in the disease progression.3 An aggressive treatment approach is often warranted because of the biologically aggressive nature of this disease. Full or partial sacrectomy is often the only option that offers the possibility of a long-term cure.4 A sacrectomy is a destructive procedure that can lead to mechanical instability depending on the extent of the surgical resection. When the entire sacrum is removed, there is an obvious need for lumbar-pelvic fixation; however, traditionally, partial sacrectomy procedures have been successfully performed without the need for instrumentation.3,4
This report describes the case of a patient with a noninstrumented sacrectomy procedure distal to the S2 foramen that resulted in an insufficiency fracture. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 66-year-old woman presented with severe lower back pain of a month’s duration. Her pain was localized to the coccyx area and did not radiate to the lower legs. Although the pain could not be elicited by palpation, pain occurred when sitting and increased when standing for prolonged periods. Three weeks prior to the patient’s initial office visit, she noticed transient constipation and urinary retention. She denied any fever, chills, nausea, vomiting, unexplained weight loss, weight gain, and abdominal pain. There were no motor deficits in the lower limbs. Sensation was intact in the lower limbs except for the posterior aspect of the left leg down to the popliteal fossa, where light touch perception was absent. She recalled the loss of sensation in this area 20 years earlier, and it had neither progressed nor abated since then. She had a history of osteoarthritis and had been diagnosed with degenerative disc disease 20 years ago.
A radiographic review of her lumbar spine showed significant spinal stenosis and degenerative disease of the lumbar spine on non–contrast-enhanced magnetic resonance imaging (MRI). The MRI also revealed a large, soft-tissue mass at the S3-S4 level, eroding most of the S3 vertebral body and extending into the S4 vertebral body. The MRI images used for this analysis were insufficient in providing a complete portrayal of the entire mass. Because of these uncertainties, contrast-enhanced and non–contrast-enhanced pelvic MRIs were taken. The MRI analyses identified a mass density replacing the lower sacrum and upper coccyx that was bright in intensity on T2 and dim on T1 sequences. Sagittal imaging measurements were 5.9×2.5 cm and 4.4 cm right-to-left on coronal imaging. The mass extended beyond the involved sacrococcygeal segments and dorsally beyond the normal cortical margin of the sacrum and coccyx (Figures 1A, 1B). Next, a computer tomographic–guided needle biopsy through a posterior paraspinal approach was obtained. The biopsy consisted of fragments of a malignant neoplasm consistent with physaliferous cells. The specimen was positive for pankeratin, keratin AE1/AE3, epithelial membrane antigen, and S100 protein. This supported a diagnosis of a sacral chordoma. An en bloc sacrectomy at S2; lumbar laminectomy at L5, S1, and S2; and thecal sac transection at the S3 nerve roots were planned.
Surgical Procedure
The patient was placed in the prone position after a colostomy and harvesting of a rectus flap in the supine position. A midline incision was made from the spinous process of L5 down through the tip of the coccyx, and soft tissues were elevated while maintaining hemostasis. The most distal part of the coccyx was transected, and using a combination of electrocautery and paraspinal elevators, rectal and peritoneal tissues were elevated off the ventral component of the coccyx until a hand could easily reach the bifurcation of the iliac vessels. Electrocautery transected paraspinal muscles at the S1 and S2 levels while the more cranial paraspinal musculature was elevated to allow for a laminectomy. The spinous processes were removed from L5 and the sacrum with a Leksell rongeur. A high-speed burr thinned the dorsal lamina components of L5, S1, and the leading edge of S2. The L5, S1, and S2 nerve roots were identified. The gluteal muscles were elevated and the sacral coccygeal ligaments were transected. After identifying the sciatic notches, the S2 nerves exiting the foramen were identified, followed out through the sciatic notch, and a wire was passed through this region. Three 2-0 silk ties were applied to the exposed portion of the S3 and S4 nerve roots, and the nerves were transected because they were integrally involved with the tumor. Using a series of high-speed burrs and osteotomes, lateral cuts were made through the sciatic notch. The sacrum was osteotomized at the S2 sacral foramen through the anterior component with an osteotome, while a hand protected the ventral structures. The remaining parts of the S3 and S4 dorsal nerve roots were transected. An incision through the peritoneum was made to access the rectus flap, and a plastic surgeon closed the wounds and secured the flap.
Postoperative Course
The patient’s final pathology confirmed a chordoma with negative margins. Postoperatively, the rectus flap became ischemic and a wound infection developed. It was irrigated, débrided, and treated with vacuum-assisted closure (VAC), in addition to perioperative antibiotic administration. An abdominal computed tomography (CT) scan did not show any fistula, and her wound remained healthy, pink, and viable as her VAC was changed every 3 days. Because the patient’s nutritional status was compromised, she started nutritional supplements in addition to a regular diet. Physical therapy was prescribed and the patient began bladder training with self-catheterization after a failed voiding trial attempt. After 2 months of convalescence, the patient had mobilized well and had progressed to walking without an ambulatory aide.
At her third postoperative month, the patient noted new onset of extreme pain in the groin and left thigh regions. The patient was examined and appeared to have a stable neurological exam. She had reproducible pain with a FABER (Flexion, Abduction, External Rotation, and Extension) test. MRI showed increased signal on short tau inversion recovery (STIR) sequences and T2-weighted images that was consistent with a left sacral ala stress fracture with a vertically oriented fracture line (Figures 2A, 2B). The patient was asked to begin utilizing a walker for ambulatory assistance, but her weight-bearing status was not changed. Over the course of 3 months, the patient noted a resolution of her pain. All postoperative MRI images confirmed the patient to be disease-free; and in addition, all of her follow-up radiographs showed a stable pelvic ring (Figures 3A, 3B). At her 2-year follow-up, the patient remained disease- and pain-free.
Discussion
Full discussions of the mechanical considerations of a partial sacrectomy have been described previously5-8; however, surgeons typically consider the need for lumbar-pelvic stabilization when the surgical resection requires a violation of the S1 body. Approximately two-thirds of sacral tumors occur at or below the level of the S2 body.8 These lesions of the caudal sacrum can sometimes be effectively resected with transverse partial sacrectomy. Great care is taken to resect only the portion of the sacrum necessary for local disease control, sparing as much of the sacroiliac joint and as many of the lumbosacral nerve roots as possible.
Under normal conditions, the sacroiliac articulation is stabilized by both its geometric interface and its extraordinarily strong ligaments. This spatial arrangement conveys stability primarily against caudal migration of the sacrum. The sacroiliac, sacrotuberous, sacrospinous, and lumbosacral ligaments, which are among the strongest ligaments in the body, primarily act to provide stability to the pelvic ring by preventing diastasis. The combination of these factors renders the spinopelvic segment especially stable. Previously, 2 biomechanical studies that specifically looked at extreme loading patterns to better understand the need for lumbar-pelvic instrumentation predicted a fracture pattern when there was an inability of the base of the sacral ala to resist shear.8,9 This is precisely where our patient’s insufficiency fracture occurred.
To our knowledge, this is the first reported in vivo evidence of this fracture pattern. While this patient’s potential history of osteoporosis may have elevated or contributed to her risk for fracture, her preoperative bone densitometry, with T scores of -1.0 on the left and right femur necks and 0.8 on her L1-L4 anteroposterior spine, would argue against this risk factor. None of these values represent a truly osteoporotic patient. It would appear that our patient sustained the fracture pattern predicted by Hugate and colleagues.8
The edema seen on the MRI most likely represents a fracture; however, sacroiliitis and infection are also potential diagnoses. Because there was no tumor in this region on the preoperative scans, we thought that a residual tumor was unlikely. The signal changes seen on T2 MRI sequences represent edema. The use of a bone scan that detects healing bone may have been a useful additional study to confirm this fracture as opposed to sacroiliitis. A CT scan would have been a potentially useful study to provide detail of fracture displacement and the overall fracture pattern. Standing plain radiographs are best for viewing fracture displacement with weight-bearing.
Surgeons contemplating performing partial sacrectomies should bear in mind that, even with preservation of the S1 body, a potential for fracture exists as evidenced by our patient. In our opinion, this patient did not require instrumentation but a more gradual rehabilitation program.
Chordomas persist as one of the rarer malignancies, accounting for approximately 1% to 4% of primary bone cancers.1 When chordomas occur, these tumors localize predominantly in the sacrococcygeal region.2 In addition to the urgency for addressing a relatively fast-growing tumor, the anatomical complexity of this area complicates the potential treatments. Furthermore, because of the lack of definitive symptoms, diagnosis is often difficult and typically occurs later in the disease progression.3 An aggressive treatment approach is often warranted because of the biologically aggressive nature of this disease. Full or partial sacrectomy is often the only option that offers the possibility of a long-term cure.4 A sacrectomy is a destructive procedure that can lead to mechanical instability depending on the extent of the surgical resection. When the entire sacrum is removed, there is an obvious need for lumbar-pelvic fixation; however, traditionally, partial sacrectomy procedures have been successfully performed without the need for instrumentation.3,4
This report describes the case of a patient with a noninstrumented sacrectomy procedure distal to the S2 foramen that resulted in an insufficiency fracture. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 66-year-old woman presented with severe lower back pain of a month’s duration. Her pain was localized to the coccyx area and did not radiate to the lower legs. Although the pain could not be elicited by palpation, pain occurred when sitting and increased when standing for prolonged periods. Three weeks prior to the patient’s initial office visit, she noticed transient constipation and urinary retention. She denied any fever, chills, nausea, vomiting, unexplained weight loss, weight gain, and abdominal pain. There were no motor deficits in the lower limbs. Sensation was intact in the lower limbs except for the posterior aspect of the left leg down to the popliteal fossa, where light touch perception was absent. She recalled the loss of sensation in this area 20 years earlier, and it had neither progressed nor abated since then. She had a history of osteoarthritis and had been diagnosed with degenerative disc disease 20 years ago.
A radiographic review of her lumbar spine showed significant spinal stenosis and degenerative disease of the lumbar spine on non–contrast-enhanced magnetic resonance imaging (MRI). The MRI also revealed a large, soft-tissue mass at the S3-S4 level, eroding most of the S3 vertebral body and extending into the S4 vertebral body. The MRI images used for this analysis were insufficient in providing a complete portrayal of the entire mass. Because of these uncertainties, contrast-enhanced and non–contrast-enhanced pelvic MRIs were taken. The MRI analyses identified a mass density replacing the lower sacrum and upper coccyx that was bright in intensity on T2 and dim on T1 sequences. Sagittal imaging measurements were 5.9×2.5 cm and 4.4 cm right-to-left on coronal imaging. The mass extended beyond the involved sacrococcygeal segments and dorsally beyond the normal cortical margin of the sacrum and coccyx (Figures 1A, 1B). Next, a computer tomographic–guided needle biopsy through a posterior paraspinal approach was obtained. The biopsy consisted of fragments of a malignant neoplasm consistent with physaliferous cells. The specimen was positive for pankeratin, keratin AE1/AE3, epithelial membrane antigen, and S100 protein. This supported a diagnosis of a sacral chordoma. An en bloc sacrectomy at S2; lumbar laminectomy at L5, S1, and S2; and thecal sac transection at the S3 nerve roots were planned.
Surgical Procedure
The patient was placed in the prone position after a colostomy and harvesting of a rectus flap in the supine position. A midline incision was made from the spinous process of L5 down through the tip of the coccyx, and soft tissues were elevated while maintaining hemostasis. The most distal part of the coccyx was transected, and using a combination of electrocautery and paraspinal elevators, rectal and peritoneal tissues were elevated off the ventral component of the coccyx until a hand could easily reach the bifurcation of the iliac vessels. Electrocautery transected paraspinal muscles at the S1 and S2 levels while the more cranial paraspinal musculature was elevated to allow for a laminectomy. The spinous processes were removed from L5 and the sacrum with a Leksell rongeur. A high-speed burr thinned the dorsal lamina components of L5, S1, and the leading edge of S2. The L5, S1, and S2 nerve roots were identified. The gluteal muscles were elevated and the sacral coccygeal ligaments were transected. After identifying the sciatic notches, the S2 nerves exiting the foramen were identified, followed out through the sciatic notch, and a wire was passed through this region. Three 2-0 silk ties were applied to the exposed portion of the S3 and S4 nerve roots, and the nerves were transected because they were integrally involved with the tumor. Using a series of high-speed burrs and osteotomes, lateral cuts were made through the sciatic notch. The sacrum was osteotomized at the S2 sacral foramen through the anterior component with an osteotome, while a hand protected the ventral structures. The remaining parts of the S3 and S4 dorsal nerve roots were transected. An incision through the peritoneum was made to access the rectus flap, and a plastic surgeon closed the wounds and secured the flap.
Postoperative Course
The patient’s final pathology confirmed a chordoma with negative margins. Postoperatively, the rectus flap became ischemic and a wound infection developed. It was irrigated, débrided, and treated with vacuum-assisted closure (VAC), in addition to perioperative antibiotic administration. An abdominal computed tomography (CT) scan did not show any fistula, and her wound remained healthy, pink, and viable as her VAC was changed every 3 days. Because the patient’s nutritional status was compromised, she started nutritional supplements in addition to a regular diet. Physical therapy was prescribed and the patient began bladder training with self-catheterization after a failed voiding trial attempt. After 2 months of convalescence, the patient had mobilized well and had progressed to walking without an ambulatory aide.
At her third postoperative month, the patient noted new onset of extreme pain in the groin and left thigh regions. The patient was examined and appeared to have a stable neurological exam. She had reproducible pain with a FABER (Flexion, Abduction, External Rotation, and Extension) test. MRI showed increased signal on short tau inversion recovery (STIR) sequences and T2-weighted images that was consistent with a left sacral ala stress fracture with a vertically oriented fracture line (Figures 2A, 2B). The patient was asked to begin utilizing a walker for ambulatory assistance, but her weight-bearing status was not changed. Over the course of 3 months, the patient noted a resolution of her pain. All postoperative MRI images confirmed the patient to be disease-free; and in addition, all of her follow-up radiographs showed a stable pelvic ring (Figures 3A, 3B). At her 2-year follow-up, the patient remained disease- and pain-free.
Discussion
Full discussions of the mechanical considerations of a partial sacrectomy have been described previously5-8; however, surgeons typically consider the need for lumbar-pelvic stabilization when the surgical resection requires a violation of the S1 body. Approximately two-thirds of sacral tumors occur at or below the level of the S2 body.8 These lesions of the caudal sacrum can sometimes be effectively resected with transverse partial sacrectomy. Great care is taken to resect only the portion of the sacrum necessary for local disease control, sparing as much of the sacroiliac joint and as many of the lumbosacral nerve roots as possible.
Under normal conditions, the sacroiliac articulation is stabilized by both its geometric interface and its extraordinarily strong ligaments. This spatial arrangement conveys stability primarily against caudal migration of the sacrum. The sacroiliac, sacrotuberous, sacrospinous, and lumbosacral ligaments, which are among the strongest ligaments in the body, primarily act to provide stability to the pelvic ring by preventing diastasis. The combination of these factors renders the spinopelvic segment especially stable. Previously, 2 biomechanical studies that specifically looked at extreme loading patterns to better understand the need for lumbar-pelvic instrumentation predicted a fracture pattern when there was an inability of the base of the sacral ala to resist shear.8,9 This is precisely where our patient’s insufficiency fracture occurred.
To our knowledge, this is the first reported in vivo evidence of this fracture pattern. While this patient’s potential history of osteoporosis may have elevated or contributed to her risk for fracture, her preoperative bone densitometry, with T scores of -1.0 on the left and right femur necks and 0.8 on her L1-L4 anteroposterior spine, would argue against this risk factor. None of these values represent a truly osteoporotic patient. It would appear that our patient sustained the fracture pattern predicted by Hugate and colleagues.8
The edema seen on the MRI most likely represents a fracture; however, sacroiliitis and infection are also potential diagnoses. Because there was no tumor in this region on the preoperative scans, we thought that a residual tumor was unlikely. The signal changes seen on T2 MRI sequences represent edema. The use of a bone scan that detects healing bone may have been a useful additional study to confirm this fracture as opposed to sacroiliitis. A CT scan would have been a potentially useful study to provide detail of fracture displacement and the overall fracture pattern. Standing plain radiographs are best for viewing fracture displacement with weight-bearing.
Surgeons contemplating performing partial sacrectomies should bear in mind that, even with preservation of the S1 body, a potential for fracture exists as evidenced by our patient. In our opinion, this patient did not require instrumentation but a more gradual rehabilitation program.
1. Varga PP, Lazary A. Chordoma of the sacrum: “en bloc” total sacrectomy and lumbopelvic reconstruction. Eur Spine. 2010;19(6):1039-1040.
2. Heffelfinger MJ, Dahlin DC, MacCarty CS, Beabout JW. Chordomas and cartilaginous tumors at the skull base. Cancer. 1973; 32(2):410-420.
3. Varga PP, Bors I, Lazary A. Sacral tumors and management. Orthop Clin North Am. 2009;40(1):105-123.
4. Puri A, Agarwal MG, Shah M, et al. Decision making in primary sacral tumors. Spine J. 2009;9(5):396-403.
5. Cheng L, Yu Y, Zhu R, et al. Structural stability of different reconstruction techniques following total sacrectomy: a biomechanical study. Clin Biomech (Bristol, Avon). 2011;26 (10):977-981.
6. Yu BS, Zhuang XM, Li ZM, et al. Biomechanical effects of the extent of sacrectomy on the stability of lumbo-iliac reconstruction using iliac screw techniques: What level of sacrectomy requires the bilateral dual iliac screw technique? Clin Biomech (Bristol, Avon). 2010;25(9):867-872.
7. Yu B, Zheng Z, Zhuang X, et al. Biomechanical effects of transverse partial sacrectomy on the sacroiliac joints: an in vitro human cadaveric investigation of the borderline of sacroiliac joint instability. Spine (Phila Pa 1976). 2009;34(13):1370-1375.
8. Hugate RR Jr, Dickey ID, Phimolsarnti R, Yaszemski MJ, Sim FH. Mechanical effects of partial sacrectomy: when is reconstruction necessary? Clin Orthop. 2006;450:82-88.
9. Gunterberg B, Romanus B, Stener B. Pelvic strength after major amputation of the sacrum. An experimental study. Acta Orthop Scand. 1976; 47(6):635-642.
1. Varga PP, Lazary A. Chordoma of the sacrum: “en bloc” total sacrectomy and lumbopelvic reconstruction. Eur Spine. 2010;19(6):1039-1040.
2. Heffelfinger MJ, Dahlin DC, MacCarty CS, Beabout JW. Chordomas and cartilaginous tumors at the skull base. Cancer. 1973; 32(2):410-420.
3. Varga PP, Bors I, Lazary A. Sacral tumors and management. Orthop Clin North Am. 2009;40(1):105-123.
4. Puri A, Agarwal MG, Shah M, et al. Decision making in primary sacral tumors. Spine J. 2009;9(5):396-403.
5. Cheng L, Yu Y, Zhu R, et al. Structural stability of different reconstruction techniques following total sacrectomy: a biomechanical study. Clin Biomech (Bristol, Avon). 2011;26 (10):977-981.
6. Yu BS, Zhuang XM, Li ZM, et al. Biomechanical effects of the extent of sacrectomy on the stability of lumbo-iliac reconstruction using iliac screw techniques: What level of sacrectomy requires the bilateral dual iliac screw technique? Clin Biomech (Bristol, Avon). 2010;25(9):867-872.
7. Yu B, Zheng Z, Zhuang X, et al. Biomechanical effects of transverse partial sacrectomy on the sacroiliac joints: an in vitro human cadaveric investigation of the borderline of sacroiliac joint instability. Spine (Phila Pa 1976). 2009;34(13):1370-1375.
8. Hugate RR Jr, Dickey ID, Phimolsarnti R, Yaszemski MJ, Sim FH. Mechanical effects of partial sacrectomy: when is reconstruction necessary? Clin Orthop. 2006;450:82-88.
9. Gunterberg B, Romanus B, Stener B. Pelvic strength after major amputation of the sacrum. An experimental study. Acta Orthop Scand. 1976; 47(6):635-642.
Surgery for Blastomycosis of the Spine
Blastomycosis is a rare fungal infection that primarily produces acute lung infections but may on occasion disseminate to multiple sites, including the skin, bone, central nervous system (CNS), and oropharynx.1-30 In the case of a primary infection of the lung, if there is a high index of suspicion and a thorough diagnostic workup, the diagnosis can be made from sputum or bronchoscopy.24 Patients present with acute pneumonia that either resolves spontaneously or proceeds to chronic pneumonia with extrapulmonary spread to multiple organs, including the spine. Once vertebral involvement occurs, an untreated infection may result in vertebral body destruction and paraspinal and epidural abscess formation followed by neurologic injury and loss of structural integrity of the spine.11,13,17,23,27,29
In this article, we present a case of blastomycosis of the vertebral body and provide a detailed review of the literature concerning this extremely rare infection of the spine. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 30-year-old African American man with known pulmonary blastomycosis, for which he had been treated with oral itraconazole 200 mg twice daily for 6 months, was admitted to the hospital with a 2-month history of mild thoracolumbar back pain. He reported transient numbness and tingling in the lower extremities but no weakness. He denied weight loss, fatigue, appetite loss, and significant night pain. On physical examination, he was alert and oriented, well nourished, and in no acute distress. Percussion revealed limited range of motion and pain. Further examination of the spine demonstrated no spasm, swelling, erythema, or drainage. The lower extremities had intact sensation, motor strength, reflexes, and pulses, and clonus was absent. White blood cell count was 8100 cells/μL (normal), erythrocyte sedimentation rate was 77 mm/h (normal range, 0-20 mm/h), and C-reactive protein level was 57.2 mg/L (normal, ≤ 10 mg/L). The patient was HIV-negative. Chest radiographs were normal except for a small pleural effusion. Radiographs showed a destructive lesion of T11 with an extensive paravertebral and retropleural abscess tracking a spinal level above and below with extension into the spinal canal (Figure 1).
As the patient had signs of spinal cord compression, he was taken to surgery for incision and drainage and culture procurement and corpectomy of T11 with autogenous rib graft. One week later, he was stabilized with posterior fusion and instrumentation (Figure 2). Gram stain of the specimen demonstrated broad-based budding yeast forms 15 to 20 micrometers in size, consistent with blastomycosis. Cultures were positive for Blastomyces dermatitidis. Histopathologic slides (Figure 3) of the surgical pathology specimen showed granulomatous inflammation. Oral itraconazole 200 mg twice daily was continued, as it has been found to be efficacious in treating immunocompetent patients with blastomycosis17 and is considered the medication of choice for non–life-threatening, non-CNS blastomycosis. (Intravenous amphotericin B was ruled out because of its known serious side effects, such as bone marrow suppression and renal function impairment10; itraconazole was the better alternative.) The patient was placed in a thoracolumbar orthosis and discharged. As the effect of presence of instrumentation in the setting of a fungal infection is unknown, it was deemed prudent to maintain the patient on chronic antifungal suppression. One year after surgery, computed tomography (CT) showed solid osseous bridging through the cage crossing the T11 vertebral body, from the inferior endplate of T10 through the superior endplate of T12 (Figure 4). In addition, there had been no recurrence of the spinal infection, and the patient was neurologically intact and doing well.
Discussion
North American blastomycosis (B dermatitidis) is a ubiquitous dimorphic fungus that occurs worldwide and on occasion causes serious infections in humans.9,23,26,29 It was first characterized in 1894 by Gilchrist and Stokes (Gilchrist disease) when they recovered the fungus from the lung tissue of a patient.3 In North America, blastomycosis infections occur from central Canada to the Gulf Coast to east of the Mississippi River.2,5,7,8,13,14,17,21,22,24,27,29 Additional cases of the disease have been reported in Africa,9,16,23,28 Asia,12,19 and South America7,8 (Table [on pages E270-E271]). Recent epidemiologic studies have linked transmission of the disease to bodies of water and have questioned previous reports of male predominance and racial preference for African Americans (Table).
Blastomycosis is acquired when inhaled fungus (airborne conidia spores) causes a primary pulmonary infection or, rarely, when there is direct inoculation through the skin. The differential diagnosis includes neoplasm, tuberculosis, actinomycosis, bacterial infections, cryptococcosis, and coccidioidomycosis.3,9,12,20,25,31 Blastomycosis occurs in adults and children.1-30 The rate of mortality is much higher in immunocompromised patients. Initial symptoms include fever, chills, fatigue, malaise, myalgia, arthalgia, weight loss, and stigmata of chronic disease.1-30 Acute pulmonary infection with blastomycosis generally resolves spontaneously but may progress to acute respiratory distress syndrome, which has a mortality rate of 50% to 89%.19 With systemic dissemination, the infection may spread to other organs11—there is a particular predilection for the skin9,20,29—and to the long bones7,16 and the oropharynx.16,26,28
In 50% to 64% of cases, bone involvement may be the first disease manifestation.6,7,16,22 Osseous involvement with blastomycosis most commonly affects the long bones15 but may include the vertebrae,1-29 the ribs,26 and the carpal or tarsal bones.7,16 The most common vertebral involvement occurs in the thoracic or lumbar spine1,2,7-9,11-14,17,19,21-24,26 and typically results in destruction of the body, development of a paraspinal abscess, and potential extension into the spinal canal, causing an epidural abscess and development of chronic draining cutaneous sinuses.2,7,9,11-13,16,17,19,22,23,26,28,29 In the present case, we do not know whether the vertebral body was involved before the patient presented with mid-thoracolumbar back pain. There may have been bony involvement during initial presentation.
Diagnosis is often difficult because of a low index of suspicion, leading to a significant delay in treatment. Primary pulmonary infections are successfully diagnosed 86% of the time from sputum and 92% of the time from bronchoscopy.19 Once the infection involves the spine, plain radiographs, CT, and magnetic resonance imaging (MRI) can be used to identify not only the bony involvement but also any adjacent soft-tissue extension.13 The radiographic findings, typical of tuberculosis or a neoplasm, include disc space narrowing, vertebral body destruction and collapse, late segmental kyphotic deformity, and development of a psoas abscess or a retropleural abscess.7,26 Such abscesses lend themselves well to fine-needle aspiration,7,8,11,13,14,17,19,26 which, when combined with CT and MRI guidance, reliably assists in the diagnosis of blastomycosis.1,13,17 If fine-needle aspiration fails, then open biopsy and surgical débridement specimens may be effective in the diagnosis.2,9,12,21,22,27
The mortality rate for systemic blastomycosis exceeded 90% before the development of antifungal medications, and these medications remain the primary treatment for most initial infections.15 For severe infections in critically ill patients and for patients with CNS involvement, amphotericin B has been effective, with cure rates approaching 97%.17 Itraconazole, which is well tolerated, has replaced ketoconazole as the preferred long-term oral treatment for blastomycosis. Cure rates for itraconazole approach 90% when treatment is instituted over 2 years in a compliant patient.10,19,20 Nonsurgical (antifungal) treatment for blastomycosis of the spine has also proved successful in neurologically intact patients.7,9,11,26,28
A case involving the spine and requiring surgical drainage was first reported in 19085; since then, only a few more cases have been reported.1,2,5,7-9,11-14,16,17,19,21-24,26-29 Thus, the literature includes very little information that can be used to establish indications for surgery for a blastomycotic infection of the spine. However, there is enough evidence to establish that surgery is indicated for patients who have a known blastomycosis infection and are developing neurologic or structural loss of integrity of the spinal column or have an abscess that requires drainage and débridement.
Our patient had been on long-term antifungal treatment but nevertheless developed a destructive spinal lesion with a concurrent epidural and retropleural abscess. Given his risk of pathologic fracture, we performed anterior débridement and stabilization followed by posterior fusion and instrumentation. We are unaware of any other cases in which an anterior titanium cage was combined with rib autograft after anterior débridement and vertebrectomy combined with posterior instrumentation for blastomycosis. This technique proved very useful, as it allowed for immediate stabilization of the spine. Therefore, the treatment goal is similar to that for any destructive infection that fails medical treatment: preservation of neurologic function, stabilization of spinal vertebrae, débridement of abscess cavity, and definitive culture procurement.
Conclusion
Although there is little reported information regarding surgical indications for blastomycotic vertebral osteomyelitis that has failed medical management—in patients with a destructive lesion and compromise of both the spinal canal and the integrity of the vertebral column—anterior débridement and stabilization followed by posterior fusion and instrumentation are useful in preventing vertebral collapse, further canal compromise, and possible cord injury.
1. Akhtar I, Flowers R, Siddiqi A, Heard K, Baliga M. Fine needle aspiration biopsy of vertebral and paravertebral lesions: retrospective study of 124 cases [published correction appears in Acta Cytol. 2006;50(5):600]. Acta Cytol. 2006;50(4):364-371.
2. Arvin MC, Gehring RL, Crecelius JL, Curfman MF. Man with progressive lower back pain. Indiana Med. 1991;84(8):554-556.
3. Baylin GJ, Wear JM. Blastomycosis and actinomycosis of the spine. Am J Roentgenol Radium Ther Nucl Med. 1953;69(3):395-398.
4. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am. 2003;17(1):21-40.
5. Brewer GE, Wood FC. XII. Blastomycosis of the spine: double lesion: two operations: recovery. Ann Surg. 1908;48(6):889-896.
6. Carman WF, Frean JA, Crewe-Brown HH, Culligan GA, Young CN. Blastomycosis in Africa. A review of known cases diagnosed between 1951 and 1987. Mycopathologica. 1989;107(1):25-32.
7. Challapalli M, Cunningham DG. North American blastomycosis of the vertebrae in an adolescent. Clin Infect Dis. 1996;23(4):853-854.
8. Detrisac DA, Harding WG, Greiner AL, Dunn CR, Mayfield FH. Vertebral North American blastomycosis. Surg Neurol. 1980;13(4):311-312.
9. Frean J, Blumberg L, Woolf M. Disseminated blastomycosis masquerading as tuberculosis. J Infect. 1993;26(2):203-206.
10. Goodman LS, Brunton LL, Chabner B, Knollman BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill Medical; 2011.
11. Gottlieb JR, Eismont FJ. Nonoperative treatment of vertebral blastomycosis osteomyelitis associated with paraspinal abscess and cord compression. A case report. J Bone Joint Surg Am. 2006;88(4):854-856.
12. Güler N, Palanduz A, Ones U, et al. Progressive vertebral blastomycosis mimicking tuberculosis. Pediatr Infect Dis J. 1995;14(9):816-818.
13. Hadjipavlou AG, Mader JT, Nauta HJ, Necessary JT, Chaljub G, Adesokan A. Blastomycosis of the lumbar spine: case report and review of the literature, with emphasis on diagnostic laboratory tools and management. Eur Spine J. 1998;7(5):416-421.
14. Hardjasudarma M, Willis B, Black-Payne C, Edwards R. Pediatric spinal blastomycosis: case report. Neurosurgery. 1995;37(3):534-536.
15. Jahangir AA, Heck RK. Blastomycosis: case report of an isolated lesion in the distal fibula. Am J Orthop. 2010;39(3):E22-E24.
16. Koen AF, Blumberg LH. North American blastomycosis in South Africa simulating tuberculosis. Clin Radiol. 1999;54(4):260-262.
17. Lagging LM, Breland CM, Kennedy DJ, Milligan TW, Sokol-Anderson ML, Westblom TU. Delayed treatment of pulmonary blastomycosis causing vertebral osteomyelitis, paraspinal abscess, and spinal cord compression. Scand J Infect Dis. 1994;26(1):111-115.
18. MacDonald PB, Black GB, MacKenzie R. Orthopaedic manifestations of blastomycosis. J Bone Joint Surg Am. 1990;72(6):860-864.
19. Mahiquez M, Bunton KL, Carney G, Weinstein MA, Small JM. Nonsurgical treatment of lumbosacral blastomycosis involving L2–S1: a case report. Spine. 2008;33(13):E442-E446.
20. McKinnell JA, Pappas PG. Blastomycosis: new insights into diagnosis, prevention, and treatment. Clin Chest Med. 2009;30(2):227-239.
21. Moore RM, Green NE. Blastomycosis of bone. A report of six cases. J Bone Joint Surg Am. 1982;64(7):1097-1101.
22. Muñiz AE, Evans T. Chronic paronychia, osteomyelitis, and paravertebral abscess in a child with blastomycosis. J Emerg Med. 2000;19(3):245-248.
23. Osmond JD, Schweitzer G, Dunbar JM, Villet W. Blastomycosis of the spine with paraplegia. S Afr Med J. 1971;45(16):431-434.
24. Parr AM, Fewer D. Intramedullary blastomycosis in a child: case report. Can J Neurol Sci. 2004;31(2):282-285.
25. Rein MF, Fischetti JL, Sande MA. Osteomyelitis caused by concurrent infection with Mycobacterium tuberculosis and Blastomyces dermatitidis. Am Rev Respir Dis. 1974;109(2):286-289.
26. Saccente M, Abernathy RS, Pappas PG, Shah HR, Bradsher RW. Vertebral blastomycosis with paravertebral abscess: report of eight cases and review of the literature. Clin Infect Dis. 1998;26(2):413-418.
27. Titrud LA. Blastomycosis of the cervical spine. Minn Med. 1975;58(10):729-732.
28. Vandepitte J, Gatti F. A case of North American blastomycosis in Africa. Its existence in Republic of Zaire. Ann Soc Belg Med Trop. 1972;52(4):467-479.
29. Voris HC, Greenwood RC. Blastomycosis of the spine with invasion of the spinal canal. Proc Inst Med Chic. 1947;16(17):463.
30. Witorsch P, Utz JP. North American blastomycosis: a study of 40 patients. Medicine. 1968;47(3):169-200.
31. Lucio E, Adesokan A, Hadjipavlou AG, Crow WN, Adegboyega PA. Pyogenic spondylodiskitis: a radiologic/pathologic and culture correlation study. Arch Pathol Lab Med. 2000;124(5):712-716.
Blastomycosis is a rare fungal infection that primarily produces acute lung infections but may on occasion disseminate to multiple sites, including the skin, bone, central nervous system (CNS), and oropharynx.1-30 In the case of a primary infection of the lung, if there is a high index of suspicion and a thorough diagnostic workup, the diagnosis can be made from sputum or bronchoscopy.24 Patients present with acute pneumonia that either resolves spontaneously or proceeds to chronic pneumonia with extrapulmonary spread to multiple organs, including the spine. Once vertebral involvement occurs, an untreated infection may result in vertebral body destruction and paraspinal and epidural abscess formation followed by neurologic injury and loss of structural integrity of the spine.11,13,17,23,27,29
In this article, we present a case of blastomycosis of the vertebral body and provide a detailed review of the literature concerning this extremely rare infection of the spine. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 30-year-old African American man with known pulmonary blastomycosis, for which he had been treated with oral itraconazole 200 mg twice daily for 6 months, was admitted to the hospital with a 2-month history of mild thoracolumbar back pain. He reported transient numbness and tingling in the lower extremities but no weakness. He denied weight loss, fatigue, appetite loss, and significant night pain. On physical examination, he was alert and oriented, well nourished, and in no acute distress. Percussion revealed limited range of motion and pain. Further examination of the spine demonstrated no spasm, swelling, erythema, or drainage. The lower extremities had intact sensation, motor strength, reflexes, and pulses, and clonus was absent. White blood cell count was 8100 cells/μL (normal), erythrocyte sedimentation rate was 77 mm/h (normal range, 0-20 mm/h), and C-reactive protein level was 57.2 mg/L (normal, ≤ 10 mg/L). The patient was HIV-negative. Chest radiographs were normal except for a small pleural effusion. Radiographs showed a destructive lesion of T11 with an extensive paravertebral and retropleural abscess tracking a spinal level above and below with extension into the spinal canal (Figure 1).
As the patient had signs of spinal cord compression, he was taken to surgery for incision and drainage and culture procurement and corpectomy of T11 with autogenous rib graft. One week later, he was stabilized with posterior fusion and instrumentation (Figure 2). Gram stain of the specimen demonstrated broad-based budding yeast forms 15 to 20 micrometers in size, consistent with blastomycosis. Cultures were positive for Blastomyces dermatitidis. Histopathologic slides (Figure 3) of the surgical pathology specimen showed granulomatous inflammation. Oral itraconazole 200 mg twice daily was continued, as it has been found to be efficacious in treating immunocompetent patients with blastomycosis17 and is considered the medication of choice for non–life-threatening, non-CNS blastomycosis. (Intravenous amphotericin B was ruled out because of its known serious side effects, such as bone marrow suppression and renal function impairment10; itraconazole was the better alternative.) The patient was placed in a thoracolumbar orthosis and discharged. As the effect of presence of instrumentation in the setting of a fungal infection is unknown, it was deemed prudent to maintain the patient on chronic antifungal suppression. One year after surgery, computed tomography (CT) showed solid osseous bridging through the cage crossing the T11 vertebral body, from the inferior endplate of T10 through the superior endplate of T12 (Figure 4). In addition, there had been no recurrence of the spinal infection, and the patient was neurologically intact and doing well.
Discussion
North American blastomycosis (B dermatitidis) is a ubiquitous dimorphic fungus that occurs worldwide and on occasion causes serious infections in humans.9,23,26,29 It was first characterized in 1894 by Gilchrist and Stokes (Gilchrist disease) when they recovered the fungus from the lung tissue of a patient.3 In North America, blastomycosis infections occur from central Canada to the Gulf Coast to east of the Mississippi River.2,5,7,8,13,14,17,21,22,24,27,29 Additional cases of the disease have been reported in Africa,9,16,23,28 Asia,12,19 and South America7,8 (Table [on pages E270-E271]). Recent epidemiologic studies have linked transmission of the disease to bodies of water and have questioned previous reports of male predominance and racial preference for African Americans (Table).
Blastomycosis is acquired when inhaled fungus (airborne conidia spores) causes a primary pulmonary infection or, rarely, when there is direct inoculation through the skin. The differential diagnosis includes neoplasm, tuberculosis, actinomycosis, bacterial infections, cryptococcosis, and coccidioidomycosis.3,9,12,20,25,31 Blastomycosis occurs in adults and children.1-30 The rate of mortality is much higher in immunocompromised patients. Initial symptoms include fever, chills, fatigue, malaise, myalgia, arthalgia, weight loss, and stigmata of chronic disease.1-30 Acute pulmonary infection with blastomycosis generally resolves spontaneously but may progress to acute respiratory distress syndrome, which has a mortality rate of 50% to 89%.19 With systemic dissemination, the infection may spread to other organs11—there is a particular predilection for the skin9,20,29—and to the long bones7,16 and the oropharynx.16,26,28
In 50% to 64% of cases, bone involvement may be the first disease manifestation.6,7,16,22 Osseous involvement with blastomycosis most commonly affects the long bones15 but may include the vertebrae,1-29 the ribs,26 and the carpal or tarsal bones.7,16 The most common vertebral involvement occurs in the thoracic or lumbar spine1,2,7-9,11-14,17,19,21-24,26 and typically results in destruction of the body, development of a paraspinal abscess, and potential extension into the spinal canal, causing an epidural abscess and development of chronic draining cutaneous sinuses.2,7,9,11-13,16,17,19,22,23,26,28,29 In the present case, we do not know whether the vertebral body was involved before the patient presented with mid-thoracolumbar back pain. There may have been bony involvement during initial presentation.
