A 49‐year‐old woman with history of rheumatic fever necessitating mechanical mitral valve replacement and a cerebrovascular accident of presumed embolic etiology presented with several months of progressive fatigue, weakness, arthralgias, and myalgias. After an extensive workup, a rheumatologist in the community diagnosed her with systemic lupus erythematosus and dermatomyositis. The patient refused therapy with corticosteroids and disease‐modifying agents, citing concerns of adverse effects. She consulted a naturopathic clinician, who gave her Rejuvenator Pills, Super Booster pill, Genesis Juice, and alkaline water (Table 1).

Several weeks later, the patient developed dusky erythematous plaques on her anterior and posterior trunk, face, and proximal extremities. Over the next several weeks, she became progressively weak until she was ultimately bedbound. The plaques over her back began to denude. Upon admission to an outside hospital, she was diagnosed with warfarin‐related skin necrosis, superinfected decubitus ulcers, and severe anemia. She refused blood transfusion, and was discharged home with clindamycin and iron. After her clinical status deteriorated over the subsequent week, she arrived at our hospital by ambulance.

In addition to the herbal medications she had recently started, she had been taking warfarin, furosemide, nitroglycerin via skin patch, and aspirin for over 10 years. On exam, she was febrile, tachycardic, hypotensive, and toxic‐appearing. Conjunctivitis was absent. Her mucous membranes were dry, with easily removable white and yellowish deposits on the buccal mucosa. No lesions or ulcerations were present. Dermatologic exam demonstrated confluent scaly, violaceous erythematous patches and plaques covering 60% of the total body surface area with focal areas that were denuded. Large areas of denuded skin were present over the back, inframammary folds, and underneath her abdominal pannus (Figures 1 and 2). Nikolsky's sign was present. She was oriented to person only.

Figure 1

Figure 2

Initial laboratory studies were significant for the following: white blood cell count = 12,800 cells/mm³, hemoglobin = 7.3 g/dL, creatinine = 11.2 mg/dL, blood urea nitrogen = 136 mg/dL, and bicarbonate level = 15 mmol/L. She was admitted to the medical intensive care unit for presumed sepsis. Aggressive resuscitation and broad spectrum antibiotics were administered. A thorough workup for infection, including blood and urine cultures, chest radiography, and lumbar puncture, was unremarkable. Antinuclear antibodies (ANAs) were present in a 1:2560 titer; with a nucleolar and speckled pattern and cytoplasmic antibodies. Additional rheumatologic workup revealed positive anti‐Smith antibody and weakly positive antiribonuclear protein antibody. Pathology from a punch biopsy performed by a dermatology consultant on hospital day 2 demonstrated full‐thickness skin necrosis with scant perivascular infiltrate. While the patient's family had disposed of the pill containers, they had kept several pills. These were sent for analysis, which did not reveal contamination with heavy metals or allopathic medications.

The patient was ultimately diagnosed with TEN and systemic lupus erythematosus with overlap syndrome, and intravenous methylprednisolone was administered. Broad‐spectrum antibiotics were administered for 48 hours, but stopped after workup for infection proved unrevealing. Wound care was mupirocin ointment with petrolatum dressings twice daily as per the hospital's TEN protocol. The patient's course was complicated by acidosis requiring hemodialysis and several tonic‐clonic seizures, a result of presumed lupus cerebritis due to rapidly progressive lesions on serial magnetic resonance images (MRIs) with a negative lumbar puncture. Renal biopsy demonstrated acute tubular necrosis and collapsing glomerulopathy. The patient ultimately recovered, and was discharged to a rehabilitation facility. In follow‐up several months later, she had healing skin with residual dyspigmentation and normal renal function. She was ambulatory and fully oriented, but complained of persistent memory difficulties.

Discussion

While use of complementary or alternative medicine (CAM) is widespread, physicians often underestimate the prevalence of CAM use in their patients. Only one‐half of primary care practitioners are aware of the risk for serious adverse reactions from CAMs.1 This case demonstrates the need for hospitalists to obtain a thorough medication history, including probing for CAM use, when evaluating a new patient. The delayed diagnosis of TEN, whether due to failure to elicit CAM use or recognize the clinical presentation, delayed appropriate treatment by a week and this patient developed potentially lethal complications.

Stevens‐Johnson syndrome (SJS) and TEN lie on a spectrum of disorders involving separation of the epidermis from the dermis when tension is applied to the skin, associated with mucositis, conjunctivitis, and generalized toxicity. The rash is dusky and erythematous, and Nikolsky's sign (separation of the epidermis from the dermis with tension applied to the skin) is present. These entities most commonly develop secondary to medications or infections. Most reactions occur within 60 days of drug initiation. The rash progressives over 1 to 15 days, and the rate of healing is variable. The overall mortality is 30% and is predicted by the SCORTEN system, which incorporates laboratory data, patient history, and the extent of skin breakdown.2 Treatment is primarily supportive; the use of corticosteroids, nonsteroidal immunosuppressive agents, intravenous immunoglobulin (IVIG), or plasmapheresis remains controversial.3

Case reports have described the development of SJS or TEN with CAM use. For example, 1 patient repeatedly developed SJS, with each episode occurring after exposure to an herbal medication containing red clover, burdock, queen's delight, poke root, prickly ash, sassafras bark, and passion flower.4 Similar to our case, identifying the exact agent responsible for TEN was impossible due to large numbers of herbal medications combined into a single pill. SJS and TEN are not limited to Western herbal medicines. Traditional Chinese medications are one of the most common causes of SJS and TEN in East Asia,5 although adulteration with allopathic medications is common in this setting. Ayurvedic medications,6 an ophiopogonis‐containing health drink,7 ginseng,8 and Gingko biloba9, 10 have also been implicated.

Conclusions

This case demonstrates the difficulty in making a diagnosis of CAM‐induced toxicity and identifying the likely agent responsible. Hospitalists must have a high index of suspicion of CAM‐associated toxicity to make this diagnosis, especially when admitting patients who may not volunteer CAM use without direct questioning.

A 49‐year‐old woman with history of rheumatic fever necessitating mechanical mitral valve replacement and a cerebrovascular accident of presumed embolic etiology presented with several months of progressive fatigue, weakness, arthralgias, and myalgias. After an extensive workup, a rheumatologist in the community diagnosed her with systemic lupus erythematosus and dermatomyositis. The patient refused therapy with corticosteroids and disease‐modifying agents, citing concerns of adverse effects. She consulted a naturopathic clinician, who gave her Rejuvenator Pills, Super Booster pill, Genesis Juice, and alkaline water (Table 1).

Several weeks later, the patient developed dusky erythematous plaques on her anterior and posterior trunk, face, and proximal extremities. Over the next several weeks, she became progressively weak until she was ultimately bedbound. The plaques over her back began to denude. Upon admission to an outside hospital, she was diagnosed with warfarin‐related skin necrosis, superinfected decubitus ulcers, and severe anemia. She refused blood transfusion, and was discharged home with clindamycin and iron. After her clinical status deteriorated over the subsequent week, she arrived at our hospital by ambulance.

In addition to the herbal medications she had recently started, she had been taking warfarin, furosemide, nitroglycerin via skin patch, and aspirin for over 10 years. On exam, she was febrile, tachycardic, hypotensive, and toxic‐appearing. Conjunctivitis was absent. Her mucous membranes were dry, with easily removable white and yellowish deposits on the buccal mucosa. No lesions or ulcerations were present. Dermatologic exam demonstrated confluent scaly, violaceous erythematous patches and plaques covering 60% of the total body surface area with focal areas that were denuded. Large areas of denuded skin were present over the back, inframammary folds, and underneath her abdominal pannus (Figures 1 and 2). Nikolsky's sign was present. She was oriented to person only.

Figure 1

Figure 2

Initial laboratory studies were significant for the following: white blood cell count = 12,800 cells/mm³, hemoglobin = 7.3 g/dL, creatinine = 11.2 mg/dL, blood urea nitrogen = 136 mg/dL, and bicarbonate level = 15 mmol/L. She was admitted to the medical intensive care unit for presumed sepsis. Aggressive resuscitation and broad spectrum antibiotics were administered. A thorough workup for infection, including blood and urine cultures, chest radiography, and lumbar puncture, was unremarkable. Antinuclear antibodies (ANAs) were present in a 1:2560 titer; with a nucleolar and speckled pattern and cytoplasmic antibodies. Additional rheumatologic workup revealed positive anti‐Smith antibody and weakly positive antiribonuclear protein antibody. Pathology from a punch biopsy performed by a dermatology consultant on hospital day 2 demonstrated full‐thickness skin necrosis with scant perivascular infiltrate. While the patient's family had disposed of the pill containers, they had kept several pills. These were sent for analysis, which did not reveal contamination with heavy metals or allopathic medications.

The patient was ultimately diagnosed with TEN and systemic lupus erythematosus with overlap syndrome, and intravenous methylprednisolone was administered. Broad‐spectrum antibiotics were administered for 48 hours, but stopped after workup for infection proved unrevealing. Wound care was mupirocin ointment with petrolatum dressings twice daily as per the hospital's TEN protocol. The patient's course was complicated by acidosis requiring hemodialysis and several tonic‐clonic seizures, a result of presumed lupus cerebritis due to rapidly progressive lesions on serial magnetic resonance images (MRIs) with a negative lumbar puncture. Renal biopsy demonstrated acute tubular necrosis and collapsing glomerulopathy. The patient ultimately recovered, and was discharged to a rehabilitation facility. In follow‐up several months later, she had healing skin with residual dyspigmentation and normal renal function. She was ambulatory and fully oriented, but complained of persistent memory difficulties.

Discussion

While use of complementary or alternative medicine (CAM) is widespread, physicians often underestimate the prevalence of CAM use in their patients. Only one‐half of primary care practitioners are aware of the risk for serious adverse reactions from CAMs.1 This case demonstrates the need for hospitalists to obtain a thorough medication history, including probing for CAM use, when evaluating a new patient. The delayed diagnosis of TEN, whether due to failure to elicit CAM use or recognize the clinical presentation, delayed appropriate treatment by a week and this patient developed potentially lethal complications.

Stevens‐Johnson syndrome (SJS) and TEN lie on a spectrum of disorders involving separation of the epidermis from the dermis when tension is applied to the skin, associated with mucositis, conjunctivitis, and generalized toxicity. The rash is dusky and erythematous, and Nikolsky's sign (separation of the epidermis from the dermis with tension applied to the skin) is present. These entities most commonly develop secondary to medications or infections. Most reactions occur within 60 days of drug initiation. The rash progressives over 1 to 15 days, and the rate of healing is variable. The overall mortality is 30% and is predicted by the SCORTEN system, which incorporates laboratory data, patient history, and the extent of skin breakdown.2 Treatment is primarily supportive; the use of corticosteroids, nonsteroidal immunosuppressive agents, intravenous immunoglobulin (IVIG), or plasmapheresis remains controversial.3

Case reports have described the development of SJS or TEN with CAM use. For example, 1 patient repeatedly developed SJS, with each episode occurring after exposure to an herbal medication containing red clover, burdock, queen's delight, poke root, prickly ash, sassafras bark, and passion flower.4 Similar to our case, identifying the exact agent responsible for TEN was impossible due to large numbers of herbal medications combined into a single pill. SJS and TEN are not limited to Western herbal medicines. Traditional Chinese medications are one of the most common causes of SJS and TEN in East Asia,5 although adulteration with allopathic medications is common in this setting. Ayurvedic medications,6 an ophiopogonis‐containing health drink,7 ginseng,8 and Gingko biloba9, 10 have also been implicated.