Diagnosis is often difficult because of a low index of suspicion, leading to a significant delay in treatment. Primary pulmonary infections are successfully diagnosed 86% of the time from sputum and 92% of the time from bronchoscopy.19 Once the infection involves the spine, plain radiographs, CT, and magnetic resonance imaging (MRI) can be used to identify not only the bony involvement but also any adjacent soft-tissue extension.13 The radiographic findings, typical of tuberculosis or a neoplasm, include disc space narrowing, vertebral body destruction and collapse, late segmental kyphotic deformity, and development of a psoas abscess or a retropleural abscess.7,26 Such abscesses lend themselves well to fine-needle aspiration,7,8,11,13,14,17,19,26 which, when combined with CT and MRI guidance, reliably assists in the diagnosis of blastomycosis.1,13,17 If fine-needle aspiration fails, then open biopsy and surgical débridement specimens may be effective in the diagnosis.2,9,12,21,22,27
The mortality rate for systemic blastomycosis exceeded 90% before the development of antifungal medications, and these medications remain the primary treatment for most initial infections.15 For severe infections in critically ill patients and for patients with CNS involvement, amphotericin B has been effective, with cure rates approaching 97%.17 Itraconazole, which is well tolerated, has replaced ketoconazole as the preferred long-term oral treatment for blastomycosis. Cure rates for itraconazole approach 90% when treatment is instituted over 2 years in a compliant patient.10,19,20 Nonsurgical (antifungal) treatment for blastomycosis of the spine has also proved successful in neurologically intact patients.7,9,11,26,28
A case involving the spine and requiring surgical drainage was first reported in 19085; since then, only a few more cases have been reported.1,2,5,7-9,11-14,16,17,19,21-24,26-29 Thus, the literature includes very little information that can be used to establish indications for surgery for a blastomycotic infection of the spine. However, there is enough evidence to establish that surgery is indicated for patients who have a known blastomycosis infection and are developing neurologic or structural loss of integrity of the spinal column or have an abscess that requires drainage and débridement.
Our patient had been on long-term antifungal treatment but nevertheless developed a destructive spinal lesion with a concurrent epidural and retropleural abscess. Given his risk of pathologic fracture, we performed anterior débridement and stabilization followed by posterior fusion and instrumentation. We are unaware of any other cases in which an anterior titanium cage was combined with rib autograft after anterior débridement and vertebrectomy combined with posterior instrumentation for blastomycosis. This technique proved very useful, as it allowed for immediate stabilization of the spine. Therefore, the treatment goal is similar to that for any destructive infection that fails medical treatment: preservation of neurologic function, stabilization of spinal vertebrae, débridement of abscess cavity, and definitive culture procurement.
Conclusion
Although there is little reported information regarding surgical indications for blastomycotic vertebral osteomyelitis that has failed medical management—in patients with a destructive lesion and compromise of both the spinal canal and the integrity of the vertebral column—anterior débridement and stabilization followed by posterior fusion and instrumentation are useful in preventing vertebral collapse, further canal compromise, and possible cord injury.
Blastomycosis is a rare fungal infection that primarily produces acute lung infections but may on occasion disseminate to multiple sites, including the skin, bone, central nervous system (CNS), and oropharynx.1-30 In the case of a primary infection of the lung, if there is a high index of suspicion and a thorough diagnostic workup, the diagnosis can be made from sputum or bronchoscopy.24 Patients present with acute pneumonia that either resolves spontaneously or proceeds to chronic pneumonia with extrapulmonary spread to multiple organs, including the spine. Once vertebral involvement occurs, an untreated infection may result in vertebral body destruction and paraspinal and epidural abscess formation followed by neurologic injury and loss of structural integrity of the spine.11,13,17,23,27,29
In this article, we present a case of blastomycosis of the vertebral body and provide a detailed review of the literature concerning this extremely rare infection of the spine. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 30-year-old African American man with known pulmonary blastomycosis, for which he had been treated with oral itraconazole 200 mg twice daily for 6 months, was admitted to the hospital with a 2-month history of mild thoracolumbar back pain. He reported transient numbness and tingling in the lower extremities but no weakness. He denied weight loss, fatigue, appetite loss, and significant night pain. On physical examination, he was alert and oriented, well nourished, and in no acute distress. Percussion revealed limited range of motion and pain. Further examination of the spine demonstrated no spasm, swelling, erythema, or drainage. The lower extremities had intact sensation, motor strength, reflexes, and pulses, and clonus was absent. White blood cell count was 8100 cells/μL (normal), erythrocyte sedimentation rate was 77 mm/h (normal range, 0-20 mm/h), and C-reactive protein level was 57.2 mg/L (normal, ≤ 10 mg/L). The patient was HIV-negative. Chest radiographs were normal except for a small pleural effusion. Radiographs showed a destructive lesion of T11 with an extensive paravertebral and retropleural abscess tracking a spinal level above and below with extension into the spinal canal (Figure 1).
As the patient had signs of spinal cord compression, he was taken to surgery for incision and drainage and culture procurement and corpectomy of T11 with autogenous rib graft. One week later, he was stabilized with posterior fusion and instrumentation (Figure 2). Gram stain of the specimen demonstrated broad-based budding yeast forms 15 to 20 micrometers in size, consistent with blastomycosis. Cultures were positive for Blastomyces dermatitidis. Histopathologic slides (Figure 3) of the surgical pathology specimen showed granulomatous inflammation. Oral itraconazole 200 mg twice daily was continued, as it has been found to be efficacious in treating immunocompetent patients with blastomycosis17 and is considered the medication of choice for non–life-threatening, non-CNS blastomycosis. (Intravenous amphotericin B was ruled out because of its known serious side effects, such as bone marrow suppression and renal function impairment10; itraconazole was the better alternative.) The patient was placed in a thoracolumbar orthosis and discharged. As the effect of presence of instrumentation in the setting of a fungal infection is unknown, it was deemed prudent to maintain the patient on chronic antifungal suppression. One year after surgery, computed tomography (CT) showed solid osseous bridging through the cage crossing the T11 vertebral body, from the inferior endplate of T10 through the superior endplate of T12 (Figure 4). In addition, there had been no recurrence of the spinal infection, and the patient was neurologically intact and doing well.
Discussion
North American blastomycosis (B dermatitidis) is a ubiquitous dimorphic fungus that occurs worldwide and on occasion causes serious infections in humans.9,23,26,29 It was first characterized in 1894 by Gilchrist and Stokes (Gilchrist disease) when they recovered the fungus from the lung tissue of a patient.3 In North America, blastomycosis infections occur from central Canada to the Gulf Coast to east of the Mississippi River.2,5,7,8,13,14,17,21,22,24,27,29 Additional cases of the disease have been reported in Africa,9,16,23,28 Asia,12,19 and South America7,8 (Table [on pages E270-E271]). Recent epidemiologic studies have linked transmission of the disease to bodies of water and have questioned previous reports of male predominance and racial preference for African Americans (Table).
Blastomycosis is acquired when inhaled fungus (airborne conidia spores) causes a primary pulmonary infection or, rarely, when there is direct inoculation through the skin. The differential diagnosis includes neoplasm, tuberculosis, actinomycosis, bacterial infections, cryptococcosis, and coccidioidomycosis.3,9,12,20,25,31 Blastomycosis occurs in adults and children.1-30 The rate of mortality is much higher in immunocompromised patients. Initial symptoms include fever, chills, fatigue, malaise, myalgia, arthalgia, weight loss, and stigmata of chronic disease.1-30 Acute pulmonary infection with blastomycosis generally resolves spontaneously but may progress to acute respiratory distress syndrome, which has a mortality rate of 50% to 89%.19 With systemic dissemination, the infection may spread to other organs11—there is a particular predilection for the skin9,20,29—and to the long bones7,16 and the oropharynx.16,26,28
In 50% to 64% of cases, bone involvement may be the first disease manifestation.6,7,16,22 Osseous involvement with blastomycosis most commonly affects the long bones15 but may include the vertebrae,1-29 the ribs,26 and the carpal or tarsal bones.7,16 The most common vertebral involvement occurs in the thoracic or lumbar spine1,2,7-9,11-14,17,19,21-24,26 and typically results in destruction of the body, development of a paraspinal abscess, and potential extension into the spinal canal, causing an epidural abscess and development of chronic draining cutaneous sinuses.2,7,9,11-13,16,17,19,22,23,26,28,29 In the present case, we do not know whether the vertebral body was involved before the patient presented with mid-thoracolumbar back pain. There may have been bony involvement during initial presentation.
Diagnosis is often difficult because of a low index of suspicion, leading to a significant delay in treatment. Primary pulmonary infections are successfully diagnosed 86% of the time from sputum and 92% of the time from bronchoscopy.19 Once the infection involves the spine, plain radiographs, CT, and magnetic resonance imaging (MRI) can be used to identify not only the bony involvement but also any adjacent soft-tissue extension.13 The radiographic findings, typical of tuberculosis or a neoplasm, include disc space narrowing, vertebral body destruction and collapse, late segmental kyphotic deformity, and development of a psoas abscess or a retropleural abscess.7,26 Such abscesses lend themselves well to fine-needle aspiration,7,8,11,13,14,17,19,26 which, when combined with CT and MRI guidance, reliably assists in the diagnosis of blastomycosis.1,13,17 If fine-needle aspiration fails, then open biopsy and surgical débridement specimens may be effective in the diagnosis.2,9,12,21,22,27
The mortality rate for systemic blastomycosis exceeded 90% before the development of antifungal medications, and these medications remain the primary treatment for most initial infections.15 For severe infections in critically ill patients and for patients with CNS involvement, amphotericin B has been effective, with cure rates approaching 97%.17 Itraconazole, which is well tolerated, has replaced ketoconazole as the preferred long-term oral treatment for blastomycosis. Cure rates for itraconazole approach 90% when treatment is instituted over 2 years in a compliant patient.10,19,20 Nonsurgical (antifungal) treatment for blastomycosis of the spine has also proved successful in neurologically intact patients.7,9,11,26,28
A case involving the spine and requiring surgical drainage was first reported in 19085; since then, only a few more cases have been reported.1,2,5,7-9,11-14,16,17,19,21-24,26-29 Thus, the literature includes very little information that can be used to establish indications for surgery for a blastomycotic infection of the spine. However, there is enough evidence to establish that surgery is indicated for patients who have a known blastomycosis infection and are developing neurologic or structural loss of integrity of the spinal column or have an abscess that requires drainage and débridement.
Our patient had been on long-term antifungal treatment but nevertheless developed a destructive spinal lesion with a concurrent epidural and retropleural abscess. Given his risk of pathologic fracture, we performed anterior débridement and stabilization followed by posterior fusion and instrumentation. We are unaware of any other cases in which an anterior titanium cage was combined with rib autograft after anterior débridement and vertebrectomy combined with posterior instrumentation for blastomycosis. This technique proved very useful, as it allowed for immediate stabilization of the spine. Therefore, the treatment goal is similar to that for any destructive infection that fails medical treatment: preservation of neurologic function, stabilization of spinal vertebrae, débridement of abscess cavity, and definitive culture procurement.
Conclusion
Although there is little reported information regarding surgical indications for blastomycotic vertebral osteomyelitis that has failed medical management—in patients with a destructive lesion and compromise of both the spinal canal and the integrity of the vertebral column—anterior débridement and stabilization followed by posterior fusion and instrumentation are useful in preventing vertebral collapse, further canal compromise, and possible cord injury.
1. Akhtar I, Flowers R, Siddiqi A, Heard K, Baliga M. Fine needle aspiration biopsy of vertebral and paravertebral lesions: retrospective study of 124 cases [published correction appears in Acta Cytol. 2006;50(5):600]. Acta Cytol. 2006;50(4):364-371.
2. Arvin MC, Gehring RL, Crecelius JL, Curfman MF. Man with progressive lower back pain. Indiana Med. 1991;84(8):554-556.
3. Baylin GJ, Wear JM. Blastomycosis and actinomycosis of the spine. Am J Roentgenol Radium Ther Nucl Med. 1953;69(3):395-398.
4. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am. 2003;17(1):21-40.
5. Brewer GE, Wood FC. XII. Blastomycosis of the spine: double lesion: two operations: recovery. Ann Surg. 1908;48(6):889-896.
6. Carman WF, Frean JA, Crewe-Brown HH, Culligan GA, Young CN. Blastomycosis in Africa. A review of known cases diagnosed between 1951 and 1987. Mycopathologica. 1989;107(1):25-32.
7. Challapalli M, Cunningham DG. North American blastomycosis of the vertebrae in an adolescent. Clin Infect Dis. 1996;23(4):853-854.
8. Detrisac DA, Harding WG, Greiner AL, Dunn CR, Mayfield FH. Vertebral North American blastomycosis. Surg Neurol. 1980;13(4):311-312.
9. Frean J, Blumberg L, Woolf M. Disseminated blastomycosis masquerading as tuberculosis. J Infect. 1993;26(2):203-206.
10. Goodman LS, Brunton LL, Chabner B, Knollman BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill Medical; 2011.
11. Gottlieb JR, Eismont FJ. Nonoperative treatment of vertebral blastomycosis osteomyelitis associated with paraspinal abscess and cord compression. A case report. J Bone Joint Surg Am. 2006;88(4):854-856.
12. Güler N, Palanduz A, Ones U, et al. Progressive vertebral blastomycosis mimicking tuberculosis. Pediatr Infect Dis J. 1995;14(9):816-818.
13. Hadjipavlou AG, Mader JT, Nauta HJ, Necessary JT, Chaljub G, Adesokan A. Blastomycosis of the lumbar spine: case report and review of the literature, with emphasis on diagnostic laboratory tools and management. Eur Spine J. 1998;7(5):416-421.
14. Hardjasudarma M, Willis B, Black-Payne C, Edwards R. Pediatric spinal blastomycosis: case report. Neurosurgery. 1995;37(3):534-536.
15. Jahangir AA, Heck RK. Blastomycosis: case report of an isolated lesion in the distal fibula. Am J Orthop. 2010;39(3):E22-E24.
16. Koen AF, Blumberg LH. North American blastomycosis in South Africa simulating tuberculosis. Clin Radiol. 1999;54(4):260-262.
17. Lagging LM, Breland CM, Kennedy DJ, Milligan TW, Sokol-Anderson ML, Westblom TU. Delayed treatment of pulmonary blastomycosis causing vertebral osteomyelitis, paraspinal abscess, and spinal cord compression. Scand J Infect Dis. 1994;26(1):111-115.
18. MacDonald PB, Black GB, MacKenzie R. Orthopaedic manifestations of blastomycosis. J Bone Joint Surg Am. 1990;72(6):860-864.
19. Mahiquez M, Bunton KL, Carney G, Weinstein MA, Small JM. Nonsurgical treatment of lumbosacral blastomycosis involving L2–S1: a case report. Spine. 2008;33(13):E442-E446.
20. McKinnell JA, Pappas PG. Blastomycosis: new insights into diagnosis, prevention, and treatment. Clin Chest Med. 2009;30(2):227-239.
21. Moore RM, Green NE. Blastomycosis of bone. A report of six cases. J Bone Joint Surg Am. 1982;64(7):1097-1101.
22. Muñiz AE, Evans T. Chronic paronychia, osteomyelitis, and paravertebral abscess in a child with blastomycosis. J Emerg Med. 2000;19(3):245-248.
23. Osmond JD, Schweitzer G, Dunbar JM, Villet W. Blastomycosis of the spine with paraplegia. S Afr Med J. 1971;45(16):431-434.
24. Parr AM, Fewer D. Intramedullary blastomycosis in a child: case report. Can J Neurol Sci. 2004;31(2):282-285.
25. Rein MF, Fischetti JL, Sande MA. Osteomyelitis caused by concurrent infection with Mycobacterium tuberculosis and Blastomyces dermatitidis. Am Rev Respir Dis. 1974;109(2):286-289.
26. Saccente M, Abernathy RS, Pappas PG, Shah HR, Bradsher RW. Vertebral blastomycosis with paravertebral abscess: report of eight cases and review of the literature. Clin Infect Dis. 1998;26(2):413-418.
27. Titrud LA. Blastomycosis of the cervical spine. Minn Med. 1975;58(10):729-732.
28. Vandepitte J, Gatti F. A case of North American blastomycosis in Africa. Its existence in Republic of Zaire. Ann Soc Belg Med Trop. 1972;52(4):467-479.
29. Voris HC, Greenwood RC. Blastomycosis of the spine with invasion of the spinal canal. Proc Inst Med Chic. 1947;16(17):463.
30. Witorsch P, Utz JP. North American blastomycosis: a study of 40 patients. Medicine. 1968;47(3):169-200.
31. Lucio E, Adesokan A, Hadjipavlou AG, Crow WN, Adegboyega PA. Pyogenic spondylodiskitis: a radiologic/pathologic and culture correlation study. Arch Pathol Lab Med. 2000;124(5):712-716.
1. Akhtar I, Flowers R, Siddiqi A, Heard K, Baliga M. Fine needle aspiration biopsy of vertebral and paravertebral lesions: retrospective study of 124 cases [published correction appears in Acta Cytol. 2006;50(5):600]. Acta Cytol. 2006;50(4):364-371.
2. Arvin MC, Gehring RL, Crecelius JL, Curfman MF. Man with progressive lower back pain. Indiana Med. 1991;84(8):554-556.
3. Baylin GJ, Wear JM. Blastomycosis and actinomycosis of the spine. Am J Roentgenol Radium Ther Nucl Med. 1953;69(3):395-398.
4. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am. 2003;17(1):21-40.
5. Brewer GE, Wood FC. XII. Blastomycosis of the spine: double lesion: two operations: recovery. Ann Surg. 1908;48(6):889-896.
6. Carman WF, Frean JA, Crewe-Brown HH, Culligan GA, Young CN. Blastomycosis in Africa. A review of known cases diagnosed between 1951 and 1987. Mycopathologica. 1989;107(1):25-32.
7. Challapalli M, Cunningham DG. North American blastomycosis of the vertebrae in an adolescent. Clin Infect Dis. 1996;23(4):853-854.
8. Detrisac DA, Harding WG, Greiner AL, Dunn CR, Mayfield FH. Vertebral North American blastomycosis. Surg Neurol. 1980;13(4):311-312.
9. Frean J, Blumberg L, Woolf M. Disseminated blastomycosis masquerading as tuberculosis. J Infect. 1993;26(2):203-206.
10. Goodman LS, Brunton LL, Chabner B, Knollman BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill Medical; 2011.
11. Gottlieb JR, Eismont FJ. Nonoperative treatment of vertebral blastomycosis osteomyelitis associated with paraspinal abscess and cord compression. A case report. J Bone Joint Surg Am. 2006;88(4):854-856.
12. Güler N, Palanduz A, Ones U, et al. Progressive vertebral blastomycosis mimicking tuberculosis. Pediatr Infect Dis J. 1995;14(9):816-818.
13. Hadjipavlou AG, Mader JT, Nauta HJ, Necessary JT, Chaljub G, Adesokan A. Blastomycosis of the lumbar spine: case report and review of the literature, with emphasis on diagnostic laboratory tools and management. Eur Spine J. 1998;7(5):416-421.
14. Hardjasudarma M, Willis B, Black-Payne C, Edwards R. Pediatric spinal blastomycosis: case report. Neurosurgery. 1995;37(3):534-536.
15. Jahangir AA, Heck RK. Blastomycosis: case report of an isolated lesion in the distal fibula. Am J Orthop. 2010;39(3):E22-E24.
16. Koen AF, Blumberg LH. North American blastomycosis in South Africa simulating tuberculosis. Clin Radiol. 1999;54(4):260-262.
17. Lagging LM, Breland CM, Kennedy DJ, Milligan TW, Sokol-Anderson ML, Westblom TU. Delayed treatment of pulmonary blastomycosis causing vertebral osteomyelitis, paraspinal abscess, and spinal cord compression. Scand J Infect Dis. 1994;26(1):111-115.
18. MacDonald PB, Black GB, MacKenzie R. Orthopaedic manifestations of blastomycosis. J Bone Joint Surg Am. 1990;72(6):860-864.
19. Mahiquez M, Bunton KL, Carney G, Weinstein MA, Small JM. Nonsurgical treatment of lumbosacral blastomycosis involving L2–S1: a case report. Spine. 2008;33(13):E442-E446.
20. McKinnell JA, Pappas PG. Blastomycosis: new insights into diagnosis, prevention, and treatment. Clin Chest Med. 2009;30(2):227-239.
21. Moore RM, Green NE. Blastomycosis of bone. A report of six cases. J Bone Joint Surg Am. 1982;64(7):1097-1101.
22. Muñiz AE, Evans T. Chronic paronychia, osteomyelitis, and paravertebral abscess in a child with blastomycosis. J Emerg Med. 2000;19(3):245-248.
23. Osmond JD, Schweitzer G, Dunbar JM, Villet W. Blastomycosis of the spine with paraplegia. S Afr Med J. 1971;45(16):431-434.
24. Parr AM, Fewer D. Intramedullary blastomycosis in a child: case report. Can J Neurol Sci. 2004;31(2):282-285.
25. Rein MF, Fischetti JL, Sande MA. Osteomyelitis caused by concurrent infection with Mycobacterium tuberculosis and Blastomyces dermatitidis. Am Rev Respir Dis. 1974;109(2):286-289.
26. Saccente M, Abernathy RS, Pappas PG, Shah HR, Bradsher RW. Vertebral blastomycosis with paravertebral abscess: report of eight cases and review of the literature. Clin Infect Dis. 1998;26(2):413-418.
27. Titrud LA. Blastomycosis of the cervical spine. Minn Med. 1975;58(10):729-732.
28. Vandepitte J, Gatti F. A case of North American blastomycosis in Africa. Its existence in Republic of Zaire. Ann Soc Belg Med Trop. 1972;52(4):467-479.
29. Voris HC, Greenwood RC. Blastomycosis of the spine with invasion of the spinal canal. Proc Inst Med Chic. 1947;16(17):463.
30. Witorsch P, Utz JP. North American blastomycosis: a study of 40 patients. Medicine. 1968;47(3):169-200.
31. Lucio E, Adesokan A, Hadjipavlou AG, Crow WN, Adegboyega PA. Pyogenic spondylodiskitis: a radiologic/pathologic and culture correlation study. Arch Pathol Lab Med. 2000;124(5):712-716.
Dynamic Magnetic Resonance Imaging of Partial-Thickness Retearing of Distal Biceps Tendon After Endobutton Repair
Retearing after repair of the distal biceps tendon is rare.1 Heterotopic ossification (HO) is also considered uncommon, though reported rates in the literature vary widely, depending on repair and follow-up methods.1-3
In this article, we report a case of ruptured distal biceps tendon repaired with a 1-incision Endobutton technique with longitudinal clinical and imaging follow-up, and we discuss the potential biomechanical and rehabilitative implications of clinically occult retearing after repair.
This case is unique in that the patient was a physician who procured multiple magnetic resonance imaging (MRI) examinations during the postoperative period and again at 1-year follow-up. We witnessed formation of a small focus of HO, which entered and significantly narrowed the radioulnar space on forearm pronation on dynamic MRI. There was no obvious clinical evidence for retearing; high-grade partial-thickness tendon retearing was diagnosed on MRI. This prompted a gentler rehabilitation protocol. Subsequent scar formation and tendon remodeling allowed the patient to return to full activity by 1-year follow-up, confirming recent reports that intrasubstance signal abnormalities4 and even rerupture on MRI are not correlated with symptoms.5 The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A healthy right-hand–dominant 32-year-old man was rock climbing when he heard a pop and felt sudden weakness in his right elbow. The injury occurred during eccentric contraction, while he was climbing a 45° overhanging wall with his right elbow fully extended and forearm maximally pronated. Immediately after injury, he noticed obvious deformity in the right arm. Before this incident, there was no history of elbow symptoms or any medication use.
Physical examination revealed distortion of the biceps with a palpable defect in the right elbow consistent with a complete biceps tendon rupture. This was confirmed on MRI, which showed avulsion of the distal biceps tendon from its insertion on the radius. There was 4 cm of proximal retraction of the tendon, which was kept at the level of the joint line by a partially intact lacertus fibrosis (Figure 1).
As the patient was physically active, operative treatment was chosen with the expectation of restoration to full function and strength. Six days after injury, surgery was performed using a 1-incision anterior approach with an Endobutton technique, as first described by Bain and colleagues6 and subsequently detailed by other authors.7 The diameter of the distal biceps tendon after attachment to the Endobutton (Arthrex, Naples, Florida) was measured, and a corresponding 7-mm unicortical tunnel was drilled into the radial tuberosity. During surgery, there was full range of motion (ROM) at the elbow and forearm. Before closure, the wound was copiously irrigated to minimize the potential of HO. In our practice, we do not routinely administer prophylactic anti-inflammatory drugs to low-risk patients because of the theoretical risks for delayed tendon–bone healing8 and inferior healing strength.9 The theoretical, expected postoperative appearance is illustrated in Figure 2.
For 7 days after surgery, the patient wore a posterior elbow splint in a flexed, supinated position. Afterward, rehabilitation initially consisted of passive ROM progressing to active ROM at postoperative week 4. Pronation was slow to return, but essentially full ROM was regained by 7 weeks after surgery. Seven weeks after surgery, a radiograph showed a small amount of HO near the radial tuberosity (Figure 3A). However, the patient was clinically progressing well, and by 9 weeks was comfortably performing slow, controlled arm curls with a 10-lb weight. Despite the clinical improvements, MRI 9 weeks after surgery showed high-grade partial-thickness retearing of the distal biceps tendon without significant retraction. With dynamic MRI, it was evident that the focus of HO near but external to the distal tendon entered the radioulnar space on pronation (Figures 3B–3D). On axial images of the center of the cortical tunnel, the short-axis diameter of the heterotopic bone measured 2.5 mm, and the bone clearly was occupying part of the radioulnar space during pronation. As the patient was not having pain and was increasing in strength, the clinical team resumed rehabilitation, albeit at a gentler pace.
By 1-year follow-up, the patient had returned to preinjury activity levels, which included rock climbing and weightlifting without pain or loss of strength. One year after surgery, radiographs and MRI showed maturation of heterotopic bone, which was incorporated with scar tissue along the remodeled distal biceps tendon remnant (Figures 4A-4C).
Discussion
Distal biceps tendon ruptures historically have been considered relatively rare injuries. Postrepair complications are uncommon but well known. HO has been described with all distal biceps tendon repair techniques, but rates vary depending on follow-up method. Given the data reported, HO is thought to have a higher incidence with the 2-incision technique than with the 1-incision technique.10 The literature includes fewer reports of HO with the Endobutton technique11,12 than with the suture anchor technique.3 Incidence of HO after distal biceps tendon repair has been reported to be as high as 50%, with Marnitz and colleagues5 suggesting that its presence does not necessarily affect clinical outcome. This was confirmed in our patient’s case.
A much rarer complication of repair is rerupture, which can be asymptomatic or symptomatic.5 The most common failure site, discovered during surgery, is the fixation site.2,13 The true incidence of rerupture is unknown, as MRI typically is not obtained for asymptomatic patients. However, Marnitz and colleagues5 recently found increased intratendinous signal and thickness of repaired tendons in the majority of intact postoperative cases and no significant correlation between any MRI features, including tendon rerupture, and clinical measures. This was confirmed in our patient’s case, in which the MRI-based diagnosis of partial retear was not correlated with adverse clinical outcome at 1-year follow-up. Marnitz and colleagues5 hypothesized that the increased thickness of the repaired tendon would predispose the patient to impingement.
Our patient had no demonstrable loss of motion during surgery. However, postoperative dynamic MRI clearly showed insufficient room in the pronated radioulnar space for both heterotopic bone and repaired biceps tendon. It is possible that a space-occupying peritendinous hematoma or HO soon after surgery caused early loss of pronation. In a study of 10 volunteers, mean radioulnar distance was 4.0 mm (range, 2.1-6.0 mm) at its minimum in pronation.14 We used the same technique to measure our patient’s radioulnar space in active semipronation: 7 mm. This diameter was the same as that of the distal biceps tendon during surgery (Figure 3D). Had our patient been in maximum pronation during imaging, we would have expected a further decrease in radioulnar distance. Given the insufficient room in this case, it is possible that, during the attempt to regain full pronation, attritional wear of the repaired biceps tendon occurred with a corresponding maturation of the focus of heterotopic bone. Supporting this theory is the patient’s lack of history of traumatic loading, which would have suggested tensile failure of the repair. By 1-year follow-up, scar-tissue maturation and remodeling had occurred, and there was sufficient overall biomechanical strength to withstand return to normal activity.
The literature includes multiple reports of in vitro biomechanical studies of various types of distal biceps tendon fixation,15-17 and multiple authors have demonstrated the superior pullout strength of cortical fixation buttons,18,19 such as the Endobutton. It is important to note that all biomechanical tests are performed in cadaveric specimens and are therefore likely applicable only at time zero, after in vivo repair. In part stemming from the results of these cadaveric biomechanical tests, earlier and more aggressive rehabilitation protocols have been developed with the assumption that time zero is the weakest point.20 If in fact the native repaired biceps tendon is retorn and remodeled, there will exist a nadir in strength because of the high concentration of biomechanically inferior type III collagen in scar tissue (as opposed to the very strong type I collagen in native tendons).21 In the absence of complete rerupture, biomechanical strength would continue to improve during scar maturation and continued healing, leading to the typical excellent clinical result, as seen in our case.
This case report illustrates the dynamic MRI appearance of a small focus of HO after distal biceps tendon repair and adds to the time-zero cadaveric data of distal biceps tendon repair. The small focus of HO near the repaired distal tendon may have caused tendon impingement in pronation because of its space-occupying nature and possible attritional tendon wear. A gentler rehabilitation protocol for this pattern of HO, during a period in which biomechanically inferior scar tissue is maturing, may be warranted. Despite the high rates of clinical success with distal biceps tendon repair, there is lack of agreement between ex vivo cadaveric studies and the in vivo scenario. A prospective study involving a larger series of patients with postoperative dynamic MRI examinations would be useful to better understand the true in vivo course of distal biceps tendon repair.
1. Cohen MS. Complications of distal biceps tendon repairs. Sports Med Arthrosc. 2008;16(3):148-153.
2. Bisson L, Moyer M, Lanighan K, Marzo J. Complications associated with repair of a distal biceps rupture using the modified two-incision technique. J Shoulder Elbow Surg. 2008;17(1 suppl):67S-71S.
3. Gallinet D, Dietsch E, Barbier-Brion B, Lerais JM, Obert L. Suture anchor reinsertion of distal biceps rupture: clinical results and radiological assessment of tendon healing. Orthop Traumatol Surg Res. 2011;97(3):252-259.
4. Schmidt CC, Diaz VA, Weir DM, Latona CR, Miller MC. Repaired distal biceps magnetic resonance imaging anatomy compared with outcome. J Shoulder Elbow Surg. 2012;21(12):1623-1631.
5. Marnitz T, Spiegel D, Hug K, et al. MR imaging findings in flexed abducted supinated (FABS) position and clinical presentation following refixation of distal biceps tendon rupture using bioabsorbable suture anchors. Rofo. 2012;184(5):432-436.
6. Bain GI, Prem H, Heptinstall RJ, Verhellen R, Paix D. Repair of distal biceps tendon rupture: a new technique using the Endobutton. J Shoulder Elbow Surg. 2000;9(2):120-126.
7. King J, Bollier M. Repair of distal biceps tendon ruptures using the Endobutton. J Am Acad Orthop Surg. 2008;16(8):490-494.
8. Cohen DB, Kawamura S, Ehteshami JR, Rodeo SA. Indomethacin and celecoxib impair rotator cuff tendon-to-bone healing. Am J Sports Med. 2006;34(3):362-369.
9. Ferry ST, Dahners LE, Afshari HM, Weinhold PS. The effects of common anti-inflammatory drugs on the healing rat patellar tendon. Am J Sports Med. 2007;35(8):1326-1333.
10. Miyamoto RG, Elser F, Millett PJ. Distal biceps tendon injuries. J Bone Joint Surg Am. 2010;92(11):2128-2138.
11. Dillon MT, Lepore DJ. Heterotopic ossification after single-incision distal biceps tendon repair with an Endobutton. J Surg Orthop Adv. 2011;20(3):198-201.
12. Peeters T, Ching-Soon NG, Jansen N, Sneyers C, Declercq G, Verstreken F. Functional outcome after repair of distal biceps tendon ruptures using the Endobutton technique. J Shoulder Elbow Surg. 2009;18(2):283-287.
13. Katolik LI, Fernandez J, Cohen MS. Acute failure of distal biceps reconstruction: a case report. J Shoulder Elbow Surg. 2007;16(5):e10-e12.
14. Seiler JG 3rd, Parker LM, Chamberland PD, Sherbourne GM, Carpenter WA. The distal biceps tendon. Two potential mechanisms involved in its rupture: arterial supply and mechanical impingement. J Shoulder Elbow Surg. 1995;4(3):149-156.
15. Siebenlist S, Lenich A, Buchholz A, et al. Biomechanical in vitro validation of intramedullary cortical button fixation for distal biceps tendon repair: a new technique. Am J Sports Med. 2011;39(8):1762-1768.
16. Pereira DS, Kvitne RS, Liang M, Giacobetti FB, Ebramzadeh E. Surgical repair of distal biceps tendon ruptures: a biomechanical comparison of two techniques. Am J Sports Med. 2002;30(3):432-436.
17. Lemos SE, Ebramzedeh E, Kvitne RS. A new technique: in vitro suture anchor fixation has superior yield strength to bone tunnel fixation for distal biceps tendon repair. Am J Sports Med. 2004;32(2):406-410.
18. Kettler M, Lunger J, Kuhn V, Mutschler W, Tingart MJ. Failure strengths in distal biceps tendon repair. Am J Sports Med. 2007;35(9):1544-1548.
19. Mazzocca AD, Burton KJ, Romeo AA, Santangelo S, Adams DA, Arciero RA. Biomechanical evaluation of 4 techniques of distal biceps brachii tendon repair. Am J Sports Med. 2007;35(2):252-258.
20. Spencer EE Jr, Tisdale A, Kostka K, Ivy RE. Is therapy necessary after distal biceps tendon repair? Hand (N Y). 2008;3(4):316-319.
21. Maffulli N, Ewen SWB, Waterston SW, Reaper J, Barrass V. Tenocytes from ruptured and tendinopathic Achilles tendons produce greater quantities of type III collagen than tenocytes from normal Achilles tendons. Am J Sports Med. 2000;28(4):499-505.
Retearing after repair of the distal biceps tendon is rare.1 Heterotopic ossification (HO) is also considered uncommon, though reported rates in the literature vary widely, depending on repair and follow-up methods.1-3
In this article, we report a case of ruptured distal biceps tendon repaired with a 1-incision Endobutton technique with longitudinal clinical and imaging follow-up, and we discuss the potential biomechanical and rehabilitative implications of clinically occult retearing after repair.
This case is unique in that the patient was a physician who procured multiple magnetic resonance imaging (MRI) examinations during the postoperative period and again at 1-year follow-up. We witnessed formation of a small focus of HO, which entered and significantly narrowed the radioulnar space on forearm pronation on dynamic MRI. There was no obvious clinical evidence for retearing; high-grade partial-thickness tendon retearing was diagnosed on MRI. This prompted a gentler rehabilitation protocol. Subsequent scar formation and tendon remodeling allowed the patient to return to full activity by 1-year follow-up, confirming recent reports that intrasubstance signal abnormalities4 and even rerupture on MRI are not correlated with symptoms.5 The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A healthy right-hand–dominant 32-year-old man was rock climbing when he heard a pop and felt sudden weakness in his right elbow. The injury occurred during eccentric contraction, while he was climbing a 45° overhanging wall with his right elbow fully extended and forearm maximally pronated. Immediately after injury, he noticed obvious deformity in the right arm. Before this incident, there was no history of elbow symptoms or any medication use.
Physical examination revealed distortion of the biceps with a palpable defect in the right elbow consistent with a complete biceps tendon rupture. This was confirmed on MRI, which showed avulsion of the distal biceps tendon from its insertion on the radius. There was 4 cm of proximal retraction of the tendon, which was kept at the level of the joint line by a partially intact lacertus fibrosis (Figure 1).
As the patient was physically active, operative treatment was chosen with the expectation of restoration to full function and strength. Six days after injury, surgery was performed using a 1-incision anterior approach with an Endobutton technique, as first described by Bain and colleagues6 and subsequently detailed by other authors.7 The diameter of the distal biceps tendon after attachment to the Endobutton (Arthrex, Naples, Florida) was measured, and a corresponding 7-mm unicortical tunnel was drilled into the radial tuberosity. During surgery, there was full range of motion (ROM) at the elbow and forearm. Before closure, the wound was copiously irrigated to minimize the potential of HO. In our practice, we do not routinely administer prophylactic anti-inflammatory drugs to low-risk patients because of the theoretical risks for delayed tendon–bone healing8 and inferior healing strength.9 The theoretical, expected postoperative appearance is illustrated in Figure 2.
For 7 days after surgery, the patient wore a posterior elbow splint in a flexed, supinated position. Afterward, rehabilitation initially consisted of passive ROM progressing to active ROM at postoperative week 4. Pronation was slow to return, but essentially full ROM was regained by 7 weeks after surgery. Seven weeks after surgery, a radiograph showed a small amount of HO near the radial tuberosity (Figure 3A). However, the patient was clinically progressing well, and by 9 weeks was comfortably performing slow, controlled arm curls with a 10-lb weight. Despite the clinical improvements, MRI 9 weeks after surgery showed high-grade partial-thickness retearing of the distal biceps tendon without significant retraction. With dynamic MRI, it was evident that the focus of HO near but external to the distal tendon entered the radioulnar space on pronation (Figures 3B–3D). On axial images of the center of the cortical tunnel, the short-axis diameter of the heterotopic bone measured 2.5 mm, and the bone clearly was occupying part of the radioulnar space during pronation. As the patient was not having pain and was increasing in strength, the clinical team resumed rehabilitation, albeit at a gentler pace.
By 1-year follow-up, the patient had returned to preinjury activity levels, which included rock climbing and weightlifting without pain or loss of strength. One year after surgery, radiographs and MRI showed maturation of heterotopic bone, which was incorporated with scar tissue along the remodeled distal biceps tendon remnant (Figures 4A-4C).
Discussion
Distal biceps tendon ruptures historically have been considered relatively rare injuries. Postrepair complications are uncommon but well known. HO has been described with all distal biceps tendon repair techniques, but rates vary depending on follow-up method. Given the data reported, HO is thought to have a higher incidence with the 2-incision technique than with the 1-incision technique.10 The literature includes fewer reports of HO with the Endobutton technique11,12 than with the suture anchor technique.3 Incidence of HO after distal biceps tendon repair has been reported to be as high as 50%, with Marnitz and colleagues5 suggesting that its presence does not necessarily affect clinical outcome. This was confirmed in our patient’s case.