Conclusions

This case demonstrates the difficulty in making a diagnosis of CAM‐induced toxicity and identifying the likely agent responsible. Hospitalists must have a high index of suspicion of CAM‐associated toxicity to make this diagnosis, especially when admitting patients who may not volunteer CAM use without direct questioning.

A 49‐year‐old woman with history of rheumatic fever necessitating mechanical mitral valve replacement and a cerebrovascular accident of presumed embolic etiology presented with several months of progressive fatigue, weakness, arthralgias, and myalgias. After an extensive workup, a rheumatologist in the community diagnosed her with systemic lupus erythematosus and dermatomyositis. The patient refused therapy with corticosteroids and disease‐modifying agents, citing concerns of adverse effects. She consulted a naturopathic clinician, who gave her Rejuvenator Pills, Super Booster pill, Genesis Juice, and alkaline water (Table 1).

Several weeks later, the patient developed dusky erythematous plaques on her anterior and posterior trunk, face, and proximal extremities. Over the next several weeks, she became progressively weak until she was ultimately bedbound. The plaques over her back began to denude. Upon admission to an outside hospital, she was diagnosed with warfarin‐related skin necrosis, superinfected decubitus ulcers, and severe anemia. She refused blood transfusion, and was discharged home with clindamycin and iron. After her clinical status deteriorated over the subsequent week, she arrived at our hospital by ambulance.

In addition to the herbal medications she had recently started, she had been taking warfarin, furosemide, nitroglycerin via skin patch, and aspirin for over 10 years. On exam, she was febrile, tachycardic, hypotensive, and toxic‐appearing. Conjunctivitis was absent. Her mucous membranes were dry, with easily removable white and yellowish deposits on the buccal mucosa. No lesions or ulcerations were present. Dermatologic exam demonstrated confluent scaly, violaceous erythematous patches and plaques covering 60% of the total body surface area with focal areas that were denuded. Large areas of denuded skin were present over the back, inframammary folds, and underneath her abdominal pannus (Figures 1 and 2). Nikolsky's sign was present. She was oriented to person only.

Figure 1

Figure 2

Initial laboratory studies were significant for the following: white blood cell count = 12,800 cells/mm³, hemoglobin = 7.3 g/dL, creatinine = 11.2 mg/dL, blood urea nitrogen = 136 mg/dL, and bicarbonate level = 15 mmol/L. She was admitted to the medical intensive care unit for presumed sepsis. Aggressive resuscitation and broad spectrum antibiotics were administered. A thorough workup for infection, including blood and urine cultures, chest radiography, and lumbar puncture, was unremarkable. Antinuclear antibodies (ANAs) were present in a 1:2560 titer; with a nucleolar and speckled pattern and cytoplasmic antibodies. Additional rheumatologic workup revealed positive anti‐Smith antibody and weakly positive antiribonuclear protein antibody. Pathology from a punch biopsy performed by a dermatology consultant on hospital day 2 demonstrated full‐thickness skin necrosis with scant perivascular infiltrate. While the patient's family had disposed of the pill containers, they had kept several pills. These were sent for analysis, which did not reveal contamination with heavy metals or allopathic medications.

The patient was ultimately diagnosed with TEN and systemic lupus erythematosus with overlap syndrome, and intravenous methylprednisolone was administered. Broad‐spectrum antibiotics were administered for 48 hours, but stopped after workup for infection proved unrevealing. Wound care was mupirocin ointment with petrolatum dressings twice daily as per the hospital's TEN protocol. The patient's course was complicated by acidosis requiring hemodialysis and several tonic‐clonic seizures, a result of presumed lupus cerebritis due to rapidly progressive lesions on serial magnetic resonance images (MRIs) with a negative lumbar puncture. Renal biopsy demonstrated acute tubular necrosis and collapsing glomerulopathy. The patient ultimately recovered, and was discharged to a rehabilitation facility. In follow‐up several months later, she had healing skin with residual dyspigmentation and normal renal function. She was ambulatory and fully oriented, but complained of persistent memory difficulties.

Discussion

While use of complementary or alternative medicine (CAM) is widespread, physicians often underestimate the prevalence of CAM use in their patients. Only one‐half of primary care practitioners are aware of the risk for serious adverse reactions from CAMs.1 This case demonstrates the need for hospitalists to obtain a thorough medication history, including probing for CAM use, when evaluating a new patient. The delayed diagnosis of TEN, whether due to failure to elicit CAM use or recognize the clinical presentation, delayed appropriate treatment by a week and this patient developed potentially lethal complications.

Stevens‐Johnson syndrome (SJS) and TEN lie on a spectrum of disorders involving separation of the epidermis from the dermis when tension is applied to the skin, associated with mucositis, conjunctivitis, and generalized toxicity. The rash is dusky and erythematous, and Nikolsky's sign (separation of the epidermis from the dermis with tension applied to the skin) is present. These entities most commonly develop secondary to medications or infections. Most reactions occur within 60 days of drug initiation. The rash progressives over 1 to 15 days, and the rate of healing is variable. The overall mortality is 30% and is predicted by the SCORTEN system, which incorporates laboratory data, patient history, and the extent of skin breakdown.2 Treatment is primarily supportive; the use of corticosteroids, nonsteroidal immunosuppressive agents, intravenous immunoglobulin (IVIG), or plasmapheresis remains controversial.3

Case reports have described the development of SJS or TEN with CAM use. For example, 1 patient repeatedly developed SJS, with each episode occurring after exposure to an herbal medication containing red clover, burdock, queen's delight, poke root, prickly ash, sassafras bark, and passion flower.4 Similar to our case, identifying the exact agent responsible for TEN was impossible due to large numbers of herbal medications combined into a single pill. SJS and TEN are not limited to Western herbal medicines. Traditional Chinese medications are one of the most common causes of SJS and TEN in East Asia,5 although adulteration with allopathic medications is common in this setting. Ayurvedic medications,6 an ophiopogonis‐containing health drink,7 ginseng,8 and Gingko biloba9, 10 have also been implicated.

Conclusions

This case demonstrates the difficulty in making a diagnosis of CAM‐induced toxicity and identifying the likely agent responsible. Hospitalists must have a high index of suspicion of CAM‐associated toxicity to make this diagnosis, especially when admitting patients who may not volunteer CAM use without direct questioning.

A 49‐year‐old man with a history of hypertension presented to our hospital with a 2‐week history of sharp pain in the right upper abdomen and right lower chest radiating to the back. The patient reported a few days of fevers, chills, drenching night sweats, shortness of breath, malaise, and fatigue. He denied recent travel. Vital signs were temperature 38.4C, blood pressure 119/74 mmHg, heart rate 95 beats/minutes, respiratory rate 16 breaths/minutes, and oxygen saturation 96% on 5 L nasal cannula. Physical examination revealed poor dentition, right upper abdominal quadrant tenderness, and dullness to percussion over the right lung base.

Initial labs showed white blood count (WBC) 22,540/mm³, alkaline phosphatase 280 units/L, bilirubin 1.1 mg/dL, aspartate aminotransferase (AST) 28 units/L, alanine aminotransferase (ALT) 33 units/L. Blood cultures were negative. An human immunodeficiency virus (HIV)1/HIV2 antibody screen was negative. Computed tomography (CT) of the chest demonstrated a large cystic lesion in the diaphragmatic dome of the liver with multiple lesions in the right lobe of the liver. Elevation of the right hemidiaphragm and moderate right pleural effusion were noted. CT abdomen showed multiple areas of fluid collection within the liver suspicious for liver abscesses (see Figure 1). Multiple gallstones were seen within gallbladder with a large stone in the region of the gallbladder neck vs. cystic duct without evidence of extrahepatic biliary dilatation. There was mild distention of the appendix with minimal soft tissue stranding.

Figure 1

The patient underwent ultrasound‐guided drainage of the largest liver abscess. Cultures from the aspiration grew Fusobacterium nucleatum. The patient's stool studies for ova and parasites were negative. The patient was started on piperacillin/tazobactam and metronidazole, then switched to ertapenem. A hepatobiliary iminodiacetic acid (HIDA) scan confirmed cholecystitis, and the patient underwent open cholecystectomy. Pathology on the gallbladder returned as chronic cholecystitis with cholelithiasis. A full dental examination revealed possible periapical abscesses of teeth #12 and #30 and stringent daily oral hygiene was recommended. Tooth extraction was initially recommended but ultimately postponed. Plans were made for dental follow‐up.

With continued antibiotic treatment, the patient's fevers resolved and leukocytosis improved. A follow‐up CT abdomen/pelvis obtained on hospital day 10 showed a reduction in size of the multiple liver abscesses. There was also increased prominence of the appendix with mild stranding. The patient was taken for appendectomy. Pathology was consistent with acute appendicitis with focal fat necrosis. The patient was ultimately discharged with the plan being to continue ertapenem until radiographic resolution of all the abscesses was demonstrated.

Discussion

Pyogenic liver abscesses are infrequently encountered in the western population, but when present, result in significant morbidity and mortality.1 Mortality rates range from 6% to 31%, decreased from 100% mortality in the preantibiotic era.1 The leading cause of pyogenic liver abscesses has been in the past ascribed to ruptured appendicitis.2 However, biliary tract pathology is now the leading cause, accounting for 43% to 60% of cases.2 In addition, hematogenous seeding of infection from the oral cavity has been recognized in the literature as a potential source of infection in the development of pyogenic liver abscesses.2

The empiric treatment of pyogenic liver abscesses is intravenous broad‐spectrum antibiotics, most commonly metronidazole in combination with quinolones, aminoglycosides, third generation cephalosporins, carbapenems, piperacillin/tazobactam, ampicillin‐sulbactam, or amoxicillin/clavulanate.1 The optimal treatment course is controversial but suggested to include 2 weeks to 3 weeks of intravenous antibiotics followed by at least 3 weeks to 4 weeks of oral antibiotics.1

According to a study of 84 patients hospitalized with pyogenic liver abscesses of which 70 cases were cultured, the most typical organisms isolated from liver abscesses are Streptococcus spp. (40.5%), Escherichia coli (27.4%), Klebsiella spp. (14.3%), and anaerobic organisms (17.9%).1 The anaerobic Gram‐negative bacterium Fusobacterium nucleatum, known to play a role in periodontal disease, is an uncommon cause of liver abscesses: a review of the literature revealed only 14 cases of liver abscesses caused by Fusobacterium nucleatum, five cases of which occurred in patients with known immunodeficiency, and a retrospective study of 70 cases of liver abscesses revealed only 2 cases linked to this bacterium.1, 2 Though accounting for a minority of cases of pyogenic liver abscesses, it is commonly cited as a cause of liver abscesses resulting from spread of infection from the oral cavity. Four case reports have implicated severe dental disease or recent dental work in the development of pyogenic liver abscesses involving Fusobacterium nucleatum.2 For example, a literature search revealed a case report of a patient with a liver abscess due to Fusobacterium nucleatum resulting from hematogenous spread of infection from the oral cavity.2

Although Fusobacterium has rarely been reported in biliary culture from patients with cholangitis or gangrenous cholecystitis,3 this organism has been identified as a causative organism in appendicitis. In two separate studies of 41 children with appendicitis and 30 patients older than 12 years with gangrenous or perforated appendicitis, Fusobacterium nucleatum or Fusobacterium spp. were isolated in 44% and 33% of cases, respectively.4, 5 Nevertheless, the mechanism of appendicitis causing liver abscesses is thought to be by direct spread via the peritoneum after perforation.2 Thus, despite the isolation of this bacterium from appendectomy specimens, appendicitis is less likely the source of infection in this patient given that there is no evidence that appendiceal perforation occurred in this case.