A much rarer complication of repair is rerupture, which can be asymptomatic or symptomatic.5 The most common failure site, discovered during surgery, is the fixation site.2,13 The true incidence of rerupture is unknown, as MRI typically is not obtained for asymptomatic patients. However, Marnitz and colleagues5 recently found increased intratendinous signal and thickness of repaired tendons in the majority of intact postoperative cases and no significant correlation between any MRI features, including tendon rerupture, and clinical measures. This was confirmed in our patient’s case, in which the MRI-based diagnosis of partial retear was not correlated with adverse clinical outcome at 1-year follow-up. Marnitz and colleagues5 hypothesized that the increased thickness of the repaired tendon would predispose the patient to impingement.
Our patient had no demonstrable loss of motion during surgery. However, postoperative dynamic MRI clearly showed insufficient room in the pronated radioulnar space for both heterotopic bone and repaired biceps tendon. It is possible that a space-occupying peritendinous hematoma or HO soon after surgery caused early loss of pronation. In a study of 10 volunteers, mean radioulnar distance was 4.0 mm (range, 2.1-6.0 mm) at its minimum in pronation.14 We used the same technique to measure our patient’s radioulnar space in active semipronation: 7 mm. This diameter was the same as that of the distal biceps tendon during surgery (Figure 3D). Had our patient been in maximum pronation during imaging, we would have expected a further decrease in radioulnar distance. Given the insufficient room in this case, it is possible that, during the attempt to regain full pronation, attritional wear of the repaired biceps tendon occurred with a corresponding maturation of the focus of heterotopic bone. Supporting this theory is the patient’s lack of history of traumatic loading, which would have suggested tensile failure of the repair. By 1-year follow-up, scar-tissue maturation and remodeling had occurred, and there was sufficient overall biomechanical strength to withstand return to normal activity.
The literature includes multiple reports of in vitro biomechanical studies of various types of distal biceps tendon fixation,15-17 and multiple authors have demonstrated the superior pullout strength of cortical fixation buttons,18,19 such as the Endobutton. It is important to note that all biomechanical tests are performed in cadaveric specimens and are therefore likely applicable only at time zero, after in vivo repair. In part stemming from the results of these cadaveric biomechanical tests, earlier and more aggressive rehabilitation protocols have been developed with the assumption that time zero is the weakest point.20 If in fact the native repaired biceps tendon is retorn and remodeled, there will exist a nadir in strength because of the high concentration of biomechanically inferior type III collagen in scar tissue (as opposed to the very strong type I collagen in native tendons).21 In the absence of complete rerupture, biomechanical strength would continue to improve during scar maturation and continued healing, leading to the typical excellent clinical result, as seen in our case.
This case report illustrates the dynamic MRI appearance of a small focus of HO after distal biceps tendon repair and adds to the time-zero cadaveric data of distal biceps tendon repair. The small focus of HO near the repaired distal tendon may have caused tendon impingement in pronation because of its space-occupying nature and possible attritional tendon wear. A gentler rehabilitation protocol for this pattern of HO, during a period in which biomechanically inferior scar tissue is maturing, may be warranted. Despite the high rates of clinical success with distal biceps tendon repair, there is lack of agreement between ex vivo cadaveric studies and the in vivo scenario. A prospective study involving a larger series of patients with postoperative dynamic MRI examinations would be useful to better understand the true in vivo course of distal biceps tendon repair.
Retearing after repair of the distal biceps tendon is rare.1 Heterotopic ossification (HO) is also considered uncommon, though reported rates in the literature vary widely, depending on repair and follow-up methods.1-3
In this article, we report a case of ruptured distal biceps tendon repaired with a 1-incision Endobutton technique with longitudinal clinical and imaging follow-up, and we discuss the potential biomechanical and rehabilitative implications of clinically occult retearing after repair.
This case is unique in that the patient was a physician who procured multiple magnetic resonance imaging (MRI) examinations during the postoperative period and again at 1-year follow-up. We witnessed formation of a small focus of HO, which entered and significantly narrowed the radioulnar space on forearm pronation on dynamic MRI. There was no obvious clinical evidence for retearing; high-grade partial-thickness tendon retearing was diagnosed on MRI. This prompted a gentler rehabilitation protocol. Subsequent scar formation and tendon remodeling allowed the patient to return to full activity by 1-year follow-up, confirming recent reports that intrasubstance signal abnormalities4 and even rerupture on MRI are not correlated with symptoms.5 The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A healthy right-hand–dominant 32-year-old man was rock climbing when he heard a pop and felt sudden weakness in his right elbow. The injury occurred during eccentric contraction, while he was climbing a 45° overhanging wall with his right elbow fully extended and forearm maximally pronated. Immediately after injury, he noticed obvious deformity in the right arm. Before this incident, there was no history of elbow symptoms or any medication use.
Physical examination revealed distortion of the biceps with a palpable defect in the right elbow consistent with a complete biceps tendon rupture. This was confirmed on MRI, which showed avulsion of the distal biceps tendon from its insertion on the radius. There was 4 cm of proximal retraction of the tendon, which was kept at the level of the joint line by a partially intact lacertus fibrosis (Figure 1).
As the patient was physically active, operative treatment was chosen with the expectation of restoration to full function and strength. Six days after injury, surgery was performed using a 1-incision anterior approach with an Endobutton technique, as first described by Bain and colleagues6 and subsequently detailed by other authors.7 The diameter of the distal biceps tendon after attachment to the Endobutton (Arthrex, Naples, Florida) was measured, and a corresponding 7-mm unicortical tunnel was drilled into the radial tuberosity. During surgery, there was full range of motion (ROM) at the elbow and forearm. Before closure, the wound was copiously irrigated to minimize the potential of HO. In our practice, we do not routinely administer prophylactic anti-inflammatory drugs to low-risk patients because of the theoretical risks for delayed tendon–bone healing8 and inferior healing strength.9 The theoretical, expected postoperative appearance is illustrated in Figure 2.
For 7 days after surgery, the patient wore a posterior elbow splint in a flexed, supinated position. Afterward, rehabilitation initially consisted of passive ROM progressing to active ROM at postoperative week 4. Pronation was slow to return, but essentially full ROM was regained by 7 weeks after surgery. Seven weeks after surgery, a radiograph showed a small amount of HO near the radial tuberosity (Figure 3A). However, the patient was clinically progressing well, and by 9 weeks was comfortably performing slow, controlled arm curls with a 10-lb weight. Despite the clinical improvements, MRI 9 weeks after surgery showed high-grade partial-thickness retearing of the distal biceps tendon without significant retraction. With dynamic MRI, it was evident that the focus of HO near but external to the distal tendon entered the radioulnar space on pronation (Figures 3B–3D). On axial images of the center of the cortical tunnel, the short-axis diameter of the heterotopic bone measured 2.5 mm, and the bone clearly was occupying part of the radioulnar space during pronation. As the patient was not having pain and was increasing in strength, the clinical team resumed rehabilitation, albeit at a gentler pace.
By 1-year follow-up, the patient had returned to preinjury activity levels, which included rock climbing and weightlifting without pain or loss of strength. One year after surgery, radiographs and MRI showed maturation of heterotopic bone, which was incorporated with scar tissue along the remodeled distal biceps tendon remnant (Figures 4A-4C).
Discussion
Distal biceps tendon ruptures historically have been considered relatively rare injuries. Postrepair complications are uncommon but well known. HO has been described with all distal biceps tendon repair techniques, but rates vary depending on follow-up method. Given the data reported, HO is thought to have a higher incidence with the 2-incision technique than with the 1-incision technique.10 The literature includes fewer reports of HO with the Endobutton technique11,12 than with the suture anchor technique.3 Incidence of HO after distal biceps tendon repair has been reported to be as high as 50%, with Marnitz and colleagues5 suggesting that its presence does not necessarily affect clinical outcome. This was confirmed in our patient’s case.
A much rarer complication of repair is rerupture, which can be asymptomatic or symptomatic.5 The most common failure site, discovered during surgery, is the fixation site.2,13 The true incidence of rerupture is unknown, as MRI typically is not obtained for asymptomatic patients. However, Marnitz and colleagues5 recently found increased intratendinous signal and thickness of repaired tendons in the majority of intact postoperative cases and no significant correlation between any MRI features, including tendon rerupture, and clinical measures. This was confirmed in our patient’s case, in which the MRI-based diagnosis of partial retear was not correlated with adverse clinical outcome at 1-year follow-up. Marnitz and colleagues5 hypothesized that the increased thickness of the repaired tendon would predispose the patient to impingement.
Our patient had no demonstrable loss of motion during surgery. However, postoperative dynamic MRI clearly showed insufficient room in the pronated radioulnar space for both heterotopic bone and repaired biceps tendon. It is possible that a space-occupying peritendinous hematoma or HO soon after surgery caused early loss of pronation. In a study of 10 volunteers, mean radioulnar distance was 4.0 mm (range, 2.1-6.0 mm) at its minimum in pronation.14 We used the same technique to measure our patient’s radioulnar space in active semipronation: 7 mm. This diameter was the same as that of the distal biceps tendon during surgery (Figure 3D). Had our patient been in maximum pronation during imaging, we would have expected a further decrease in radioulnar distance. Given the insufficient room in this case, it is possible that, during the attempt to regain full pronation, attritional wear of the repaired biceps tendon occurred with a corresponding maturation of the focus of heterotopic bone. Supporting this theory is the patient’s lack of history of traumatic loading, which would have suggested tensile failure of the repair. By 1-year follow-up, scar-tissue maturation and remodeling had occurred, and there was sufficient overall biomechanical strength to withstand return to normal activity.
The literature includes multiple reports of in vitro biomechanical studies of various types of distal biceps tendon fixation,15-17 and multiple authors have demonstrated the superior pullout strength of cortical fixation buttons,18,19 such as the Endobutton. It is important to note that all biomechanical tests are performed in cadaveric specimens and are therefore likely applicable only at time zero, after in vivo repair. In part stemming from the results of these cadaveric biomechanical tests, earlier and more aggressive rehabilitation protocols have been developed with the assumption that time zero is the weakest point.20 If in fact the native repaired biceps tendon is retorn and remodeled, there will exist a nadir in strength because of the high concentration of biomechanically inferior type III collagen in scar tissue (as opposed to the very strong type I collagen in native tendons).21 In the absence of complete rerupture, biomechanical strength would continue to improve during scar maturation and continued healing, leading to the typical excellent clinical result, as seen in our case.
This case report illustrates the dynamic MRI appearance of a small focus of HO after distal biceps tendon repair and adds to the time-zero cadaveric data of distal biceps tendon repair. The small focus of HO near the repaired distal tendon may have caused tendon impingement in pronation because of its space-occupying nature and possible attritional tendon wear. A gentler rehabilitation protocol for this pattern of HO, during a period in which biomechanically inferior scar tissue is maturing, may be warranted. Despite the high rates of clinical success with distal biceps tendon repair, there is lack of agreement between ex vivo cadaveric studies and the in vivo scenario. A prospective study involving a larger series of patients with postoperative dynamic MRI examinations would be useful to better understand the true in vivo course of distal biceps tendon repair.
1. Cohen MS. Complications of distal biceps tendon repairs. Sports Med Arthrosc. 2008;16(3):148-153.
2. Bisson L, Moyer M, Lanighan K, Marzo J. Complications associated with repair of a distal biceps rupture using the modified two-incision technique. J Shoulder Elbow Surg. 2008;17(1 suppl):67S-71S.
3. Gallinet D, Dietsch E, Barbier-Brion B, Lerais JM, Obert L. Suture anchor reinsertion of distal biceps rupture: clinical results and radiological assessment of tendon healing. Orthop Traumatol Surg Res. 2011;97(3):252-259.
4. Schmidt CC, Diaz VA, Weir DM, Latona CR, Miller MC. Repaired distal biceps magnetic resonance imaging anatomy compared with outcome. J Shoulder Elbow Surg. 2012;21(12):1623-1631.
5. Marnitz T, Spiegel D, Hug K, et al. MR imaging findings in flexed abducted supinated (FABS) position and clinical presentation following refixation of distal biceps tendon rupture using bioabsorbable suture anchors. Rofo. 2012;184(5):432-436.
6. Bain GI, Prem H, Heptinstall RJ, Verhellen R, Paix D. Repair of distal biceps tendon rupture: a new technique using the Endobutton. J Shoulder Elbow Surg. 2000;9(2):120-126.
7. King J, Bollier M. Repair of distal biceps tendon ruptures using the Endobutton. J Am Acad Orthop Surg. 2008;16(8):490-494.
8. Cohen DB, Kawamura S, Ehteshami JR, Rodeo SA. Indomethacin and celecoxib impair rotator cuff tendon-to-bone healing. Am J Sports Med. 2006;34(3):362-369.
9. Ferry ST, Dahners LE, Afshari HM, Weinhold PS. The effects of common anti-inflammatory drugs on the healing rat patellar tendon. Am J Sports Med. 2007;35(8):1326-1333.
10. Miyamoto RG, Elser F, Millett PJ. Distal biceps tendon injuries. J Bone Joint Surg Am. 2010;92(11):2128-2138.
11. Dillon MT, Lepore DJ. Heterotopic ossification after single-incision distal biceps tendon repair with an Endobutton. J Surg Orthop Adv. 2011;20(3):198-201.
12. Peeters T, Ching-Soon NG, Jansen N, Sneyers C, Declercq G, Verstreken F. Functional outcome after repair of distal biceps tendon ruptures using the Endobutton technique. J Shoulder Elbow Surg. 2009;18(2):283-287.
13. Katolik LI, Fernandez J, Cohen MS. Acute failure of distal biceps reconstruction: a case report. J Shoulder Elbow Surg. 2007;16(5):e10-e12.
14. Seiler JG 3rd, Parker LM, Chamberland PD, Sherbourne GM, Carpenter WA. The distal biceps tendon. Two potential mechanisms involved in its rupture: arterial supply and mechanical impingement. J Shoulder Elbow Surg. 1995;4(3):149-156.
15. Siebenlist S, Lenich A, Buchholz A, et al. Biomechanical in vitro validation of intramedullary cortical button fixation for distal biceps tendon repair: a new technique. Am J Sports Med. 2011;39(8):1762-1768.
16. Pereira DS, Kvitne RS, Liang M, Giacobetti FB, Ebramzadeh E. Surgical repair of distal biceps tendon ruptures: a biomechanical comparison of two techniques. Am J Sports Med. 2002;30(3):432-436.
17. Lemos SE, Ebramzedeh E, Kvitne RS. A new technique: in vitro suture anchor fixation has superior yield strength to bone tunnel fixation for distal biceps tendon repair. Am J Sports Med. 2004;32(2):406-410.
18. Kettler M, Lunger J, Kuhn V, Mutschler W, Tingart MJ. Failure strengths in distal biceps tendon repair. Am J Sports Med. 2007;35(9):1544-1548.
19. Mazzocca AD, Burton KJ, Romeo AA, Santangelo S, Adams DA, Arciero RA. Biomechanical evaluation of 4 techniques of distal biceps brachii tendon repair. Am J Sports Med. 2007;35(2):252-258.
20. Spencer EE Jr, Tisdale A, Kostka K, Ivy RE. Is therapy necessary after distal biceps tendon repair? Hand (N Y). 2008;3(4):316-319.
21. Maffulli N, Ewen SWB, Waterston SW, Reaper J, Barrass V. Tenocytes from ruptured and tendinopathic Achilles tendons produce greater quantities of type III collagen than tenocytes from normal Achilles tendons. Am J Sports Med. 2000;28(4):499-505.
1. Cohen MS. Complications of distal biceps tendon repairs. Sports Med Arthrosc. 2008;16(3):148-153.
2. Bisson L, Moyer M, Lanighan K, Marzo J. Complications associated with repair of a distal biceps rupture using the modified two-incision technique. J Shoulder Elbow Surg. 2008;17(1 suppl):67S-71S.
3. Gallinet D, Dietsch E, Barbier-Brion B, Lerais JM, Obert L. Suture anchor reinsertion of distal biceps rupture: clinical results and radiological assessment of tendon healing. Orthop Traumatol Surg Res. 2011;97(3):252-259.
4. Schmidt CC, Diaz VA, Weir DM, Latona CR, Miller MC. Repaired distal biceps magnetic resonance imaging anatomy compared with outcome. J Shoulder Elbow Surg. 2012;21(12):1623-1631.
5. Marnitz T, Spiegel D, Hug K, et al. MR imaging findings in flexed abducted supinated (FABS) position and clinical presentation following refixation of distal biceps tendon rupture using bioabsorbable suture anchors. Rofo. 2012;184(5):432-436.
6. Bain GI, Prem H, Heptinstall RJ, Verhellen R, Paix D. Repair of distal biceps tendon rupture: a new technique using the Endobutton. J Shoulder Elbow Surg. 2000;9(2):120-126.
7. King J, Bollier M. Repair of distal biceps tendon ruptures using the Endobutton. J Am Acad Orthop Surg. 2008;16(8):490-494.
8. Cohen DB, Kawamura S, Ehteshami JR, Rodeo SA. Indomethacin and celecoxib impair rotator cuff tendon-to-bone healing. Am J Sports Med. 2006;34(3):362-369.
9. Ferry ST, Dahners LE, Afshari HM, Weinhold PS. The effects of common anti-inflammatory drugs on the healing rat patellar tendon. Am J Sports Med. 2007;35(8):1326-1333.
10. Miyamoto RG, Elser F, Millett PJ. Distal biceps tendon injuries. J Bone Joint Surg Am. 2010;92(11):2128-2138.
11. Dillon MT, Lepore DJ. Heterotopic ossification after single-incision distal biceps tendon repair with an Endobutton. J Surg Orthop Adv. 2011;20(3):198-201.
12. Peeters T, Ching-Soon NG, Jansen N, Sneyers C, Declercq G, Verstreken F. Functional outcome after repair of distal biceps tendon ruptures using the Endobutton technique. J Shoulder Elbow Surg. 2009;18(2):283-287.
13. Katolik LI, Fernandez J, Cohen MS. Acute failure of distal biceps reconstruction: a case report. J Shoulder Elbow Surg. 2007;16(5):e10-e12.
14. Seiler JG 3rd, Parker LM, Chamberland PD, Sherbourne GM, Carpenter WA. The distal biceps tendon. Two potential mechanisms involved in its rupture: arterial supply and mechanical impingement. J Shoulder Elbow Surg. 1995;4(3):149-156.
15. Siebenlist S, Lenich A, Buchholz A, et al. Biomechanical in vitro validation of intramedullary cortical button fixation for distal biceps tendon repair: a new technique. Am J Sports Med. 2011;39(8):1762-1768.
16. Pereira DS, Kvitne RS, Liang M, Giacobetti FB, Ebramzadeh E. Surgical repair of distal biceps tendon ruptures: a biomechanical comparison of two techniques. Am J Sports Med. 2002;30(3):432-436.
17. Lemos SE, Ebramzedeh E, Kvitne RS. A new technique: in vitro suture anchor fixation has superior yield strength to bone tunnel fixation for distal biceps tendon repair. Am J Sports Med. 2004;32(2):406-410.
18. Kettler M, Lunger J, Kuhn V, Mutschler W, Tingart MJ. Failure strengths in distal biceps tendon repair. Am J Sports Med. 2007;35(9):1544-1548.
19. Mazzocca AD, Burton KJ, Romeo AA, Santangelo S, Adams DA, Arciero RA. Biomechanical evaluation of 4 techniques of distal biceps brachii tendon repair. Am J Sports Med. 2007;35(2):252-258.
20. Spencer EE Jr, Tisdale A, Kostka K, Ivy RE. Is therapy necessary after distal biceps tendon repair? Hand (N Y). 2008;3(4):316-319.
21. Maffulli N, Ewen SWB, Waterston SW, Reaper J, Barrass V. Tenocytes from ruptured and tendinopathic Achilles tendons produce greater quantities of type III collagen than tenocytes from normal Achilles tendons. Am J Sports Med. 2000;28(4):499-505.
Breast cancer with brain metastases in pregnancy
Breast cancer during pregnancy is a therapeutic challenge. Evidence to guide management in metastatic breast cancer during pregnancy is limited, mainly because of a lack of randomized trials. Care needs to be individualized with interdisciplinary collaboration. We present the case of a young woman with HER2/neu overexpressed inflammatory breast cancer who became pregnant while on treatment, refused termination of pregnancy, and developed brain metastasis during the second trimester of pregnancy, posing a management dilemma.
Click on the PDF icon at the top of this introduction to read the full article.
Breast cancer during pregnancy is a therapeutic challenge. Evidence to guide management in metastatic breast cancer during pregnancy is limited, mainly because of a lack of randomized trials. Care needs to be individualized with interdisciplinary collaboration. We present the case of a young woman with HER2/neu overexpressed inflammatory breast cancer who became pregnant while on treatment, refused termination of pregnancy, and developed brain metastasis during the second trimester of pregnancy, posing a management dilemma.
Click on the PDF icon at the top of this introduction to read the full article.
Breast cancer during pregnancy is a therapeutic challenge. Evidence to guide management in metastatic breast cancer during pregnancy is limited, mainly because of a lack of randomized trials. Care needs to be individualized with interdisciplinary collaboration. We present the case of a young woman with HER2/neu overexpressed inflammatory breast cancer who became pregnant while on treatment, refused termination of pregnancy, and developed brain metastasis during the second trimester of pregnancy, posing a management dilemma.
Click on the PDF icon at the top of this introduction to read the full article.
Stent Thrombosis: A Disease for All Clinicians
Percutaneous coronary intervention (PCI) using coronary artery stent implantation is commonly used to treat symptomatic high-risk and unstable coronary artery disease (CAD). The use of stents has improved the safety and efficacy of PCI by reducing the need for repeat revascularization, reducing acute vessel closure requiring emergent coronary artery bypass graft surgery, and expanding the use of PCI to more complex diseases. Nevertheless, stents carry the risk of sudden thrombotic occlusion or stent thrombosis, particularly during the first several days or weeks after implantation. In turn, stent thrombosis can lead to acute myocardial infarction (MI) and a mortality rate > 25%.1,2
This article highlights 2 cases of patients with stent thrombosis and discusses its pathophysiology, clinical features, and risk-avoidance strategies. Given the high prevalence of CAD and ubiquitous PCI procedures in the U.S. health care system, it is essential that not only cardiologists, but all clinicians and health care providers who care for patients with coronary stents understand how to help prevent and manage this life-threatening clinical entity.1
Case 1
A 56-year-old man presented to his primary care physician with exertion-related angina. The patient had a history of type 2 diabetes mellitus, dyslipidemia, systemic hypertension, obesity, and CAD status post MI in 2002 treated with a bare metal stent (BMS) to the left circumflex coronary artery (LCx). A stress myocardial perfusion imaging with 99mTc-sestamibi revealed moderate reversible exercise-induced myocardial ischemia involving the inferior and inferoapical wall segments of the left ventricle with associated hypokinesia.
Coronary angiography revealed nonsignificant disease of the left anterior descending artery (LAD) and LCx, a patent LCx stent, and a 95% mid-right coronary artery (RCA) obstruction with delayed (TIMI grade 2) antegrade flow. The distal right posterior descending artery filled via left to right collaterals from the LAD.
Percutaneous coronary intervention was performed on the RCA lesion 8 days after the patient was started on dual antiplatelet therapy (DAPT) with aspirin 81 mg and clopidogrel 75 mg (including 300 mg loading dose on the day of the diagnostic angiogram). The mid RCA was treated with a drug-eluting stent (DES) and a BMS in a nonoverlapping fashion with an excellent angiographic result. The patient was instructed to continue DAPT with aspirin 325 mg daily and clopidogrel 75 mg daily for 12 months.
Three days post PCI, the patient arrived at the emergency department with angina of 1-hour duration associated with shortness of breath and diaphoresis. He reported strict adherence to DAPT.
Initial vital signs were normal. The electrocardiogram (ECG) showed ST segment elevation (1-2 mm) on leads III, aVF, and V5 to V6, suggestive of an acute inferolateral injury pattern for which emergent coronary angiography was performed. Angiography showed a 100% proximal RCA occlusion at the proximal edge of the most proximal stent with absence of any antegrade flow beyond the occlusion (TIMI grade 0 flow). This finding was diagnostic of definite angiographic subacute stent thrombosis. The patient underwent successful aspiration thrombectomy, balloon angioplasty, and restoration of normal TIMI grade 3 flow with a door-to-balloon time of 86 minutes.
Because stent thrombosis is relatively unexpected after an excellent angiographic result and DAPT adherence, the possibility of clopidogrel resistance was considered as a major contributor for the thrombotic event. Platelet aggregation tests showed adequate prolongation of collagen/epinephrine (COL-EPI) > 300 seconds (normal: 81-153 seconds), but inadequate prolongation of collagen/adenosindiphosphate (COL-ADP) of 109 seconds (normal: 53-105 seconds) while on clopidogrel. Therefore, the patient was switched to prasugrel.
The patient was discharged home after 5 days of observation at the cardiac care unit without any post-MI complications. During a follow-up appointment 1 month after discharge, he was clinically stable and free of cardiovascular symptoms. Workup performed for acquired or inherited thrombophilia was negative. He continued taking DAPT (daily aspirin 325 mg orally and prasugrel 10 mg orally) for 12 months. After completing 12 months of DAPT, he was maintained on aspirin 81 mg daily. At 24 months’ follow-up, he remained free of recurrent angina with no further cardiovascular events.
Case 2
An 84-year-old man with a medical history of dyslipidemia, paroxysmal atrial fibrillation, previous stroke, and peptic ulcer disease was brought to the emergency department following an episode of near syncope in the early morning hours. The patient revealed that he had experienced neck pain since midnight. The 12-lead ECG showed normal sinus rhythm with 2 mm ST segment elevation in leads II, III, aVF, V5-V6, and ST segment depression in V2, and Q waves in inferior leads. A right-sided ECG showed ST segment elevation in V4, suggestive of right ventricle infarction.
The patient remained hypotensive (83/49 mm Hg) despite isotonic fluid administration (about 1.5-2.0 liters of 0.9 normal saline at 999 mL/h). A dopamine drip for persistent hypotension was started, and he was taken emergently to the catheterization laboratory for primary PCI. Coronary angiography showed no significant left CAD and a 100% mid-RCA occlusion with faint left-to-right collaterals. After aspiration thrombectomy, bare metal RCA stenting was performed. Transient no-reflow was treated with intracoronary nicardipine and nitroglycerin. The patient continued to be in shock, and an intra-aortic balloon pump was inserted and 1:1 counterpulsation was initiated.
Following admission to the coronary care unit, the patient’s mean arterial pressure improved. Inotropes were weaned off 2 days after PCI, and the intra-aortic balloon pump was removed. During his stay, the post-MI course was uneventful except for an episode of asymptomatic paroxysmal atrial flutter and nonspecific back dermatitis attributed to a prolonged recumbent position.
The patient was transferred to the internal medicine ward for medical therapy optimization and the initiation of low-intensity cardiac rehabilitation. After 2 days on the ward, discharge planning was initiated. However, he developed an episode of atrial fibrillation with fast ventricular response. Metoprolol 5 mg IV bolus was given, and the ventricular rate was controlled. At that point, the dose of long-acting beta-blocker (metoprolol succinate) was optimized, he was started on full-dose anticoagulation (warfarin), and clopidogrel was discontinued. Two days later, the patient reported back pruritus, and an erythematous raised rash on his back spreading to the torso was noticed. An aspirin allergy was suspected as the trigger for the rash, thus aspirin was also discontinued.
Three days later, the patient developed recurrent neck pain (angina) with radiation to his shoulders and left arm. The ECG revealed re-elevation of the ST segment (inferior, posterior, and lateral leads). He received reloading of clopidogrel 600 mg and aspirin 325 mg. Also, an eptifibatide IV bolus followed by an infusion was given for immediate antiplatelet action. He was transferred for emergent coronary angiography with suspected subacute stent thrombosis.
Upon arrival to the catheterization lab, the patient was awake and alert but in mild respiratory distress. Intravenous dopamine was started due to hypotension (systolic blood pressure was about 85 mm Hg). Limited RCA angiography showed a large clot burden with a partially thrombosed stent and TIMI grade 3 flow. After intracoronary eptifibatide and nicardipine were given, successful aspiration thrombectomy was performed twice with partial removal of thrombus. In-stent high-pressure balloon angioplasty was performed and optimal stenting was confirmed by intravascular ultrasound (IVUS) criteria. However, a residual layered thrombus along the distal stent edge was noticed. The patient tolerated the procedure without complications.
Dual antiplatelet therapy with aspirin and clopidogrel for 12 months was recommended. The eptifibatide infusion was continued for 48 hours. The jaw pain, shortness of breath, and ECG changes disappeared, but the patient remained on vasopressors for the following 7 days.
Around 1 week after the stent thrombosis event, the patient was found pulseless. Advanced cardiopulmonary resuscitation was started. ST segment elevation in lead II was noted on the cardiac monitor. There was no return of spontaneous circulation after 20 minutes, and the patient was pronounced dead. The autopsy revealed a patent RCA stent without evidence of occlusion, a large transmural inferior MI, left ventricular rupture, and hemopericardium.
Discussion
Stent thrombosis is an uncommon complication after coronary stent implantation. Based on the Academic Research Consortium criteria, definite stent thrombosis is defined as a clinical event with symptoms suggestive of an acute coronary syndrome (ACS) with angiography or pathology that confirms the presence of stent thrombosis.2 Probable stent thrombosis is defined as an unexplained death within 30 days or MI involving the territory of the target vessel without angiographic confirmation of stent thrombosis.2 Finally, possible stent thrombosis is any unexplained death after 30 days.2
Based on timing, stent thrombosis is divided by acute (< 24 hours post stent implantation), subacute (24 hours to 30 days post stent implantation), late (> 30 days post stent implantation), and very late (> 12 months post stent implantation).3 However, most cases (up to 60%) occur within the first 30 days after placement, irrespective of stent type.4
The incidence of subacute stent thrombosis is reported to approach 1% during the first 30 days postprocedure but may be as high as 5% or 10% depending on associated clinical and angiographic variables (Table 1).5 The strongest clinical predictors of stent thrombosis are premature cessation of antiplatelet therapy, renal insufficiency, diabetes mellitus, and ACS.2,6 Lesion and procedural characteristics associated with increased risk of stent thrombosis include bifurcation lesions, longer stent length, multiple implanted stents, stent underexpansion, and/or stent malapposition.6-9 Stent type (drug or non–drug-eluting) has no impact on the risk of stent thrombosis during the first 30 days postprocedure.10,11
The clinical events related to late stent thrombosis, although rare, carry a mortality rate of up to 45%.12 The specific risk factors for late and very late stent thrombosis are less well defined but relate to delayed neointimal coverage, ongoing vessel inflammation, and the development of neoatherosclerosis within stents.13,14
Rationale for the Use of Dual Antiplatelet Regimen
Stent thrombosis is a platelet-mediated process related to a heightened state of systemic and intracoronary thrombogenicity and inflammation.15 Stent under-expansion enhances abnormal shear stress, which explains as many as 80% of these events.13,15,16 Stent thrombosis also has been frequently related to inadequate neointimal coverage.14 Angioscopic studies, especially with DES, suggest that stent endothelialization is delayed or incomplete, observing a correlation between the areas of uncovered stent surface and thrombosis.14,17
In the early days of coronary stenting, during the 1990s, the risk of acute and subacute stent thrombosis approached 20%.18,19 Initial attempts to reduce the risk included combining aspirin and warfarin, but at the expense of a marked increase in bleeding complications and prolonged hospital stays.20,21 In 1995, it became clear through the pivotal observations of Colombo and colleagues that incomplete expansion of the stent (documented by IVUS) was a major contributor to the risk of stent thrombosis.16 By using noncompliant balloons at high pressure (14-20 atmospheres) for stent postdilatation combined with DAPT (aspirin and ticlopidine), the high rates of early stent thrombosis were markedly reduced to the current level of 1% to 2%.16
Colombo and colleagues’ observations were prospectively evaluated in the Stent Anticoagulation Regimen Study (STARS) trial.22 Patients who underwent successful stenting were randomized to aspirin alone, aspirin and warfarin, or aspirin and ticlopidine. The STARS trial showed convincingly that the combination of aspirin and ticlopidine was superior to the other 2 regimens, reducing the stent thrombosis rate to only 0.5% (compared with 2.7% for aspirin and warfarin, and 3.6% for aspirin alone).22 Afterward, DAPT became the standard of care following coronary stenting.23
Although ticlopidine was the first widely used thienopyridine for the prevention of stent thrombosis, hematologic adverse events (AEs) (eg, neutropenia, thrombotic thrombocytopenia purpura) limited its use.24 Consequently, ticlopidine was replaced with clopidogrel, which seemed to offer similar efficacy but significantly fewer AEs.25
The current American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guidelines for the prevention of ST after coronary stent implantation state that after PCI:
- Aspirin use should be continued indefinitely.
- The duration of adenosine diphosphate antagonists depends on the stent type (BMS or DES) and the indication for implantation (ACS or non-ACS).
a. Patients receiving a stent (BMS or DES) for ACS therapy should be given 1 of the following for at least 12 months:
i. Clopidogrel 75 mg daily
ii. Prasugrel 10 mg daily
iii. Ticagrelor 90 mg twice daily
b. In patients receiving DES for a non-ACS indication, clopidogrel should be given for at least 12 months if the patient is not at high risk for bleeding.
c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months.23
Clopidogrel Hyporesponse
As shown in case 1, stent thrombosis may still occur in a patient on DAPT because of individual variability in platelet response to clopidogrel.5 Clopidogrel hyporesponse, also known as clopidogrel resistance, has been recognized as clinically significant because of its prevalence and association with poor outcomes.5 Its prevalence may range between 4% and 30%, although the definitions of clopidogrel hyporesponse varied between studies.26
Clopidogrel hyporesponse is defined as an inadequate inhibition of platelet function measured by nonspecific ex-vivo laboratory methods.27,28 The relationship between clopidogrel resistance (nonresponders), stent thrombosis, and ischemic events has been clearly established.5,29
Given the devastating consequences of stent thrombosis, efforts were directed to identify those patients at highest risk. One such effort has been focused on the measurement of platelet function, allowing for the identification of patients who do not respond adequately to antiplatelet therapy.15,28,30,31 However, the treatment of high-residual platelet reactivity as confirmed by laboratory assessment has not shown to clinically correlate with any benefit in the prevention of ST.6,15,29-31 Therefore, the current ACC/AHA/SCAI PCI guidelines do not recommend the routine clinical use of platelet function testing to screen patients treated with clopidogrel who are undergoing PCI.23
Clopidogrel is a prodrug, metabolized to its active form via the cytochrome P450 enzyme system before it can inhibit platelet function.32 Accordingly, certain genetic variation in enzyme activity, or polymorphisms, would be expected to influence its clinical effectiveness.33,34 The most common of these polymorphisms, CYP2C19*2, has been associated (in vitro) with reduced concentrations of active clopidogrel metabolites and with diminished platelet inhibition.35,36 As a result, the FDA has added a safety alert to the prescribing information for clopidogrel concerning how genetic differences in the metabolism of this agent can affect its effectiveness, ways to test for these genetic differences, and advice concerning alternative dosing strategies or use of other medications in poor metabolizers of clopidogrel.37 Although the routine clinical use of genetic testing to screen patients treated with clopidogrel who are undergoing PCI is not recommended, it may be considered in patients undergoing elective high-risk PCI procedures (eg, unprotected left main, last patent coronary artery, or bifurcating left main).23
The newer inhibitors of ADP-induced platelet activation, prasugrel and ticagrelor, are not prodrugs, and thus, their action is not affected by this genetic variability. Accordingly, these drugs have shown a more consistent, stronger, and faster inhibition of platelet aggregation compared with clopidogrel.36-39 In the pivotal trials (TRITON-TIMI 38 and PLATO), these agents have also been shown to be more effective in reducing the incidence of stent thrombosis.36,37,40,41 Therefore, in cases where clopidogrel resistance/hyporesponse is suspected in the setting of DAPT, such as stent thrombosis, guidelines recommend the use of 1 of these agents.23
Premature Discontinuation of Antiplatelet Therapy
As illustrated in case 2, premature discontinuation of antiplatelet therapy may be fatal, as it is associated with a marked increase in the risk of stent thrombosis. Indeed, premature discontinuation of DAPT is the leading independent predictor for stent thrombosis.12,42,43 Premature discontinuation of DAPT is defined when one or both agents (aspirin, ADP-antagonists) are suspended within 30 days of BMS placement or within 1 year of DES placement. In the case of DES, the first 6 months after implantation seem to be most critical. In a large observational study of patients treated with DES, stent thrombosis occurred in 29% of those patients in whom antiplatelet therapy was prematurely discontinued.12
In order to minimize the risk of premature DAPT discontinuation, one should address its causes. There are patient- and physician-related factors that may influence an early discontinuation of aspirin, thienopyridine, or both agents. Patient-related factors were identified in the PREMIER registry, including older age, not having completed high school, not being married, and/or not seeking health care because of costs.42 Another important but often overlooked factor that has an impact on adherence with prolonged DAPT post-DES implantation is nuisance or superficial bleeding.44 Physician-related factors include not providing discharge instructions for medication use and ill-advised instructions given by health care providers to discontinue therapy before procedures with a low risk of bleeding (eg, dental cleaning, cataract surgery, colonoscopy, skin biopsy).42
In addition, the perioperative management of DAPT during the first several weeks after coronary stenting has been shown to critically influence outcomes. In a study by Sharma and colleagues, fatal cases of stent thrombosis occurred after the discontinuation of antiplatelet therapy for noncardiac surgery among patients with BMS implantation within the past 90 days.43
In selected cases when a noncardiac procedure cannot be delayed for 1 year, recognizing the impact of the specific timing for the discontinuation of the antiplatelet regimen is essential. Kaluza and colleagues reported on 40 patients treated with BMS who underwent noncardiac surgery within 6 weeks of the stent implantation.45 Seven patients had an MI, of which 6 were fatal. Stent thrombosis was presumed to be the cause of all MIs. In 5 of 7 cases, ticlopidine was withheld before surgery.45
All clinicians should be aware of the following recommendations to avoid catastrophic cardiovascular complications related to premature discontinuation of DAPT during the perioperative setting:
- Elective procedures should be deferred until patients have completed an appropriate course of thienopyridine therapy (12 months after DES and a minimum of 4 weeks for BMS implantation).
- For those patients treated with DES who are to undergo a nonelective procedure that mandates discontinuation of thienopyridine therapy, the possibility of procedure postponement for completion of DAPT for at least 6 months should be judiciously deliberated. If the procedure cannot be postponed, aspirin should be continued if at all possible and the thienopyridine restarted as soon as possible after the procedure.42,46,47
Conclusion
Stent thrombosis is a rare but devastating complication of coronary stent implantation. Although it can occur at any time after stent placement, the majority of events occur within the first month. The use of optimal stenting techniques and adherence to DAPT are required to minimize the risk of stent thrombosis. Several clinical and procedural predictors have been related to an increased risk of stent thrombosis. The premature cessation of DAPT is the most important risk factor for stent thrombosis.
All physicians should ensure patients are properly and thoroughly educated about the reasons they are prescribed DAPT and the significant risks associated with prematurely discontinuing such therapy. All clinicians, especially noncardiologists, should realize the importance of close communication with a cardiologist or interventional cardiologist in situations when premature discontinuation is being considered for a specific reason.
Table 2 summarizes a framework of the most relevant factors that should be taken into account before, during, and after stent implantation, both by interventional cardiologists, as well as by all clinicians involved in the care of the patient. Given current procedural volumes (> 1 million PCI procedures are performed in the U.S. annually) and because the risk of stent thrombosis is both time and treatment dependent, it is of paramount importance that, not only cardiologists, but all physicians know the impact of stent thrombosis in their patients and how to avoid situations that may increase its risk.1 Team-approach decisions about antiplatelet therapy after stent placement, especially within the first 12 months, and a patient-centered mind-set are indispensable to optimize patient outcomes.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
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18. Serruys PW, Strauss BH, Beatt KJ, et al. Angiographic follow-up after placement of a self-expanding coronary-artery stent. N Engl J Med. 1991;324(1):13-17.
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25. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH; CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000;102(6):624-629.
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28. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol. 2007;50(19):1822-1834.
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31. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51(20):1925-1934.
32. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92-99.
33. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244-2247.
34. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354-362.
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36. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: A subanalysis of a randomised trial. Lancet. 2008;371(9621):1353-1363.
37. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
38. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29(1):21-30.
39. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study. Circulation. 2009;120(25):2577-2585.
40. Wiviott SD, Trenk D, Frelinger AL, et al; PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932.
41. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: The RESPOND study. Circulation. 2010;121(10):1188-1199.
42. Spertus, JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: Results from the PREMIER registry. Circulation. 2006;113(24):2803-2809.
43. Sharma AK, Ajani AE, Hamwi SM, et al. Major noncardiac surgery following coronary stenting: When is it safe to operate? Catheter Cardiovasc Interv. 2004;63(2):141-145.
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47. Grines CL, Bonow RO, Casey DE Jr, et al; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: A science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol. 2007;49(6):734-739.
Percutaneous coronary intervention (PCI) using coronary artery stent implantation is commonly used to treat symptomatic high-risk and unstable coronary artery disease (CAD). The use of stents has improved the safety and efficacy of PCI by reducing the need for repeat revascularization, reducing acute vessel closure requiring emergent coronary artery bypass graft surgery, and expanding the use of PCI to more complex diseases. Nevertheless, stents carry the risk of sudden thrombotic occlusion or stent thrombosis, particularly during the first several days or weeks after implantation. In turn, stent thrombosis can lead to acute myocardial infarction (MI) and a mortality rate > 25%.1,2
This article highlights 2 cases of patients with stent thrombosis and discusses its pathophysiology, clinical features, and risk-avoidance strategies. Given the high prevalence of CAD and ubiquitous PCI procedures in the U.S. health care system, it is essential that not only cardiologists, but all clinicians and health care providers who care for patients with coronary stents understand how to help prevent and manage this life-threatening clinical entity.1
Case 1
A 56-year-old man presented to his primary care physician with exertion-related angina. The patient had a history of type 2 diabetes mellitus, dyslipidemia, systemic hypertension, obesity, and CAD status post MI in 2002 treated with a bare metal stent (BMS) to the left circumflex coronary artery (LCx). A stress myocardial perfusion imaging with 99mTc-sestamibi revealed moderate reversible exercise-induced myocardial ischemia involving the inferior and inferoapical wall segments of the left ventricle with associated hypokinesia.
Coronary angiography revealed nonsignificant disease of the left anterior descending artery (LAD) and LCx, a patent LCx stent, and a 95% mid-right coronary artery (RCA) obstruction with delayed (TIMI grade 2) antegrade flow. The distal right posterior descending artery filled via left to right collaterals from the LAD.
Percutaneous coronary intervention was performed on the RCA lesion 8 days after the patient was started on dual antiplatelet therapy (DAPT) with aspirin 81 mg and clopidogrel 75 mg (including 300 mg loading dose on the day of the diagnostic angiogram). The mid RCA was treated with a drug-eluting stent (DES) and a BMS in a nonoverlapping fashion with an excellent angiographic result. The patient was instructed to continue DAPT with aspirin 325 mg daily and clopidogrel 75 mg daily for 12 months.
Three days post PCI, the patient arrived at the emergency department with angina of 1-hour duration associated with shortness of breath and diaphoresis. He reported strict adherence to DAPT.
Initial vital signs were normal. The electrocardiogram (ECG) showed ST segment elevation (1-2 mm) on leads III, aVF, and V5 to V6, suggestive of an acute inferolateral injury pattern for which emergent coronary angiography was performed. Angiography showed a 100% proximal RCA occlusion at the proximal edge of the most proximal stent with absence of any antegrade flow beyond the occlusion (TIMI grade 0 flow). This finding was diagnostic of definite angiographic subacute stent thrombosis. The patient underwent successful aspiration thrombectomy, balloon angioplasty, and restoration of normal TIMI grade 3 flow with a door-to-balloon time of 86 minutes.
Because stent thrombosis is relatively unexpected after an excellent angiographic result and DAPT adherence, the possibility of clopidogrel resistance was considered as a major contributor for the thrombotic event. Platelet aggregation tests showed adequate prolongation of collagen/epinephrine (COL-EPI) > 300 seconds (normal: 81-153 seconds), but inadequate prolongation of collagen/adenosindiphosphate (COL-ADP) of 109 seconds (normal: 53-105 seconds) while on clopidogrel. Therefore, the patient was switched to prasugrel.
The patient was discharged home after 5 days of observation at the cardiac care unit without any post-MI complications. During a follow-up appointment 1 month after discharge, he was clinically stable and free of cardiovascular symptoms. Workup performed for acquired or inherited thrombophilia was negative. He continued taking DAPT (daily aspirin 325 mg orally and prasugrel 10 mg orally) for 12 months. After completing 12 months of DAPT, he was maintained on aspirin 81 mg daily. At 24 months’ follow-up, he remained free of recurrent angina with no further cardiovascular events.
Case 2
An 84-year-old man with a medical history of dyslipidemia, paroxysmal atrial fibrillation, previous stroke, and peptic ulcer disease was brought to the emergency department following an episode of near syncope in the early morning hours. The patient revealed that he had experienced neck pain since midnight. The 12-lead ECG showed normal sinus rhythm with 2 mm ST segment elevation in leads II, III, aVF, V5-V6, and ST segment depression in V2, and Q waves in inferior leads. A right-sided ECG showed ST segment elevation in V4, suggestive of right ventricle infarction.
The patient remained hypotensive (83/49 mm Hg) despite isotonic fluid administration (about 1.5-2.0 liters of 0.9 normal saline at 999 mL/h). A dopamine drip for persistent hypotension was started, and he was taken emergently to the catheterization laboratory for primary PCI. Coronary angiography showed no significant left CAD and a 100% mid-RCA occlusion with faint left-to-right collaterals. After aspiration thrombectomy, bare metal RCA stenting was performed. Transient no-reflow was treated with intracoronary nicardipine and nitroglycerin. The patient continued to be in shock, and an intra-aortic balloon pump was inserted and 1:1 counterpulsation was initiated.
Following admission to the coronary care unit, the patient’s mean arterial pressure improved. Inotropes were weaned off 2 days after PCI, and the intra-aortic balloon pump was removed. During his stay, the post-MI course was uneventful except for an episode of asymptomatic paroxysmal atrial flutter and nonspecific back dermatitis attributed to a prolonged recumbent position.
The patient was transferred to the internal medicine ward for medical therapy optimization and the initiation of low-intensity cardiac rehabilitation. After 2 days on the ward, discharge planning was initiated. However, he developed an episode of atrial fibrillation with fast ventricular response. Metoprolol 5 mg IV bolus was given, and the ventricular rate was controlled. At that point, the dose of long-acting beta-blocker (metoprolol succinate) was optimized, he was started on full-dose anticoagulation (warfarin), and clopidogrel was discontinued. Two days later, the patient reported back pruritus, and an erythematous raised rash on his back spreading to the torso was noticed. An aspirin allergy was suspected as the trigger for the rash, thus aspirin was also discontinued.
Three days later, the patient developed recurrent neck pain (angina) with radiation to his shoulders and left arm. The ECG revealed re-elevation of the ST segment (inferior, posterior, and lateral leads). He received reloading of clopidogrel 600 mg and aspirin 325 mg. Also, an eptifibatide IV bolus followed by an infusion was given for immediate antiplatelet action. He was transferred for emergent coronary angiography with suspected subacute stent thrombosis.
Upon arrival to the catheterization lab, the patient was awake and alert but in mild respiratory distress. Intravenous dopamine was started due to hypotension (systolic blood pressure was about 85 mm Hg). Limited RCA angiography showed a large clot burden with a partially thrombosed stent and TIMI grade 3 flow. After intracoronary eptifibatide and nicardipine were given, successful aspiration thrombectomy was performed twice with partial removal of thrombus. In-stent high-pressure balloon angioplasty was performed and optimal stenting was confirmed by intravascular ultrasound (IVUS) criteria. However, a residual layered thrombus along the distal stent edge was noticed. The patient tolerated the procedure without complications.
Dual antiplatelet therapy with aspirin and clopidogrel for 12 months was recommended. The eptifibatide infusion was continued for 48 hours. The jaw pain, shortness of breath, and ECG changes disappeared, but the patient remained on vasopressors for the following 7 days.
Around 1 week after the stent thrombosis event, the patient was found pulseless. Advanced cardiopulmonary resuscitation was started. ST segment elevation in lead II was noted on the cardiac monitor. There was no return of spontaneous circulation after 20 minutes, and the patient was pronounced dead. The autopsy revealed a patent RCA stent without evidence of occlusion, a large transmural inferior MI, left ventricular rupture, and hemopericardium.
Discussion
Stent thrombosis is an uncommon complication after coronary stent implantation. Based on the Academic Research Consortium criteria, definite stent thrombosis is defined as a clinical event with symptoms suggestive of an acute coronary syndrome (ACS) with angiography or pathology that confirms the presence of stent thrombosis.2 Probable stent thrombosis is defined as an unexplained death within 30 days or MI involving the territory of the target vessel without angiographic confirmation of stent thrombosis.2 Finally, possible stent thrombosis is any unexplained death after 30 days.2
Based on timing, stent thrombosis is divided by acute (< 24 hours post stent implantation), subacute (24 hours to 30 days post stent implantation), late (> 30 days post stent implantation), and very late (> 12 months post stent implantation).3 However, most cases (up to 60%) occur within the first 30 days after placement, irrespective of stent type.4
The incidence of subacute stent thrombosis is reported to approach 1% during the first 30 days postprocedure but may be as high as 5% or 10% depending on associated clinical and angiographic variables (Table 1).5 The strongest clinical predictors of stent thrombosis are premature cessation of antiplatelet therapy, renal insufficiency, diabetes mellitus, and ACS.2,6 Lesion and procedural characteristics associated with increased risk of stent thrombosis include bifurcation lesions, longer stent length, multiple implanted stents, stent underexpansion, and/or stent malapposition.6-9 Stent type (drug or non–drug-eluting) has no impact on the risk of stent thrombosis during the first 30 days postprocedure.10,11
The clinical events related to late stent thrombosis, although rare, carry a mortality rate of up to 45%.12 The specific risk factors for late and very late stent thrombosis are less well defined but relate to delayed neointimal coverage, ongoing vessel inflammation, and the development of neoatherosclerosis within stents.13,14
Rationale for the Use of Dual Antiplatelet Regimen
Stent thrombosis is a platelet-mediated process related to a heightened state of systemic and intracoronary thrombogenicity and inflammation.15 Stent under-expansion enhances abnormal shear stress, which explains as many as 80% of these events.13,15,16 Stent thrombosis also has been frequently related to inadequate neointimal coverage.14 Angioscopic studies, especially with DES, suggest that stent endothelialization is delayed or incomplete, observing a correlation between the areas of uncovered stent surface and thrombosis.14,17
In the early days of coronary stenting, during the 1990s, the risk of acute and subacute stent thrombosis approached 20%.18,19 Initial attempts to reduce the risk included combining aspirin and warfarin, but at the expense of a marked increase in bleeding complications and prolonged hospital stays.20,21 In 1995, it became clear through the pivotal observations of Colombo and colleagues that incomplete expansion of the stent (documented by IVUS) was a major contributor to the risk of stent thrombosis.16 By using noncompliant balloons at high pressure (14-20 atmospheres) for stent postdilatation combined with DAPT (aspirin and ticlopidine), the high rates of early stent thrombosis were markedly reduced to the current level of 1% to 2%.16
Colombo and colleagues’ observations were prospectively evaluated in the Stent Anticoagulation Regimen Study (STARS) trial.22 Patients who underwent successful stenting were randomized to aspirin alone, aspirin and warfarin, or aspirin and ticlopidine. The STARS trial showed convincingly that the combination of aspirin and ticlopidine was superior to the other 2 regimens, reducing the stent thrombosis rate to only 0.5% (compared with 2.7% for aspirin and warfarin, and 3.6% for aspirin alone).22 Afterward, DAPT became the standard of care following coronary stenting.23
Although ticlopidine was the first widely used thienopyridine for the prevention of stent thrombosis, hematologic adverse events (AEs) (eg, neutropenia, thrombotic thrombocytopenia purpura) limited its use.24 Consequently, ticlopidine was replaced with clopidogrel, which seemed to offer similar efficacy but significantly fewer AEs.25
The current American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guidelines for the prevention of ST after coronary stent implantation state that after PCI:
- Aspirin use should be continued indefinitely.
- The duration of adenosine diphosphate antagonists depends on the stent type (BMS or DES) and the indication for implantation (ACS or non-ACS).
a. Patients receiving a stent (BMS or DES) for ACS therapy should be given 1 of the following for at least 12 months:
i. Clopidogrel 75 mg daily
ii. Prasugrel 10 mg daily
iii. Ticagrelor 90 mg twice daily
b. In patients receiving DES for a non-ACS indication, clopidogrel should be given for at least 12 months if the patient is not at high risk for bleeding.
c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months.23
Clopidogrel Hyporesponse
As shown in case 1, stent thrombosis may still occur in a patient on DAPT because of individual variability in platelet response to clopidogrel.5 Clopidogrel hyporesponse, also known as clopidogrel resistance, has been recognized as clinically significant because of its prevalence and association with poor outcomes.5 Its prevalence may range between 4% and 30%, although the definitions of clopidogrel hyporesponse varied between studies.26
Clopidogrel hyporesponse is defined as an inadequate inhibition of platelet function measured by nonspecific ex-vivo laboratory methods.27,28 The relationship between clopidogrel resistance (nonresponders), stent thrombosis, and ischemic events has been clearly established.5,29
Given the devastating consequences of stent thrombosis, efforts were directed to identify those patients at highest risk. One such effort has been focused on the measurement of platelet function, allowing for the identification of patients who do not respond adequately to antiplatelet therapy.15,28,30,31 However, the treatment of high-residual platelet reactivity as confirmed by laboratory assessment has not shown to clinically correlate with any benefit in the prevention of ST.6,15,29-31 Therefore, the current ACC/AHA/SCAI PCI guidelines do not recommend the routine clinical use of platelet function testing to screen patients treated with clopidogrel who are undergoing PCI.23
Clopidogrel is a prodrug, metabolized to its active form via the cytochrome P450 enzyme system before it can inhibit platelet function.32 Accordingly, certain genetic variation in enzyme activity, or polymorphisms, would be expected to influence its clinical effectiveness.33,34 The most common of these polymorphisms, CYP2C19*2, has been associated (in vitro) with reduced concentrations of active clopidogrel metabolites and with diminished platelet inhibition.35,36 As a result, the FDA has added a safety alert to the prescribing information for clopidogrel concerning how genetic differences in the metabolism of this agent can affect its effectiveness, ways to test for these genetic differences, and advice concerning alternative dosing strategies or use of other medications in poor metabolizers of clopidogrel.37 Although the routine clinical use of genetic testing to screen patients treated with clopidogrel who are undergoing PCI is not recommended, it may be considered in patients undergoing elective high-risk PCI procedures (eg, unprotected left main, last patent coronary artery, or bifurcating left main).23
The newer inhibitors of ADP-induced platelet activation, prasugrel and ticagrelor, are not prodrugs, and thus, their action is not affected by this genetic variability. Accordingly, these drugs have shown a more consistent, stronger, and faster inhibition of platelet aggregation compared with clopidogrel.36-39 In the pivotal trials (TRITON-TIMI 38 and PLATO), these agents have also been shown to be more effective in reducing the incidence of stent thrombosis.36,37,40,41 Therefore, in cases where clopidogrel resistance/hyporesponse is suspected in the setting of DAPT, such as stent thrombosis, guidelines recommend the use of 1 of these agents.23
Premature Discontinuation of Antiplatelet Therapy
As illustrated in case 2, premature discontinuation of antiplatelet therapy may be fatal, as it is associated with a marked increase in the risk of stent thrombosis. Indeed, premature discontinuation of DAPT is the leading independent predictor for stent thrombosis.12,42,43 Premature discontinuation of DAPT is defined when one or both agents (aspirin, ADP-antagonists) are suspended within 30 days of BMS placement or within 1 year of DES placement. In the case of DES, the first 6 months after implantation seem to be most critical. In a large observational study of patients treated with DES, stent thrombosis occurred in 29% of those patients in whom antiplatelet therapy was prematurely discontinued.12
In order to minimize the risk of premature DAPT discontinuation, one should address its causes. There are patient- and physician-related factors that may influence an early discontinuation of aspirin, thienopyridine, or both agents. Patient-related factors were identified in the PREMIER registry, including older age, not having completed high school, not being married, and/or not seeking health care because of costs.42 Another important but often overlooked factor that has an impact on adherence with prolonged DAPT post-DES implantation is nuisance or superficial bleeding.44 Physician-related factors include not providing discharge instructions for medication use and ill-advised instructions given by health care providers to discontinue therapy before procedures with a low risk of bleeding (eg, dental cleaning, cataract surgery, colonoscopy, skin biopsy).42
In addition, the perioperative management of DAPT during the first several weeks after coronary stenting has been shown to critically influence outcomes. In a study by Sharma and colleagues, fatal cases of stent thrombosis occurred after the discontinuation of antiplatelet therapy for noncardiac surgery among patients with BMS implantation within the past 90 days.43
In selected cases when a noncardiac procedure cannot be delayed for 1 year, recognizing the impact of the specific timing for the discontinuation of the antiplatelet regimen is essential. Kaluza and colleagues reported on 40 patients treated with BMS who underwent noncardiac surgery within 6 weeks of the stent implantation.45 Seven patients had an MI, of which 6 were fatal. Stent thrombosis was presumed to be the cause of all MIs. In 5 of 7 cases, ticlopidine was withheld before surgery.45
All clinicians should be aware of the following recommendations to avoid catastrophic cardiovascular complications related to premature discontinuation of DAPT during the perioperative setting:
- Elective procedures should be deferred until patients have completed an appropriate course of thienopyridine therapy (12 months after DES and a minimum of 4 weeks for BMS implantation).
- For those patients treated with DES who are to undergo a nonelective procedure that mandates discontinuation of thienopyridine therapy, the possibility of procedure postponement for completion of DAPT for at least 6 months should be judiciously deliberated. If the procedure cannot be postponed, aspirin should be continued if at all possible and the thienopyridine restarted as soon as possible after the procedure.42,46,47
Conclusion
Stent thrombosis is a rare but devastating complication of coronary stent implantation. Although it can occur at any time after stent placement, the majority of events occur within the first month. The use of optimal stenting techniques and adherence to DAPT are required to minimize the risk of stent thrombosis. Several clinical and procedural predictors have been related to an increased risk of stent thrombosis. The premature cessation of DAPT is the most important risk factor for stent thrombosis.
All physicians should ensure patients are properly and thoroughly educated about the reasons they are prescribed DAPT and the significant risks associated with prematurely discontinuing such therapy. All clinicians, especially noncardiologists, should realize the importance of close communication with a cardiologist or interventional cardiologist in situations when premature discontinuation is being considered for a specific reason.
Table 2 summarizes a framework of the most relevant factors that should be taken into account before, during, and after stent implantation, both by interventional cardiologists, as well as by all clinicians involved in the care of the patient. Given current procedural volumes (> 1 million PCI procedures are performed in the U.S. annually) and because the risk of stent thrombosis is both time and treatment dependent, it is of paramount importance that, not only cardiologists, but all physicians know the impact of stent thrombosis in their patients and how to avoid situations that may increase its risk.1 Team-approach decisions about antiplatelet therapy after stent placement, especially within the first 12 months, and a patient-centered mind-set are indispensable to optimize patient outcomes.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Percutaneous coronary intervention (PCI) using coronary artery stent implantation is commonly used to treat symptomatic high-risk and unstable coronary artery disease (CAD). The use of stents has improved the safety and efficacy of PCI by reducing the need for repeat revascularization, reducing acute vessel closure requiring emergent coronary artery bypass graft surgery, and expanding the use of PCI to more complex diseases. Nevertheless, stents carry the risk of sudden thrombotic occlusion or stent thrombosis, particularly during the first several days or weeks after implantation. In turn, stent thrombosis can lead to acute myocardial infarction (MI) and a mortality rate > 25%.1,2
This article highlights 2 cases of patients with stent thrombosis and discusses its pathophysiology, clinical features, and risk-avoidance strategies. Given the high prevalence of CAD and ubiquitous PCI procedures in the U.S. health care system, it is essential that not only cardiologists, but all clinicians and health care providers who care for patients with coronary stents understand how to help prevent and manage this life-threatening clinical entity.1
Case 1
A 56-year-old man presented to his primary care physician with exertion-related angina. The patient had a history of type 2 diabetes mellitus, dyslipidemia, systemic hypertension, obesity, and CAD status post MI in 2002 treated with a bare metal stent (BMS) to the left circumflex coronary artery (LCx). A stress myocardial perfusion imaging with 99mTc-sestamibi revealed moderate reversible exercise-induced myocardial ischemia involving the inferior and inferoapical wall segments of the left ventricle with associated hypokinesia.
Coronary angiography revealed nonsignificant disease of the left anterior descending artery (LAD) and LCx, a patent LCx stent, and a 95% mid-right coronary artery (RCA) obstruction with delayed (TIMI grade 2) antegrade flow. The distal right posterior descending artery filled via left to right collaterals from the LAD.
Percutaneous coronary intervention was performed on the RCA lesion 8 days after the patient was started on dual antiplatelet therapy (DAPT) with aspirin 81 mg and clopidogrel 75 mg (including 300 mg loading dose on the day of the diagnostic angiogram). The mid RCA was treated with a drug-eluting stent (DES) and a BMS in a nonoverlapping fashion with an excellent angiographic result. The patient was instructed to continue DAPT with aspirin 325 mg daily and clopidogrel 75 mg daily for 12 months.
Three days post PCI, the patient arrived at the emergency department with angina of 1-hour duration associated with shortness of breath and diaphoresis. He reported strict adherence to DAPT.
Initial vital signs were normal. The electrocardiogram (ECG) showed ST segment elevation (1-2 mm) on leads III, aVF, and V5 to V6, suggestive of an acute inferolateral injury pattern for which emergent coronary angiography was performed. Angiography showed a 100% proximal RCA occlusion at the proximal edge of the most proximal stent with absence of any antegrade flow beyond the occlusion (TIMI grade 0 flow). This finding was diagnostic of definite angiographic subacute stent thrombosis. The patient underwent successful aspiration thrombectomy, balloon angioplasty, and restoration of normal TIMI grade 3 flow with a door-to-balloon time of 86 minutes.
Because stent thrombosis is relatively unexpected after an excellent angiographic result and DAPT adherence, the possibility of clopidogrel resistance was considered as a major contributor for the thrombotic event. Platelet aggregation tests showed adequate prolongation of collagen/epinephrine (COL-EPI) > 300 seconds (normal: 81-153 seconds), but inadequate prolongation of collagen/adenosindiphosphate (COL-ADP) of 109 seconds (normal: 53-105 seconds) while on clopidogrel. Therefore, the patient was switched to prasugrel.
The patient was discharged home after 5 days of observation at the cardiac care unit without any post-MI complications. During a follow-up appointment 1 month after discharge, he was clinically stable and free of cardiovascular symptoms. Workup performed for acquired or inherited thrombophilia was negative. He continued taking DAPT (daily aspirin 325 mg orally and prasugrel 10 mg orally) for 12 months. After completing 12 months of DAPT, he was maintained on aspirin 81 mg daily. At 24 months’ follow-up, he remained free of recurrent angina with no further cardiovascular events.
Case 2
An 84-year-old man with a medical history of dyslipidemia, paroxysmal atrial fibrillation, previous stroke, and peptic ulcer disease was brought to the emergency department following an episode of near syncope in the early morning hours. The patient revealed that he had experienced neck pain since midnight. The 12-lead ECG showed normal sinus rhythm with 2 mm ST segment elevation in leads II, III, aVF, V5-V6, and ST segment depression in V2, and Q waves in inferior leads. A right-sided ECG showed ST segment elevation in V4, suggestive of right ventricle infarction.
The patient remained hypotensive (83/49 mm Hg) despite isotonic fluid administration (about 1.5-2.0 liters of 0.9 normal saline at 999 mL/h). A dopamine drip for persistent hypotension was started, and he was taken emergently to the catheterization laboratory for primary PCI. Coronary angiography showed no significant left CAD and a 100% mid-RCA occlusion with faint left-to-right collaterals. After aspiration thrombectomy, bare metal RCA stenting was performed. Transient no-reflow was treated with intracoronary nicardipine and nitroglycerin. The patient continued to be in shock, and an intra-aortic balloon pump was inserted and 1:1 counterpulsation was initiated.
Following admission to the coronary care unit, the patient’s mean arterial pressure improved. Inotropes were weaned off 2 days after PCI, and the intra-aortic balloon pump was removed. During his stay, the post-MI course was uneventful except for an episode of asymptomatic paroxysmal atrial flutter and nonspecific back dermatitis attributed to a prolonged recumbent position.
The patient was transferred to the internal medicine ward for medical therapy optimization and the initiation of low-intensity cardiac rehabilitation. After 2 days on the ward, discharge planning was initiated. However, he developed an episode of atrial fibrillation with fast ventricular response. Metoprolol 5 mg IV bolus was given, and the ventricular rate was controlled. At that point, the dose of long-acting beta-blocker (metoprolol succinate) was optimized, he was started on full-dose anticoagulation (warfarin), and clopidogrel was discontinued. Two days later, the patient reported back pruritus, and an erythematous raised rash on his back spreading to the torso was noticed. An aspirin allergy was suspected as the trigger for the rash, thus aspirin was also discontinued.
Three days later, the patient developed recurrent neck pain (angina) with radiation to his shoulders and left arm. The ECG revealed re-elevation of the ST segment (inferior, posterior, and lateral leads). He received reloading of clopidogrel 600 mg and aspirin 325 mg. Also, an eptifibatide IV bolus followed by an infusion was given for immediate antiplatelet action. He was transferred for emergent coronary angiography with suspected subacute stent thrombosis.
Upon arrival to the catheterization lab, the patient was awake and alert but in mild respiratory distress. Intravenous dopamine was started due to hypotension (systolic blood pressure was about 85 mm Hg). Limited RCA angiography showed a large clot burden with a partially thrombosed stent and TIMI grade 3 flow. After intracoronary eptifibatide and nicardipine were given, successful aspiration thrombectomy was performed twice with partial removal of thrombus. In-stent high-pressure balloon angioplasty was performed and optimal stenting was confirmed by intravascular ultrasound (IVUS) criteria. However, a residual layered thrombus along the distal stent edge was noticed. The patient tolerated the procedure without complications.
Dual antiplatelet therapy with aspirin and clopidogrel for 12 months was recommended. The eptifibatide infusion was continued for 48 hours. The jaw pain, shortness of breath, and ECG changes disappeared, but the patient remained on vasopressors for the following 7 days.
Around 1 week after the stent thrombosis event, the patient was found pulseless. Advanced cardiopulmonary resuscitation was started. ST segment elevation in lead II was noted on the cardiac monitor. There was no return of spontaneous circulation after 20 minutes, and the patient was pronounced dead. The autopsy revealed a patent RCA stent without evidence of occlusion, a large transmural inferior MI, left ventricular rupture, and hemopericardium.
Discussion
Stent thrombosis is an uncommon complication after coronary stent implantation. Based on the Academic Research Consortium criteria, definite stent thrombosis is defined as a clinical event with symptoms suggestive of an acute coronary syndrome (ACS) with angiography or pathology that confirms the presence of stent thrombosis.2 Probable stent thrombosis is defined as an unexplained death within 30 days or MI involving the territory of the target vessel without angiographic confirmation of stent thrombosis.2 Finally, possible stent thrombosis is any unexplained death after 30 days.2
Based on timing, stent thrombosis is divided by acute (< 24 hours post stent implantation), subacute (24 hours to 30 days post stent implantation), late (> 30 days post stent implantation), and very late (> 12 months post stent implantation).3 However, most cases (up to 60%) occur within the first 30 days after placement, irrespective of stent type.4
The incidence of subacute stent thrombosis is reported to approach 1% during the first 30 days postprocedure but may be as high as 5% or 10% depending on associated clinical and angiographic variables (Table 1).5 The strongest clinical predictors of stent thrombosis are premature cessation of antiplatelet therapy, renal insufficiency, diabetes mellitus, and ACS.2,6 Lesion and procedural characteristics associated with increased risk of stent thrombosis include bifurcation lesions, longer stent length, multiple implanted stents, stent underexpansion, and/or stent malapposition.6-9 Stent type (drug or non–drug-eluting) has no impact on the risk of stent thrombosis during the first 30 days postprocedure.10,11
The clinical events related to late stent thrombosis, although rare, carry a mortality rate of up to 45%.12 The specific risk factors for late and very late stent thrombosis are less well defined but relate to delayed neointimal coverage, ongoing vessel inflammation, and the development of neoatherosclerosis within stents.13,14
Rationale for the Use of Dual Antiplatelet Regimen
Stent thrombosis is a platelet-mediated process related to a heightened state of systemic and intracoronary thrombogenicity and inflammation.15 Stent under-expansion enhances abnormal shear stress, which explains as many as 80% of these events.13,15,16 Stent thrombosis also has been frequently related to inadequate neointimal coverage.14 Angioscopic studies, especially with DES, suggest that stent endothelialization is delayed or incomplete, observing a correlation between the areas of uncovered stent surface and thrombosis.14,17
In the early days of coronary stenting, during the 1990s, the risk of acute and subacute stent thrombosis approached 20%.18,19 Initial attempts to reduce the risk included combining aspirin and warfarin, but at the expense of a marked increase in bleeding complications and prolonged hospital stays.20,21 In 1995, it became clear through the pivotal observations of Colombo and colleagues that incomplete expansion of the stent (documented by IVUS) was a major contributor to the risk of stent thrombosis.16 By using noncompliant balloons at high pressure (14-20 atmospheres) for stent postdilatation combined with DAPT (aspirin and ticlopidine), the high rates of early stent thrombosis were markedly reduced to the current level of 1% to 2%.16
Colombo and colleagues’ observations were prospectively evaluated in the Stent Anticoagulation Regimen Study (STARS) trial.22 Patients who underwent successful stenting were randomized to aspirin alone, aspirin and warfarin, or aspirin and ticlopidine. The STARS trial showed convincingly that the combination of aspirin and ticlopidine was superior to the other 2 regimens, reducing the stent thrombosis rate to only 0.5% (compared with 2.7% for aspirin and warfarin, and 3.6% for aspirin alone).22 Afterward, DAPT became the standard of care following coronary stenting.23
Although ticlopidine was the first widely used thienopyridine for the prevention of stent thrombosis, hematologic adverse events (AEs) (eg, neutropenia, thrombotic thrombocytopenia purpura) limited its use.24 Consequently, ticlopidine was replaced with clopidogrel, which seemed to offer similar efficacy but significantly fewer AEs.25
The current American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guidelines for the prevention of ST after coronary stent implantation state that after PCI:
- Aspirin use should be continued indefinitely.
- The duration of adenosine diphosphate antagonists depends on the stent type (BMS or DES) and the indication for implantation (ACS or non-ACS).
a. Patients receiving a stent (BMS or DES) for ACS therapy should be given 1 of the following for at least 12 months:
i. Clopidogrel 75 mg daily
ii. Prasugrel 10 mg daily
iii. Ticagrelor 90 mg twice daily
b. In patients receiving DES for a non-ACS indication, clopidogrel should be given for at least 12 months if the patient is not at high risk for bleeding.
c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months.23
Clopidogrel Hyporesponse
As shown in case 1, stent thrombosis may still occur in a patient on DAPT because of individual variability in platelet response to clopidogrel.5 Clopidogrel hyporesponse, also known as clopidogrel resistance, has been recognized as clinically significant because of its prevalence and association with poor outcomes.5 Its prevalence may range between 4% and 30%, although the definitions of clopidogrel hyporesponse varied between studies.26
Clopidogrel hyporesponse is defined as an inadequate inhibition of platelet function measured by nonspecific ex-vivo laboratory methods.27,28 The relationship between clopidogrel resistance (nonresponders), stent thrombosis, and ischemic events has been clearly established.5,29
Given the devastating consequences of stent thrombosis, efforts were directed to identify those patients at highest risk. One such effort has been focused on the measurement of platelet function, allowing for the identification of patients who do not respond adequately to antiplatelet therapy.15,28,30,31 However, the treatment of high-residual platelet reactivity as confirmed by laboratory assessment has not shown to clinically correlate with any benefit in the prevention of ST.6,15,29-31 Therefore, the current ACC/AHA/SCAI PCI guidelines do not recommend the routine clinical use of platelet function testing to screen patients treated with clopidogrel who are undergoing PCI.23
Clopidogrel is a prodrug, metabolized to its active form via the cytochrome P450 enzyme system before it can inhibit platelet function.32 Accordingly, certain genetic variation in enzyme activity, or polymorphisms, would be expected to influence its clinical effectiveness.33,34 The most common of these polymorphisms, CYP2C19*2, has been associated (in vitro) with reduced concentrations of active clopidogrel metabolites and with diminished platelet inhibition.35,36 As a result, the FDA has added a safety alert to the prescribing information for clopidogrel concerning how genetic differences in the metabolism of this agent can affect its effectiveness, ways to test for these genetic differences, and advice concerning alternative dosing strategies or use of other medications in poor metabolizers of clopidogrel.37 Although the routine clinical use of genetic testing to screen patients treated with clopidogrel who are undergoing PCI is not recommended, it may be considered in patients undergoing elective high-risk PCI procedures (eg, unprotected left main, last patent coronary artery, or bifurcating left main).23
The newer inhibitors of ADP-induced platelet activation, prasugrel and ticagrelor, are not prodrugs, and thus, their action is not affected by this genetic variability. Accordingly, these drugs have shown a more consistent, stronger, and faster inhibition of platelet aggregation compared with clopidogrel.36-39 In the pivotal trials (TRITON-TIMI 38 and PLATO), these agents have also been shown to be more effective in reducing the incidence of stent thrombosis.36,37,40,41 Therefore, in cases where clopidogrel resistance/hyporesponse is suspected in the setting of DAPT, such as stent thrombosis, guidelines recommend the use of 1 of these agents.23
Premature Discontinuation of Antiplatelet Therapy
As illustrated in case 2, premature discontinuation of antiplatelet therapy may be fatal, as it is associated with a marked increase in the risk of stent thrombosis. Indeed, premature discontinuation of DAPT is the leading independent predictor for stent thrombosis.12,42,43 Premature discontinuation of DAPT is defined when one or both agents (aspirin, ADP-antagonists) are suspended within 30 days of BMS placement or within 1 year of DES placement. In the case of DES, the first 6 months after implantation seem to be most critical. In a large observational study of patients treated with DES, stent thrombosis occurred in 29% of those patients in whom antiplatelet therapy was prematurely discontinued.12
In order to minimize the risk of premature DAPT discontinuation, one should address its causes. There are patient- and physician-related factors that may influence an early discontinuation of aspirin, thienopyridine, or both agents. Patient-related factors were identified in the PREMIER registry, including older age, not having completed high school, not being married, and/or not seeking health care because of costs.42 Another important but often overlooked factor that has an impact on adherence with prolonged DAPT post-DES implantation is nuisance or superficial bleeding.44 Physician-related factors include not providing discharge instructions for medication use and ill-advised instructions given by health care providers to discontinue therapy before procedures with a low risk of bleeding (eg, dental cleaning, cataract surgery, colonoscopy, skin biopsy).42
In addition, the perioperative management of DAPT during the first several weeks after coronary stenting has been shown to critically influence outcomes. In a study by Sharma and colleagues, fatal cases of stent thrombosis occurred after the discontinuation of antiplatelet therapy for noncardiac surgery among patients with BMS implantation within the past 90 days.43
In selected cases when a noncardiac procedure cannot be delayed for 1 year, recognizing the impact of the specific timing for the discontinuation of the antiplatelet regimen is essential. Kaluza and colleagues reported on 40 patients treated with BMS who underwent noncardiac surgery within 6 weeks of the stent implantation.45 Seven patients had an MI, of which 6 were fatal. Stent thrombosis was presumed to be the cause of all MIs. In 5 of 7 cases, ticlopidine was withheld before surgery.45
All clinicians should be aware of the following recommendations to avoid catastrophic cardiovascular complications related to premature discontinuation of DAPT during the perioperative setting:
- Elective procedures should be deferred until patients have completed an appropriate course of thienopyridine therapy (12 months after DES and a minimum of 4 weeks for BMS implantation).
- For those patients treated with DES who are to undergo a nonelective procedure that mandates discontinuation of thienopyridine therapy, the possibility of procedure postponement for completion of DAPT for at least 6 months should be judiciously deliberated. If the procedure cannot be postponed, aspirin should be continued if at all possible and the thienopyridine restarted as soon as possible after the procedure.42,46,47
Conclusion
Stent thrombosis is a rare but devastating complication of coronary stent implantation. Although it can occur at any time after stent placement, the majority of events occur within the first month. The use of optimal stenting techniques and adherence to DAPT are required to minimize the risk of stent thrombosis. Several clinical and procedural predictors have been related to an increased risk of stent thrombosis. The premature cessation of DAPT is the most important risk factor for stent thrombosis.
All physicians should ensure patients are properly and thoroughly educated about the reasons they are prescribed DAPT and the significant risks associated with prematurely discontinuing such therapy. All clinicians, especially noncardiologists, should realize the importance of close communication with a cardiologist or interventional cardiologist in situations when premature discontinuation is being considered for a specific reason.
Table 2 summarizes a framework of the most relevant factors that should be taken into account before, during, and after stent implantation, both by interventional cardiologists, as well as by all clinicians involved in the care of the patient. Given current procedural volumes (> 1 million PCI procedures are performed in the U.S. annually) and because the risk of stent thrombosis is both time and treatment dependent, it is of paramount importance that, not only cardiologists, but all physicians know the impact of stent thrombosis in their patients and how to avoid situations that may increase its risk.1 Team-approach decisions about antiplatelet therapy after stent placement, especially within the first 12 months, and a patient-centered mind-set are indispensable to optimize patient outcomes.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. Ryan J, Cohen DJ. Are drug-eluting stents cost-effective? It depends on whom you ask. Circulation. 2006;114(16):1736-1744.