Our patient was found to have dental abscesses, cholecystitis requiring cholecystectomy, and appendicitis requiring appendectomyall of which, to varying degrees, were plausible sources of infection by virtue of their known role in the development of pyogenic liver abscesses. Although periodontal disease was the likely source of Fusobacterium nucleatum infection, we could not exclude the leading causes of pyogenic liver abscesses, appendicitis and/or biliary tract disease. As a result, the patient underwent 2 surgeries and was counseled to maintain good oral hygiene in order to eliminate all persisting sources of infection.

This was an unusual case in which the question What is the source of infection? appears to have had multiple correct answers. We theorize that leaving any 1 of the 3 possible sources of infection in place could have led to treatment failure. This patient is a humbling reminder that not every clinical problem will have one clear solution. In such cases, all possible underlying conditions need to be managed appropriately to achieve the desired outcome.

A 49‐year‐old man with a history of hypertension presented to our hospital with a 2‐week history of sharp pain in the right upper abdomen and right lower chest radiating to the back. The patient reported a few days of fevers, chills, drenching night sweats, shortness of breath, malaise, and fatigue. He denied recent travel. Vital signs were temperature 38.4C, blood pressure 119/74 mmHg, heart rate 95 beats/minutes, respiratory rate 16 breaths/minutes, and oxygen saturation 96% on 5 L nasal cannula. Physical examination revealed poor dentition, right upper abdominal quadrant tenderness, and dullness to percussion over the right lung base.

Initial labs showed white blood count (WBC) 22,540/mm³, alkaline phosphatase 280 units/L, bilirubin 1.1 mg/dL, aspartate aminotransferase (AST) 28 units/L, alanine aminotransferase (ALT) 33 units/L. Blood cultures were negative. An human immunodeficiency virus (HIV)1/HIV2 antibody screen was negative. Computed tomography (CT) of the chest demonstrated a large cystic lesion in the diaphragmatic dome of the liver with multiple lesions in the right lobe of the liver. Elevation of the right hemidiaphragm and moderate right pleural effusion were noted. CT abdomen showed multiple areas of fluid collection within the liver suspicious for liver abscesses (see Figure 1). Multiple gallstones were seen within gallbladder with a large stone in the region of the gallbladder neck vs. cystic duct without evidence of extrahepatic biliary dilatation. There was mild distention of the appendix with minimal soft tissue stranding.

Figure 1

The patient underwent ultrasound‐guided drainage of the largest liver abscess. Cultures from the aspiration grew Fusobacterium nucleatum. The patient's stool studies for ova and parasites were negative. The patient was started on piperacillin/tazobactam and metronidazole, then switched to ertapenem. A hepatobiliary iminodiacetic acid (HIDA) scan confirmed cholecystitis, and the patient underwent open cholecystectomy. Pathology on the gallbladder returned as chronic cholecystitis with cholelithiasis. A full dental examination revealed possible periapical abscesses of teeth #12 and #30 and stringent daily oral hygiene was recommended. Tooth extraction was initially recommended but ultimately postponed. Plans were made for dental follow‐up.

With continued antibiotic treatment, the patient's fevers resolved and leukocytosis improved. A follow‐up CT abdomen/pelvis obtained on hospital day 10 showed a reduction in size of the multiple liver abscesses. There was also increased prominence of the appendix with mild stranding. The patient was taken for appendectomy. Pathology was consistent with acute appendicitis with focal fat necrosis. The patient was ultimately discharged with the plan being to continue ertapenem until radiographic resolution of all the abscesses was demonstrated.

Discussion

Pyogenic liver abscesses are infrequently encountered in the western population, but when present, result in significant morbidity and mortality.1 Mortality rates range from 6% to 31%, decreased from 100% mortality in the preantibiotic era.1 The leading cause of pyogenic liver abscesses has been in the past ascribed to ruptured appendicitis.2 However, biliary tract pathology is now the leading cause, accounting for 43% to 60% of cases.2 In addition, hematogenous seeding of infection from the oral cavity has been recognized in the literature as a potential source of infection in the development of pyogenic liver abscesses.2

The empiric treatment of pyogenic liver abscesses is intravenous broad‐spectrum antibiotics, most commonly metronidazole in combination with quinolones, aminoglycosides, third generation cephalosporins, carbapenems, piperacillin/tazobactam, ampicillin‐sulbactam, or amoxicillin/clavulanate.1 The optimal treatment course is controversial but suggested to include 2 weeks to 3 weeks of intravenous antibiotics followed by at least 3 weeks to 4 weeks of oral antibiotics.1

According to a study of 84 patients hospitalized with pyogenic liver abscesses of which 70 cases were cultured, the most typical organisms isolated from liver abscesses are Streptococcus spp. (40.5%), Escherichia coli (27.4%), Klebsiella spp. (14.3%), and anaerobic organisms (17.9%).1 The anaerobic Gram‐negative bacterium Fusobacterium nucleatum, known to play a role in periodontal disease, is an uncommon cause of liver abscesses: a review of the literature revealed only 14 cases of liver abscesses caused by Fusobacterium nucleatum, five cases of which occurred in patients with known immunodeficiency, and a retrospective study of 70 cases of liver abscesses revealed only 2 cases linked to this bacterium.1, 2 Though accounting for a minority of cases of pyogenic liver abscesses, it is commonly cited as a cause of liver abscesses resulting from spread of infection from the oral cavity. Four case reports have implicated severe dental disease or recent dental work in the development of pyogenic liver abscesses involving Fusobacterium nucleatum.2 For example, a literature search revealed a case report of a patient with a liver abscess due to Fusobacterium nucleatum resulting from hematogenous spread of infection from the oral cavity.2

Although Fusobacterium has rarely been reported in biliary culture from patients with cholangitis or gangrenous cholecystitis,3 this organism has been identified as a causative organism in appendicitis. In two separate studies of 41 children with appendicitis and 30 patients older than 12 years with gangrenous or perforated appendicitis, Fusobacterium nucleatum or Fusobacterium spp. were isolated in 44% and 33% of cases, respectively.4, 5 Nevertheless, the mechanism of appendicitis causing liver abscesses is thought to be by direct spread via the peritoneum after perforation.2 Thus, despite the isolation of this bacterium from appendectomy specimens, appendicitis is less likely the source of infection in this patient given that there is no evidence that appendiceal perforation occurred in this case.

Our patient was found to have dental abscesses, cholecystitis requiring cholecystectomy, and appendicitis requiring appendectomyall of which, to varying degrees, were plausible sources of infection by virtue of their known role in the development of pyogenic liver abscesses. Although periodontal disease was the likely source of Fusobacterium nucleatum infection, we could not exclude the leading causes of pyogenic liver abscesses, appendicitis and/or biliary tract disease. As a result, the patient underwent 2 surgeries and was counseled to maintain good oral hygiene in order to eliminate all persisting sources of infection.

This was an unusual case in which the question What is the source of infection? appears to have had multiple correct answers. We theorize that leaving any 1 of the 3 possible sources of infection in place could have led to treatment failure. This patient is a humbling reminder that not every clinical problem will have one clear solution. In such cases, all possible underlying conditions need to be managed appropriately to achieve the desired outcome.

A 49‐year‐old man with a history of hypertension presented to our hospital with a 2‐week history of sharp pain in the right upper abdomen and right lower chest radiating to the back. The patient reported a few days of fevers, chills, drenching night sweats, shortness of breath, malaise, and fatigue. He denied recent travel. Vital signs were temperature 38.4C, blood pressure 119/74 mmHg, heart rate 95 beats/minutes, respiratory rate 16 breaths/minutes, and oxygen saturation 96% on 5 L nasal cannula. Physical examination revealed poor dentition, right upper abdominal quadrant tenderness, and dullness to percussion over the right lung base.

Initial labs showed white blood count (WBC) 22,540/mm³, alkaline phosphatase 280 units/L, bilirubin 1.1 mg/dL, aspartate aminotransferase (AST) 28 units/L, alanine aminotransferase (ALT) 33 units/L. Blood cultures were negative. An human immunodeficiency virus (HIV)1/HIV2 antibody screen was negative. Computed tomography (CT) of the chest demonstrated a large cystic lesion in the diaphragmatic dome of the liver with multiple lesions in the right lobe of the liver. Elevation of the right hemidiaphragm and moderate right pleural effusion were noted. CT abdomen showed multiple areas of fluid collection within the liver suspicious for liver abscesses (see Figure 1). Multiple gallstones were seen within gallbladder with a large stone in the region of the gallbladder neck vs. cystic duct without evidence of extrahepatic biliary dilatation. There was mild distention of the appendix with minimal soft tissue stranding.

Figure 1

The patient underwent ultrasound‐guided drainage of the largest liver abscess. Cultures from the aspiration grew Fusobacterium nucleatum. The patient's stool studies for ova and parasites were negative. The patient was started on piperacillin/tazobactam and metronidazole, then switched to ertapenem. A hepatobiliary iminodiacetic acid (HIDA) scan confirmed cholecystitis, and the patient underwent open cholecystectomy. Pathology on the gallbladder returned as chronic cholecystitis with cholelithiasis. A full dental examination revealed possible periapical abscesses of teeth #12 and #30 and stringent daily oral hygiene was recommended. Tooth extraction was initially recommended but ultimately postponed. Plans were made for dental follow‐up.

With continued antibiotic treatment, the patient's fevers resolved and leukocytosis improved. A follow‐up CT abdomen/pelvis obtained on hospital day 10 showed a reduction in size of the multiple liver abscesses. There was also increased prominence of the appendix with mild stranding. The patient was taken for appendectomy. Pathology was consistent with acute appendicitis with focal fat necrosis. The patient was ultimately discharged with the plan being to continue ertapenem until radiographic resolution of all the abscesses was demonstrated.