2. Cutlip DE, Windecker S, Mehran R, et al; Academic Research Consortium. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation. 2007;115(17):2344-2351.
3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
4. Palmerini T, Kirtane AJ, Serruys PW, et al. Stent thrombosis with everolimus-eluting stents: Meta-analysis of comparative randomized controlled trials. Circ Cardiovasc Interv. 2012;5(3):357-364.
5. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: Clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49(14):1505-1516.
6. Moussa I, Di Mario C, Reimers B, Akiyama T, Tobis J, Colombo A. Subacute stent thrombosis in the era of intravascular ultrasound-guided coronary stenting without anticoagulation: Frequency, predictors and clinical outcome. J Am Coll Cardiol. 1997;29(1):6-12.
7. Fujii K, Carlier SG, Mintz GS, et al. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: An intravascular ultrasound study. J Am Coll Cardiol. 2005;45(7):995-998.
8. Uren NG, Schwarzacher SP, Metz JA, et al; POST Registry Investigators. Predictors and outcomes of stent thrombosis: An intravascular ultrasound registry. Eur Heart J. 2002;23(2):124-132.
9. Cook S, Wenaweser P, Togni M, et al. Intravascular ultrasound in very late DES-stent thrombosis (abstr). J Am Coll Cardiol. 2006;47(suppl B):9B.
10. Moreno R, Fernández C, Hernández R, et al. Drug-eluting stent thrombosis: Results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol. 2005;45(6):954-959.
11. Ellis SG, Colombo A, Grube E, et al. Incidence, timing, and correlates of stent thrombosis with the polymeric paclitaxel drug-eluting stent: A TAXUS II, IV, V, and VI meta-analysis of 3,445 patients followed for up to 3 years. J Am Coll Cardiol. 2007;49(10):1043-1051.
12. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):2126-2130.
13. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: A pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001;103(15):1967-1971.
14. Kotani J, Awata M, Nanto S, et al. Incomplete neointimal coverage of sirolimus-eluting stents: Angioscopic findings. J Am Coll Cardiol. 2006;47(10):2108–2111.
15. Cheneau E, Leborgne L, Mintz GS, et al. Predictors of subacute stent thrombosis: Results of a systematic intravascular ultrasound study. Circulation. 2003;108(1):43-47.
16. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation achieved with intravascular ultrasound guidance. Circulation. 1995;91(6):1676-1688.
17. Oyabu J, Ueda Y, Ogasawara N, Okada K, Hirayama A, Kodama K. Angioscopic evaluation of neointima coverage: Sirolimus-drug eluting stent versus bare metal stent. Am Heart J. 2006;152(6):1168-1174.
18. Serruys PW, Strauss BH, Beatt KJ, et al. Angiographic follow-up after placement of a self-expanding coronary-artery stent. N Engl J Med. 1991;324(1):13-17.
19. Schatz RA, Baim DS, Leon M, et al. Clinical experience with the Palmaz-Schatz coronary stent. Initial results of a multicenter study. Circulation. 1991:83(1):148-161.
20. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med. 1994;331(8):496-501.
21. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med. 1994;331(8):489-495.
22. Leon MD, Baim DS, Gordon P, et al. Clinical and angiographic results from the STent Anticoagulation Regimen Study (STARS) (abstr). Circulation. 1996;94(suppl I):I-685.
23. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: A report of the American College of Cardiology Foundation/American Heart Association Task Force of Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58(24):e44-e122.
24. Bennett CL, Davidson CJ, Raisch DW, Weinberg PD, Bennett RH, Feldman MD. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med. 1999;159(21):2524-2528.
25. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH; CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000;102(6):624-629.
26. Wang, TH, Bhatt DL, Topol EJ. Aspirin and clopidogrel resistance: An emerging clinical entity. Eur Heart J. 2006;27(6):647-654.
27. Vats HS, Hocking WG, Rezkalla SH. Suspected clopidogrel resistance in a patient with acute stent thrombosis. Nat Clin Pract Cardiovasc Med. 2006;3(4):226-230.
28. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol. 2007;50(19):1822-1834.
29. Fitzgerald DJ, Maree A. Aspirin and clopidogrel resistance. Hematology Am Soc Hematol Educ Program. 2007;2007(1):114-120.
30. Cattaneo M. Resistance to antiplatelet drugs: Molecular mechanisms and laboratory detection. J Thromb Haemost. 2007;5(suppl 1):230-237.
31. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51(20):1925-1934.
32. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92-99.
33. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244-2247.
34. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354-362.
35. U.S. Food and Drug Administration. Plavix (clopidogrel): Reduced effectiveness in patients who are poor metabolizers of the drug. U.S. Food and Drug Administration Website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm204256.htm. Updated September 6, 2013. Accessed September 4, 2014.
36. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: A subanalysis of a randomised trial. Lancet. 2008;371(9621):1353-1363.
37. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
38. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29(1):21-30.
39. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study. Circulation. 2009;120(25):2577-2585.
40. Wiviott SD, Trenk D, Frelinger AL, et al; PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932.
41. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: The RESPOND study. Circulation. 2010;121(10):1188-1199.
42. Spertus, JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: Results from the PREMIER registry. Circulation. 2006;113(24):2803-2809.
43. Sharma AK, Ajani AE, Hamwi SM, et al. Major noncardiac surgery following coronary stenting: When is it safe to operate? Catheter Cardiovasc Interv. 2004;63(2):141-145.
44. Ben-Dor I, Torguson R, Scheinowitz M, et al. Incidence, correlates, and clinical impact of nuisance bleeding after antiplatelet therapy for patients with drug-eluting stents. Am Heart J. 2010;159(5):871-875.
45. Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol. 2000;35(5):1288-1294.
46. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation. 2007;116(7):745-754.
47. Grines CL, Bonow RO, Casey DE Jr, et al; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: A science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol. 2007;49(6):734-739.
1. Ryan J, Cohen DJ. Are drug-eluting stents cost-effective? It depends on whom you ask. Circulation. 2006;114(16):1736-1744.
2. Cutlip DE, Windecker S, Mehran R, et al; Academic Research Consortium. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation. 2007;115(17):2344-2351.
3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
4. Palmerini T, Kirtane AJ, Serruys PW, et al. Stent thrombosis with everolimus-eluting stents: Meta-analysis of comparative randomized controlled trials. Circ Cardiovasc Interv. 2012;5(3):357-364.
5. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: Clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49(14):1505-1516.
6. Moussa I, Di Mario C, Reimers B, Akiyama T, Tobis J, Colombo A. Subacute stent thrombosis in the era of intravascular ultrasound-guided coronary stenting without anticoagulation: Frequency, predictors and clinical outcome. J Am Coll Cardiol. 1997;29(1):6-12.
7. Fujii K, Carlier SG, Mintz GS, et al. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: An intravascular ultrasound study. J Am Coll Cardiol. 2005;45(7):995-998.
8. Uren NG, Schwarzacher SP, Metz JA, et al; POST Registry Investigators. Predictors and outcomes of stent thrombosis: An intravascular ultrasound registry. Eur Heart J. 2002;23(2):124-132.
9. Cook S, Wenaweser P, Togni M, et al. Intravascular ultrasound in very late DES-stent thrombosis (abstr). J Am Coll Cardiol. 2006;47(suppl B):9B.
10. Moreno R, Fernández C, Hernández R, et al. Drug-eluting stent thrombosis: Results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol. 2005;45(6):954-959.
11. Ellis SG, Colombo A, Grube E, et al. Incidence, timing, and correlates of stent thrombosis with the polymeric paclitaxel drug-eluting stent: A TAXUS II, IV, V, and VI meta-analysis of 3,445 patients followed for up to 3 years. J Am Coll Cardiol. 2007;49(10):1043-1051.
12. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):2126-2130.
13. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: A pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001;103(15):1967-1971.
14. Kotani J, Awata M, Nanto S, et al. Incomplete neointimal coverage of sirolimus-eluting stents: Angioscopic findings. J Am Coll Cardiol. 2006;47(10):2108–2111.
15. Cheneau E, Leborgne L, Mintz GS, et al. Predictors of subacute stent thrombosis: Results of a systematic intravascular ultrasound study. Circulation. 2003;108(1):43-47.
16. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation achieved with intravascular ultrasound guidance. Circulation. 1995;91(6):1676-1688.
17. Oyabu J, Ueda Y, Ogasawara N, Okada K, Hirayama A, Kodama K. Angioscopic evaluation of neointima coverage: Sirolimus-drug eluting stent versus bare metal stent. Am Heart J. 2006;152(6):1168-1174.
18. Serruys PW, Strauss BH, Beatt KJ, et al. Angiographic follow-up after placement of a self-expanding coronary-artery stent. N Engl J Med. 1991;324(1):13-17.
19. Schatz RA, Baim DS, Leon M, et al. Clinical experience with the Palmaz-Schatz coronary stent. Initial results of a multicenter study. Circulation. 1991:83(1):148-161.
20. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med. 1994;331(8):496-501.
21. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med. 1994;331(8):489-495.
22. Leon MD, Baim DS, Gordon P, et al. Clinical and angiographic results from the STent Anticoagulation Regimen Study (STARS) (abstr). Circulation. 1996;94(suppl I):I-685.
23. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: A report of the American College of Cardiology Foundation/American Heart Association Task Force of Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58(24):e44-e122.
24. Bennett CL, Davidson CJ, Raisch DW, Weinberg PD, Bennett RH, Feldman MD. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med. 1999;159(21):2524-2528.
25. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH; CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000;102(6):624-629.
26. Wang, TH, Bhatt DL, Topol EJ. Aspirin and clopidogrel resistance: An emerging clinical entity. Eur Heart J. 2006;27(6):647-654.
27. Vats HS, Hocking WG, Rezkalla SH. Suspected clopidogrel resistance in a patient with acute stent thrombosis. Nat Clin Pract Cardiovasc Med. 2006;3(4):226-230.
28. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol. 2007;50(19):1822-1834.
29. Fitzgerald DJ, Maree A. Aspirin and clopidogrel resistance. Hematology Am Soc Hematol Educ Program. 2007;2007(1):114-120.
30. Cattaneo M. Resistance to antiplatelet drugs: Molecular mechanisms and laboratory detection. J Thromb Haemost. 2007;5(suppl 1):230-237.
31. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51(20):1925-1934.
32. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92-99.
33. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244-2247.
34. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354-362.
35. U.S. Food and Drug Administration. Plavix (clopidogrel): Reduced effectiveness in patients who are poor metabolizers of the drug. U.S. Food and Drug Administration Website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm204256.htm. Updated September 6, 2013. Accessed September 4, 2014.
36. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: A subanalysis of a randomised trial. Lancet. 2008;371(9621):1353-1363.
37. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
38. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29(1):21-30.
39. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study. Circulation. 2009;120(25):2577-2585.
40. Wiviott SD, Trenk D, Frelinger AL, et al; PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932.
41. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: The RESPOND study. Circulation. 2010;121(10):1188-1199.
42. Spertus, JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: Results from the PREMIER registry. Circulation. 2006;113(24):2803-2809.
43. Sharma AK, Ajani AE, Hamwi SM, et al. Major noncardiac surgery following coronary stenting: When is it safe to operate? Catheter Cardiovasc Interv. 2004;63(2):141-145.
44. Ben-Dor I, Torguson R, Scheinowitz M, et al. Incidence, correlates, and clinical impact of nuisance bleeding after antiplatelet therapy for patients with drug-eluting stents. Am Heart J. 2010;159(5):871-875.
45. Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol. 2000;35(5):1288-1294.
46. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation. 2007;116(7):745-754.
47. Grines CL, Bonow RO, Casey DE Jr, et al; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: A science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol. 2007;49(6):734-739.
Imaging Use in Focal Rhabdomyolysis of the Left Shoulder
Rhabdomyolysis involves the breakdown of skeletal muscle with the release of intracellular contents into the extracellular space and circulation.1 Diffuse rhabdomyolysis has been found in athletes due to overexertion. However, focal rhabdomyolysis is rare.2,3 The clinical presentation of focal rhabdomyolysis is subtle and nonspecific, with swelling, vague pain, weakness, fatigue, and tea-colored urine.
Early recognition and prompt management are crucial to prevent complications such as compression syndrome, acute renal failure, disseminated intravascular coagulation, cardiac dysrhythmia, or even cardiac arrest. Sonography and magnetic resonance imaging (MRI) can, therefore, be a complementary part of the diagnosis and assessment of the extent of rhabdomyolysis.4-7
Case History
The patient was a 34-year-old white man with a history of polysubstance abuse who presented to the emergency department (ED) with numbness and weakness in the left arm and hand, pain in the left side of his neck, and 3 days of intermittent amnesia with confusion. He had used IV heroin about 2 weeks prior to admission and used tobacco and alcohol daily. He reported no current medications or known allergies. The patient was in a monogamous relationship with a same-sex partner.
On physical examination, vital signs were within normal limits. He was in distress, confused, and disoriented as to time and place. An extremity examination revealed 1/5 strength in the extensors of the left elbow, left wrist, and left fingers with normal strength noted in the right upper extremity as well as the lower extremities. No sensory deficits were noted. The patient’s skin was warm and dry. Remarkable laboratory findings included creatine kinase (CK) 1,744 U/L, creatinine (Cr) 1.9 mg/dL, ALT 1,065 U/L, AST 319 U/L, ALP 159 U/L. A urine toxicology screen was positive for cocaine and opiates, and the urine analysis dip was negative for red blood cells, white blood cells, and protein. A differential diagnosis favored a left arm inflammatory reaction to IV drugs, although rhabdomyolysis was questioned.
A neurology consult was obtained, and a bedside electroencephalography test was performed in the ED by the neurologist, showing mild left occipital slow wave abnormality with no epileptiform discharges. A chest X-ray and computed tomography (CT) scan of the head and cervical spine were unremarkable, other than incidental mild prominence of the ventricles.
Over the next 24 hours, the patient was hydrated with IV normal saline without bicarbonate. His altered mental status, urine output, and biochemical abnormalities returned to normal, except for the serum CK, which decreased to 917 U/L. He had minimal improvement in his left upper extremity nerve palsy symptoms; however, he was deemed to be stable for discharge with follow-up in the clinic.
Instead of a clinic follow-up, the patient returned to the ED 7 days later, with progressive weakness of the left arm, forearm, and wrist. The patient noted that his weakness was so significant that he had to move his left arm with his right arm. He also reported extremity swelling and increasing paresthesias involving the lateral aspect of his left arm and hand, dizziness, and left neck pain. A physical examination revealed 3/5 strength at the left deltoid and left triceps, and 0/5 strength in the left fingers and grip. Remeasurement of CK was 54 U/L and Cr was 0.9 mg/dL. Compartment pressures were not measured.
Magnetic resonance imaging using multiplanar spin echo T1 and fast spin T2 weighted and post-IV 16cc Omniscan contrast sequences of the left shoulder were performed, showing multiple patchy T2 hyperintense focal areas with peripheral enhancement in the muscles of the posterior shoulder and in the tissues adjacent to the brachial plexus in the neck and shoulder (Figures 1A, 1B, and 1C). Sonography with matrix array linear 6-15 MH3 transducer was performed, which demonstrated patchy focal hypoechoic areas of muscle with enlarged, thickened, and disrupted muscle, representing devitalized muscle without any drainable fluid collection or abscess (Figures 2A, 2B, 2C, and 2D).
Magnetic resonance imaging and magnetic resonance angiogram scans of the brain and cervical spine with and without contrast were unremarkable. At that time, a definitive diagnosis was made of focal rhabdomyolysis and compressive neuropathy of the brachial plexus posterior cord, leading to brachial plexopathy of the left shoulder.
The patient was treated with hydration, a left arm sling, elevated left arm, and ibuprofen 600 mg qid to reduce inflammation. His swelling decreased markedly, and there was a slight improvement in pain and mobility at a 2-week neurology clinic follow-up. The patient lost contact after that.
Discussion
Rhabdomyolysis is caused by diverse etiologies. Most commonly, it is generalized and occurs due to overexertion, crush injury, steroid use, metabolic abnormalities, and certain medications and illicit drugs.1,2 The most likely etiology of rhabdomyolysis in patients presenting to the ED without significant trauma is of substance abuse, especially with ethanol, heroin, amphetamines, cocaine, and other sedatives or stimulants.1-3 The patient presented in this case study had a history of drug abuse, with a positive urine toxicology screen for cocaine and opiates. He had been intermittently confused and amnesic for 3 days prior to presentation, during which he may have been lying on his shoulder for a prolonged period.
Focal rhabdomyolysis and acute compression at the posterior shoulder leading to compressive brachial plexopathy is rare, with only 3 cases reported in the literature, all occurring with IV drug use.1-3 This patient had compression of the brachial plexus posterior cord from rhabdomyolysis and prolonged immobilization. Intravenous drug abusers may delay medical care due to perceived illicit drug effects and frequently present to the ED confused, agitated, or obtunded. Acute extremity swelling, a palpable lump, and pain can be due to various etiologies, such as trauma, fluid collection, muscle tear, myopathy, venous thrombosis, neoplasm, or rhabdomyolysis.
Diagnosis of nontraumatic rhabdomyolysis depends on clinical history and biochemical tests, such as serum CK and urine myoglobin.1,8 Creatine kinase is present in large quantities in the myocytes and is 100% sensitive as a marker for rhabdomyolysis.1,8 Creatine kinase may increase acutely > 1,000 U/L, suggesting muscle lysis and necrosis as etiology for pain as opposed to other causes such as hematomas, abscesses, or venous thrombi.1,9 Serum CK decreases rapidly at a rate of 39% per day, and it may normalize by the time a patient presents for medical care.1,10-12 Imaging plays a significant complimentary role. During the patient’s second ED presentation, the CK was normal at 54 U/L, whereas ultrasound and MRI findings were suggestive of focal muscle abnormalities.
Although there are diverse etiologies of rhabdomyolysis, the ultimate consequences of rhabdomyolysis are muscle cell membrane injury, metabolism malfunction, and destruction of the myofibril, resulting in inflammatory changes, such as muscle edema, hemorrhage, and myonecrosis and disruption of muscle fibers.1,2,8,9,13 This may cause an alteration in muscle size, shape, and echogenicity on sonography and abnormal signal intensity on MRI.13 The sensitivity of MRI in the detection of muscle involvement is higher than that of CT or ultrasound due to the high soft tissue contrast.4,13,14 Specificity of all 3 modalities is low and not reported.
Although the sensitivity of ultrasound is lower than that of MRI, use of ultrasound in neuromuscular evaluation has been increasing recently due to technical refinements. Ultrasound can be effectively used as a first-line screening modality, especially in an emergency.5 Magnetic resonance imaging best assesses the distribution and extension of the affected muscles, especially when fasciotomy is considered for treatment, and initially reveals edema, inflammation, and findings of myonecrosis; muscle atrophy and fatty degeneration occur later.4,13-15 Typical MRI findings include increased signal intensity on T2-weighted and STIR (short-tau inversion recovery) sequences and variable enhancement on T1 postcontrast images, as was seen in this case, which indicated edema, inflammation, and necrosis of the muscle tissue.
Shintani and colleagues described the reversibility of the MRI findings, showing that the high-intensity lesions seen on T2-weighted images resolved in parallel with the clinical course.14,16 Lu and colleagues investigated 10 patients with rhabdomyolysis and found 2 distinct imaging types: Type 1 shows homogenous signal changes and enhancement in the affected muscles, and Type 2 shows rim enhancement on contrast-enhanced MRI, a “stipple sign” indicating areas of myonecrosis.17 Magnetic resonance imaging signal alterations in the musculature can be nonspecific and overlap with those of inflammatory myopathies such as polymyositis, connective tissue diseases with inflammatory myositis, muscle infection, muscle infarction such as diabetic myonecrosis, muscle contusion, drug-induced myotoxicity, corticosteroids use, and use of cholesterol-lowering agents.18,19
Sonography is a useful screening modality for pain and swelling of the extremity, because it can detect a muscle tear, muscle sprain, and fluid collection, especially in emergent cases. There is scant literature about sonographic findings in rhabdomyolysis and compression nerve entrapment. The sonographic findings of rhabdomyolysis are local disorganization of the damaged muscle, decreased muscle echogenicity, and enlargement of the muscle, with preservation of the muscle boundaries.5-7
Intramuscular hyperechoic areas are seen due to hypercontractility of injured muscle. In this case, noted findings included patchy, irregular, hypoechoic areas, enlargement of the muscles and tendons, and irregular hyperechoic areas without focal defects. These findings differentiated an abnormality from a muscle tear or rupture, as these often show a focal muscle gap and focal defect, signifying the ruptured muscle retracting.
A study by Su and colleagues used the large number of crush injuries after an earthquake in China.5 The characteristic sonographic findings were edema and thickened disrupted striated muscle, good overall muscle continuity, vague muscle texture, and enhanced cloudy or ground-glass-like echo. There was no blood flow signal in the hypoechoic areas.6 Ultrasound was deemed a cost-effective, easily available modality by the authors.
Conclusion
Nontraumatic, focal rhabdomyolysis is rare and should be detected and differentiated from other causes of swelling, lump, pain, or other muscle disorders to prevent late complications. Sonography is an important screening diagnostic modality. MRI is used for assessment of the extent and distribution of injury. Awareness and familiarity with imaging findings can play a significant role, along with clinical and laboratory findings in the diagnosis and management of rhabdomyolysis.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
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1. Richards JR. Rhabdomyolysis and drugs of abuse. J Emerg Med. 2000;19(1):51-56.
2. Farkash U, Shabshin N, Pritsch Perry M. Rhabdomyolysis of the deltoid muscle in a bodybuilder using anabolic-androgenic steroids: A case report. J Athl Train. 2009;44(1):98-100.
3. Mubarak SJ, Owen CA, Hargens AR, Garetto LP, Akeson WH. Acute compartment syndromes: Diagnosis and treatment with the aid of the wick catheter. J Bone Joint Surg Am. 1978;60(8):1091-1095.
4. Lamminen AE, Hekali PE, Tiula E, Suramo I, Korhola OA. Acute rhabdomyolysis: Evaluation with magnetic resonance imaging compared with computed tomography and ultrasonography. Br J Radiol. 1989;62(736):326-330.
5. Su BH, Qui L, Fu P, Luo Y, Tao Y, Peng YL. Ultrasonic appearance of rhabdomyolysis in patients with crush injury in the Wenchuan earthquake. Chin Med J (Engl). 2009;122(16):1872-1876.
6. Chiu Y-N, Wang T-G, Hsu C-Y, et al. Sonographic diagnosis of rhabdomyolysis. J Med Ultrasound. 2008;16(2):158-162.
7. Kaplan GN. Ultrasonic appearance of rhabdomyolysis. AJR Am J Roentgenol. 1980;134(2):375-377.
8. Spector R, Choudhury A, Cancilla P, Lakin R. Alcohol myopathy. Diagnosis by alcohol challenge. JAMA. 1979;242(15):1648-1649.
9. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore). 1982;61(3):141-152.
10. Knochel JP. Mechanisms of rhabdomyolysis. Curr Opin Rheumatol. 1993;5(6):725-731.
11. Cadnapaphornchai P, Taher S, McDonald FD. Acute drug-association rhabdomyolysis: An examination of its diverse renal manifestations and complications. Am J Med Sci. 1980;280(2):66-72.
12. Curry SC, Chang D, Connor D. Drug and toxin-induced rhabdomyolysis. Ann Emerg Med. 1989;18(10):1068-1084.
13. May D, Disler DG, Jones EA, Balkissoon AA, Manaster BJ. Abnormal signal intensity in skeletal muscle at MR imaging: Patterns, pearls, and pitfalls. RadioGraphics. 2000;20(spec no):S295-S315.
14. Moratalla MB, Braun P, Fornas GM. Importance of MRI in the diagnosis and treatment of rhabdomyolysis. Eur J Radiol. 2008;65(2):311-315.
15. Beltran J, Rosenberg ZS. Diagnosis of compressive and entrapment neurorpathies of the upper extremity: Value of MR imaging. AJR Am J Roentgenol. 1994;163(3):525-531.
16. Shintani S, Shiigai T. Repeat MRI in acute rhabdomyolysis: Correlation with clinicopathological findings. J Comput Assist Tomogr. 1993;17(5):786-791.
17. Lu CH, Tsang YM, Yu CW, et al. Rhabdomyolysis: Magnetic resonance imaging and computed tomography findings. J Comput Assist Tomogr. 2007;31(3):368-374.
18. Schulze M, Kötter I, Ernemann U, et al. MRI findings in inflammatory muscle diseases and their noninflammatory mimics. AJR Am J Roentgenol. 2009;192(6):1708-1716.
19. Adams EM, Chow CK, Premkumar A, Plotz PH. The idiopathic inflammatory myopathies: Spectrum of MR imaging findings. Radiographics. 1995;15(3):563-574.
Rhabdomyolysis involves the breakdown of skeletal muscle with the release of intracellular contents into the extracellular space and circulation.1 Diffuse rhabdomyolysis has been found in athletes due to overexertion. However, focal rhabdomyolysis is rare.2,3 The clinical presentation of focal rhabdomyolysis is subtle and nonspecific, with swelling, vague pain, weakness, fatigue, and tea-colored urine.
Early recognition and prompt management are crucial to prevent complications such as compression syndrome, acute renal failure, disseminated intravascular coagulation, cardiac dysrhythmia, or even cardiac arrest. Sonography and magnetic resonance imaging (MRI) can, therefore, be a complementary part of the diagnosis and assessment of the extent of rhabdomyolysis.4-7
Case History
The patient was a 34-year-old white man with a history of polysubstance abuse who presented to the emergency department (ED) with numbness and weakness in the left arm and hand, pain in the left side of his neck, and 3 days of intermittent amnesia with confusion. He had used IV heroin about 2 weeks prior to admission and used tobacco and alcohol daily. He reported no current medications or known allergies. The patient was in a monogamous relationship with a same-sex partner.
On physical examination, vital signs were within normal limits. He was in distress, confused, and disoriented as to time and place. An extremity examination revealed 1/5 strength in the extensors of the left elbow, left wrist, and left fingers with normal strength noted in the right upper extremity as well as the lower extremities. No sensory deficits were noted. The patient’s skin was warm and dry. Remarkable laboratory findings included creatine kinase (CK) 1,744 U/L, creatinine (Cr) 1.9 mg/dL, ALT 1,065 U/L, AST 319 U/L, ALP 159 U/L. A urine toxicology screen was positive for cocaine and opiates, and the urine analysis dip was negative for red blood cells, white blood cells, and protein. A differential diagnosis favored a left arm inflammatory reaction to IV drugs, although rhabdomyolysis was questioned.
A neurology consult was obtained, and a bedside electroencephalography test was performed in the ED by the neurologist, showing mild left occipital slow wave abnormality with no epileptiform discharges. A chest X-ray and computed tomography (CT) scan of the head and cervical spine were unremarkable, other than incidental mild prominence of the ventricles.
Over the next 24 hours, the patient was hydrated with IV normal saline without bicarbonate. His altered mental status, urine output, and biochemical abnormalities returned to normal, except for the serum CK, which decreased to 917 U/L. He had minimal improvement in his left upper extremity nerve palsy symptoms; however, he was deemed to be stable for discharge with follow-up in the clinic.
Instead of a clinic follow-up, the patient returned to the ED 7 days later, with progressive weakness of the left arm, forearm, and wrist. The patient noted that his weakness was so significant that he had to move his left arm with his right arm. He also reported extremity swelling and increasing paresthesias involving the lateral aspect of his left arm and hand, dizziness, and left neck pain. A physical examination revealed 3/5 strength at the left deltoid and left triceps, and 0/5 strength in the left fingers and grip. Remeasurement of CK was 54 U/L and Cr was 0.9 mg/dL. Compartment pressures were not measured.
Magnetic resonance imaging using multiplanar spin echo T1 and fast spin T2 weighted and post-IV 16cc Omniscan contrast sequences of the left shoulder were performed, showing multiple patchy T2 hyperintense focal areas with peripheral enhancement in the muscles of the posterior shoulder and in the tissues adjacent to the brachial plexus in the neck and shoulder (Figures 1A, 1B, and 1C). Sonography with matrix array linear 6-15 MH3 transducer was performed, which demonstrated patchy focal hypoechoic areas of muscle with enlarged, thickened, and disrupted muscle, representing devitalized muscle without any drainable fluid collection or abscess (Figures 2A, 2B, 2C, and 2D).
Magnetic resonance imaging and magnetic resonance angiogram scans of the brain and cervical spine with and without contrast were unremarkable. At that time, a definitive diagnosis was made of focal rhabdomyolysis and compressive neuropathy of the brachial plexus posterior cord, leading to brachial plexopathy of the left shoulder.
The patient was treated with hydration, a left arm sling, elevated left arm, and ibuprofen 600 mg qid to reduce inflammation. His swelling decreased markedly, and there was a slight improvement in pain and mobility at a 2-week neurology clinic follow-up. The patient lost contact after that.
Discussion
Rhabdomyolysis is caused by diverse etiologies. Most commonly, it is generalized and occurs due to overexertion, crush injury, steroid use, metabolic abnormalities, and certain medications and illicit drugs.1,2 The most likely etiology of rhabdomyolysis in patients presenting to the ED without significant trauma is of substance abuse, especially with ethanol, heroin, amphetamines, cocaine, and other sedatives or stimulants.1-3 The patient presented in this case study had a history of drug abuse, with a positive urine toxicology screen for cocaine and opiates. He had been intermittently confused and amnesic for 3 days prior to presentation, during which he may have been lying on his shoulder for a prolonged period.
Focal rhabdomyolysis and acute compression at the posterior shoulder leading to compressive brachial plexopathy is rare, with only 3 cases reported in the literature, all occurring with IV drug use.1-3 This patient had compression of the brachial plexus posterior cord from rhabdomyolysis and prolonged immobilization. Intravenous drug abusers may delay medical care due to perceived illicit drug effects and frequently present to the ED confused, agitated, or obtunded. Acute extremity swelling, a palpable lump, and pain can be due to various etiologies, such as trauma, fluid collection, muscle tear, myopathy, venous thrombosis, neoplasm, or rhabdomyolysis.
Diagnosis of nontraumatic rhabdomyolysis depends on clinical history and biochemical tests, such as serum CK and urine myoglobin.1,8 Creatine kinase is present in large quantities in the myocytes and is 100% sensitive as a marker for rhabdomyolysis.1,8 Creatine kinase may increase acutely > 1,000 U/L, suggesting muscle lysis and necrosis as etiology for pain as opposed to other causes such as hematomas, abscesses, or venous thrombi.1,9 Serum CK decreases rapidly at a rate of 39% per day, and it may normalize by the time a patient presents for medical care.1,10-12 Imaging plays a significant complimentary role. During the patient’s second ED presentation, the CK was normal at 54 U/L, whereas ultrasound and MRI findings were suggestive of focal muscle abnormalities.
Although there are diverse etiologies of rhabdomyolysis, the ultimate consequences of rhabdomyolysis are muscle cell membrane injury, metabolism malfunction, and destruction of the myofibril, resulting in inflammatory changes, such as muscle edema, hemorrhage, and myonecrosis and disruption of muscle fibers.1,2,8,9,13 This may cause an alteration in muscle size, shape, and echogenicity on sonography and abnormal signal intensity on MRI.13 The sensitivity of MRI in the detection of muscle involvement is higher than that of CT or ultrasound due to the high soft tissue contrast.4,13,14 Specificity of all 3 modalities is low and not reported.
Although the sensitivity of ultrasound is lower than that of MRI, use of ultrasound in neuromuscular evaluation has been increasing recently due to technical refinements. Ultrasound can be effectively used as a first-line screening modality, especially in an emergency.5 Magnetic resonance imaging best assesses the distribution and extension of the affected muscles, especially when fasciotomy is considered for treatment, and initially reveals edema, inflammation, and findings of myonecrosis; muscle atrophy and fatty degeneration occur later.4,13-15 Typical MRI findings include increased signal intensity on T2-weighted and STIR (short-tau inversion recovery) sequences and variable enhancement on T1 postcontrast images, as was seen in this case, which indicated edema, inflammation, and necrosis of the muscle tissue.
Shintani and colleagues described the reversibility of the MRI findings, showing that the high-intensity lesions seen on T2-weighted images resolved in parallel with the clinical course.14,16 Lu and colleagues investigated 10 patients with rhabdomyolysis and found 2 distinct imaging types: Type 1 shows homogenous signal changes and enhancement in the affected muscles, and Type 2 shows rim enhancement on contrast-enhanced MRI, a “stipple sign” indicating areas of myonecrosis.17 Magnetic resonance imaging signal alterations in the musculature can be nonspecific and overlap with those of inflammatory myopathies such as polymyositis, connective tissue diseases with inflammatory myositis, muscle infection, muscle infarction such as diabetic myonecrosis, muscle contusion, drug-induced myotoxicity, corticosteroids use, and use of cholesterol-lowering agents.18,19
Sonography is a useful screening modality for pain and swelling of the extremity, because it can detect a muscle tear, muscle sprain, and fluid collection, especially in emergent cases. There is scant literature about sonographic findings in rhabdomyolysis and compression nerve entrapment. The sonographic findings of rhabdomyolysis are local disorganization of the damaged muscle, decreased muscle echogenicity, and enlargement of the muscle, with preservation of the muscle boundaries.5-7
Intramuscular hyperechoic areas are seen due to hypercontractility of injured muscle. In this case, noted findings included patchy, irregular, hypoechoic areas, enlargement of the muscles and tendons, and irregular hyperechoic areas without focal defects. These findings differentiated an abnormality from a muscle tear or rupture, as these often show a focal muscle gap and focal defect, signifying the ruptured muscle retracting.
A study by Su and colleagues used the large number of crush injuries after an earthquake in China.5 The characteristic sonographic findings were edema and thickened disrupted striated muscle, good overall muscle continuity, vague muscle texture, and enhanced cloudy or ground-glass-like echo. There was no blood flow signal in the hypoechoic areas.6 Ultrasound was deemed a cost-effective, easily available modality by the authors.
Conclusion
Nontraumatic, focal rhabdomyolysis is rare and should be detected and differentiated from other causes of swelling, lump, pain, or other muscle disorders to prevent late complications. Sonography is an important screening diagnostic modality. MRI is used for assessment of the extent and distribution of injury. Awareness and familiarity with imaging findings can play a significant role, along with clinical and laboratory findings in the diagnosis and management of rhabdomyolysis.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Rhabdomyolysis involves the breakdown of skeletal muscle with the release of intracellular contents into the extracellular space and circulation.1 Diffuse rhabdomyolysis has been found in athletes due to overexertion. However, focal rhabdomyolysis is rare.2,3 The clinical presentation of focal rhabdomyolysis is subtle and nonspecific, with swelling, vague pain, weakness, fatigue, and tea-colored urine.
Early recognition and prompt management are crucial to prevent complications such as compression syndrome, acute renal failure, disseminated intravascular coagulation, cardiac dysrhythmia, or even cardiac arrest. Sonography and magnetic resonance imaging (MRI) can, therefore, be a complementary part of the diagnosis and assessment of the extent of rhabdomyolysis.4-7
Case History
The patient was a 34-year-old white man with a history of polysubstance abuse who presented to the emergency department (ED) with numbness and weakness in the left arm and hand, pain in the left side of his neck, and 3 days of intermittent amnesia with confusion. He had used IV heroin about 2 weeks prior to admission and used tobacco and alcohol daily. He reported no current medications or known allergies. The patient was in a monogamous relationship with a same-sex partner.
On physical examination, vital signs were within normal limits. He was in distress, confused, and disoriented as to time and place. An extremity examination revealed 1/5 strength in the extensors of the left elbow, left wrist, and left fingers with normal strength noted in the right upper extremity as well as the lower extremities. No sensory deficits were noted. The patient’s skin was warm and dry. Remarkable laboratory findings included creatine kinase (CK) 1,744 U/L, creatinine (Cr) 1.9 mg/dL, ALT 1,065 U/L, AST 319 U/L, ALP 159 U/L. A urine toxicology screen was positive for cocaine and opiates, and the urine analysis dip was negative for red blood cells, white blood cells, and protein. A differential diagnosis favored a left arm inflammatory reaction to IV drugs, although rhabdomyolysis was questioned.
A neurology consult was obtained, and a bedside electroencephalography test was performed in the ED by the neurologist, showing mild left occipital slow wave abnormality with no epileptiform discharges. A chest X-ray and computed tomography (CT) scan of the head and cervical spine were unremarkable, other than incidental mild prominence of the ventricles.
Over the next 24 hours, the patient was hydrated with IV normal saline without bicarbonate. His altered mental status, urine output, and biochemical abnormalities returned to normal, except for the serum CK, which decreased to 917 U/L. He had minimal improvement in his left upper extremity nerve palsy symptoms; however, he was deemed to be stable for discharge with follow-up in the clinic.
Instead of a clinic follow-up, the patient returned to the ED 7 days later, with progressive weakness of the left arm, forearm, and wrist. The patient noted that his weakness was so significant that he had to move his left arm with his right arm. He also reported extremity swelling and increasing paresthesias involving the lateral aspect of his left arm and hand, dizziness, and left neck pain. A physical examination revealed 3/5 strength at the left deltoid and left triceps, and 0/5 strength in the left fingers and grip. Remeasurement of CK was 54 U/L and Cr was 0.9 mg/dL. Compartment pressures were not measured.
Magnetic resonance imaging using multiplanar spin echo T1 and fast spin T2 weighted and post-IV 16cc Omniscan contrast sequences of the left shoulder were performed, showing multiple patchy T2 hyperintense focal areas with peripheral enhancement in the muscles of the posterior shoulder and in the tissues adjacent to the brachial plexus in the neck and shoulder (Figures 1A, 1B, and 1C). Sonography with matrix array linear 6-15 MH3 transducer was performed, which demonstrated patchy focal hypoechoic areas of muscle with enlarged, thickened, and disrupted muscle, representing devitalized muscle without any drainable fluid collection or abscess (Figures 2A, 2B, 2C, and 2D).
Magnetic resonance imaging and magnetic resonance angiogram scans of the brain and cervical spine with and without contrast were unremarkable. At that time, a definitive diagnosis was made of focal rhabdomyolysis and compressive neuropathy of the brachial plexus posterior cord, leading to brachial plexopathy of the left shoulder.
The patient was treated with hydration, a left arm sling, elevated left arm, and ibuprofen 600 mg qid to reduce inflammation. His swelling decreased markedly, and there was a slight improvement in pain and mobility at a 2-week neurology clinic follow-up. The patient lost contact after that.
Discussion
Rhabdomyolysis is caused by diverse etiologies. Most commonly, it is generalized and occurs due to overexertion, crush injury, steroid use, metabolic abnormalities, and certain medications and illicit drugs.1,2 The most likely etiology of rhabdomyolysis in patients presenting to the ED without significant trauma is of substance abuse, especially with ethanol, heroin, amphetamines, cocaine, and other sedatives or stimulants.1-3 The patient presented in this case study had a history of drug abuse, with a positive urine toxicology screen for cocaine and opiates. He had been intermittently confused and amnesic for 3 days prior to presentation, during which he may have been lying on his shoulder for a prolonged period.
Focal rhabdomyolysis and acute compression at the posterior shoulder leading to compressive brachial plexopathy is rare, with only 3 cases reported in the literature, all occurring with IV drug use.1-3 This patient had compression of the brachial plexus posterior cord from rhabdomyolysis and prolonged immobilization. Intravenous drug abusers may delay medical care due to perceived illicit drug effects and frequently present to the ED confused, agitated, or obtunded. Acute extremity swelling, a palpable lump, and pain can be due to various etiologies, such as trauma, fluid collection, muscle tear, myopathy, venous thrombosis, neoplasm, or rhabdomyolysis.
Diagnosis of nontraumatic rhabdomyolysis depends on clinical history and biochemical tests, such as serum CK and urine myoglobin.1,8 Creatine kinase is present in large quantities in the myocytes and is 100% sensitive as a marker for rhabdomyolysis.1,8 Creatine kinase may increase acutely > 1,000 U/L, suggesting muscle lysis and necrosis as etiology for pain as opposed to other causes such as hematomas, abscesses, or venous thrombi.1,9 Serum CK decreases rapidly at a rate of 39% per day, and it may normalize by the time a patient presents for medical care.1,10-12 Imaging plays a significant complimentary role. During the patient’s second ED presentation, the CK was normal at 54 U/L, whereas ultrasound and MRI findings were suggestive of focal muscle abnormalities.
Although there are diverse etiologies of rhabdomyolysis, the ultimate consequences of rhabdomyolysis are muscle cell membrane injury, metabolism malfunction, and destruction of the myofibril, resulting in inflammatory changes, such as muscle edema, hemorrhage, and myonecrosis and disruption of muscle fibers.1,2,8,9,13 This may cause an alteration in muscle size, shape, and echogenicity on sonography and abnormal signal intensity on MRI.13 The sensitivity of MRI in the detection of muscle involvement is higher than that of CT or ultrasound due to the high soft tissue contrast.4,13,14 Specificity of all 3 modalities is low and not reported.
Although the sensitivity of ultrasound is lower than that of MRI, use of ultrasound in neuromuscular evaluation has been increasing recently due to technical refinements. Ultrasound can be effectively used as a first-line screening modality, especially in an emergency.5 Magnetic resonance imaging best assesses the distribution and extension of the affected muscles, especially when fasciotomy is considered for treatment, and initially reveals edema, inflammation, and findings of myonecrosis; muscle atrophy and fatty degeneration occur later.4,13-15 Typical MRI findings include increased signal intensity on T2-weighted and STIR (short-tau inversion recovery) sequences and variable enhancement on T1 postcontrast images, as was seen in this case, which indicated edema, inflammation, and necrosis of the muscle tissue.
Shintani and colleagues described the reversibility of the MRI findings, showing that the high-intensity lesions seen on T2-weighted images resolved in parallel with the clinical course.14,16 Lu and colleagues investigated 10 patients with rhabdomyolysis and found 2 distinct imaging types: Type 1 shows homogenous signal changes and enhancement in the affected muscles, and Type 2 shows rim enhancement on contrast-enhanced MRI, a “stipple sign” indicating areas of myonecrosis.17 Magnetic resonance imaging signal alterations in the musculature can be nonspecific and overlap with those of inflammatory myopathies such as polymyositis, connective tissue diseases with inflammatory myositis, muscle infection, muscle infarction such as diabetic myonecrosis, muscle contusion, drug-induced myotoxicity, corticosteroids use, and use of cholesterol-lowering agents.18,19
Sonography is a useful screening modality for pain and swelling of the extremity, because it can detect a muscle tear, muscle sprain, and fluid collection, especially in emergent cases. There is scant literature about sonographic findings in rhabdomyolysis and compression nerve entrapment. The sonographic findings of rhabdomyolysis are local disorganization of the damaged muscle, decreased muscle echogenicity, and enlargement of the muscle, with preservation of the muscle boundaries.5-7
Intramuscular hyperechoic areas are seen due to hypercontractility of injured muscle. In this case, noted findings included patchy, irregular, hypoechoic areas, enlargement of the muscles and tendons, and irregular hyperechoic areas without focal defects. These findings differentiated an abnormality from a muscle tear or rupture, as these often show a focal muscle gap and focal defect, signifying the ruptured muscle retracting.
A study by Su and colleagues used the large number of crush injuries after an earthquake in China.5 The characteristic sonographic findings were edema and thickened disrupted striated muscle, good overall muscle continuity, vague muscle texture, and enhanced cloudy or ground-glass-like echo. There was no blood flow signal in the hypoechoic areas.6 Ultrasound was deemed a cost-effective, easily available modality by the authors.
Conclusion
Nontraumatic, focal rhabdomyolysis is rare and should be detected and differentiated from other causes of swelling, lump, pain, or other muscle disorders to prevent late complications. Sonography is an important screening diagnostic modality. MRI is used for assessment of the extent and distribution of injury. Awareness and familiarity with imaging findings can play a significant role, along with clinical and laboratory findings in the diagnosis and management of rhabdomyolysis.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
:
1. Richards JR. Rhabdomyolysis and drugs of abuse. J Emerg Med. 2000;19(1):51-56.
2. Farkash U, Shabshin N, Pritsch Perry M. Rhabdomyolysis of the deltoid muscle in a bodybuilder using anabolic-androgenic steroids: A case report. J Athl Train. 2009;44(1):98-100.
3. Mubarak SJ, Owen CA, Hargens AR, Garetto LP, Akeson WH. Acute compartment syndromes: Diagnosis and treatment with the aid of the wick catheter. J Bone Joint Surg Am. 1978;60(8):1091-1095.
4. Lamminen AE, Hekali PE, Tiula E, Suramo I, Korhola OA. Acute rhabdomyolysis: Evaluation with magnetic resonance imaging compared with computed tomography and ultrasonography. Br J Radiol. 1989;62(736):326-330.
5. Su BH, Qui L, Fu P, Luo Y, Tao Y, Peng YL. Ultrasonic appearance of rhabdomyolysis in patients with crush injury in the Wenchuan earthquake. Chin Med J (Engl). 2009;122(16):1872-1876.
6. Chiu Y-N, Wang T-G, Hsu C-Y, et al. Sonographic diagnosis of rhabdomyolysis. J Med Ultrasound. 2008;16(2):158-162.
7. Kaplan GN. Ultrasonic appearance of rhabdomyolysis. AJR Am J Roentgenol. 1980;134(2):375-377.
8. Spector R, Choudhury A, Cancilla P, Lakin R. Alcohol myopathy. Diagnosis by alcohol challenge. JAMA. 1979;242(15):1648-1649.
9. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore). 1982;61(3):141-152.
10. Knochel JP. Mechanisms of rhabdomyolysis. Curr Opin Rheumatol. 1993;5(6):725-731.
11. Cadnapaphornchai P, Taher S, McDonald FD. Acute drug-association rhabdomyolysis: An examination of its diverse renal manifestations and complications. Am J Med Sci. 1980;280(2):66-72.
12. Curry SC, Chang D, Connor D. Drug and toxin-induced rhabdomyolysis. Ann Emerg Med. 1989;18(10):1068-1084.
13. May D, Disler DG, Jones EA, Balkissoon AA, Manaster BJ. Abnormal signal intensity in skeletal muscle at MR imaging: Patterns, pearls, and pitfalls. RadioGraphics. 2000;20(spec no):S295-S315.
14. Moratalla MB, Braun P, Fornas GM. Importance of MRI in the diagnosis and treatment of rhabdomyolysis. Eur J Radiol. 2008;65(2):311-315.
15. Beltran J, Rosenberg ZS. Diagnosis of compressive and entrapment neurorpathies of the upper extremity: Value of MR imaging. AJR Am J Roentgenol. 1994;163(3):525-531.
16. Shintani S, Shiigai T. Repeat MRI in acute rhabdomyolysis: Correlation with clinicopathological findings. J Comput Assist Tomogr. 1993;17(5):786-791.
17. Lu CH, Tsang YM, Yu CW, et al. Rhabdomyolysis: Magnetic resonance imaging and computed tomography findings. J Comput Assist Tomogr. 2007;31(3):368-374.
18. Schulze M, Kötter I, Ernemann U, et al. MRI findings in inflammatory muscle diseases and their noninflammatory mimics. AJR Am J Roentgenol. 2009;192(6):1708-1716.
19. Adams EM, Chow CK, Premkumar A, Plotz PH. The idiopathic inflammatory myopathies: Spectrum of MR imaging findings. Radiographics. 1995;15(3):563-574.
:
1. Richards JR. Rhabdomyolysis and drugs of abuse. J Emerg Med. 2000;19(1):51-56.
2. Farkash U, Shabshin N, Pritsch Perry M. Rhabdomyolysis of the deltoid muscle in a bodybuilder using anabolic-androgenic steroids: A case report. J Athl Train. 2009;44(1):98-100.
3. Mubarak SJ, Owen CA, Hargens AR, Garetto LP, Akeson WH. Acute compartment syndromes: Diagnosis and treatment with the aid of the wick catheter. J Bone Joint Surg Am. 1978;60(8):1091-1095.
4. Lamminen AE, Hekali PE, Tiula E, Suramo I, Korhola OA. Acute rhabdomyolysis: Evaluation with magnetic resonance imaging compared with computed tomography and ultrasonography. Br J Radiol. 1989;62(736):326-330.
5. Su BH, Qui L, Fu P, Luo Y, Tao Y, Peng YL. Ultrasonic appearance of rhabdomyolysis in patients with crush injury in the Wenchuan earthquake. Chin Med J (Engl). 2009;122(16):1872-1876.
6. Chiu Y-N, Wang T-G, Hsu C-Y, et al. Sonographic diagnosis of rhabdomyolysis. J Med Ultrasound. 2008;16(2):158-162.
7. Kaplan GN. Ultrasonic appearance of rhabdomyolysis. AJR Am J Roentgenol. 1980;134(2):375-377.
8. Spector R, Choudhury A, Cancilla P, Lakin R. Alcohol myopathy. Diagnosis by alcohol challenge. JAMA. 1979;242(15):1648-1649.
9. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore). 1982;61(3):141-152.
10. Knochel JP. Mechanisms of rhabdomyolysis. Curr Opin Rheumatol. 1993;5(6):725-731.
11. Cadnapaphornchai P, Taher S, McDonald FD. Acute drug-association rhabdomyolysis: An examination of its diverse renal manifestations and complications. Am J Med Sci. 1980;280(2):66-72.
12. Curry SC, Chang D, Connor D. Drug and toxin-induced rhabdomyolysis. Ann Emerg Med. 1989;18(10):1068-1084.
13. May D, Disler DG, Jones EA, Balkissoon AA, Manaster BJ. Abnormal signal intensity in skeletal muscle at MR imaging: Patterns, pearls, and pitfalls. RadioGraphics. 2000;20(spec no):S295-S315.
14. Moratalla MB, Braun P, Fornas GM. Importance of MRI in the diagnosis and treatment of rhabdomyolysis. Eur J Radiol. 2008;65(2):311-315.
15. Beltran J, Rosenberg ZS. Diagnosis of compressive and entrapment neurorpathies of the upper extremity: Value of MR imaging. AJR Am J Roentgenol. 1994;163(3):525-531.
16. Shintani S, Shiigai T. Repeat MRI in acute rhabdomyolysis: Correlation with clinicopathological findings. J Comput Assist Tomogr. 1993;17(5):786-791.
17. Lu CH, Tsang YM, Yu CW, et al. Rhabdomyolysis: Magnetic resonance imaging and computed tomography findings. J Comput Assist Tomogr. 2007;31(3):368-374.
18. Schulze M, Kötter I, Ernemann U, et al. MRI findings in inflammatory muscle diseases and their noninflammatory mimics. AJR Am J Roentgenol. 2009;192(6):1708-1716.
19. Adams EM, Chow CK, Premkumar A, Plotz PH. The idiopathic inflammatory myopathies: Spectrum of MR imaging findings. Radiographics. 1995;15(3):563-574.
Lack of energy, petechiae, elevated PSA level—Dx?
THE CASE
A 57-year-old Hispanic man sought treatment because he had been feeling tired for a few weeks. He had not seen a physician for 15 years. When he came in, his temperature was 98.8°F, blood pressure was 132/82 mm Hg, pulse was 82 beats/min, respiration rate was 16 breaths/min, and oxygen saturation was 93% on room air. Examination of the head, neck, and respiratory and cardiovascular systems was normal. Skin examination showed petechiae and bruising on his abdomen, left ankle, right thigh, and bilateral shin area. His abdomen was nontender with no organomegaly. There was no focal neurological finding or spinal tenderness. Our patient had no chills, chest pains, shortness of breath, headache, dizziness, or loss of consciousness. There was no hematemesis, melena, hematuria, edema, or weight loss. He had no medical or surgical history and denied substance abuse or taking any medications recently; he did use alcohol previously.
Results of some initial lab tests were abnormal, including a decreased white blood cell count (5.82/mcL), platelet count (29 x 103/mcL), hemoglobin (8.6 g/dL), and hematocrit (27%) (TABLE). A peripheral blood smear showed decreased normocytic red blood cells and scattered schistocytes. His prostate-specific antigen (PSA) level was elevated at 212 ng/mL.
The patient’s coagulation profile was normal, and his von Willebrand factor (vWF) protease (ADAMTS-13) level was within normal limits (13.83). Antineutrophil cytoplasmic antibody and antinuclear antibody tests were negative. Testing for pulmonary embolism was negative, as was testing for human immunodeficiency virus. An abdominal ultrasound was normal, as well.
THE DIAGNOSIS
Based on our patient’s abnormal blood test results and the presence of petechiae and bruising, we diagnosed thrombotic thrombocytopenic purpura (TTP). The patient’s elevated PSA prompted us to order computed tomography of the chest and abdomen, which showed an enlarged prostate gland and mixed lytic sclerotic lesions in T3 to T5 and T9 vertebrae and in his ribs. A bone marrow biopsy revealed metastatic prostatic adenocarcinoma and a bone scan confirmed multiple metastases in the spine, pelvis, and shoulders.
DISCUSSION
TTP is a rare disorder of increased clotting in small blood vessels throughout the body that can include thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, renal dysfunction, and neurological deficits.1 It’s important to maintain a high index of suspicion for TTP because the condition is a hematologic medical emergency that can quickly cause multiorgan failure and death.2
Almost always an acquired condition, TTP can be idiopathic or secondary to another condition, such as collagen vascular diseases, transplants, certain drugs, infections, pregnancy, or cancer.3 In idiopathic TTP, the cause of the condition is believed to be reduced activity of ADAMTS-13, the protease that breaks vWF into smaller pieces—thus preventing the formation of unnecessary blood clots.
In cancer-associated TTP, which could be a complication resulting from chemotherapy or a manifestation of cancer itself,3 ADAMTS-13 level is normal and the condition is likely the result of an increased tumor cell load, which leads to endothelial damage and fragmentation of red blood cells (RBC) as they traverse the injured microvasculature.4 In an analysis of 154 cases of “solid” cancer-related MAHA, Lechner and Obermeier5 found 23 cases were related to prostate cancer, as was the case with our patient.
Treatment for TTP is plasma exchange. The mortality rate of untreated TTP can exceed 90%, but plasma exchange therapy has reduced that rate to <20%.6 It has been suggested that proteolysis of vWF may play a central role in the efficacy of plasma exchange for TTP.7
Our patient was hospitalized and received 2 units of packed RBCs. He also received plasma exchange for 9 days with minimal response. On Day 5, our patient was started on leuprorelin and parenteral steroids. Soon after, his platelet count rose to 33 × 103/mcL and lactate dehydrogenase decreased. He was discharged approximately one week after the steroids were started.
After several months of outpatient treatment with leuprorelin and bicalutamide, the patient’s platelet count normalized to 212 × 103/mcL (from 29 × 103/mcL), alkaline phosphatase decreased to 402 U/L (from 1919 U/L), and PSA levels trended downward to 8.63 ng/mL (from 212 ng/mL). He continued to receive care from our oncology clinic for the next several months and his PSA level continued to decline. However, at his last few visits, his PSA level had trended up, suggesting progression of his prostate cancer. The patient has not followed up with our clinic recently.
THE TAKEAWAY
Suspect TTP in patients who present with unexplained petechiae and bruising, and whose blood work reveals thrombocytopenia and MAHA.2 Patients with TTP who do not respond to plasma exchange should be evaluated for underlying cancer or other potential secondary causes.3 Patients with cancer-associated TTP may respond to steroid therapy.
1. Lichtin AE, Schreiber AD, Hurwitz S, et al. Efficacy of intensive plasmapheresis in thrombotic thrombocytopenic purpura. Archives Intern Med. 1987;147:2122-2126.
2. Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med. 2014;5:15-23.
3. Chang JC, Naqvi T. Thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer. Oncologist. 2003;8:375-380.
4. Pirrotta MT, Bucalossi A, Forconi F, et al. Thrombotic thrombocytopenic purpura secondary to an occult adenocarcinoma. Oncologist. 2005;10:299-300.
5. Lechner K, Obermeier HL. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. Medicine (Baltimore). 2012;91: 195-205.
6. Oberic L, Buffet, M, Scwarzinger M, et al; Reference Center for the Management of Thrombotic Microangiopathies. Cancer awareness in atypical thrombotic microangiopathies. Oncologist. 2009;14:769-779.
7. Zheng X, Chung D, Takayama TK, et al. Structure of von Willebrand factor-cleaving protease (ADAMTS 13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001;276:41059-41063.
THE CASE
A 57-year-old Hispanic man sought treatment because he had been feeling tired for a few weeks. He had not seen a physician for 15 years. When he came in, his temperature was 98.8°F, blood pressure was 132/82 mm Hg, pulse was 82 beats/min, respiration rate was 16 breaths/min, and oxygen saturation was 93% on room air. Examination of the head, neck, and respiratory and cardiovascular systems was normal. Skin examination showed petechiae and bruising on his abdomen, left ankle, right thigh, and bilateral shin area. His abdomen was nontender with no organomegaly. There was no focal neurological finding or spinal tenderness. Our patient had no chills, chest pains, shortness of breath, headache, dizziness, or loss of consciousness. There was no hematemesis, melena, hematuria, edema, or weight loss. He had no medical or surgical history and denied substance abuse or taking any medications recently; he did use alcohol previously.
Results of some initial lab tests were abnormal, including a decreased white blood cell count (5.82/mcL), platelet count (29 x 103/mcL), hemoglobin (8.6 g/dL), and hematocrit (27%) (TABLE). A peripheral blood smear showed decreased normocytic red blood cells and scattered schistocytes. His prostate-specific antigen (PSA) level was elevated at 212 ng/mL.
The patient’s coagulation profile was normal, and his von Willebrand factor (vWF) protease (ADAMTS-13) level was within normal limits (13.83). Antineutrophil cytoplasmic antibody and antinuclear antibody tests were negative. Testing for pulmonary embolism was negative, as was testing for human immunodeficiency virus. An abdominal ultrasound was normal, as well.
THE DIAGNOSIS
Based on our patient’s abnormal blood test results and the presence of petechiae and bruising, we diagnosed thrombotic thrombocytopenic purpura (TTP). The patient’s elevated PSA prompted us to order computed tomography of the chest and abdomen, which showed an enlarged prostate gland and mixed lytic sclerotic lesions in T3 to T5 and T9 vertebrae and in his ribs. A bone marrow biopsy revealed metastatic prostatic adenocarcinoma and a bone scan confirmed multiple metastases in the spine, pelvis, and shoulders.
DISCUSSION
TTP is a rare disorder of increased clotting in small blood vessels throughout the body that can include thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, renal dysfunction, and neurological deficits.1 It’s important to maintain a high index of suspicion for TTP because the condition is a hematologic medical emergency that can quickly cause multiorgan failure and death.2
Almost always an acquired condition, TTP can be idiopathic or secondary to another condition, such as collagen vascular diseases, transplants, certain drugs, infections, pregnancy, or cancer.3 In idiopathic TTP, the cause of the condition is believed to be reduced activity of ADAMTS-13, the protease that breaks vWF into smaller pieces—thus preventing the formation of unnecessary blood clots.
In cancer-associated TTP, which could be a complication resulting from chemotherapy or a manifestation of cancer itself,3 ADAMTS-13 level is normal and the condition is likely the result of an increased tumor cell load, which leads to endothelial damage and fragmentation of red blood cells (RBC) as they traverse the injured microvasculature.4 In an analysis of 154 cases of “solid” cancer-related MAHA, Lechner and Obermeier5 found 23 cases were related to prostate cancer, as was the case with our patient.
Treatment for TTP is plasma exchange. The mortality rate of untreated TTP can exceed 90%, but plasma exchange therapy has reduced that rate to <20%.6 It has been suggested that proteolysis of vWF may play a central role in the efficacy of plasma exchange for TTP.7
Our patient was hospitalized and received 2 units of packed RBCs. He also received plasma exchange for 9 days with minimal response. On Day 5, our patient was started on leuprorelin and parenteral steroids. Soon after, his platelet count rose to 33 × 103/mcL and lactate dehydrogenase decreased. He was discharged approximately one week after the steroids were started.
After several months of outpatient treatment with leuprorelin and bicalutamide, the patient’s platelet count normalized to 212 × 103/mcL (from 29 × 103/mcL), alkaline phosphatase decreased to 402 U/L (from 1919 U/L), and PSA levels trended downward to 8.63 ng/mL (from 212 ng/mL). He continued to receive care from our oncology clinic for the next several months and his PSA level continued to decline. However, at his last few visits, his PSA level had trended up, suggesting progression of his prostate cancer. The patient has not followed up with our clinic recently.
THE TAKEAWAY
Suspect TTP in patients who present with unexplained petechiae and bruising, and whose blood work reveals thrombocytopenia and MAHA.2 Patients with TTP who do not respond to plasma exchange should be evaluated for underlying cancer or other potential secondary causes.3 Patients with cancer-associated TTP may respond to steroid therapy.
THE CASE
A 57-year-old Hispanic man sought treatment because he had been feeling tired for a few weeks. He had not seen a physician for 15 years. When he came in, his temperature was 98.8°F, blood pressure was 132/82 mm Hg, pulse was 82 beats/min, respiration rate was 16 breaths/min, and oxygen saturation was 93% on room air. Examination of the head, neck, and respiratory and cardiovascular systems was normal. Skin examination showed petechiae and bruising on his abdomen, left ankle, right thigh, and bilateral shin area. His abdomen was nontender with no organomegaly. There was no focal neurological finding or spinal tenderness. Our patient had no chills, chest pains, shortness of breath, headache, dizziness, or loss of consciousness. There was no hematemesis, melena, hematuria, edema, or weight loss. He had no medical or surgical history and denied substance abuse or taking any medications recently; he did use alcohol previously.
Results of some initial lab tests were abnormal, including a decreased white blood cell count (5.82/mcL), platelet count (29 x 103/mcL), hemoglobin (8.6 g/dL), and hematocrit (27%) (TABLE). A peripheral blood smear showed decreased normocytic red blood cells and scattered schistocytes. His prostate-specific antigen (PSA) level was elevated at 212 ng/mL.
The patient’s coagulation profile was normal, and his von Willebrand factor (vWF) protease (ADAMTS-13) level was within normal limits (13.83). Antineutrophil cytoplasmic antibody and antinuclear antibody tests were negative. Testing for pulmonary embolism was negative, as was testing for human immunodeficiency virus. An abdominal ultrasound was normal, as well.
THE DIAGNOSIS
Based on our patient’s abnormal blood test results and the presence of petechiae and bruising, we diagnosed thrombotic thrombocytopenic purpura (TTP). The patient’s elevated PSA prompted us to order computed tomography of the chest and abdomen, which showed an enlarged prostate gland and mixed lytic sclerotic lesions in T3 to T5 and T9 vertebrae and in his ribs. A bone marrow biopsy revealed metastatic prostatic adenocarcinoma and a bone scan confirmed multiple metastases in the spine, pelvis, and shoulders.
DISCUSSION
TTP is a rare disorder of increased clotting in small blood vessels throughout the body that can include thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, renal dysfunction, and neurological deficits.1 It’s important to maintain a high index of suspicion for TTP because the condition is a hematologic medical emergency that can quickly cause multiorgan failure and death.2
Almost always an acquired condition, TTP can be idiopathic or secondary to another condition, such as collagen vascular diseases, transplants, certain drugs, infections, pregnancy, or cancer.3 In idiopathic TTP, the cause of the condition is believed to be reduced activity of ADAMTS-13, the protease that breaks vWF into smaller pieces—thus preventing the formation of unnecessary blood clots.
In cancer-associated TTP, which could be a complication resulting from chemotherapy or a manifestation of cancer itself,3 ADAMTS-13 level is normal and the condition is likely the result of an increased tumor cell load, which leads to endothelial damage and fragmentation of red blood cells (RBC) as they traverse the injured microvasculature.4 In an analysis of 154 cases of “solid” cancer-related MAHA, Lechner and Obermeier5 found 23 cases were related to prostate cancer, as was the case with our patient.
Treatment for TTP is plasma exchange. The mortality rate of untreated TTP can exceed 90%, but plasma exchange therapy has reduced that rate to <20%.6 It has been suggested that proteolysis of vWF may play a central role in the efficacy of plasma exchange for TTP.7
Our patient was hospitalized and received 2 units of packed RBCs. He also received plasma exchange for 9 days with minimal response. On Day 5, our patient was started on leuprorelin and parenteral steroids. Soon after, his platelet count rose to 33 × 103/mcL and lactate dehydrogenase decreased. He was discharged approximately one week after the steroids were started.
After several months of outpatient treatment with leuprorelin and bicalutamide, the patient’s platelet count normalized to 212 × 103/mcL (from 29 × 103/mcL), alkaline phosphatase decreased to 402 U/L (from 1919 U/L), and PSA levels trended downward to 8.63 ng/mL (from 212 ng/mL). He continued to receive care from our oncology clinic for the next several months and his PSA level continued to decline. However, at his last few visits, his PSA level had trended up, suggesting progression of his prostate cancer. The patient has not followed up with our clinic recently.
THE TAKEAWAY
Suspect TTP in patients who present with unexplained petechiae and bruising, and whose blood work reveals thrombocytopenia and MAHA.2 Patients with TTP who do not respond to plasma exchange should be evaluated for underlying cancer or other potential secondary causes.3 Patients with cancer-associated TTP may respond to steroid therapy.
1. Lichtin AE, Schreiber AD, Hurwitz S, et al. Efficacy of intensive plasmapheresis in thrombotic thrombocytopenic purpura. Archives Intern Med. 1987;147:2122-2126.
2. Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med. 2014;5:15-23.
3. Chang JC, Naqvi T. Thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer. Oncologist. 2003;8:375-380.
4. Pirrotta MT, Bucalossi A, Forconi F, et al. Thrombotic thrombocytopenic purpura secondary to an occult adenocarcinoma. Oncologist. 2005;10:299-300.
5. Lechner K, Obermeier HL. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. Medicine (Baltimore). 2012;91: 195-205.
6. Oberic L, Buffet, M, Scwarzinger M, et al; Reference Center for the Management of Thrombotic Microangiopathies. Cancer awareness in atypical thrombotic microangiopathies. Oncologist. 2009;14:769-779.
7. Zheng X, Chung D, Takayama TK, et al. Structure of von Willebrand factor-cleaving protease (ADAMTS 13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001;276:41059-41063.
1. Lichtin AE, Schreiber AD, Hurwitz S, et al. Efficacy of intensive plasmapheresis in thrombotic thrombocytopenic purpura. Archives Intern Med. 1987;147:2122-2126.
2. Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med. 2014;5:15-23.
3. Chang JC, Naqvi T. Thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer. Oncologist. 2003;8:375-380.
4. Pirrotta MT, Bucalossi A, Forconi F, et al. Thrombotic thrombocytopenic purpura secondary to an occult adenocarcinoma. Oncologist. 2005;10:299-300.
5. Lechner K, Obermeier HL. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. Medicine (Baltimore). 2012;91: 195-205.
6. Oberic L, Buffet, M, Scwarzinger M, et al; Reference Center for the Management of Thrombotic Microangiopathies. Cancer awareness in atypical thrombotic microangiopathies. Oncologist. 2009;14:769-779.
7. Zheng X, Chung D, Takayama TK, et al. Structure of von Willebrand factor-cleaving protease (ADAMTS 13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001;276:41059-41063.
My Most Unusual Case: Cesarean Scar Ectopic Pregnancy
Cesarean scar ectopic pregnancy (CSEP) is a challenging diagnosis that warrants consideration when performing ultrasound on a pregnant patient with a previous history of cesarean delivery. It is suspected when ballooning of the lower uterine segment is noted on ultrasound,1 when a trophoblast is seen at a presumed cesarean scar beneath the utero-vesicular fold, and when myometrium between the gestational sac and bladder wall is thin (<8 mm).2
Ectopic Pregnancy
Ectopic pregnancy affects approximately 2% of all pregnancies and is the leading cause of first-trimester maternal mortality.3 As front-line care providers, it is imperative that emergency physicians (EPs) recognize cases of ectopic implantation to avoid devastating outcomes.
The majority of ectopic pregnancies (97%) are located in the fallopian tubes; however, many other locations are possible, including implantation in the scar from a previous cesarean delivery.1,4 The frequency of such ectopic pregnancies is on the rise, consistent with the increasing number of cesarean deliveries performed worldwide.5 These cases present a special diagnostic challenge because patients often present asymptomatically or with painless vaginal bleeding; moreover, visualization via bedside ultrasound can be deceiving,5 and it is easy to mistake a CSEP for a viable intrauterine pregnancy.
Case
A 22-year-old woman with type 1 diabetes mellitus (DM) presented to the ED complaining of 3 days of worsening nausea and elevated blood glucose levels. She stated that although she had been taking her insulin regimen as prescribed, her symptoms progressively worsened. On the day of presentation, she developed moderate diffuse nonradiating dull abdominal pain and had several episodes of nonbloody, nonbilious emesis. She denied being pregnant and stated that her last menstrual period was 14 days ago; she further denied any vaginal discharge or bleeding. A review of her systems was otherwise benign.
In addition to type 1 DM, the patient also had a history of migraine headaches and an obstetric history of gravida 3, para 3, aborta 0. Each birth was via cesarean delivery and without complication. Her current medications included insulin glargine (Lantus) 25 units subcutaneously every night at bedtime; insulin aspart (Novolog) 7 units subcutaneously three times a day; zolpidem (Ambien) 10 mg orally every night at bedtime. A chart review was notable for several presentations of diabetic ketoacidosis (DKA) secondary to noncompliance with her diabetes regimen.
Physical examination was notable for a well-developed, well-nourished 22 year old that appeared uncomfortable but in no acute distress. Her abdomen was soft and nondistended, with diffuse moderate tenderness to palpation but no rebound or guarding. The remainder of the physical
The initial workup revealed DKA and pregnancy. Significant laboratory values included: finger-stick blood glucose, 441 mg/dL; serum ketones, 2.1 mmol/L (normal range, 0.0-0.5); anion gap, 15; and urinalysis 4+ glucose, 2+ ketones; and quantitative β-human chorionic gonadotropin (β-HCG), 5,282 IU/L (normal range, 0-5.0 IU/L ).examination was otherwise benign.
After receiving insulin, intravenous (IV) fluids, pain medication, and antiemetics, the patient stated she felt much better. She was then admitted to the inpatient floor for management of DKA and discharged uneventfully several days later. Emergency bedside transabdominal and transvaginal ultrasounds were performed by the emergency staff and identified an intrauterine gestational sac and yolk sac. The EP ordered a consultation with an obstetrician-gynecologist (OB-GYN), who saw the patient in the ED and agreed with the findings, and noted the gestational sac was consistent with a date of 5 weeks, 1 day.
Six days after discharge, however, she returned to the ED complaining of several days of weakness, vomiting, and lower abdominal pain. Significant laboratory values included: urinalysis with 4+ ketones, 1+ bacteria, + nitrites; and quantitative β-HCG 25,925 IU/L (expected range, 0-5.0); serum glucose 206 mg/dL; serum ketones 0.8 (expected range, 0-0.5); and anion gap, 12.
An emergency ultrasound identified a gestational sac, yolk sac, fetal pole, and fetal heart tones; an OB-GYN ultrasound had consistent findings, with an estimated gestational age of 6 weeks, 6 days. The patient responded well to IV fluids and antiemetics, and was asymptomatic when she was admitted to the ED observation unit for continued monitoring, fluids, and antiemetics as needed. Several hours later she again began to complain of nausea, vomiting, and poorly localized abdominal discomfort. As these symptoms persisted, the OB-GYN team returned to reevaluate the patient.
Discussion
Cesarean scar ectopic pregnancy was first described in the obstetric literature in 1978 and originally thought to be an exceedingly rare occurrence.5,6 With both the increasing number of cesarean deliveries performed and improvement in imaging technology, it is now believed that uterine scar ectopic pregnancy makes up as much as 6.1% of ectopic pregnancies in patients with a prior cesarean delivery.7 This diagnosis is well-documented in the obstetric and radiology literature, yet has never been discussed in an emergency medicine publication. Searching through both Pubmed and EMBase using the terms “cesarean” and “ectopic” yields no EM literature on the topic of CSEP. This is concerning because ultrasound of the pregnant patient is now a routine function of EPs.
Clinical history can be helpful in differentiating CSEP from alternative diagnoses. Patients undergoing spontaneous abortion are more likely to have lower abdominal cramping and experience greater loss of blood. While there is no correlation between the number of cesarean deliveries a woman has had and the likelihood of developing a CSEP, factors that impede myometrial healing (eg, preterm cesarean, cesarean after arrest of first stage of labor, chorioamnionitis) do, however, increase a patient’s risk of developing CSEP.5
Similar to tubal ectopic pregnancy, CSEP oftentimes presents early with mild, nonspecific symptoms. Thirty-nine percent of cases present with light, painless vaginal bleeding while only 25% present with abdominal pain. Moreover, 37% of cases are asymptomatic at the time of diagnosis.5
One study by found the mean gestational age at diagnosis to be 7.5 weeks.5 Delayed diagnosis places the patient at risk for uterine rupture, hemorrhage, and maternal death, making suspicion and prompt diagnosis by bedside ED ultrasound essential.7,8
Regardless of one’s clinical suspicion, the diagnosis is made (or ruled out) through ultrasound. Uterine scar ectopic pregnancy is suspected when ballooning of the lower uterine segment is noted,1 when a trophoblast is seen at a presumed cesarean scar beneath the utero-vesicular fold, and when myometrium between the gestational sac and bladder wall is thin (<8 mm).2 As seen with this patient, the diagnosis is challenging as a uterine scar ectopic pregnancy can easily be mistaken for an intrauterine pregnancy. The clinician must make every effort to ensure that the pregnancy is surrounded by appropriate myometrium. It is much easier to diagnose an ectopic pregnancy far removed from the uterus, where the uterus and pregnancy are easily visualized and independent.
Management of patients with CSEP remains outside of the scope of EM, and there is no consensus among our colleagues in OB-GYN on optimal management of these patients. Options include systemic or local injection of methotrexate and potassium chloride, or minimally invasive surgery for removal.5
As bedside ultrasound by EPs becomes standard of care for first-trimester pregnancies, a greater awareness of emergent obstetric pathologies becomes necessary. Vigilance and proper ultrasound technique will enable the EP to make the diagnosis of CSEP, minimizing maternal morbidity and mortality.
Drs Haight and Watkins are residents in the division of emergency medicine, Washington University School of Medicine, Saint Louis, Missouri. Dr Kane is a clinical instructor in the division of emergency medicine, Washington University School of Medicine, Saint Louis, Missouri.
- Moschos E, Sreenarasimhaiah S, Twickler DM. First-trimester diagnosis of cesarean scar ectopic pregnancy. J Clin Ultrasound. 2008;36(8):504-511.
- Vial Y, Petignat P, Hohlfeld P. Pregnancy in a cesarean scar. Ultrasound Obstet Gynecol. 2000;16(6): 592-593.
- Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy—United States, 1970-1989. MMWR CDC Surveill Summ. 1993;42(6):73-85.
- Molinaro TA, Barnhart KT. Ectopic pregnancies in unusual locations. Semin Reprod Med. 2007;25(2):123-130.
- Rotas MA, Haberman S, Levgur M. Cesarean scar ectopic pregnancies: etiology, diagnosis, and management. Obstet Gynecol. 2006;107(6):1373-1381.
- Larsen JV, Solomon MH. Pregnancy in a uterine scar sacculus—an unusual cause of postabortal haemorrhage. A case report. S Afr Med J. 1978;53(4):142-143.
- Seow KM, Huang LW, Lin YH, Lin MY, Tsai YL, Hwang JL. Caesarean scar pregnancy: issues in management. Ultrasound Obstet Gynecol. 2004;23(3):247-253.
- Einenkel J, Stumpp P, Kösling S, Horn LC, Höckel M. A misdiagnosed case of caesarean scar pregnancy. Arch Gynecol Obstet. 2005;271(2):178-181.
Cesarean scar ectopic pregnancy (CSEP) is a challenging diagnosis that warrants consideration when performing ultrasound on a pregnant patient with a previous history of cesarean delivery. It is suspected when ballooning of the lower uterine segment is noted on ultrasound,1 when a trophoblast is seen at a presumed cesarean scar beneath the utero-vesicular fold, and when myometrium between the gestational sac and bladder wall is thin (<8 mm).2
Ectopic Pregnancy
Ectopic pregnancy affects approximately 2% of all pregnancies and is the leading cause of first-trimester maternal mortality.3 As front-line care providers, it is imperative that emergency physicians (EPs) recognize cases of ectopic implantation to avoid devastating outcomes.
The majority of ectopic pregnancies (97%) are located in the fallopian tubes; however, many other locations are possible, including implantation in the scar from a previous cesarean delivery.1,4 The frequency of such ectopic pregnancies is on the rise, consistent with the increasing number of cesarean deliveries performed worldwide.5 These cases present a special diagnostic challenge because patients often present asymptomatically or with painless vaginal bleeding; moreover, visualization via bedside ultrasound can be deceiving,5 and it is easy to mistake a CSEP for a viable intrauterine pregnancy.
Case
A 22-year-old woman with type 1 diabetes mellitus (DM) presented to the ED complaining of 3 days of worsening nausea and elevated blood glucose levels. She stated that although she had been taking her insulin regimen as prescribed, her symptoms progressively worsened. On the day of presentation, she developed moderate diffuse nonradiating dull abdominal pain and had several episodes of nonbloody, nonbilious emesis. She denied being pregnant and stated that her last menstrual period was 14 days ago; she further denied any vaginal discharge or bleeding. A review of her systems was otherwise benign.
In addition to type 1 DM, the patient also had a history of migraine headaches and an obstetric history of gravida 3, para 3, aborta 0. Each birth was via cesarean delivery and without complication. Her current medications included insulin glargine (Lantus) 25 units subcutaneously every night at bedtime; insulin aspart (Novolog) 7 units subcutaneously three times a day; zolpidem (Ambien) 10 mg orally every night at bedtime. A chart review was notable for several presentations of diabetic ketoacidosis (DKA) secondary to noncompliance with her diabetes regimen.