Discussion

Pyogenic liver abscesses are infrequently encountered in the western population, but when present, result in significant morbidity and mortality.1 Mortality rates range from 6% to 31%, decreased from 100% mortality in the preantibiotic era.1 The leading cause of pyogenic liver abscesses has been in the past ascribed to ruptured appendicitis.2 However, biliary tract pathology is now the leading cause, accounting for 43% to 60% of cases.2 In addition, hematogenous seeding of infection from the oral cavity has been recognized in the literature as a potential source of infection in the development of pyogenic liver abscesses.2

The empiric treatment of pyogenic liver abscesses is intravenous broad‐spectrum antibiotics, most commonly metronidazole in combination with quinolones, aminoglycosides, third generation cephalosporins, carbapenems, piperacillin/tazobactam, ampicillin‐sulbactam, or amoxicillin/clavulanate.1 The optimal treatment course is controversial but suggested to include 2 weeks to 3 weeks of intravenous antibiotics followed by at least 3 weeks to 4 weeks of oral antibiotics.1

According to a study of 84 patients hospitalized with pyogenic liver abscesses of which 70 cases were cultured, the most typical organisms isolated from liver abscesses are Streptococcus spp. (40.5%), Escherichia coli (27.4%), Klebsiella spp. (14.3%), and anaerobic organisms (17.9%).1 The anaerobic Gram‐negative bacterium Fusobacterium nucleatum, known to play a role in periodontal disease, is an uncommon cause of liver abscesses: a review of the literature revealed only 14 cases of liver abscesses caused by Fusobacterium nucleatum, five cases of which occurred in patients with known immunodeficiency, and a retrospective study of 70 cases of liver abscesses revealed only 2 cases linked to this bacterium.1, 2 Though accounting for a minority of cases of pyogenic liver abscesses, it is commonly cited as a cause of liver abscesses resulting from spread of infection from the oral cavity. Four case reports have implicated severe dental disease or recent dental work in the development of pyogenic liver abscesses involving Fusobacterium nucleatum.2 For example, a literature search revealed a case report of a patient with a liver abscess due to Fusobacterium nucleatum resulting from hematogenous spread of infection from the oral cavity.2

Although Fusobacterium has rarely been reported in biliary culture from patients with cholangitis or gangrenous cholecystitis,3 this organism has been identified as a causative organism in appendicitis. In two separate studies of 41 children with appendicitis and 30 patients older than 12 years with gangrenous or perforated appendicitis, Fusobacterium nucleatum or Fusobacterium spp. were isolated in 44% and 33% of cases, respectively.4, 5 Nevertheless, the mechanism of appendicitis causing liver abscesses is thought to be by direct spread via the peritoneum after perforation.2 Thus, despite the isolation of this bacterium from appendectomy specimens, appendicitis is less likely the source of infection in this patient given that there is no evidence that appendiceal perforation occurred in this case.

Our patient was found to have dental abscesses, cholecystitis requiring cholecystectomy, and appendicitis requiring appendectomyall of which, to varying degrees, were plausible sources of infection by virtue of their known role in the development of pyogenic liver abscesses. Although periodontal disease was the likely source of Fusobacterium nucleatum infection, we could not exclude the leading causes of pyogenic liver abscesses, appendicitis and/or biliary tract disease. As a result, the patient underwent 2 surgeries and was counseled to maintain good oral hygiene in order to eliminate all persisting sources of infection.

This was an unusual case in which the question What is the source of infection? appears to have had multiple correct answers. We theorize that leaving any 1 of the 3 possible sources of infection in place could have led to treatment failure. This patient is a humbling reminder that not every clinical problem will have one clear solution. In such cases, all possible underlying conditions need to be managed appropriately to achieve the desired outcome.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalized patients.13 Major efforts are underway to increase appropriate VTE prophylaxis (VTEP)4 and adherence to VTEP guidelines are increasingly used as a quality of care measure. National 2008 VTEP guidelines suggest that all medical patients ill enough to require hospitalization, particularly those requiring admission to the Intensive Care Unit (ICU), have at least a moderate risk of developing VTE and prophylaxis is recommended.4 Hospitalized patients with end‐stage liver disease (ESLD), despite their coagulopathy, are known to be at risk for VTE48 and may be VTEP candidates.

Based on available literature, it is unknown whether pharmacologic VTEP should be utilized in acutely ill, hospitalized patients with ESLD, particularly in those admitted with variceal bleeding. These patients are at high risk for rebleeding, with the highest risk in the first 5 days.9 Early rebleeding, defined as recurrent bleeding within 6 weeks of initial bleed, declined from 47% in the 1980s to 13% by 2000 because of increased early endoscopic intervention and use of medications to prevent rebleeding.911 In multicenter cohort studies, D'Amico and De Franchis12 reported that 13% of patients with variceal bleeding had uncontrolled bleeding, rebleeding, or death within 5 days of admission while Bahmba et al.13 reported a 16% rate of rebleeding within 5 days. We are unaware of prior reports regarding the safety of VTEP in this high‐risk group of patients.

Objective

We sought to describe rebleeding in a series of 22 patients with ESLD admitted with variceal bleeding who received pharmacologic VTEP.

Methods

We identified all patients 18 years and older with upper gastrointestinal bleeding admitted to Harborview Medical Center, a 400‐bed urban county teaching hospital in Seattle, Washington, between January 1, 2003 and December 31, 2005 (Figure 1), just prior to medical center‐wide implementation of a VTEP guideline. Potential cases were identified using administrative data based on 8 discharge diagnoses (Supporting Information Appendix 1) and 10 procedure codes (Supporting Information Appendix 2).14 Inpatient pharmacy data indicating continuous octreotide infusion were used to refine the sample. At our institution, it is a standard of care to initiate octreotide in patients admitted with variceal bleeding. We excluded patients who did not have ESLD (defined as evidence of cirrhosis and associated complications including but not limited to ascites, encephalopathy, variceal bleeding, portal hypertension) documented in their problem list or past medical history and those with no variceal bleeding based on medical record review. We identified cases receiving pharmacologic VTEP, either subcutaneous unfractionated heparin (UFH) or low molecular weight heparin (LMWH), during hospitalization from pharmacy records.

Figure 1

We obtained demographic and clinical data from administrative billing systems, electronic and paper medical records, and inpatient pharmacy databases and verified transfusion data from the Puget Sound Blood Center. We abstracted esophagogastroduodenoscopy (EGD) findings indicating high risk of rebleeding including variceal grade and stigmata of recent bleeding such as red spots or wales.15, 16 Data were abstracted by the first 3 authors (AS, MS, KJ) and reviewed again by 2 authors (AS, KJ) blinded to the others' abstractions.

We calculated Model for ESLD (MELD) scores on admission. These scores correlate with 3 month mortality in ESLD.17 We tabulated 5 factors shown in some studies to predict bleeding including high International Normalized Ratio (INR) (>1.5), low hematocrit (25%), low platelet count (100,000 per microliter), active bleeding at EGD, and transfusion of four or more units of red cells within 24 hours of admission.1013

We defined rebleeding as a decrease in hematocrit of greater than 5 percentage points compared with postresuscitation hematocrit, transfusion of additional red cells more than 48 hours after initial resuscitation, repeat unscheduled EGD, or return to the ICU for therapies related to rebleeding.18 The University of Washington Human Subjects Board approved this study.

Results

Of 224 patients initially identified, 36 received pharmacologic VTEP. We excluded 14 who did not have ESLD (n = 1) or did not have a variceal bleed (n = 13). The remaining 22 patients form the sample described in Figure 1.

The median age of patients was 52 years (range 42‐85) and 77% were men (Table 1). Twenty‐one of 22 patients (95%) were initially admitted to the ICU; median length of stay was 8 days (range 4‐30). Median MELD score on admission was 15 (range 825). On EGD, the number of variceal columns ranged from 1 to 4; 17 patients (77%) had at least 3. A total of 15 patients (68%) had stigmata of recent bleeding and 16 (72%) underwent banding (range 16 bands). All patients had at least 1 bleeding risk factor (Table 1) of which the most common factors observed were initial transfusion of 4 or more units of red cells (50%, n = 11), INR > 1.5 (45%, n = 10), and hematocrit 25% (45%, n = 10).

A total of 12 patients (55%) received 5000 units of UFH every 8 hours, 8 (36%) received 5000 units UFH every 12 hours, and 2 (9%) received LMWH. VTEP was initiated as early as day of admission and as late as day 19. Median VTEP start date was hospital day 4. Median duration of of VTEP was 5 days.

Only 1 patient (4.5%) rebled after VTEP initiation. The patient received UFH every 8 hours starting on hospital day 6, and rebleeding occurred on day 9. Repeat EGD showed ulcers at banding sites. The patient was restarted on VTEP on hospital day 13 without recurrence of rebleeding. This patient had a MELD score of 24, initial INR >2, hematocrit 25%, had grade 3 varices and stigmata of recent bleeding on EGD, and received 4 units of packed red cells. These values are similar to those of the cohort as a whole (Table 1). This patient also was diagnosed with DVT while receiving VTEP on hospital day 15. This patient's coagulopathy was in the setting of terminal illness; the patient expired on hospital day 25.

One additional patient rebled prior to VTEP initiation on day 3 with repeat EGD showing a bleeding varix. This patient was nevertheless started on VTEP 4 days after rebleeding. Despite use of VTEP, this patient was diagnosed with DVT on hospital day 9 (and may well have had the DVT at the time of VTEP initiation). The patient was transitioned to therapeutic dose heparin which was tolerated without recurrence of rebleeding.

There were no other confirmed cases of DVT in this series. One additional patient underwent angiogram that showed no pulmonary embolism; 2 other patients underwent lower extremity ultrasounds that were negative for DVT.

Discussion

At our medical center, only a few inpatients with ESLD admitted with variceal bleed received VTEP. These patients were seemingly at high risk for bleeding and rebleeding given high MELD scores, variceal bleeding, and presence of at least one clinical factor suggesting bleeding risk, and in several cases 3 or more such factors.13, 18 Despite this, only 1 patient rebled while receiving VTEP. We captured rebleeding rates only during the index hospitalization. We therefore may underestimate early rebleeding rates.1013 Nevertheless, our inpatient data included complete coverage of the earliest period after the index bleeds and the period during which patients were exposed to VTEP, which should be the time of highest rebleeding risk related to VTEP exposure. Interestingly the patient who rebled while on VTEP was also diagnosed with VTE while on VTEP. Two patients (9%) in our sample were diagnosed with VTE.

This case series is limited by its small sample size, retrospective nature, single center observation, and perhaps especially by possible selection bias. We were unable to specifically quantify rebleeding risk. Several authors have identified individual factors associated with rebleeding,1013 these were tabulated for patients in this case series (Table 1) and all patients had at least 1 of these factors. Concurrent infection and hepatic vein pressure gradient have been shown to predict rebleeding;9, 19 we were unable to identify these factors in our data.