Physical examination was notable for a well-developed, well-nourished 22 year old that appeared uncomfortable but in no acute distress. Her abdomen was soft and nondistended, with diffuse moderate tenderness to palpation but no rebound or guarding. The remainder of the physical
The initial workup revealed DKA and pregnancy. Significant laboratory values included: finger-stick blood glucose, 441 mg/dL; serum ketones, 2.1 mmol/L (normal range, 0.0-0.5); anion gap, 15; and urinalysis 4+ glucose, 2+ ketones; and quantitative β-human chorionic gonadotropin (β-HCG), 5,282 IU/L (normal range, 0-5.0 IU/L ).examination was otherwise benign.
After receiving insulin, intravenous (IV) fluids, pain medication, and antiemetics, the patient stated she felt much better. She was then admitted to the inpatient floor for management of DKA and discharged uneventfully several days later. Emergency bedside transabdominal and transvaginal ultrasounds were performed by the emergency staff and identified an intrauterine gestational sac and yolk sac. The EP ordered a consultation with an obstetrician-gynecologist (OB-GYN), who saw the patient in the ED and agreed with the findings, and noted the gestational sac was consistent with a date of 5 weeks, 1 day.
Six days after discharge, however, she returned to the ED complaining of several days of weakness, vomiting, and lower abdominal pain. Significant laboratory values included: urinalysis with 4+ ketones, 1+ bacteria, + nitrites; and quantitative β-HCG 25,925 IU/L (expected range, 0-5.0); serum glucose 206 mg/dL; serum ketones 0.8 (expected range, 0-0.5); and anion gap, 12.
An emergency ultrasound identified a gestational sac, yolk sac, fetal pole, and fetal heart tones; an OB-GYN ultrasound had consistent findings, with an estimated gestational age of 6 weeks, 6 days. The patient responded well to IV fluids and antiemetics, and was asymptomatic when she was admitted to the ED observation unit for continued monitoring, fluids, and antiemetics as needed. Several hours later she again began to complain of nausea, vomiting, and poorly localized abdominal discomfort. As these symptoms persisted, the OB-GYN team returned to reevaluate the patient.
Discussion
Cesarean scar ectopic pregnancy was first described in the obstetric literature in 1978 and originally thought to be an exceedingly rare occurrence.5,6 With both the increasing number of cesarean deliveries performed and improvement in imaging technology, it is now believed that uterine scar ectopic pregnancy makes up as much as 6.1% of ectopic pregnancies in patients with a prior cesarean delivery.7 This diagnosis is well-documented in the obstetric and radiology literature, yet has never been discussed in an emergency medicine publication. Searching through both Pubmed and EMBase using the terms “cesarean” and “ectopic” yields no EM literature on the topic of CSEP. This is concerning because ultrasound of the pregnant patient is now a routine function of EPs.
Clinical history can be helpful in differentiating CSEP from alternative diagnoses. Patients undergoing spontaneous abortion are more likely to have lower abdominal cramping and experience greater loss of blood. While there is no correlation between the number of cesarean deliveries a woman has had and the likelihood of developing a CSEP, factors that impede myometrial healing (eg, preterm cesarean, cesarean after arrest of first stage of labor, chorioamnionitis) do, however, increase a patient’s risk of developing CSEP.5
Similar to tubal ectopic pregnancy, CSEP oftentimes presents early with mild, nonspecific symptoms. Thirty-nine percent of cases present with light, painless vaginal bleeding while only 25% present with abdominal pain. Moreover, 37% of cases are asymptomatic at the time of diagnosis.5
One study by found the mean gestational age at diagnosis to be 7.5 weeks.5 Delayed diagnosis places the patient at risk for uterine rupture, hemorrhage, and maternal death, making suspicion and prompt diagnosis by bedside ED ultrasound essential.7,8
Regardless of one’s clinical suspicion, the diagnosis is made (or ruled out) through ultrasound. Uterine scar ectopic pregnancy is suspected when ballooning of the lower uterine segment is noted,1 when a trophoblast is seen at a presumed cesarean scar beneath the utero-vesicular fold, and when myometrium between the gestational sac and bladder wall is thin (<8 mm).2 As seen with this patient, the diagnosis is challenging as a uterine scar ectopic pregnancy can easily be mistaken for an intrauterine pregnancy. The clinician must make every effort to ensure that the pregnancy is surrounded by appropriate myometrium. It is much easier to diagnose an ectopic pregnancy far removed from the uterus, where the uterus and pregnancy are easily visualized and independent.
Management of patients with CSEP remains outside of the scope of EM, and there is no consensus among our colleagues in OB-GYN on optimal management of these patients. Options include systemic or local injection of methotrexate and potassium chloride, or minimally invasive surgery for removal.5
As bedside ultrasound by EPs becomes standard of care for first-trimester pregnancies, a greater awareness of emergent obstetric pathologies becomes necessary. Vigilance and proper ultrasound technique will enable the EP to make the diagnosis of CSEP, minimizing maternal morbidity and mortality.
Drs Haight and Watkins are residents in the division of emergency medicine, Washington University School of Medicine, Saint Louis, Missouri. Dr Kane is a clinical instructor in the division of emergency medicine, Washington University School of Medicine, Saint Louis, Missouri.
Cesarean scar ectopic pregnancy (CSEP) is a challenging diagnosis that warrants consideration when performing ultrasound on a pregnant patient with a previous history of cesarean delivery. It is suspected when ballooning of the lower uterine segment is noted on ultrasound,1 when a trophoblast is seen at a presumed cesarean scar beneath the utero-vesicular fold, and when myometrium between the gestational sac and bladder wall is thin (<8 mm).2
Ectopic Pregnancy
Ectopic pregnancy affects approximately 2% of all pregnancies and is the leading cause of first-trimester maternal mortality.3 As front-line care providers, it is imperative that emergency physicians (EPs) recognize cases of ectopic implantation to avoid devastating outcomes.
The majority of ectopic pregnancies (97%) are located in the fallopian tubes; however, many other locations are possible, including implantation in the scar from a previous cesarean delivery.1,4 The frequency of such ectopic pregnancies is on the rise, consistent with the increasing number of cesarean deliveries performed worldwide.5 These cases present a special diagnostic challenge because patients often present asymptomatically or with painless vaginal bleeding; moreover, visualization via bedside ultrasound can be deceiving,5 and it is easy to mistake a CSEP for a viable intrauterine pregnancy.
Case
A 22-year-old woman with type 1 diabetes mellitus (DM) presented to the ED complaining of 3 days of worsening nausea and elevated blood glucose levels. She stated that although she had been taking her insulin regimen as prescribed, her symptoms progressively worsened. On the day of presentation, she developed moderate diffuse nonradiating dull abdominal pain and had several episodes of nonbloody, nonbilious emesis. She denied being pregnant and stated that her last menstrual period was 14 days ago; she further denied any vaginal discharge or bleeding. A review of her systems was otherwise benign.
In addition to type 1 DM, the patient also had a history of migraine headaches and an obstetric history of gravida 3, para 3, aborta 0. Each birth was via cesarean delivery and without complication. Her current medications included insulin glargine (Lantus) 25 units subcutaneously every night at bedtime; insulin aspart (Novolog) 7 units subcutaneously three times a day; zolpidem (Ambien) 10 mg orally every night at bedtime. A chart review was notable for several presentations of diabetic ketoacidosis (DKA) secondary to noncompliance with her diabetes regimen.
Physical examination was notable for a well-developed, well-nourished 22 year old that appeared uncomfortable but in no acute distress. Her abdomen was soft and nondistended, with diffuse moderate tenderness to palpation but no rebound or guarding. The remainder of the physical
The initial workup revealed DKA and pregnancy. Significant laboratory values included: finger-stick blood glucose, 441 mg/dL; serum ketones, 2.1 mmol/L (normal range, 0.0-0.5); anion gap, 15; and urinalysis 4+ glucose, 2+ ketones; and quantitative β-human chorionic gonadotropin (β-HCG), 5,282 IU/L (normal range, 0-5.0 IU/L ).examination was otherwise benign.
After receiving insulin, intravenous (IV) fluids, pain medication, and antiemetics, the patient stated she felt much better. She was then admitted to the inpatient floor for management of DKA and discharged uneventfully several days later. Emergency bedside transabdominal and transvaginal ultrasounds were performed by the emergency staff and identified an intrauterine gestational sac and yolk sac. The EP ordered a consultation with an obstetrician-gynecologist (OB-GYN), who saw the patient in the ED and agreed with the findings, and noted the gestational sac was consistent with a date of 5 weeks, 1 day.
Six days after discharge, however, she returned to the ED complaining of several days of weakness, vomiting, and lower abdominal pain. Significant laboratory values included: urinalysis with 4+ ketones, 1+ bacteria, + nitrites; and quantitative β-HCG 25,925 IU/L (expected range, 0-5.0); serum glucose 206 mg/dL; serum ketones 0.8 (expected range, 0-0.5); and anion gap, 12.
An emergency ultrasound identified a gestational sac, yolk sac, fetal pole, and fetal heart tones; an OB-GYN ultrasound had consistent findings, with an estimated gestational age of 6 weeks, 6 days. The patient responded well to IV fluids and antiemetics, and was asymptomatic when she was admitted to the ED observation unit for continued monitoring, fluids, and antiemetics as needed. Several hours later she again began to complain of nausea, vomiting, and poorly localized abdominal discomfort. As these symptoms persisted, the OB-GYN team returned to reevaluate the patient.
Discussion
Cesarean scar ectopic pregnancy was first described in the obstetric literature in 1978 and originally thought to be an exceedingly rare occurrence.5,6 With both the increasing number of cesarean deliveries performed and improvement in imaging technology, it is now believed that uterine scar ectopic pregnancy makes up as much as 6.1% of ectopic pregnancies in patients with a prior cesarean delivery.7 This diagnosis is well-documented in the obstetric and radiology literature, yet has never been discussed in an emergency medicine publication. Searching through both Pubmed and EMBase using the terms “cesarean” and “ectopic” yields no EM literature on the topic of CSEP. This is concerning because ultrasound of the pregnant patient is now a routine function of EPs.
Clinical history can be helpful in differentiating CSEP from alternative diagnoses. Patients undergoing spontaneous abortion are more likely to have lower abdominal cramping and experience greater loss of blood. While there is no correlation between the number of cesarean deliveries a woman has had and the likelihood of developing a CSEP, factors that impede myometrial healing (eg, preterm cesarean, cesarean after arrest of first stage of labor, chorioamnionitis) do, however, increase a patient’s risk of developing CSEP.5
Similar to tubal ectopic pregnancy, CSEP oftentimes presents early with mild, nonspecific symptoms. Thirty-nine percent of cases present with light, painless vaginal bleeding while only 25% present with abdominal pain. Moreover, 37% of cases are asymptomatic at the time of diagnosis.5
One study by found the mean gestational age at diagnosis to be 7.5 weeks.5 Delayed diagnosis places the patient at risk for uterine rupture, hemorrhage, and maternal death, making suspicion and prompt diagnosis by bedside ED ultrasound essential.7,8
Regardless of one’s clinical suspicion, the diagnosis is made (or ruled out) through ultrasound. Uterine scar ectopic pregnancy is suspected when ballooning of the lower uterine segment is noted,1 when a trophoblast is seen at a presumed cesarean scar beneath the utero-vesicular fold, and when myometrium between the gestational sac and bladder wall is thin (<8 mm).2 As seen with this patient, the diagnosis is challenging as a uterine scar ectopic pregnancy can easily be mistaken for an intrauterine pregnancy. The clinician must make every effort to ensure that the pregnancy is surrounded by appropriate myometrium. It is much easier to diagnose an ectopic pregnancy far removed from the uterus, where the uterus and pregnancy are easily visualized and independent.
Management of patients with CSEP remains outside of the scope of EM, and there is no consensus among our colleagues in OB-GYN on optimal management of these patients. Options include systemic or local injection of methotrexate and potassium chloride, or minimally invasive surgery for removal.5
As bedside ultrasound by EPs becomes standard of care for first-trimester pregnancies, a greater awareness of emergent obstetric pathologies becomes necessary. Vigilance and proper ultrasound technique will enable the EP to make the diagnosis of CSEP, minimizing maternal morbidity and mortality.
Drs Haight and Watkins are residents in the division of emergency medicine, Washington University School of Medicine, Saint Louis, Missouri. Dr Kane is a clinical instructor in the division of emergency medicine, Washington University School of Medicine, Saint Louis, Missouri.
- Moschos E, Sreenarasimhaiah S, Twickler DM. First-trimester diagnosis of cesarean scar ectopic pregnancy. J Clin Ultrasound. 2008;36(8):504-511.
- Vial Y, Petignat P, Hohlfeld P. Pregnancy in a cesarean scar. Ultrasound Obstet Gynecol. 2000;16(6): 592-593.
- Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy—United States, 1970-1989. MMWR CDC Surveill Summ. 1993;42(6):73-85.
- Molinaro TA, Barnhart KT. Ectopic pregnancies in unusual locations. Semin Reprod Med. 2007;25(2):123-130.
- Rotas MA, Haberman S, Levgur M. Cesarean scar ectopic pregnancies: etiology, diagnosis, and management. Obstet Gynecol. 2006;107(6):1373-1381.
- Larsen JV, Solomon MH. Pregnancy in a uterine scar sacculus—an unusual cause of postabortal haemorrhage. A case report. S Afr Med J. 1978;53(4):142-143.
- Seow KM, Huang LW, Lin YH, Lin MY, Tsai YL, Hwang JL. Caesarean scar pregnancy: issues in management. Ultrasound Obstet Gynecol. 2004;23(3):247-253.
- Einenkel J, Stumpp P, Kösling S, Horn LC, Höckel M. A misdiagnosed case of caesarean scar pregnancy. Arch Gynecol Obstet. 2005;271(2):178-181.
- Moschos E, Sreenarasimhaiah S, Twickler DM. First-trimester diagnosis of cesarean scar ectopic pregnancy. J Clin Ultrasound. 2008;36(8):504-511.
- Vial Y, Petignat P, Hohlfeld P. Pregnancy in a cesarean scar. Ultrasound Obstet Gynecol. 2000;16(6): 592-593.
- Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy—United States, 1970-1989. MMWR CDC Surveill Summ. 1993;42(6):73-85.
- Molinaro TA, Barnhart KT. Ectopic pregnancies in unusual locations. Semin Reprod Med. 2007;25(2):123-130.
- Rotas MA, Haberman S, Levgur M. Cesarean scar ectopic pregnancies: etiology, diagnosis, and management. Obstet Gynecol. 2006;107(6):1373-1381.
- Larsen JV, Solomon MH. Pregnancy in a uterine scar sacculus—an unusual cause of postabortal haemorrhage. A case report. S Afr Med J. 1978;53(4):142-143.
- Seow KM, Huang LW, Lin YH, Lin MY, Tsai YL, Hwang JL. Caesarean scar pregnancy: issues in management. Ultrasound Obstet Gynecol. 2004;23(3):247-253.
- Einenkel J, Stumpp P, Kösling S, Horn LC, Höckel M. A misdiagnosed case of caesarean scar pregnancy. Arch Gynecol Obstet. 2005;271(2):178-181.
Case Studies in Toxicology: A Common Procedure, an Uncommon Complication
Case
A 35-year-old woman underwent an elective hysteroscopic myomectomy to remove a symptomatic 2.7-cm uterine leiomyoma. The procedure was uncomplicated, and the patient awoke in the postanesthesia care unit (PACU) in good condition. Two hours later, however, she developed severe shortness of breath and required bilevel positive airway pressure ventilation. Her vital signs in the PACU were: blood pressure (BP), 110/70 mm Hg; heart rate, 90 beats/minute; respiratory rate, 12 breaths/minute; temperature, 98.4°F. Oxygen saturation was 94% on room air. She was diaphoretic and tachycardic on physical examination, but her pulmonary, abdominal, and gynecologic examinations were normal. During the examination, she complained of nausea, vomited, and then became increasingly lethargic and confused.
How can this patient’s clinical presentation be explained?
Uterine fibroids are the most common pelvic tumor in women.1 Hysteroscopic myomectomy is a minimally invasive surgical procedure commonly performed to resect submucosal fibroids. The procedure takes about 60 minutes, and is often performed on an outpatient basis under general anesthesia. During the procedure, an electrosurgery device called a resectoscope is inserted through the cervix. The uterine cavity is then distended with a large volume of irrigating solution. Maneuvering the resectoscope, the surgeon then shaves the protruding fibroid layer-by-layer until it aligns with the surrounding myometrium.
Surgical complications of hysteroscopic myomectomy may produce life-threatening effects. Excessive resection of the myometrium may increase blood loss, which can cause chest pain, shortness of breath, diaphoresis, lethargy, and confusion. Uterine perforation may produce hypotension, abdominal pain and distention, infection, and vaginal bleeding.
Venous Thromboembolism
Venous thromboembolism (VTE) is a common postoperative complication, with pulmonary embolism accounting for the most common preventable cause of hospital death in the United States.2 Gynecologic surgery, especially brief procedures, are associated with among the lowest rates of VTE, however, making this an unlikely explanation in this case.3 Additionally, VTE is not expected to produce the neurological findings observed in this patient.
Negative Pressure Pulmonary Edema
An uncommon but life-threatening complication for patients undergoing general anesthesia is negative pressure pulmonary edema, or “postextubation pulmonary edema,” which is estimated to occur in up to 1 in 1,000 procedures involving mechanical ventilation. During extubation, forced inspiration against a closed glottis causes intravascular fluid to be drawn into the interstitial space leading to pulmonary edema.4
Hyponatremia
An unusual but well described complication of endoscopic surgery is hyponatremia from systemic absorption of the irrigating fluid. Fluid overload may result in pulmonary edema, and dilutional hyponatremia may cause altered mental status or seizures.
Case Continuation
A chest X-ray performed after the patient became symptomatic revealed mild bilateral pulmonary edema. Her postoperative laboratory values were: sodium, 112 mEq/L; potassium, 3.3 mEq/L; chloride, 81 mEq/L; bicarbonate, 25 mEq/L; blood urea nitrogen, 18 mg/dL; creatinine, 0.6 mg/dL. Her ammonia level was 24 mmol/L (normal range, 11-35 mmol/L). An endotracheal tube was placed after her level of consciousness declined further. Her neurological examination revealed bilateral fixed and dilated pupils. An emergent computed tomography (CT) scan of the brain revealed severe generalized swelling of the brain.
What is the cause of this patient’s hyponatremia?
Monopolar electrosurgical devices such as the resectoscope cannot be used with electrolyte-containing irrigation fluids (eg, isotonic saline or lactated Ringer’s solution). Nonconductive, nonelectrolyte solutions such as glycine 1.5%, sorbitol 3%, or mannitol 5%, are the most common irrigating fluids employed to dilate the operating field and to wash away debris and blood.5
A dilutional hyponatremia can occur when the irrigating fluid is absorbed systemically. As it was first described following transurethral resection of the prostate procedures in the 1950s, the syndrome is referred to as “TURP” syndrome. Since then, several hundred life-threatening and even fatal cases of TURP syndrome have been reported.6 The syndrome occurs with other operations including transcervical resection of the endometrium (TCRE).5 The irrigating fluid is most frequently absorbed directly into the vascular system when a vein has been severed during the electrosurgery, particularly when the infusion pressure exceeds the venous pressure.6 Additionally, extravasation of the irrigating fluid into the intraperitoneal space can occur after instrument perforation of the uterine wall in TCRE, or via the fallopian tubes.6
What are the signs and symptoms of TURP syndrome?
Mild-to-moderate TURP syndrome occurs in 1% to 8% of TURP procedures performed. Fluid absorption is slightly more common during TCRE, and occurs more often during the resection of fibroids.6 The dilutional hyponatremia can result in brain edema, as well as pharmacological effects specific to the irrigant solutes.
Symptoms of TURP syndrome are primarily neurological, with nausea being the earliest sign of a mild syndrome. A “mini” mental-status test may show transient confusion with smaller absorption volumes.7 As the fluid absorption increases, the hyponatremia worsens, resulting in cerebral edema. This manifests as encephalopathy, which includes disorientation, twitching, and seizures. Hypotension is uncommon, since the fluid is being absorbed intravascularly.6 Shortness of breath, uneasiness, chest pain, and pulmonary edema may develop from systemic fluid overload. The intra-abdominal extravasation of fluid can result in abdominal pain. Other symptoms are specific to the irrigant.
Glycine
Glycine 1.5% is the most common irrigant solution used; as such, it produces the highest incidence of TURP syndrome.8 This solution is hypoosmotic (osmolality of 200 mosm/kg) compared with the normal serum (osmolality of 280 to 296 mosm/kg).5 In addition, glycine may cause visual disturbances.8 The metabolism of glycine produces ammonia, serine, and oxalate (Figure), and 10% of patients who absorb glycine show a marked hyperammonemia, further exacerbating the neurological effects.9,10
Sorbitol and mannitol
Sorbitol and mannitol irrigation fluids are used less frequently than glycine. Sorbitol 3% is metabolized to fructose and glucose, and has an osmolality of 165 mosm/kg.6 When absorbed systemically, sorbitol’s effects are similar to those of glycine, except that it does not induce visual symptoms. Mannitol 5% solution has the advantage of being isosmotic (275 mosm/kg). It is not metabolized and is excreted entirely in the urine. The excretion of mannitol creates an osmotic diuresis, thereby preventing hyponatremia from occurring.9Sorbitol and Mannitol
What are the treatment options for TURP Syndrome? Can it be prevented?
Patients with TURP syndrome in its mildest form can be asymptomatic, but severe cases can be life threatening or fatal. Unlike the treatment for hyponatremia caused by psychogenic polydipsia or the syndrome of inappropriate antidiuretic hormone, which calls for fluid restriction, plasma volume expansion is indicated in TURP syndrome, as hypovolemia and low-cardiac output develop as soon as irrigation is discontinued.
Hypertonic saline is indicated for neurological symptoms, or if the serum sodium concentration is <120mEq/L.6 Although furosemide has been used to treat acute pulmonary edema, no studies support its routine use in the treatment of fluid absorption,6 and its use may aggravate hyponatremia and hypovolemia.
Bipolar electrosurgical systems, unlike monopolar systems, permit the use of electrolyte solutions such as isotonic saline, thereby significantly reducing the risk of hyponatremia. For hysteroscopic procedures, the American College of Obstetricians and Gynecologists recommends the use of an automated fluid pump and monitoring system, thus minimizing the fluid pressure and halting or terminating the procedure before absorption thresholds are exceeded.11
Case Conclusion
The patient was immediately given a 1 mL/kg bolus of hypertonic saline. Two hours later, her serum sodium improved to 114 mEq/L and serum sodium concentration normalized over the next 24 hours. Her cardiovascular and neurological examinations worsened, however, and she required vasopressors. Her pupils remained fixed and dilated, and she lost her corneal and gag reflexes. A repeat CT of the brain showed persistent cerebral edema with signs of herniation, and she did not recover.
Dr Nguyen is a medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.
- Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981;36(4):433-445.
- Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163(14):1711-1717.
- White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90(3):446-455.
- McConkey PP. Postobstructive Pulmonary Oedema—a case series and review. Anaest Intensive Care. 2000;28(1):72-76.
- Charney AN, Hoffman RS. Fluid, Electrolyte, and Acid-Base Principles. In: Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank’s Toxicological Emergencies. 9th ed. New York, NY: McGraw Hill; 2010:249-264.
- Hahn RG. Fluid absorption in endoscopic surgery. Br J Anaesth. 2006;96(1):8-20.
- Nilsson A, Hahn RG. Mental status after transurethral resection of the prostate. Eur Urol. 1994;26(1):1-5.
- Hahn RG. Glycine 1.5% for irrigation should be abandoned. Urol Int. 2013;91(3):249-255.
- Phillips DR, Milim SJ, Nathanson HG, Phillips RE, Haselkorn JS. Preventing hyponatremic encephalopathy: comparison of serum sodium and osmolality during operative hysteroscopy with 5.0% mannitol and 1.5% glycine distention media. J Am Assoc Gynecol Laparosc. 1997;4(5):567-576.
- Ghanem AN, Ward JP. Osmotic and metabolic sequelae of volumetric overload in relation to the TUR syndrome. Br J Urol. 1990;66(1):71-78.
- American College of Obstetricians and Gynecologists. ACOG technology assessment in obstetrics and gynecology, number 4, August 2005: hysteroscopy. Obstet Gynecol. 2005;106(2):439-442.
Case
A 35-year-old woman underwent an elective hysteroscopic myomectomy to remove a symptomatic 2.7-cm uterine leiomyoma. The procedure was uncomplicated, and the patient awoke in the postanesthesia care unit (PACU) in good condition. Two hours later, however, she developed severe shortness of breath and required bilevel positive airway pressure ventilation. Her vital signs in the PACU were: blood pressure (BP), 110/70 mm Hg; heart rate, 90 beats/minute; respiratory rate, 12 breaths/minute; temperature, 98.4°F. Oxygen saturation was 94% on room air. She was diaphoretic and tachycardic on physical examination, but her pulmonary, abdominal, and gynecologic examinations were normal. During the examination, she complained of nausea, vomited, and then became increasingly lethargic and confused.
How can this patient’s clinical presentation be explained?
Uterine fibroids are the most common pelvic tumor in women.1 Hysteroscopic myomectomy is a minimally invasive surgical procedure commonly performed to resect submucosal fibroids. The procedure takes about 60 minutes, and is often performed on an outpatient basis under general anesthesia. During the procedure, an electrosurgery device called a resectoscope is inserted through the cervix. The uterine cavity is then distended with a large volume of irrigating solution. Maneuvering the resectoscope, the surgeon then shaves the protruding fibroid layer-by-layer until it aligns with the surrounding myometrium.
Surgical complications of hysteroscopic myomectomy may produce life-threatening effects. Excessive resection of the myometrium may increase blood loss, which can cause chest pain, shortness of breath, diaphoresis, lethargy, and confusion. Uterine perforation may produce hypotension, abdominal pain and distention, infection, and vaginal bleeding.
Venous Thromboembolism
Venous thromboembolism (VTE) is a common postoperative complication, with pulmonary embolism accounting for the most common preventable cause of hospital death in the United States.2 Gynecologic surgery, especially brief procedures, are associated with among the lowest rates of VTE, however, making this an unlikely explanation in this case.3 Additionally, VTE is not expected to produce the neurological findings observed in this patient.
Negative Pressure Pulmonary Edema
An uncommon but life-threatening complication for patients undergoing general anesthesia is negative pressure pulmonary edema, or “postextubation pulmonary edema,” which is estimated to occur in up to 1 in 1,000 procedures involving mechanical ventilation. During extubation, forced inspiration against a closed glottis causes intravascular fluid to be drawn into the interstitial space leading to pulmonary edema.4
Hyponatremia
An unusual but well described complication of endoscopic surgery is hyponatremia from systemic absorption of the irrigating fluid. Fluid overload may result in pulmonary edema, and dilutional hyponatremia may cause altered mental status or seizures.
Case Continuation
A chest X-ray performed after the patient became symptomatic revealed mild bilateral pulmonary edema. Her postoperative laboratory values were: sodium, 112 mEq/L; potassium, 3.3 mEq/L; chloride, 81 mEq/L; bicarbonate, 25 mEq/L; blood urea nitrogen, 18 mg/dL; creatinine, 0.6 mg/dL. Her ammonia level was 24 mmol/L (normal range, 11-35 mmol/L). An endotracheal tube was placed after her level of consciousness declined further. Her neurological examination revealed bilateral fixed and dilated pupils. An emergent computed tomography (CT) scan of the brain revealed severe generalized swelling of the brain.
What is the cause of this patient’s hyponatremia?
Monopolar electrosurgical devices such as the resectoscope cannot be used with electrolyte-containing irrigation fluids (eg, isotonic saline or lactated Ringer’s solution). Nonconductive, nonelectrolyte solutions such as glycine 1.5%, sorbitol 3%, or mannitol 5%, are the most common irrigating fluids employed to dilate the operating field and to wash away debris and blood.5
A dilutional hyponatremia can occur when the irrigating fluid is absorbed systemically. As it was first described following transurethral resection of the prostate procedures in the 1950s, the syndrome is referred to as “TURP” syndrome. Since then, several hundred life-threatening and even fatal cases of TURP syndrome have been reported.6 The syndrome occurs with other operations including transcervical resection of the endometrium (TCRE).5 The irrigating fluid is most frequently absorbed directly into the vascular system when a vein has been severed during the electrosurgery, particularly when the infusion pressure exceeds the venous pressure.6 Additionally, extravasation of the irrigating fluid into the intraperitoneal space can occur after instrument perforation of the uterine wall in TCRE, or via the fallopian tubes.6
What are the signs and symptoms of TURP syndrome?
Mild-to-moderate TURP syndrome occurs in 1% to 8% of TURP procedures performed. Fluid absorption is slightly more common during TCRE, and occurs more often during the resection of fibroids.6 The dilutional hyponatremia can result in brain edema, as well as pharmacological effects specific to the irrigant solutes.
Symptoms of TURP syndrome are primarily neurological, with nausea being the earliest sign of a mild syndrome. A “mini” mental-status test may show transient confusion with smaller absorption volumes.7 As the fluid absorption increases, the hyponatremia worsens, resulting in cerebral edema. This manifests as encephalopathy, which includes disorientation, twitching, and seizures. Hypotension is uncommon, since the fluid is being absorbed intravascularly.6 Shortness of breath, uneasiness, chest pain, and pulmonary edema may develop from systemic fluid overload. The intra-abdominal extravasation of fluid can result in abdominal pain. Other symptoms are specific to the irrigant.
Glycine
Glycine 1.5% is the most common irrigant solution used; as such, it produces the highest incidence of TURP syndrome.8 This solution is hypoosmotic (osmolality of 200 mosm/kg) compared with the normal serum (osmolality of 280 to 296 mosm/kg).5 In addition, glycine may cause visual disturbances.8 The metabolism of glycine produces ammonia, serine, and oxalate (Figure), and 10% of patients who absorb glycine show a marked hyperammonemia, further exacerbating the neurological effects.9,10
Sorbitol and mannitol
Sorbitol and mannitol irrigation fluids are used less frequently than glycine. Sorbitol 3% is metabolized to fructose and glucose, and has an osmolality of 165 mosm/kg.6 When absorbed systemically, sorbitol’s effects are similar to those of glycine, except that it does not induce visual symptoms. Mannitol 5% solution has the advantage of being isosmotic (275 mosm/kg). It is not metabolized and is excreted entirely in the urine. The excretion of mannitol creates an osmotic diuresis, thereby preventing hyponatremia from occurring.9Sorbitol and Mannitol
What are the treatment options for TURP Syndrome? Can it be prevented?
Patients with TURP syndrome in its mildest form can be asymptomatic, but severe cases can be life threatening or fatal. Unlike the treatment for hyponatremia caused by psychogenic polydipsia or the syndrome of inappropriate antidiuretic hormone, which calls for fluid restriction, plasma volume expansion is indicated in TURP syndrome, as hypovolemia and low-cardiac output develop as soon as irrigation is discontinued.
Hypertonic saline is indicated for neurological symptoms, or if the serum sodium concentration is <120mEq/L.6 Although furosemide has been used to treat acute pulmonary edema, no studies support its routine use in the treatment of fluid absorption,6 and its use may aggravate hyponatremia and hypovolemia.
Bipolar electrosurgical systems, unlike monopolar systems, permit the use of electrolyte solutions such as isotonic saline, thereby significantly reducing the risk of hyponatremia. For hysteroscopic procedures, the American College of Obstetricians and Gynecologists recommends the use of an automated fluid pump and monitoring system, thus minimizing the fluid pressure and halting or terminating the procedure before absorption thresholds are exceeded.11
Case Conclusion
The patient was immediately given a 1 mL/kg bolus of hypertonic saline. Two hours later, her serum sodium improved to 114 mEq/L and serum sodium concentration normalized over the next 24 hours. Her cardiovascular and neurological examinations worsened, however, and she required vasopressors. Her pupils remained fixed and dilated, and she lost her corneal and gag reflexes. A repeat CT of the brain showed persistent cerebral edema with signs of herniation, and she did not recover.
Dr Nguyen is a medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.
Case
A 35-year-old woman underwent an elective hysteroscopic myomectomy to remove a symptomatic 2.7-cm uterine leiomyoma. The procedure was uncomplicated, and the patient awoke in the postanesthesia care unit (PACU) in good condition. Two hours later, however, she developed severe shortness of breath and required bilevel positive airway pressure ventilation. Her vital signs in the PACU were: blood pressure (BP), 110/70 mm Hg; heart rate, 90 beats/minute; respiratory rate, 12 breaths/minute; temperature, 98.4°F. Oxygen saturation was 94% on room air. She was diaphoretic and tachycardic on physical examination, but her pulmonary, abdominal, and gynecologic examinations were normal. During the examination, she complained of nausea, vomited, and then became increasingly lethargic and confused.
How can this patient’s clinical presentation be explained?
Uterine fibroids are the most common pelvic tumor in women.1 Hysteroscopic myomectomy is a minimally invasive surgical procedure commonly performed to resect submucosal fibroids. The procedure takes about 60 minutes, and is often performed on an outpatient basis under general anesthesia. During the procedure, an electrosurgery device called a resectoscope is inserted through the cervix. The uterine cavity is then distended with a large volume of irrigating solution. Maneuvering the resectoscope, the surgeon then shaves the protruding fibroid layer-by-layer until it aligns with the surrounding myometrium.
Surgical complications of hysteroscopic myomectomy may produce life-threatening effects. Excessive resection of the myometrium may increase blood loss, which can cause chest pain, shortness of breath, diaphoresis, lethargy, and confusion. Uterine perforation may produce hypotension, abdominal pain and distention, infection, and vaginal bleeding.
Venous Thromboembolism
Venous thromboembolism (VTE) is a common postoperative complication, with pulmonary embolism accounting for the most common preventable cause of hospital death in the United States.2 Gynecologic surgery, especially brief procedures, are associated with among the lowest rates of VTE, however, making this an unlikely explanation in this case.3 Additionally, VTE is not expected to produce the neurological findings observed in this patient.
Negative Pressure Pulmonary Edema
An uncommon but life-threatening complication for patients undergoing general anesthesia is negative pressure pulmonary edema, or “postextubation pulmonary edema,” which is estimated to occur in up to 1 in 1,000 procedures involving mechanical ventilation. During extubation, forced inspiration against a closed glottis causes intravascular fluid to be drawn into the interstitial space leading to pulmonary edema.4
Hyponatremia
An unusual but well described complication of endoscopic surgery is hyponatremia from systemic absorption of the irrigating fluid. Fluid overload may result in pulmonary edema, and dilutional hyponatremia may cause altered mental status or seizures.
Case Continuation
A chest X-ray performed after the patient became symptomatic revealed mild bilateral pulmonary edema. Her postoperative laboratory values were: sodium, 112 mEq/L; potassium, 3.3 mEq/L; chloride, 81 mEq/L; bicarbonate, 25 mEq/L; blood urea nitrogen, 18 mg/dL; creatinine, 0.6 mg/dL. Her ammonia level was 24 mmol/L (normal range, 11-35 mmol/L). An endotracheal tube was placed after her level of consciousness declined further. Her neurological examination revealed bilateral fixed and dilated pupils. An emergent computed tomography (CT) scan of the brain revealed severe generalized swelling of the brain.
What is the cause of this patient’s hyponatremia?
Monopolar electrosurgical devices such as the resectoscope cannot be used with electrolyte-containing irrigation fluids (eg, isotonic saline or lactated Ringer’s solution). Nonconductive, nonelectrolyte solutions such as glycine 1.5%, sorbitol 3%, or mannitol 5%, are the most common irrigating fluids employed to dilate the operating field and to wash away debris and blood.5
A dilutional hyponatremia can occur when the irrigating fluid is absorbed systemically. As it was first described following transurethral resection of the prostate procedures in the 1950s, the syndrome is referred to as “TURP” syndrome. Since then, several hundred life-threatening and even fatal cases of TURP syndrome have been reported.6 The syndrome occurs with other operations including transcervical resection of the endometrium (TCRE).5 The irrigating fluid is most frequently absorbed directly into the vascular system when a vein has been severed during the electrosurgery, particularly when the infusion pressure exceeds the venous pressure.6 Additionally, extravasation of the irrigating fluid into the intraperitoneal space can occur after instrument perforation of the uterine wall in TCRE, or via the fallopian tubes.6
What are the signs and symptoms of TURP syndrome?
Mild-to-moderate TURP syndrome occurs in 1% to 8% of TURP procedures performed. Fluid absorption is slightly more common during TCRE, and occurs more often during the resection of fibroids.6 The dilutional hyponatremia can result in brain edema, as well as pharmacological effects specific to the irrigant solutes.
Symptoms of TURP syndrome are primarily neurological, with nausea being the earliest sign of a mild syndrome. A “mini” mental-status test may show transient confusion with smaller absorption volumes.7 As the fluid absorption increases, the hyponatremia worsens, resulting in cerebral edema. This manifests as encephalopathy, which includes disorientation, twitching, and seizures. Hypotension is uncommon, since the fluid is being absorbed intravascularly.6 Shortness of breath, uneasiness, chest pain, and pulmonary edema may develop from systemic fluid overload. The intra-abdominal extravasation of fluid can result in abdominal pain. Other symptoms are specific to the irrigant.
Glycine
Glycine 1.5% is the most common irrigant solution used; as such, it produces the highest incidence of TURP syndrome.8 This solution is hypoosmotic (osmolality of 200 mosm/kg) compared with the normal serum (osmolality of 280 to 296 mosm/kg).5 In addition, glycine may cause visual disturbances.8 The metabolism of glycine produces ammonia, serine, and oxalate (Figure), and 10% of patients who absorb glycine show a marked hyperammonemia, further exacerbating the neurological effects.9,10
Sorbitol and mannitol
Sorbitol and mannitol irrigation fluids are used less frequently than glycine. Sorbitol 3% is metabolized to fructose and glucose, and has an osmolality of 165 mosm/kg.6 When absorbed systemically, sorbitol’s effects are similar to those of glycine, except that it does not induce visual symptoms. Mannitol 5% solution has the advantage of being isosmotic (275 mosm/kg). It is not metabolized and is excreted entirely in the urine. The excretion of mannitol creates an osmotic diuresis, thereby preventing hyponatremia from occurring.9Sorbitol and Mannitol
What are the treatment options for TURP Syndrome? Can it be prevented?
Patients with TURP syndrome in its mildest form can be asymptomatic, but severe cases can be life threatening or fatal. Unlike the treatment for hyponatremia caused by psychogenic polydipsia or the syndrome of inappropriate antidiuretic hormone, which calls for fluid restriction, plasma volume expansion is indicated in TURP syndrome, as hypovolemia and low-cardiac output develop as soon as irrigation is discontinued.
Hypertonic saline is indicated for neurological symptoms, or if the serum sodium concentration is <120mEq/L.6 Although furosemide has been used to treat acute pulmonary edema, no studies support its routine use in the treatment of fluid absorption,6 and its use may aggravate hyponatremia and hypovolemia.
Bipolar electrosurgical systems, unlike monopolar systems, permit the use of electrolyte solutions such as isotonic saline, thereby significantly reducing the risk of hyponatremia. For hysteroscopic procedures, the American College of Obstetricians and Gynecologists recommends the use of an automated fluid pump and monitoring system, thus minimizing the fluid pressure and halting or terminating the procedure before absorption thresholds are exceeded.11
Case Conclusion
The patient was immediately given a 1 mL/kg bolus of hypertonic saline. Two hours later, her serum sodium improved to 114 mEq/L and serum sodium concentration normalized over the next 24 hours. Her cardiovascular and neurological examinations worsened, however, and she required vasopressors. Her pupils remained fixed and dilated, and she lost her corneal and gag reflexes. A repeat CT of the brain showed persistent cerebral edema with signs of herniation, and she did not recover.
Dr Nguyen is a medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.
- Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981;36(4):433-445.
- Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163(14):1711-1717.
- White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90(3):446-455.
- McConkey PP. Postobstructive Pulmonary Oedema—a case series and review. Anaest Intensive Care. 2000;28(1):72-76.
- Charney AN, Hoffman RS. Fluid, Electrolyte, and Acid-Base Principles. In: Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank’s Toxicological Emergencies. 9th ed. New York, NY: McGraw Hill; 2010:249-264.
- Hahn RG. Fluid absorption in endoscopic surgery. Br J Anaesth. 2006;96(1):8-20.
- Nilsson A, Hahn RG. Mental status after transurethral resection of the prostate. Eur Urol. 1994;26(1):1-5.
- Hahn RG. Glycine 1.5% for irrigation should be abandoned. Urol Int. 2013;91(3):249-255.
- Phillips DR, Milim SJ, Nathanson HG, Phillips RE, Haselkorn JS. Preventing hyponatremic encephalopathy: comparison of serum sodium and osmolality during operative hysteroscopy with 5.0% mannitol and 1.5% glycine distention media. J Am Assoc Gynecol Laparosc. 1997;4(5):567-576.
- Ghanem AN, Ward JP. Osmotic and metabolic sequelae of volumetric overload in relation to the TUR syndrome. Br J Urol. 1990;66(1):71-78.
- American College of Obstetricians and Gynecologists. ACOG technology assessment in obstetrics and gynecology, number 4, August 2005: hysteroscopy. Obstet Gynecol. 2005;106(2):439-442.
- Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981;36(4):433-445.
- Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163(14):1711-1717.
- White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90(3):446-455.
- McConkey PP. Postobstructive Pulmonary Oedema—a case series and review. Anaest Intensive Care. 2000;28(1):72-76.
- Charney AN, Hoffman RS. Fluid, Electrolyte, and Acid-Base Principles. In: Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank’s Toxicological Emergencies. 9th ed. New York, NY: McGraw Hill; 2010:249-264.
- Hahn RG. Fluid absorption in endoscopic surgery. Br J Anaesth. 2006;96(1):8-20.
- Nilsson A, Hahn RG. Mental status after transurethral resection of the prostate. Eur Urol. 1994;26(1):1-5.
- Hahn RG. Glycine 1.5% for irrigation should be abandoned. Urol Int. 2013;91(3):249-255.
- Phillips DR, Milim SJ, Nathanson HG, Phillips RE, Haselkorn JS. Preventing hyponatremic encephalopathy: comparison of serum sodium and osmolality during operative hysteroscopy with 5.0% mannitol and 1.5% glycine distention media. J Am Assoc Gynecol Laparosc. 1997;4(5):567-576.
- Ghanem AN, Ward JP. Osmotic and metabolic sequelae of volumetric overload in relation to the TUR syndrome. Br J Urol. 1990;66(1):71-78.
- American College of Obstetricians and Gynecologists. ACOG technology assessment in obstetrics and gynecology, number 4, August 2005: hysteroscopy. Obstet Gynecol. 2005;106(2):439-442.
Clostridium Perfringens Septicemia: A Critical Emergency Department Identification
Intravascular hemolysis in the presence of infection should prompt emergency physicians (EPs) to consider Clostridium perfringens septicemia and to act quickly to treat the infection. C perfringens septicemia is a rare, rapidly fatal disease with a reported mortality rate of at least 70%.1 Its expeditious lethality is due to a combination 7-minute doubling time of the organism and its production of a multitude of virulent toxins.1
This disease is deceptive: Patients may not appear to be severely ill and may be hemodynamically stable, not meeting systemic inflammatory response syndrome (SIRS) criteria, yet they rapidly decompensate. No interventions have been shown to reliably change outcome; however, the best hope for survival lays in early identification and definitive treatment with intravenous (IV) antibiotics and surgical intervention for source control. The authors present a fatal ED case of massive acute intravascular hemolysis due to C perfringens septicemia, the result of a cryptic liver abscess.
Case
A 74-year-old man with noninsulin-dependent diabetes mellitus (DM) and hypertension was transferred from an outside hospital to a tertiary-care referral center for leukocytosis and hyperbilirubinemia, where he had presented with fatigue and jaundice. A year prior, he had a cholecystectomy complicated by accidental hepatic artery ligation necessitating biliary tract reconstruction, but had been well since that event.
At the outside hospital, blood tests revealed a white blood cell (WBC) count of 21.0 x 109/L and elevated values on liver function tests with an elevated indirect hyperbilirubinemia. A right upper quadrant ultrasound showed a poorly defined hyperechoic mass behind the liver, but no bile-duct dilation or stones.
On arrival, the patient’s vital signs were: temperature, 100.4°F; heart rate, 92 beats/minute; blood pressure, 187/98 mm Hg; respiratory rate, 18 breaths/minute. His oxygen saturation was 97% on room air. An electrocardiogram showed sinus rhythm with a nonspecific intraventricular conduction delay with strain pattern. He was awake, comfortable, and conversant and oriented to place and person, but not to time. He was markedly jaundiced with scleral icterus, dry mucosal membranes, and foul breath. His neck was supple and nontender. His heart had a regular rate and rhythm, without murmur, rubs, or gallops, and his lungs were bilaterally clear to auscultation. The patient’s obese abdomen was soft and nontender, without rebound or guarding. He moved in a coordinated manner, and had no clonus or asterixis.
Repeat laboratory evaluation revealed a WBC of 32.2 x109/L, an elevated troponin level of 0.30 ng/mL, and an increased brain natriuretic peptide (BNP) of 636.2 pg/mL. Prothrombin time (PT) and international normalized ratio (INR) were normal. The chemistry test was reported as hemolyzed. Blood samples were redrawn three additional times, but each time the laboratory reported that each sample appeared progressively more hemolyzed and they were unable to obtain testable serum (Figure 1).
During his ED workup, the patient became more pale and jaundiced and began to produce bright red urine. The authors suspected that his hemolyzed blood samples were not due to blood draw artifact, but to intravascular hemolysis. A review of the blood smear showed gram-positive positive bacilli and ghost cells, commonly observed in hemolysis. Repeat laboratory tests showed interval increases in partial thromboplastin time, PT, and INR, and a D-dimer value of 3,621 ng/mL. Fibrinogen could not be measured due to gross hemolysis.
Empiric IV vancomycin and piperacillin/tazobactam were administered, and computed tomography (CT) studies of the brain and abdomen were ordered. The CT of the brain was normal; however, CT of the abdomen revealed an air-filled abscess in the right hepatic lobe and air in the left hepatic lobe and biliary tree without biliary dilation or wall thickening (Figure 2).
After discussion with cardiology, the medical intensive care team, and general surgery services, the patient was admitted to the surgical intensive care unit (SICU) with a plan to percutaneously drain the abscess the next morning.
Six and a half hours after arriving at the ED, the patient became acutely confused, tachypneic (RR, 22 breaths/minute) and tachycardic (HR, 102 beats/minute). On arrival to the SICU, he became unresponsive and pulseless. Resuscitation attempts were unsuccessful and the patient died.
Discussion
C perfringens is an anaerobic gram-positive bacillus known for causing gas gangrene and is normally found in the human gastrointestinal (GI) and genital tracts. Individuals most at risk for C perfringens septicemia have underlying hepatobiliary or genitourinary tract disease, malignancy, immunosuppression, DM, or recent history of GI or genitourinary surgery.2,3
Hemolysis has been observed in 7% to 15% of C perfringens bacteremias.3 This is caused by C perfringens’ primary toxin, phospholipase C lecithinase (α-toxin), which splits lecithin in the red blood-cell membrane thereby damaging its structural integrity and causing hemolysis.4 Other virulent factors of C perfringens are β-, ε-, and τ- toxins, all of which cause capillary leakage by damaging the vascular endothelium.5
Hemolysis with signs of septic shock due to C perfringens infection has been almost invariably fatal in several small case series reviews.2,3 While definitive identification of C perfringens is often delayed, it may be identified on gram stain; a DNA polymerase chain reaction (PCR) test has been developed, but is not widely available.6
The deceptive severity of this patient’s illness is a hallmark of C perfringens sepsis. Many patients may appear calm and report they feel “fine.” This lack of concern, “la belle indifférence,” is also seen in patients with necrotizing soft-tissue infections.7
Patients may be hemodynamically normal or fail to meet SIRS criteria. Case series have revealed no difference in SIRS criteria between survivors and nonsurvivors of C perfringens septicemia2; however, survivors were observed to have higher plasma fibrinogen levels than nonsurvivors.2 Fibrinogen, which is a known risk factor for the development of shock,8 may be a useful prognostic indicator given the association between shock and death in C perfringens septicemia.2
These factors were evident in this case. During the first 5 hours in the ED, the patient was hemodynamically normal, meeting only one of the SIRS criteria (elevated WBC). He also exhibited a nonchalant attitude, saying he “felt fine” before his rapid decline and death. Although fibrinogen was not available, this case is a clear reminder that exclusive use of SIRS criteria and patient reporting as barometers for severity of illness can be misleading.
Treatment
First-line treatment for C Perfringens includes high-dose IV penicillin G (10-24 million units daily), clindamycin for suppression of toxin synthesis, and surgical debridement.1,10 Second-line antibiotics include penicillin derivatives, chloramphenicol, doxycycline, carbapenems, tetracycline, and metronidazole.10,11
Immediate surgical intervention may be needed for survival. Limited review studies from Tokyo and the Netherlands indicate that surgical intervention is a strong prognostic indicator of survival and should be pursued expediently.2,3 A Dutch review 3 of 40 cases in the English medical literature published since 1990 demonstrated an overall mortality rate of 80% (32 of 40 patients). Among eight patients who had a surgical intervention (eg, hysterectomy, drainage of liver abscess) two deaths (25%) occurred. Those patients medically managed had a mortality rate of 93.7% (30/32 patients). While there is an impressive difference between these two groups—the authors assert a relative risk of mortality with surgical intervention of 0.27 (95% CI 0.08 to 0.89)—they are incomparable as many individuals in the medically managed group were not candidates for surgical intervention due to multiorgan failure or death prior to diagnosis.
While the strength of evidence for the efficacy of other interventions is limited, observational data suggest novel interventions are worth considering in an attempt to save these patients. Hyperbaric oxygen therapy has been used with some success in combination with surgery for gas gangrene and necrotizing soft-tissue infections; a few observational studies have shown benefit in sepsis.11 In the setting of massive hemolysis, blood transfusion may be required.12 If hemolysis is caught in early stages, exchange transfusion may prevent further complications.13 The α-toxin antitoxin, historically used for gas gangrene, has been abandoned in the United States due to severe allergic reactions and poor efficacy.14 However, researchers in Japan are investigating the efficacy of antitoxin for C perfringens liver abscesses when multiorgan failure prohibits surgical intervention.15
Conclusion
C perfringens septicemia should be considered when intravascular hemolysis is encountered, even in patients not meeting SIRS criteria. Treatment with appropriate antibiotics and an expedited search for a source (with subsequent immediate intervention) must be initiated prior to onset of shock if there is any hope of survival. If C perfringens septicemia is suspected, clear communication with family members and consultants about the seriousness of the patient’s condition is of the upmost importance as all parties involved must be made aware of the aggressive and unrelenting course of this disease and high likelihood of death.
Dr Samuels is a third-year resident in the department of emergency medicine at Brown University, Providence, Rhode Island. Dr Hack is the division director of medical toxicology at the University of Emergency Medicine Foundation; director of the educational program in medical toxicology and an associate professor at Warren Alpert Medical School; and an attending physician in the department of emergency medicine at Brown University, Rhode Island Hospital, Miriam Hospital, Providence.
- Law ST, Lee MK. A middle-aged lady with a pyogenic liver abscess caused by Clostridium perfringens. World J Hepatol. 2012;4(8):252-255.
- Fujita H, Nishimura S, Kurosawa S, Akiya I, Nakamura-Uchiyama F, Ohnishi K. Clinical and epidemiological features of Clostridium perfringens bacteremia: a review of 18 cases over 8 year-period in a tertiary care center in metropolitan Tokyo area in Japan. Intern Med. 2010;49(22):2433-2437.
- van Bunderen CC, Bomers MK, Wesdorp E, Peerbooms P, Veenstra J. Clostridium perfringens septicaemia with massive intravascular haemolysis: a case report and review of the literature. Neth J Med. 2010;68(9):343-346.
- Hübl W, Mostbeck B, Hartleb H, Pointner H, Kofler K, Bayer PM. Investigation of the pathogenesis of massive hemolysis in a case of Clostridium perfringens septicemia. Ann Hematol. 1993;67(3):145-147.
- Hatheway CL. Toxigenic clostridia. Clin Microbiol Rev. 1990;3(1):66-98.
- Bhatnagar J, Deleon-Carnes M, Kellar KL, et al. Rapid, simultaneous detection of Clostridium sordellii and Clostridium perfringens in archived tissues by a novel PCR-based microsphere assay: diagnostic implications for pregnancy-associated toxic shock syndrome cases. Infect Dis Obstet Gynecol. 2012;2012:972845.
- Herbert M and Swadron S. Necrotizing Fasciitis [Audio Podcast]. January 2009. Emergency Medicine: Reviews and Perspectives. EM:RAP Web site. http://www.emrap.org/episode/2009/january/necrotizing. Accessed November 1, 2013.
- Lissalde-Lavigne G1, Combescure C, Muller L, et al. Simple coagulation tests improve survival reduction in patients with septic shock. J Thromb Haemost. 2008;6(4):645-653.
- Stevens DL, Maier KA, Mitten JE. Effect of antibiotics on toxin production and viability of Clostridium perfringens. Antimicrob Agents Chemother. 1987;31(2):213-218.
- Clostridium perfringens. (2012) In: Chambers HF, Eliopoulos GM, eds. The Sanford Guide to Antimicrobial Therapy. v2.02 for Android [Mobile application software]. Sperryville, VA: Antimicrobial Therapy, Inc. Retrieved from http://www.sanfordguide.com/publications/the-sanford-guide-to-antimicrobial-therapy/mobile-applications.
- Rajendran G, Bothma P, Brodbeck A. Intravascular haemolysis and septicaemia due to Clostridium perfringens liver abscess. Anaesth Intensive Care. 2010;38(5):942-945.
- Watt J, Amini A, Mosier J, et al. Treatment of severe hemolytic anemia caused by Clostridium perfringens sepsis in a liver transplant recipient. Surg Infect. (Larchmont). 2012;13(1):60-62.
- Rubenberg ML, Baker LR, McBride JA, Sevitt LH, Brain MC. Intravascular coagulation in a case of Clostridium perfringens septicaemia: treatment by exchange transfusion and heparin. Br Med J. 1967;4(5574):271-274.
- Lober B. Gas gangrene and other clostridium associated diseases. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2000:2549-2561.
- Hifumi T, Koido Y, Takahashi M, Yamamoto A. Antitoxin treatment for liver abscess caused by Clostridium perfringens. Clin Mol Hepatol. 2013;19(1):97-98.
Intravascular hemolysis in the presence of infection should prompt emergency physicians (EPs) to consider Clostridium perfringens septicemia and to act quickly to treat the infection. C perfringens septicemia is a rare, rapidly fatal disease with a reported mortality rate of at least 70%.1 Its expeditious lethality is due to a combination 7-minute doubling time of the organism and its production of a multitude of virulent toxins.1
This disease is deceptive: Patients may not appear to be severely ill and may be hemodynamically stable, not meeting systemic inflammatory response syndrome (SIRS) criteria, yet they rapidly decompensate. No interventions have been shown to reliably change outcome; however, the best hope for survival lays in early identification and definitive treatment with intravenous (IV) antibiotics and surgical intervention for source control. The authors present a fatal ED case of massive acute intravascular hemolysis due to C perfringens septicemia, the result of a cryptic liver abscess.
Case
A 74-year-old man with noninsulin-dependent diabetes mellitus (DM) and hypertension was transferred from an outside hospital to a tertiary-care referral center for leukocytosis and hyperbilirubinemia, where he had presented with fatigue and jaundice. A year prior, he had a cholecystectomy complicated by accidental hepatic artery ligation necessitating biliary tract reconstruction, but had been well since that event.
At the outside hospital, blood tests revealed a white blood cell (WBC) count of 21.0 x 109/L and elevated values on liver function tests with an elevated indirect hyperbilirubinemia. A right upper quadrant ultrasound showed a poorly defined hyperechoic mass behind the liver, but no bile-duct dilation or stones.
On arrival, the patient’s vital signs were: temperature, 100.4°F; heart rate, 92 beats/minute; blood pressure, 187/98 mm Hg; respiratory rate, 18 breaths/minute. His oxygen saturation was 97% on room air. An electrocardiogram showed sinus rhythm with a nonspecific intraventricular conduction delay with strain pattern. He was awake, comfortable, and conversant and oriented to place and person, but not to time. He was markedly jaundiced with scleral icterus, dry mucosal membranes, and foul breath. His neck was supple and nontender. His heart had a regular rate and rhythm, without murmur, rubs, or gallops, and his lungs were bilaterally clear to auscultation. The patient’s obese abdomen was soft and nontender, without rebound or guarding. He moved in a coordinated manner, and had no clonus or asterixis.
Repeat laboratory evaluation revealed a WBC of 32.2 x109/L, an elevated troponin level of 0.30 ng/mL, and an increased brain natriuretic peptide (BNP) of 636.2 pg/mL. Prothrombin time (PT) and international normalized ratio (INR) were normal. The chemistry test was reported as hemolyzed. Blood samples were redrawn three additional times, but each time the laboratory reported that each sample appeared progressively more hemolyzed and they were unable to obtain testable serum (Figure 1).
During his ED workup, the patient became more pale and jaundiced and began to produce bright red urine. The authors suspected that his hemolyzed blood samples were not due to blood draw artifact, but to intravascular hemolysis. A review of the blood smear showed gram-positive positive bacilli and ghost cells, commonly observed in hemolysis. Repeat laboratory tests showed interval increases in partial thromboplastin time, PT, and INR, and a D-dimer value of 3,621 ng/mL. Fibrinogen could not be measured due to gross hemolysis.
Empiric IV vancomycin and piperacillin/tazobactam were administered, and computed tomography (CT) studies of the brain and abdomen were ordered. The CT of the brain was normal; however, CT of the abdomen revealed an air-filled abscess in the right hepatic lobe and air in the left hepatic lobe and biliary tree without biliary dilation or wall thickening (Figure 2).
After discussion with cardiology, the medical intensive care team, and general surgery services, the patient was admitted to the surgical intensive care unit (SICU) with a plan to percutaneously drain the abscess the next morning.
Six and a half hours after arriving at the ED, the patient became acutely confused, tachypneic (RR, 22 breaths/minute) and tachycardic (HR, 102 beats/minute). On arrival to the SICU, he became unresponsive and pulseless. Resuscitation attempts were unsuccessful and the patient died.
Discussion
C perfringens is an anaerobic gram-positive bacillus known for causing gas gangrene and is normally found in the human gastrointestinal (GI) and genital tracts. Individuals most at risk for C perfringens septicemia have underlying hepatobiliary or genitourinary tract disease, malignancy, immunosuppression, DM, or recent history of GI or genitourinary surgery.2,3
Hemolysis has been observed in 7% to 15% of C perfringens bacteremias.3 This is caused by C perfringens’ primary toxin, phospholipase C lecithinase (α-toxin), which splits lecithin in the red blood-cell membrane thereby damaging its structural integrity and causing hemolysis.4 Other virulent factors of C perfringens are β-, ε-, and τ- toxins, all of which cause capillary leakage by damaging the vascular endothelium.5
Hemolysis with signs of septic shock due to C perfringens infection has been almost invariably fatal in several small case series reviews.2,3 While definitive identification of C perfringens is often delayed, it may be identified on gram stain; a DNA polymerase chain reaction (PCR) test has been developed, but is not widely available.6
The deceptive severity of this patient’s illness is a hallmark of C perfringens sepsis. Many patients may appear calm and report they feel “fine.” This lack of concern, “la belle indifférence,” is also seen in patients with necrotizing soft-tissue infections.7
Patients may be hemodynamically normal or fail to meet SIRS criteria. Case series have revealed no difference in SIRS criteria between survivors and nonsurvivors of C perfringens septicemia2; however, survivors were observed to have higher plasma fibrinogen levels than nonsurvivors.2 Fibrinogen, which is a known risk factor for the development of shock,8 may be a useful prognostic indicator given the association between shock and death in C perfringens septicemia.2
These factors were evident in this case. During the first 5 hours in the ED, the patient was hemodynamically normal, meeting only one of the SIRS criteria (elevated WBC). He also exhibited a nonchalant attitude, saying he “felt fine” before his rapid decline and death. Although fibrinogen was not available, this case is a clear reminder that exclusive use of SIRS criteria and patient reporting as barometers for severity of illness can be misleading.
Treatment
First-line treatment for C Perfringens includes high-dose IV penicillin G (10-24 million units daily), clindamycin for suppression of toxin synthesis, and surgical debridement.1,10 Second-line antibiotics include penicillin derivatives, chloramphenicol, doxycycline, carbapenems, tetracycline, and metronidazole.10,11
Immediate surgical intervention may be needed for survival. Limited review studies from Tokyo and the Netherlands indicate that surgical intervention is a strong prognostic indicator of survival and should be pursued expediently.2,3 A Dutch review 3 of 40 cases in the English medical literature published since 1990 demonstrated an overall mortality rate of 80% (32 of 40 patients). Among eight patients who had a surgical intervention (eg, hysterectomy, drainage of liver abscess) two deaths (25%) occurred. Those patients medically managed had a mortality rate of 93.7% (30/32 patients). While there is an impressive difference between these two groups—the authors assert a relative risk of mortality with surgical intervention of 0.27 (95% CI 0.08 to 0.89)—they are incomparable as many individuals in the medically managed group were not candidates for surgical intervention due to multiorgan failure or death prior to diagnosis.
While the strength of evidence for the efficacy of other interventions is limited, observational data suggest novel interventions are worth considering in an attempt to save these patients. Hyperbaric oxygen therapy has been used with some success in combination with surgery for gas gangrene and necrotizing soft-tissue infections; a few observational studies have shown benefit in sepsis.11 In the setting of massive hemolysis, blood transfusion may be required.12 If hemolysis is caught in early stages, exchange transfusion may prevent further complications.13 The α-toxin antitoxin, historically used for gas gangrene, has been abandoned in the United States due to severe allergic reactions and poor efficacy.14 However, researchers in Japan are investigating the efficacy of antitoxin for C perfringens liver abscesses when multiorgan failure prohibits surgical intervention.15
Conclusion
C perfringens septicemia should be considered when intravascular hemolysis is encountered, even in patients not meeting SIRS criteria. Treatment with appropriate antibiotics and an expedited search for a source (with subsequent immediate intervention) must be initiated prior to onset of shock if there is any hope of survival. If C perfringens septicemia is suspected, clear communication with family members and consultants about the seriousness of the patient’s condition is of the upmost importance as all parties involved must be made aware of the aggressive and unrelenting course of this disease and high likelihood of death.
Dr Samuels is a third-year resident in the department of emergency medicine at Brown University, Providence, Rhode Island. Dr Hack is the division director of medical toxicology at the University of Emergency Medicine Foundation; director of the educational program in medical toxicology and an associate professor at Warren Alpert Medical School; and an attending physician in the department of emergency medicine at Brown University, Rhode Island Hospital, Miriam Hospital, Providence.
Intravascular hemolysis in the presence of infection should prompt emergency physicians (EPs) to consider Clostridium perfringens septicemia and to act quickly to treat the infection. C perfringens septicemia is a rare, rapidly fatal disease with a reported mortality rate of at least 70%.1 Its expeditious lethality is due to a combination 7-minute doubling time of the organism and its production of a multitude of virulent toxins.1
This disease is deceptive: Patients may not appear to be severely ill and may be hemodynamically stable, not meeting systemic inflammatory response syndrome (SIRS) criteria, yet they rapidly decompensate. No interventions have been shown to reliably change outcome; however, the best hope for survival lays in early identification and definitive treatment with intravenous (IV) antibiotics and surgical intervention for source control. The authors present a fatal ED case of massive acute intravascular hemolysis due to C perfringens septicemia, the result of a cryptic liver abscess.
Case
A 74-year-old man with noninsulin-dependent diabetes mellitus (DM) and hypertension was transferred from an outside hospital to a tertiary-care referral center for leukocytosis and hyperbilirubinemia, where he had presented with fatigue and jaundice. A year prior, he had a cholecystectomy complicated by accidental hepatic artery ligation necessitating biliary tract reconstruction, but had been well since that event.
At the outside hospital, blood tests revealed a white blood cell (WBC) count of 21.0 x 109/L and elevated values on liver function tests with an elevated indirect hyperbilirubinemia. A right upper quadrant ultrasound showed a poorly defined hyperechoic mass behind the liver, but no bile-duct dilation or stones.
On arrival, the patient’s vital signs were: temperature, 100.4°F; heart rate, 92 beats/minute; blood pressure, 187/98 mm Hg; respiratory rate, 18 breaths/minute. His oxygen saturation was 97% on room air. An electrocardiogram showed sinus rhythm with a nonspecific intraventricular conduction delay with strain pattern. He was awake, comfortable, and conversant and oriented to place and person, but not to time. He was markedly jaundiced with scleral icterus, dry mucosal membranes, and foul breath. His neck was supple and nontender. His heart had a regular rate and rhythm, without murmur, rubs, or gallops, and his lungs were bilaterally clear to auscultation. The patient’s obese abdomen was soft and nontender, without rebound or guarding. He moved in a coordinated manner, and had no clonus or asterixis.
Repeat laboratory evaluation revealed a WBC of 32.2 x109/L, an elevated troponin level of 0.30 ng/mL, and an increased brain natriuretic peptide (BNP) of 636.2 pg/mL. Prothrombin time (PT) and international normalized ratio (INR) were normal. The chemistry test was reported as hemolyzed. Blood samples were redrawn three additional times, but each time the laboratory reported that each sample appeared progressively more hemolyzed and they were unable to obtain testable serum (Figure 1).
During his ED workup, the patient became more pale and jaundiced and began to produce bright red urine. The authors suspected that his hemolyzed blood samples were not due to blood draw artifact, but to intravascular hemolysis. A review of the blood smear showed gram-positive positive bacilli and ghost cells, commonly observed in hemolysis. Repeat laboratory tests showed interval increases in partial thromboplastin time, PT, and INR, and a D-dimer value of 3,621 ng/mL. Fibrinogen could not be measured due to gross hemolysis.
Empiric IV vancomycin and piperacillin/tazobactam were administered, and computed tomography (CT) studies of the brain and abdomen were ordered. The CT of the brain was normal; however, CT of the abdomen revealed an air-filled abscess in the right hepatic lobe and air in the left hepatic lobe and biliary tree without biliary dilation or wall thickening (Figure 2).
After discussion with cardiology, the medical intensive care team, and general surgery services, the patient was admitted to the surgical intensive care unit (SICU) with a plan to percutaneously drain the abscess the next morning.
Six and a half hours after arriving at the ED, the patient became acutely confused, tachypneic (RR, 22 breaths/minute) and tachycardic (HR, 102 beats/minute). On arrival to the SICU, he became unresponsive and pulseless. Resuscitation attempts were unsuccessful and the patient died.
Discussion
C perfringens is an anaerobic gram-positive bacillus known for causing gas gangrene and is normally found in the human gastrointestinal (GI) and genital tracts. Individuals most at risk for C perfringens septicemia have underlying hepatobiliary or genitourinary tract disease, malignancy, immunosuppression, DM, or recent history of GI or genitourinary surgery.2,3
Hemolysis has been observed in 7% to 15% of C perfringens bacteremias.3 This is caused by C perfringens’ primary toxin, phospholipase C lecithinase (α-toxin), which splits lecithin in the red blood-cell membrane thereby damaging its structural integrity and causing hemolysis.4 Other virulent factors of C perfringens are β-, ε-, and τ- toxins, all of which cause capillary leakage by damaging the vascular endothelium.5
Hemolysis with signs of septic shock due to C perfringens infection has been almost invariably fatal in several small case series reviews.2,3 While definitive identification of C perfringens is often delayed, it may be identified on gram stain; a DNA polymerase chain reaction (PCR) test has been developed, but is not widely available.6
The deceptive severity of this patient’s illness is a hallmark of C perfringens sepsis. Many patients may appear calm and report they feel “fine.” This lack of concern, “la belle indifférence,” is also seen in patients with necrotizing soft-tissue infections.7
Patients may be hemodynamically normal or fail to meet SIRS criteria. Case series have revealed no difference in SIRS criteria between survivors and nonsurvivors of C perfringens septicemia2; however, survivors were observed to have higher plasma fibrinogen levels than nonsurvivors.2 Fibrinogen, which is a known risk factor for the development of shock,8 may be a useful prognostic indicator given the association between shock and death in C perfringens septicemia.2
These factors were evident in this case. During the first 5 hours in the ED, the patient was hemodynamically normal, meeting only one of the SIRS criteria (elevated WBC). He also exhibited a nonchalant attitude, saying he “felt fine” before his rapid decline and death. Although fibrinogen was not available, this case is a clear reminder that exclusive use of SIRS criteria and patient reporting as barometers for severity of illness can be misleading.
Treatment
First-line treatment for C Perfringens includes high-dose IV penicillin G (10-24 million units daily), clindamycin for suppression of toxin synthesis, and surgical debridement.1,10 Second-line antibiotics include penicillin derivatives, chloramphenicol, doxycycline, carbapenems, tetracycline, and metronidazole.10,11
Immediate surgical intervention may be needed for survival. Limited review studies from Tokyo and the Netherlands indicate that surgical intervention is a strong prognostic indicator of survival and should be pursued expediently.2,3 A Dutch review 3 of 40 cases in the English medical literature published since 1990 demonstrated an overall mortality rate of 80% (32 of 40 patients). Among eight patients who had a surgical intervention (eg, hysterectomy, drainage of liver abscess) two deaths (25%) occurred. Those patients medically managed had a mortality rate of 93.7% (30/32 patients). While there is an impressive difference between these two groups—the authors assert a relative risk of mortality with surgical intervention of 0.27 (95% CI 0.08 to 0.89)—they are incomparable as many individuals in the medically managed group were not candidates for surgical intervention due to multiorgan failure or death prior to diagnosis.
While the strength of evidence for the efficacy of other interventions is limited, observational data suggest novel interventions are worth considering in an attempt to save these patients. Hyperbaric oxygen therapy has been used with some success in combination with surgery for gas gangrene and necrotizing soft-tissue infections; a few observational studies have shown benefit in sepsis.11 In the setting of massive hemolysis, blood transfusion may be required.12 If hemolysis is caught in early stages, exchange transfusion may prevent further complications.13 The α-toxin antitoxin, historically used for gas gangrene, has been abandoned in the United States due to severe allergic reactions and poor efficacy.14 However, researchers in Japan are investigating the efficacy of antitoxin for C perfringens liver abscesses when multiorgan failure prohibits surgical intervention.15
Conclusion
C perfringens septicemia should be considered when intravascular hemolysis is encountered, even in patients not meeting SIRS criteria. Treatment with appropriate antibiotics and an expedited search for a source (with subsequent immediate intervention) must be initiated prior to onset of shock if there is any hope of survival. If C perfringens septicemia is suspected, clear communication with family members and consultants about the seriousness of the patient’s condition is of the upmost importance as all parties involved must be made aware of the aggressive and unrelenting course of this disease and high likelihood of death.
Dr Samuels is a third-year resident in the department of emergency medicine at Brown University, Providence, Rhode Island. Dr Hack is the division director of medical toxicology at the University of Emergency Medicine Foundation; director of the educational program in medical toxicology and an associate professor at Warren Alpert Medical School; and an attending physician in the department of emergency medicine at Brown University, Rhode Island Hospital, Miriam Hospital, Providence.
- Law ST, Lee MK. A middle-aged lady with a pyogenic liver abscess caused by Clostridium perfringens. World J Hepatol. 2012;4(8):252-255.
- Fujita H, Nishimura S, Kurosawa S, Akiya I, Nakamura-Uchiyama F, Ohnishi K. Clinical and epidemiological features of Clostridium perfringens bacteremia: a review of 18 cases over 8 year-period in a tertiary care center in metropolitan Tokyo area in Japan. Intern Med. 2010;49(22):2433-2437.
- van Bunderen CC, Bomers MK, Wesdorp E, Peerbooms P, Veenstra J. Clostridium perfringens septicaemia with massive intravascular haemolysis: a case report and review of the literature. Neth J Med. 2010;68(9):343-346.
- Hübl W, Mostbeck B, Hartleb H, Pointner H, Kofler K, Bayer PM. Investigation of the pathogenesis of massive hemolysis in a case of Clostridium perfringens septicemia. Ann Hematol. 1993;67(3):145-147.
- Hatheway CL. Toxigenic clostridia. Clin Microbiol Rev. 1990;3(1):66-98.
- Bhatnagar J, Deleon-Carnes M, Kellar KL, et al. Rapid, simultaneous detection of Clostridium sordellii and Clostridium perfringens in archived tissues by a novel PCR-based microsphere assay: diagnostic implications for pregnancy-associated toxic shock syndrome cases. Infect Dis Obstet Gynecol. 2012;2012:972845.
- Herbert M and Swadron S. Necrotizing Fasciitis [Audio Podcast]. January 2009. Emergency Medicine: Reviews and Perspectives. EM:RAP Web site. http://www.emrap.org/episode/2009/january/necrotizing. Accessed November 1, 2013.
- Lissalde-Lavigne G1, Combescure C, Muller L, et al. Simple coagulation tests improve survival reduction in patients with septic shock. J Thromb Haemost. 2008;6(4):645-653.
- Stevens DL, Maier KA, Mitten JE. Effect of antibiotics on toxin production and viability of Clostridium perfringens. Antimicrob Agents Chemother. 1987;31(2):213-218.
- Clostridium perfringens. (2012) In: Chambers HF, Eliopoulos GM, eds. The Sanford Guide to Antimicrobial Therapy. v2.02 for Android [Mobile application software]. Sperryville, VA: Antimicrobial Therapy, Inc. Retrieved from http://www.sanfordguide.com/publications/the-sanford-guide-to-antimicrobial-therapy/mobile-applications.
- Rajendran G, Bothma P, Brodbeck A. Intravascular haemolysis and septicaemia due to Clostridium perfringens liver abscess. Anaesth Intensive Care. 2010;38(5):942-945.
- Watt J, Amini A, Mosier J, et al. Treatment of severe hemolytic anemia caused by Clostridium perfringens sepsis in a liver transplant recipient. Surg Infect. (Larchmont). 2012;13(1):60-62.
- Rubenberg ML, Baker LR, McBride JA, Sevitt LH, Brain MC. Intravascular coagulation in a case of Clostridium perfringens septicaemia: treatment by exchange transfusion and heparin. Br Med J. 1967;4(5574):271-274.
- Lober B. Gas gangrene and other clostridium associated diseases. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2000:2549-2561.
- Hifumi T, Koido Y, Takahashi M, Yamamoto A. Antitoxin treatment for liver abscess caused by Clostridium perfringens. Clin Mol Hepatol. 2013;19(1):97-98.
- Law ST, Lee MK. A middle-aged lady with a pyogenic liver abscess caused by Clostridium perfringens. World J Hepatol. 2012;4(8):252-255.
- Fujita H, Nishimura S, Kurosawa S, Akiya I, Nakamura-Uchiyama F, Ohnishi K. Clinical and epidemiological features of Clostridium perfringens bacteremia: a review of 18 cases over 8 year-period in a tertiary care center in metropolitan Tokyo area in Japan. Intern Med. 2010;49(22):2433-2437.
- van Bunderen CC, Bomers MK, Wesdorp E, Peerbooms P, Veenstra J. Clostridium perfringens septicaemia with massive intravascular haemolysis: a case report and review of the literature. Neth J Med. 2010;68(9):343-346.
- Hübl W, Mostbeck B, Hartleb H, Pointner H, Kofler K, Bayer PM. Investigation of the pathogenesis of massive hemolysis in a case of Clostridium perfringens septicemia. Ann Hematol. 1993;67(3):145-147.
- Hatheway CL. Toxigenic clostridia. Clin Microbiol Rev. 1990;3(1):66-98.
- Bhatnagar J, Deleon-Carnes M, Kellar KL, et al. Rapid, simultaneous detection of Clostridium sordellii and Clostridium perfringens in archived tissues by a novel PCR-based microsphere assay: diagnostic implications for pregnancy-associated toxic shock syndrome cases. Infect Dis Obstet Gynecol. 2012;2012:972845.
- Herbert M and Swadron S. Necrotizing Fasciitis [Audio Podcast]. January 2009. Emergency Medicine: Reviews and Perspectives. EM:RAP Web site. http://www.emrap.org/episode/2009/january/necrotizing. Accessed November 1, 2013.
- Lissalde-Lavigne G1, Combescure C, Muller L, et al. Simple coagulation tests improve survival reduction in patients with septic shock. J Thromb Haemost. 2008;6(4):645-653.
- Stevens DL, Maier KA, Mitten JE. Effect of antibiotics on toxin production and viability of Clostridium perfringens. Antimicrob Agents Chemother. 1987;31(2):213-218.
- Clostridium perfringens. (2012) In: Chambers HF, Eliopoulos GM, eds. The Sanford Guide to Antimicrobial Therapy. v2.02 for Android [Mobile application software]. Sperryville, VA: Antimicrobial Therapy, Inc. Retrieved from http://www.sanfordguide.com/publications/the-sanford-guide-to-antimicrobial-therapy/mobile-applications.
- Rajendran G, Bothma P, Brodbeck A. Intravascular haemolysis and septicaemia due to Clostridium perfringens liver abscess. Anaesth Intensive Care. 2010;38(5):942-945.
- Watt J, Amini A, Mosier J, et al. Treatment of severe hemolytic anemia caused by Clostridium perfringens sepsis in a liver transplant recipient. Surg Infect. (Larchmont). 2012;13(1):60-62.
- Rubenberg ML, Baker LR, McBride JA, Sevitt LH, Brain MC. Intravascular coagulation in a case of Clostridium perfringens septicaemia: treatment by exchange transfusion and heparin. Br Med J. 1967;4(5574):271-274.
- Lober B. Gas gangrene and other clostridium associated diseases. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2000:2549-2561.
- Hifumi T, Koido Y, Takahashi M, Yamamoto A. Antitoxin treatment for liver abscess caused by Clostridium perfringens. Clin Mol Hepatol. 2013;19(1):97-98.