There was considerable variability in this case series in timing of VTEP initiation relative to initial bleed. We were unable to characterize provider or patient characteristics that may have influenced the decision to initiate VTEP and timing. The sample size was also too small to comment upon factors associated with choice of UFH versus LMWH and any potential differences in rebleeding risk between the 2. We also did not look at outcomes postindex hospitalization so we can not comment on the extended risk of rebleeding with VTEP after discharge. However, the risk of rebleeding is highest within the first 96 hours13 and all patients in this series were hospitalized at least 4 days. Nonetheless, we captured all patients with ESLD and variceal bleeding exposed to VTEP at a large center over a three‐year period and found rebleeding rates less than what might be expected.

Conclusions

Our observations suggest that some inpatients with ESLD and variceal bleeding may tolerate pharmacologic VTEP. In this small group of patients, VTEP was associated with an unexpectedly low incidence of rebleeding. While this case series does not support broad use of VTEP in this population, the lower‐than‐expected rates of rebleeding suggest that further study of the safety and effectiveness of pharmacologic VTEP in inpatient populations with ESLD may be warranted, particularly given the recommendations of recent national VTE prophylaxis guidelines.4

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalized patients.13 Major efforts are underway to increase appropriate VTE prophylaxis (VTEP)4 and adherence to VTEP guidelines are increasingly used as a quality of care measure. National 2008 VTEP guidelines suggest that all medical patients ill enough to require hospitalization, particularly those requiring admission to the Intensive Care Unit (ICU), have at least a moderate risk of developing VTE and prophylaxis is recommended.4 Hospitalized patients with end‐stage liver disease (ESLD), despite their coagulopathy, are known to be at risk for VTE48 and may be VTEP candidates.

Based on available literature, it is unknown whether pharmacologic VTEP should be utilized in acutely ill, hospitalized patients with ESLD, particularly in those admitted with variceal bleeding. These patients are at high risk for rebleeding, with the highest risk in the first 5 days.9 Early rebleeding, defined as recurrent bleeding within 6 weeks of initial bleed, declined from 47% in the 1980s to 13% by 2000 because of increased early endoscopic intervention and use of medications to prevent rebleeding.911 In multicenter cohort studies, D'Amico and De Franchis12 reported that 13% of patients with variceal bleeding had uncontrolled bleeding, rebleeding, or death within 5 days of admission while Bahmba et al.13 reported a 16% rate of rebleeding within 5 days. We are unaware of prior reports regarding the safety of VTEP in this high‐risk group of patients.

Objective

We sought to describe rebleeding in a series of 22 patients with ESLD admitted with variceal bleeding who received pharmacologic VTEP.

Methods

We identified all patients 18 years and older with upper gastrointestinal bleeding admitted to Harborview Medical Center, a 400‐bed urban county teaching hospital in Seattle, Washington, between January 1, 2003 and December 31, 2005 (Figure 1), just prior to medical center‐wide implementation of a VTEP guideline. Potential cases were identified using administrative data based on 8 discharge diagnoses (Supporting Information Appendix 1) and 10 procedure codes (Supporting Information Appendix 2).14 Inpatient pharmacy data indicating continuous octreotide infusion were used to refine the sample. At our institution, it is a standard of care to initiate octreotide in patients admitted with variceal bleeding. We excluded patients who did not have ESLD (defined as evidence of cirrhosis and associated complications including but not limited to ascites, encephalopathy, variceal bleeding, portal hypertension) documented in their problem list or past medical history and those with no variceal bleeding based on medical record review. We identified cases receiving pharmacologic VTEP, either subcutaneous unfractionated heparin (UFH) or low molecular weight heparin (LMWH), during hospitalization from pharmacy records.

Figure 1

We obtained demographic and clinical data from administrative billing systems, electronic and paper medical records, and inpatient pharmacy databases and verified transfusion data from the Puget Sound Blood Center. We abstracted esophagogastroduodenoscopy (EGD) findings indicating high risk of rebleeding including variceal grade and stigmata of recent bleeding such as red spots or wales.15, 16 Data were abstracted by the first 3 authors (AS, MS, KJ) and reviewed again by 2 authors (AS, KJ) blinded to the others' abstractions.

We calculated Model for ESLD (MELD) scores on admission. These scores correlate with 3 month mortality in ESLD.17 We tabulated 5 factors shown in some studies to predict bleeding including high International Normalized Ratio (INR) (>1.5), low hematocrit (25%), low platelet count (100,000 per microliter), active bleeding at EGD, and transfusion of four or more units of red cells within 24 hours of admission.1013

We defined rebleeding as a decrease in hematocrit of greater than 5 percentage points compared with postresuscitation hematocrit, transfusion of additional red cells more than 48 hours after initial resuscitation, repeat unscheduled EGD, or return to the ICU for therapies related to rebleeding.18 The University of Washington Human Subjects Board approved this study.

Results

Of 224 patients initially identified, 36 received pharmacologic VTEP. We excluded 14 who did not have ESLD (n = 1) or did not have a variceal bleed (n = 13). The remaining 22 patients form the sample described in Figure 1.

The median age of patients was 52 years (range 42‐85) and 77% were men (Table 1). Twenty‐one of 22 patients (95%) were initially admitted to the ICU; median length of stay was 8 days (range 4‐30). Median MELD score on admission was 15 (range 825). On EGD, the number of variceal columns ranged from 1 to 4; 17 patients (77%) had at least 3. A total of 15 patients (68%) had stigmata of recent bleeding and 16 (72%) underwent banding (range 16 bands). All patients had at least 1 bleeding risk factor (Table 1) of which the most common factors observed were initial transfusion of 4 or more units of red cells (50%, n = 11), INR > 1.5 (45%, n = 10), and hematocrit 25% (45%, n = 10).

A total of 12 patients (55%) received 5000 units of UFH every 8 hours, 8 (36%) received 5000 units UFH every 12 hours, and 2 (9%) received LMWH. VTEP was initiated as early as day of admission and as late as day 19. Median VTEP start date was hospital day 4. Median duration of of VTEP was 5 days.

Only 1 patient (4.5%) rebled after VTEP initiation. The patient received UFH every 8 hours starting on hospital day 6, and rebleeding occurred on day 9. Repeat EGD showed ulcers at banding sites. The patient was restarted on VTEP on hospital day 13 without recurrence of rebleeding. This patient had a MELD score of 24, initial INR >2, hematocrit 25%, had grade 3 varices and stigmata of recent bleeding on EGD, and received 4 units of packed red cells. These values are similar to those of the cohort as a whole (Table 1). This patient also was diagnosed with DVT while receiving VTEP on hospital day 15. This patient's coagulopathy was in the setting of terminal illness; the patient expired on hospital day 25.

One additional patient rebled prior to VTEP initiation on day 3 with repeat EGD showing a bleeding varix. This patient was nevertheless started on VTEP 4 days after rebleeding. Despite use of VTEP, this patient was diagnosed with DVT on hospital day 9 (and may well have had the DVT at the time of VTEP initiation). The patient was transitioned to therapeutic dose heparin which was tolerated without recurrence of rebleeding.

There were no other confirmed cases of DVT in this series. One additional patient underwent angiogram that showed no pulmonary embolism; 2 other patients underwent lower extremity ultrasounds that were negative for DVT.

Discussion

At our medical center, only a few inpatients with ESLD admitted with variceal bleed received VTEP. These patients were seemingly at high risk for bleeding and rebleeding given high MELD scores, variceal bleeding, and presence of at least one clinical factor suggesting bleeding risk, and in several cases 3 or more such factors.13, 18 Despite this, only 1 patient rebled while receiving VTEP. We captured rebleeding rates only during the index hospitalization. We therefore may underestimate early rebleeding rates.1013 Nevertheless, our inpatient data included complete coverage of the earliest period after the index bleeds and the period during which patients were exposed to VTEP, which should be the time of highest rebleeding risk related to VTEP exposure. Interestingly the patient who rebled while on VTEP was also diagnosed with VTE while on VTEP. Two patients (9%) in our sample were diagnosed with VTE.

This case series is limited by its small sample size, retrospective nature, single center observation, and perhaps especially by possible selection bias. We were unable to specifically quantify rebleeding risk. Several authors have identified individual factors associated with rebleeding,1013 these were tabulated for patients in this case series (Table 1) and all patients had at least 1 of these factors. Concurrent infection and hepatic vein pressure gradient have been shown to predict rebleeding;9, 19 we were unable to identify these factors in our data.

There was considerable variability in this case series in timing of VTEP initiation relative to initial bleed. We were unable to characterize provider or patient characteristics that may have influenced the decision to initiate VTEP and timing. The sample size was also too small to comment upon factors associated with choice of UFH versus LMWH and any potential differences in rebleeding risk between the 2. We also did not look at outcomes postindex hospitalization so we can not comment on the extended risk of rebleeding with VTEP after discharge. However, the risk of rebleeding is highest within the first 96 hours13 and all patients in this series were hospitalized at least 4 days. Nonetheless, we captured all patients with ESLD and variceal bleeding exposed to VTEP at a large center over a three‐year period and found rebleeding rates less than what might be expected.

Conclusions

Our observations suggest that some inpatients with ESLD and variceal bleeding may tolerate pharmacologic VTEP. In this small group of patients, VTEP was associated with an unexpectedly low incidence of rebleeding. While this case series does not support broad use of VTEP in this population, the lower‐than‐expected rates of rebleeding suggest that further study of the safety and effectiveness of pharmacologic VTEP in inpatient populations with ESLD may be warranted, particularly given the recommendations of recent national VTE prophylaxis guidelines.4

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalized patients.13 Major efforts are underway to increase appropriate VTE prophylaxis (VTEP)4 and adherence to VTEP guidelines are increasingly used as a quality of care measure. National 2008 VTEP guidelines suggest that all medical patients ill enough to require hospitalization, particularly those requiring admission to the Intensive Care Unit (ICU), have at least a moderate risk of developing VTE and prophylaxis is recommended.4 Hospitalized patients with end‐stage liver disease (ESLD), despite their coagulopathy, are known to be at risk for VTE48 and may be VTEP candidates.

Based on available literature, it is unknown whether pharmacologic VTEP should be utilized in acutely ill, hospitalized patients with ESLD, particularly in those admitted with variceal bleeding. These patients are at high risk for rebleeding, with the highest risk in the first 5 days.9 Early rebleeding, defined as recurrent bleeding within 6 weeks of initial bleed, declined from 47% in the 1980s to 13% by 2000 because of increased early endoscopic intervention and use of medications to prevent rebleeding.911 In multicenter cohort studies, D'Amico and De Franchis12 reported that 13% of patients with variceal bleeding had uncontrolled bleeding, rebleeding, or death within 5 days of admission while Bahmba et al.13 reported a 16% rate of rebleeding within 5 days. We are unaware of prior reports regarding the safety of VTEP in this high‐risk group of patients.

Objective

We sought to describe rebleeding in a series of 22 patients with ESLD admitted with variceal bleeding who received pharmacologic VTEP.

Methods

We identified all patients 18 years and older with upper gastrointestinal bleeding admitted to Harborview Medical Center, a 400‐bed urban county teaching hospital in Seattle, Washington, between January 1, 2003 and December 31, 2005 (Figure 1), just prior to medical center‐wide implementation of a VTEP guideline. Potential cases were identified using administrative data based on 8 discharge diagnoses (Supporting Information Appendix 1) and 10 procedure codes (Supporting Information Appendix 2).14 Inpatient pharmacy data indicating continuous octreotide infusion were used to refine the sample. At our institution, it is a standard of care to initiate octreotide in patients admitted with variceal bleeding. We excluded patients who did not have ESLD (defined as evidence of cirrhosis and associated complications including but not limited to ascites, encephalopathy, variceal bleeding, portal hypertension) documented in their problem list or past medical history and those with no variceal bleeding based on medical record review. We identified cases receiving pharmacologic VTEP, either subcutaneous unfractionated heparin (UFH) or low molecular weight heparin (LMWH), during hospitalization from pharmacy records.

Figure 1

We obtained demographic and clinical data from administrative billing systems, electronic and paper medical records, and inpatient pharmacy databases and verified transfusion data from the Puget Sound Blood Center. We abstracted esophagogastroduodenoscopy (EGD) findings indicating high risk of rebleeding including variceal grade and stigmata of recent bleeding such as red spots or wales.15, 16 Data were abstracted by the first 3 authors (AS, MS, KJ) and reviewed again by 2 authors (AS, KJ) blinded to the others' abstractions.

We calculated Model for ESLD (MELD) scores on admission. These scores correlate with 3 month mortality in ESLD.17 We tabulated 5 factors shown in some studies to predict bleeding including high International Normalized Ratio (INR) (>1.5), low hematocrit (25%), low platelet count (100,000 per microliter), active bleeding at EGD, and transfusion of four or more units of red cells within 24 hours of admission.1013

We defined rebleeding as a decrease in hematocrit of greater than 5 percentage points compared with postresuscitation hematocrit, transfusion of additional red cells more than 48 hours after initial resuscitation, repeat unscheduled EGD, or return to the ICU for therapies related to rebleeding.18 The University of Washington Human Subjects Board approved this study.

Results

Of 224 patients initially identified, 36 received pharmacologic VTEP. We excluded 14 who did not have ESLD (n = 1) or did not have a variceal bleed (n = 13). The remaining 22 patients form the sample described in Figure 1.

The median age of patients was 52 years (range 42‐85) and 77% were men (Table 1). Twenty‐one of 22 patients (95%) were initially admitted to the ICU; median length of stay was 8 days (range 4‐30). Median MELD score on admission was 15 (range 825). On EGD, the number of variceal columns ranged from 1 to 4; 17 patients (77%) had at least 3. A total of 15 patients (68%) had stigmata of recent bleeding and 16 (72%) underwent banding (range 16 bands). All patients had at least 1 bleeding risk factor (Table 1) of which the most common factors observed were initial transfusion of 4 or more units of red cells (50%, n = 11), INR > 1.5 (45%, n = 10), and hematocrit 25% (45%, n = 10).

A total of 12 patients (55%) received 5000 units of UFH every 8 hours, 8 (36%) received 5000 units UFH every 12 hours, and 2 (9%) received LMWH. VTEP was initiated as early as day of admission and as late as day 19. Median VTEP start date was hospital day 4. Median duration of of VTEP was 5 days.

Only 1 patient (4.5%) rebled after VTEP initiation. The patient received UFH every 8 hours starting on hospital day 6, and rebleeding occurred on day 9. Repeat EGD showed ulcers at banding sites. The patient was restarted on VTEP on hospital day 13 without recurrence of rebleeding. This patient had a MELD score of 24, initial INR >2, hematocrit 25%, had grade 3 varices and stigmata of recent bleeding on EGD, and received 4 units of packed red cells. These values are similar to those of the cohort as a whole (Table 1). This patient also was diagnosed with DVT while receiving VTEP on hospital day 15. This patient's coagulopathy was in the setting of terminal illness; the patient expired on hospital day 25.

One additional patient rebled prior to VTEP initiation on day 3 with repeat EGD showing a bleeding varix. This patient was nevertheless started on VTEP 4 days after rebleeding. Despite use of VTEP, this patient was diagnosed with DVT on hospital day 9 (and may well have had the DVT at the time of VTEP initiation). The patient was transitioned to therapeutic dose heparin which was tolerated without recurrence of rebleeding.

There were no other confirmed cases of DVT in this series. One additional patient underwent angiogram that showed no pulmonary embolism; 2 other patients underwent lower extremity ultrasounds that were negative for DVT.

Discussion

At our medical center, only a few inpatients with ESLD admitted with variceal bleed received VTEP. These patients were seemingly at high risk for bleeding and rebleeding given high MELD scores, variceal bleeding, and presence of at least one clinical factor suggesting bleeding risk, and in several cases 3 or more such factors.13, 18 Despite this, only 1 patient rebled while receiving VTEP. We captured rebleeding rates only during the index hospitalization. We therefore may underestimate early rebleeding rates.1013 Nevertheless, our inpatient data included complete coverage of the earliest period after the index bleeds and the period during which patients were exposed to VTEP, which should be the time of highest rebleeding risk related to VTEP exposure. Interestingly the patient who rebled while on VTEP was also diagnosed with VTE while on VTEP. Two patients (9%) in our sample were diagnosed with VTE.

This case series is limited by its small sample size, retrospective nature, single center observation, and perhaps especially by possible selection bias. We were unable to specifically quantify rebleeding risk. Several authors have identified individual factors associated with rebleeding,1013 these were tabulated for patients in this case series (Table 1) and all patients had at least 1 of these factors. Concurrent infection and hepatic vein pressure gradient have been shown to predict rebleeding;9, 19 we were unable to identify these factors in our data.

There was considerable variability in this case series in timing of VTEP initiation relative to initial bleed. We were unable to characterize provider or patient characteristics that may have influenced the decision to initiate VTEP and timing. The sample size was also too small to comment upon factors associated with choice of UFH versus LMWH and any potential differences in rebleeding risk between the 2. We also did not look at outcomes postindex hospitalization so we can not comment on the extended risk of rebleeding with VTEP after discharge. However, the risk of rebleeding is highest within the first 96 hours13 and all patients in this series were hospitalized at least 4 days. Nonetheless, we captured all patients with ESLD and variceal bleeding exposed to VTEP at a large center over a three‐year period and found rebleeding rates less than what might be expected.

Conclusions

Our observations suggest that some inpatients with ESLD and variceal bleeding may tolerate pharmacologic VTEP. In this small group of patients, VTEP was associated with an unexpectedly low incidence of rebleeding. While this case series does not support broad use of VTEP in this population, the lower‐than‐expected rates of rebleeding suggest that further study of the safety and effectiveness of pharmacologic VTEP in inpatient populations with ESLD may be warranted, particularly given the recommendations of recent national VTE prophylaxis guidelines.4

Emergency department evaluation of a febrile neonate or young infant routinely includes lumbar puncture and cerebrospinal fluid (CSF) analysis to diagnose meningitis or encephalitis. In addition to CSF Gram stain and culture, clinicians generally request a laboratory report for the CSF cell count, glucose content and protein concentration. Interpretation of these ancillary tests requires knowledge of normal reference values. In adult medicine, the accepted reference value for CSF protein concentration at the level of the lumbar spine is 15 mg/dL to45 mg/dL.1 There is general consensus among reference texts and published original studies dating back to Widell2 in 1958 that adult CSF protein reference values are not valid in the pediatric population. A healthy neonate's CSF protein concentration is normally twice to 3 times that of an adult, and declines with age from birth to early childhood. The most rapid rate of decline is thought to occur in the first 6 months of life as the infant's blood‐CSF barrier matures.3 However, published studies47 differ in the reported rate, timing, and magnitude of this decline; on close review these studies have significant limitations which call into question the appropriateness of using these values in clinical practice. Perhaps in recognition of the limited evidence, textbooks of general pediatrics,810 hospital medicine,1113 emergency medicine,14, 15 infectious diseases,16, 17 neonatology,18 and neurology19, 20 frequently publish norms for pediatric CSF protein concentration without reference to any original research studies.

Because ethical considerations prohibit subjecting young infants to a potentially painfully procedure (ie, lumbar puncture) before they are able to assent, we sought to define a study population that approximates a group of healthy infants. Our objectives were to quantify age‐related declines in CSF protein concentration and to determine accurate, age‐specific reference values for CSF protein concentration in a population of neonates and young infants who presented for medical care with an indication for lumbar puncture and were subsequently found to have no condition associated with elevated or depressed CSF protein concentration.

Methods

Results

During the study period, 1064 infants age 56 days of age or younger underwent lumbar puncture in the emergency department. Of these, 689 (65%) met sequential exclusion criteria as follows: traumatic lumbar puncture (n = 330); transported from an outside medical facility (n = 90); bacterial meningitis (n = 6); noncentral nervous system serious bacterial infections (n = 135); CSF positive for herpes simplex virus by PCR (n = 2); CSF positive for enterovirus by PCR (n = 45); congenital syphilis (n = 1); seizures (n = 28); abnormal central nervous system imaging (n = 2); and ventricular shunt device (n = 1). An additional 44 patients had lumbar puncture and CSF testing but the protein assay was never done or never reported and 5 patients did not have a CSF red blood cell count available. No cases were excluded for elevated serum bilirubin. Infants may have met multiple exclusion criteria. The remaining 375 (35%) subjects were included in the final analysis. The median patient age was 36 days (interquartile range: 2247 days); 139 (37%) were 28 days of age or younger. Overall, 205 (55%) were male, 211 (56%) were black, and 145 (39%) presented during enterovirus season. Most (43 of 57) preterm infants were born between 34 weeks to 37 weeks gestation. Antibiotics were administered before lumbar puncture to 42 (11%) infants and 312 (83%) infants had fever.

The median CSF protein value was 58 mg/dL (interquartile range: 4872 mg/dL). There was an age‐related declined in CSF protein concentration (Figure 1). In linear regression, the CSF protein concentration decreased 6.8% (95% confidence interval [CI], 5.48.1%; P < 0.001) for each 1‐week increase in age.0

Figure 1

Figure 2

CSF protein concentrations were higher for infants 28 days of age than for infants 2956 days of age (P < 0.001, Wilcoxon rank‐sum test). The median CSF protein concentrations were 68 mg/dL (95th percentile value, 115 mg/dL) for infants 28 days of age and 54 mg/dL (95th percentile value, 89 mg/dL) for infants 2956 days. CSF protein concentrations by 2‐week age intervals are shown in Table 1. The 95th percentile CSF protein concentrations were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL (Table 1). CSF protein concentration decreased significantly across each age interval when compared with infants in the next highest age category (P < 0.02 for all pair‐wise comparisons, Wilcoxon rank‐sum test).

Age‐specific 95th percentile CSF protein values changed by <1% when infants receiving antibiotics before lumbar puncture were excluded (Table 1). Age‐specific CSF protein values changed minimally when preterm infants were excluded with the exception of infants 4356 days of age where the 95th percentile value was 9.7% lower than when all infants were included (Table 1); the 90th percentile values in this age group were more comparable at 75 mg/dL and 71 mg/dL, respectively, in the subgroups with and without preterm infants. Age‐specific 95th percentile CSF protein values changes by <1% when patients with CSF pleocytosis were excluded.

Discussion

We examined CSF protein values in neonates and young infants to establish reference values and to bring the literature up to date at a time when molecular tools are commonly used in clinical practice. We also quantified the age‐related decline in CSF protein concentrations over the first two months of life. Our findings provide age‐specific reference ranges for CSF protein concentrations in neonates and young infants. These findings are particularly important because a variety of infectious (eg, herpes simplex virus infection) and noninfectious (eg, subarachnoid or intraventricular hemorrhage) conditions may occur in the absence of appreciable elevations in the CSF WBC.

CSF protein concentrations depend on serum protein concentrations and on the permeability of the blood‐CSF barrier. Immaturity of the blood‐CSF barrier is thought to result in higher CSF protein concentrations for neonates and young infants compared with older children and adults. Though previous studies agree that CSF protein concentrations depend on age, the reported age‐specific values and rates of decline vary considerably.47, 3032 Additionally, these prior studies are limited by (1) small sample size, (2) variable inclusion and exclusion criteria, (3) variable laboratory techniques to quantify protein concentration in a CSF sample, and (4) presentation of mean, standard deviation, and range values rather than the 75th, 90th, or 95th percentile values necessary to define a clinically meaningful reference range.

The median and mean values found in this study were generally comparable to previously published values (Table 2). In addition, we have quantified the age‐related decline in CSF protein concentrations identified in previous studies. While our large sample size allowed us to define narrower reference intervals than most previous studies, direct comparison of values used to define reference ranges was hampered by lack of consistent reporting of data across studies. Ahmed et al.5 and Bonadio et al.4 reported only mean and standard deviation values. When data are skewed, as is the case for CSF protein values, the standard deviation will be grossly inflated, making extrapolation to percentile values unreliable. The 90th percentile value of 87 mg/dL reported by Wong et al.7 for infants 060 days of age was similar to the value of 91 mg/dL for infants 56 days of age and younger found in this study. Biou et al.6 reported the following 95th percentile values: ages 18 days, 108 mg/dL; ages 830 days, 90 mg/dL; and ages 12 months, 77 mg/dL. These values are lower than those reported in our study. The reason for such differences is not clear. The exclusion criteria were similar between the two studies though Biou et al.6 did not include preterm infants. When we excluded preterm infants from our analysis, no age‐specific result decreased by more than 5%, making the inclusion of this population an unlikely explanation for the differences between the two studies.

CSF protein concentration is a method‐dependent value; the results depend a great deal on what technique the laboratory uses. Two common methods used in the past few decades are Biuret Colorimetry and Turbidimetric; reported values are approximately 25% higher with the Biuret method compared with the Turbidimetric method.33 A CSF protein reference value is only clinically useful if the method used to define the norm is specified and equivalent to currently used methods. Similar to our study, Biou et al.6 and Wong et al.7 used the Biuret (Vitros) method. The method of protein measurement was not specified by other studies.4, 5

This study had several limitations that could cause us to overestimate the upper bound of the reference range. First, spectrum bias is possible in this observational study. Individual physicians determined whether lumbar puncture was warranted, a limitation that could potentially lead to the disproportionate inclusion of infants with conditions associated with higher CSF protein concentrations. We do not believe that this limitation would meaningfully affect our results because febrile infants 56 days of age or younger routinely undergo lumbar puncture at our institution, regardless of illness severity, and patients diagnosed with conditions known or suspected to increase CSF protein concentrations were excluded. Second, infants with aseptic meningitisa condition that can be associated with elevated CSF protein concentrationsmay have been misclassified as uninfected. Though we excluded patients with positive CSF enteroviral PCR tests, some infants were not tested and other viruses (eg, parechoviruses)34 not detected by the enterovirus PCR may also cause aseptic meningitis. Third, certain antibiotics including ampicillin and vancomycin are known to interfere with the CSF protein assay used in our laboratory.24 Forty‐two of the 375 subjects included in our final analysis received antibiotics prior to lumbar puncture. When receiving antibiotics prior to lumbar puncture were excluded from analysis, the CSF protein concentrations were within 1% of the overall study population, suggesting that antibiotic administration before lumbar puncture did not influence our results in any meaningful way. We would not expect any of these limitations to disproportionately affect patients in 1 particular age category.

In conclusion, the CSF protein concentration values reported here represent the largest series to‐date for this young age group. Our study quantifies the age‐related decline in CSF protein concentration from birth to 56 days of life. Our work designing this study, specifically the exclusion criteria, refines the approach to defining normal CSF protein values in children. As CSF protein values decline steadily with increasing age, the selection of reference values is a balance of accuracy and convenience. Age‐specific reference values by 2‐week increments would be most accurate. However, considering reference values by month of age, as is the convention for CSF WBCs, is far more practical. The 95th percentile values by age category in our study were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL. The 95th percentile values were 115 mg/dL for infants 28 days and 89 mg/dL for infants 2956 days. We feel that either approach is reasonable. These values can be used to accurately interpret the results of CSF studies in neonates and young infants.

Emergency department evaluation of a febrile neonate or young infant routinely includes lumbar puncture and cerebrospinal fluid (CSF) analysis to diagnose meningitis or encephalitis. In addition to CSF Gram stain and culture, clinicians generally request a laboratory report for the CSF cell count, glucose content and protein concentration. Interpretation of these ancillary tests requires knowledge of normal reference values. In adult medicine, the accepted reference value for CSF protein concentration at the level of the lumbar spine is 15 mg/dL to45 mg/dL.1 There is general consensus among reference texts and published original studies dating back to Widell2 in 1958 that adult CSF protein reference values are not valid in the pediatric population. A healthy neonate's CSF protein concentration is normally twice to 3 times that of an adult, and declines with age from birth to early childhood. The most rapid rate of decline is thought to occur in the first 6 months of life as the infant's blood‐CSF barrier matures.3 However, published studies47 differ in the reported rate, timing, and magnitude of this decline; on close review these studies have significant limitations which call into question the appropriateness of using these values in clinical practice. Perhaps in recognition of the limited evidence, textbooks of general pediatrics,810 hospital medicine,1113 emergency medicine,14, 15 infectious diseases,16, 17 neonatology,18 and neurology19, 20 frequently publish norms for pediatric CSF protein concentration without reference to any original research studies.

Because ethical considerations prohibit subjecting young infants to a potentially painfully procedure (ie, lumbar puncture) before they are able to assent, we sought to define a study population that approximates a group of healthy infants. Our objectives were to quantify age‐related declines in CSF protein concentration and to determine accurate, age‐specific reference values for CSF protein concentration in a population of neonates and young infants who presented for medical care with an indication for lumbar puncture and were subsequently found to have no condition associated with elevated or depressed CSF protein concentration.

Methods

Results

During the study period, 1064 infants age 56 days of age or younger underwent lumbar puncture in the emergency department. Of these, 689 (65%) met sequential exclusion criteria as follows: traumatic lumbar puncture (n = 330); transported from an outside medical facility (n = 90); bacterial meningitis (n = 6); noncentral nervous system serious bacterial infections (n = 135); CSF positive for herpes simplex virus by PCR (n = 2); CSF positive for enterovirus by PCR (n = 45); congenital syphilis (n = 1); seizures (n = 28); abnormal central nervous system imaging (n = 2); and ventricular shunt device (n = 1). An additional 44 patients had lumbar puncture and CSF testing but the protein assay was never done or never reported and 5 patients did not have a CSF red blood cell count available. No cases were excluded for elevated serum bilirubin. Infants may have met multiple exclusion criteria. The remaining 375 (35%) subjects were included in the final analysis. The median patient age was 36 days (interquartile range: 2247 days); 139 (37%) were 28 days of age or younger. Overall, 205 (55%) were male, 211 (56%) were black, and 145 (39%) presented during enterovirus season. Most (43 of 57) preterm infants were born between 34 weeks to 37 weeks gestation. Antibiotics were administered before lumbar puncture to 42 (11%) infants and 312 (83%) infants had fever.

The median CSF protein value was 58 mg/dL (interquartile range: 4872 mg/dL). There was an age‐related declined in CSF protein concentration (Figure 1). In linear regression, the CSF protein concentration decreased 6.8% (95% confidence interval [CI], 5.48.1%; P < 0.001) for each 1‐week increase in age.0

Figure 1

Figure 2

CSF protein concentrations were higher for infants 28 days of age than for infants 2956 days of age (P < 0.001, Wilcoxon rank‐sum test). The median CSF protein concentrations were 68 mg/dL (95th percentile value, 115 mg/dL) for infants 28 days of age and 54 mg/dL (95th percentile value, 89 mg/dL) for infants 2956 days. CSF protein concentrations by 2‐week age intervals are shown in Table 1. The 95th percentile CSF protein concentrations were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL (Table 1). CSF protein concentration decreased significantly across each age interval when compared with infants in the next highest age category (P < 0.02 for all pair‐wise comparisons, Wilcoxon rank‐sum test).

Age‐specific 95th percentile CSF protein values changed by <1% when infants receiving antibiotics before lumbar puncture were excluded (Table 1). Age‐specific CSF protein values changed minimally when preterm infants were excluded with the exception of infants 4356 days of age where the 95th percentile value was 9.7% lower than when all infants were included (Table 1); the 90th percentile values in this age group were more comparable at 75 mg/dL and 71 mg/dL, respectively, in the subgroups with and without preterm infants. Age‐specific 95th percentile CSF protein values changes by <1% when patients with CSF pleocytosis were excluded.

Discussion

We examined CSF protein values in neonates and young infants to establish reference values and to bring the literature up to date at a time when molecular tools are commonly used in clinical practice. We also quantified the age‐related decline in CSF protein concentrations over the first two months of life. Our findings provide age‐specific reference ranges for CSF protein concentrations in neonates and young infants. These findings are particularly important because a variety of infectious (eg, herpes simplex virus infection) and noninfectious (eg, subarachnoid or intraventricular hemorrhage) conditions may occur in the absence of appreciable elevations in the CSF WBC.

CSF protein concentrations depend on serum protein concentrations and on the permeability of the blood‐CSF barrier. Immaturity of the blood‐CSF barrier is thought to result in higher CSF protein concentrations for neonates and young infants compared with older children and adults. Though previous studies agree that CSF protein concentrations depend on age, the reported age‐specific values and rates of decline vary considerably.47, 3032 Additionally, these prior studies are limited by (1) small sample size, (2) variable inclusion and exclusion criteria, (3) variable laboratory techniques to quantify protein concentration in a CSF sample, and (4) presentation of mean, standard deviation, and range values rather than the 75th, 90th, or 95th percentile values necessary to define a clinically meaningful reference range.

The median and mean values found in this study were generally comparable to previously published values (Table 2). In addition, we have quantified the age‐related decline in CSF protein concentrations identified in previous studies. While our large sample size allowed us to define narrower reference intervals than most previous studies, direct comparison of values used to define reference ranges was hampered by lack of consistent reporting of data across studies. Ahmed et al.5 and Bonadio et al.4 reported only mean and standard deviation values. When data are skewed, as is the case for CSF protein values, the standard deviation will be grossly inflated, making extrapolation to percentile values unreliable. The 90th percentile value of 87 mg/dL reported by Wong et al.7 for infants 060 days of age was similar to the value of 91 mg/dL for infants 56 days of age and younger found in this study. Biou et al.6 reported the following 95th percentile values: ages 18 days, 108 mg/dL; ages 830 days, 90 mg/dL; and ages 12 months, 77 mg/dL. These values are lower than those reported in our study. The reason for such differences is not clear. The exclusion criteria were similar between the two studies though Biou et al.6 did not include preterm infants. When we excluded preterm infants from our analysis, no age‐specific result decreased by more than 5%, making the inclusion of this population an unlikely explanation for the differences between the two studies.

CSF protein concentration is a method‐dependent value; the results depend a great deal on what technique the laboratory uses. Two common methods used in the past few decades are Biuret Colorimetry and Turbidimetric; reported values are approximately 25% higher with the Biuret method compared with the Turbidimetric method.33 A CSF protein reference value is only clinically useful if the method used to define the norm is specified and equivalent to currently used methods. Similar to our study, Biou et al.6 and Wong et al.7 used the Biuret (Vitros) method. The method of protein measurement was not specified by other studies.4, 5

This study had several limitations that could cause us to overestimate the upper bound of the reference range. First, spectrum bias is possible in this observational study. Individual physicians determined whether lumbar puncture was warranted, a limitation that could potentially lead to the disproportionate inclusion of infants with conditions associated with higher CSF protein concentrations. We do not believe that this limitation would meaningfully affect our results because febrile infants 56 days of age or younger routinely undergo lumbar puncture at our institution, regardless of illness severity, and patients diagnosed with conditions known or suspected to increase CSF protein concentrations were excluded. Second, infants with aseptic meningitisa condition that can be associated with elevated CSF protein concentrationsmay have been misclassified as uninfected. Though we excluded patients with positive CSF enteroviral PCR tests, some infants were not tested and other viruses (eg, parechoviruses)34 not detected by the enterovirus PCR may also cause aseptic meningitis. Third, certain antibiotics including ampicillin and vancomycin are known to interfere with the CSF protein assay used in our laboratory.24 Forty‐two of the 375 subjects included in our final analysis received antibiotics prior to lumbar puncture. When receiving antibiotics prior to lumbar puncture were excluded from analysis, the CSF protein concentrations were within 1% of the overall study population, suggesting that antibiotic administration before lumbar puncture did not influence our results in any meaningful way. We would not expect any of these limitations to disproportionately affect patients in 1 particular age category.

In conclusion, the CSF protein concentration values reported here represent the largest series to‐date for this young age group. Our study quantifies the age‐related decline in CSF protein concentration from birth to 56 days of life. Our work designing this study, specifically the exclusion criteria, refines the approach to defining normal CSF protein values in children. As CSF protein values decline steadily with increasing age, the selection of reference values is a balance of accuracy and convenience. Age‐specific reference values by 2‐week increments would be most accurate. However, considering reference values by month of age, as is the convention for CSF WBCs, is far more practical. The 95th percentile values by age category in our study were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL. The 95th percentile values were 115 mg/dL for infants 28 days and 89 mg/dL for infants 2956 days. We feel that either approach is reasonable. These values can be used to accurately interpret the results of CSF studies in neonates and young infants.

Emergency department evaluation of a febrile neonate or young infant routinely includes lumbar puncture and cerebrospinal fluid (CSF) analysis to diagnose meningitis or encephalitis. In addition to CSF Gram stain and culture, clinicians generally request a laboratory report for the CSF cell count, glucose content and protein concentration. Interpretation of these ancillary tests requires knowledge of normal reference values. In adult medicine, the accepted reference value for CSF protein concentration at the level of the lumbar spine is 15 mg/dL to45 mg/dL.1 There is general consensus among reference texts and published original studies dating back to Widell2 in 1958 that adult CSF protein reference values are not valid in the pediatric population. A healthy neonate's CSF protein concentration is normally twice to 3 times that of an adult, and declines with age from birth to early childhood. The most rapid rate of decline is thought to occur in the first 6 months of life as the infant's blood‐CSF barrier matures.3 However, published studies47 differ in the reported rate, timing, and magnitude of this decline; on close review these studies have significant limitations which call into question the appropriateness of using these values in clinical practice. Perhaps in recognition of the limited evidence, textbooks of general pediatrics,810 hospital medicine,1113 emergency medicine,14, 15 infectious diseases,16, 17 neonatology,18 and neurology19, 20 frequently publish norms for pediatric CSF protein concentration without reference to any original research studies.

Because ethical considerations prohibit subjecting young infants to a potentially painfully procedure (ie, lumbar puncture) before they are able to assent, we sought to define a study population that approximates a group of healthy infants. Our objectives were to quantify age‐related declines in CSF protein concentration and to determine accurate, age‐specific reference values for CSF protein concentration in a population of neonates and young infants who presented for medical care with an indication for lumbar puncture and were subsequently found to have no condition associated with elevated or depressed CSF protein concentration.

Methods

Results

During the study period, 1064 infants age 56 days of age or younger underwent lumbar puncture in the emergency department. Of these, 689 (65%) met sequential exclusion criteria as follows: traumatic lumbar puncture (n = 330); transported from an outside medical facility (n = 90); bacterial meningitis (n = 6); noncentral nervous system serious bacterial infections (n = 135); CSF positive for herpes simplex virus by PCR (n = 2); CSF positive for enterovirus by PCR (n = 45); congenital syphilis (n = 1); seizures (n = 28); abnormal central nervous system imaging (n = 2); and ventricular shunt device (n = 1). An additional 44 patients had lumbar puncture and CSF testing but the protein assay was never done or never reported and 5 patients did not have a CSF red blood cell count available. No cases were excluded for elevated serum bilirubin. Infants may have met multiple exclusion criteria. The remaining 375 (35%) subjects were included in the final analysis. The median patient age was 36 days (interquartile range: 2247 days); 139 (37%) were 28 days of age or younger. Overall, 205 (55%) were male, 211 (56%) were black, and 145 (39%) presented during enterovirus season. Most (43 of 57) preterm infants were born between 34 weeks to 37 weeks gestation. Antibiotics were administered before lumbar puncture to 42 (11%) infants and 312 (83%) infants had fever.

The median CSF protein value was 58 mg/dL (interquartile range: 4872 mg/dL). There was an age‐related declined in CSF protein concentration (Figure 1). In linear regression, the CSF protein concentration decreased 6.8% (95% confidence interval [CI], 5.48.1%; P < 0.001) for each 1‐week increase in age.0

Figure 1

Figure 2

CSF protein concentrations were higher for infants 28 days of age than for infants 2956 days of age (P < 0.001, Wilcoxon rank‐sum test). The median CSF protein concentrations were 68 mg/dL (95th percentile value, 115 mg/dL) for infants 28 days of age and 54 mg/dL (95th percentile value, 89 mg/dL) for infants 2956 days. CSF protein concentrations by 2‐week age intervals are shown in Table 1. The 95th percentile CSF protein concentrations were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL (Table 1). CSF protein concentration decreased significantly across each age interval when compared with infants in the next highest age category (P < 0.02 for all pair‐wise comparisons, Wilcoxon rank‐sum test).

Age‐specific 95th percentile CSF protein values changed by <1% when infants receiving antibiotics before lumbar puncture were excluded (Table 1). Age‐specific CSF protein values changed minimally when preterm infants were excluded with the exception of infants 4356 days of age where the 95th percentile value was 9.7% lower than when all infants were included (Table 1); the 90th percentile values in this age group were more comparable at 75 mg/dL and 71 mg/dL, respectively, in the subgroups with and without preterm infants. Age‐specific 95th percentile CSF protein values changes by <1% when patients with CSF pleocytosis were excluded.

Discussion

We examined CSF protein values in neonates and young infants to establish reference values and to bring the literature up to date at a time when molecular tools are commonly used in clinical practice. We also quantified the age‐related decline in CSF protein concentrations over the first two months of life. Our findings provide age‐specific reference ranges for CSF protein concentrations in neonates and young infants. These findings are particularly important because a variety of infectious (eg, herpes simplex virus infection) and noninfectious (eg, subarachnoid or intraventricular hemorrhage) conditions may occur in the absence of appreciable elevations in the CSF WBC.

CSF protein concentrations depend on serum protein concentrations and on the permeability of the blood‐CSF barrier. Immaturity of the blood‐CSF barrier is thought to result in higher CSF protein concentrations for neonates and young infants compared with older children and adults. Though previous studies agree that CSF protein concentrations depend on age, the reported age‐specific values and rates of decline vary considerably.47, 3032 Additionally, these prior studies are limited by (1) small sample size, (2) variable inclusion and exclusion criteria, (3) variable laboratory techniques to quantify protein concentration in a CSF sample, and (4) presentation of mean, standard deviation, and range values rather than the 75th, 90th, or 95th percentile values necessary to define a clinically meaningful reference range.

The median and mean values found in this study were generally comparable to previously published values (Table 2). In addition, we have quantified the age‐related decline in CSF protein concentrations identified in previous studies. While our large sample size allowed us to define narrower reference intervals than most previous studies, direct comparison of values used to define reference ranges was hampered by lack of consistent reporting of data across studies. Ahmed et al.5 and Bonadio et al.4 reported only mean and standard deviation values. When data are skewed, as is the case for CSF protein values, the standard deviation will be grossly inflated, making extrapolation to percentile values unreliable. The 90th percentile value of 87 mg/dL reported by Wong et al.7 for infants 060 days of age was similar to the value of 91 mg/dL for infants 56 days of age and younger found in this study. Biou et al.6 reported the following 95th percentile values: ages 18 days, 108 mg/dL; ages 830 days, 90 mg/dL; and ages 12 months, 77 mg/dL. These values are lower than those reported in our study. The reason for such differences is not clear. The exclusion criteria were similar between the two studies though Biou et al.6 did not include preterm infants. When we excluded preterm infants from our analysis, no age‐specific result decreased by more than 5%, making the inclusion of this population an unlikely explanation for the differences between the two studies.

CSF protein concentration is a method‐dependent value; the results depend a great deal on what technique the laboratory uses. Two common methods used in the past few decades are Biuret Colorimetry and Turbidimetric; reported values are approximately 25% higher with the Biuret method compared with the Turbidimetric method.33 A CSF protein reference value is only clinically useful if the method used to define the norm is specified and equivalent to currently used methods. Similar to our study, Biou et al.6 and Wong et al.7 used the Biuret (Vitros) method. The method of protein measurement was not specified by other studies.4, 5

This study had several limitations that could cause us to overestimate the upper bound of the reference range. First, spectrum bias is possible in this observational study. Individual physicians determined whether lumbar puncture was warranted, a limitation that could potentially lead to the disproportionate inclusion of infants with conditions associated with higher CSF protein concentrations. We do not believe that this limitation would meaningfully affect our results because febrile infants 56 days of age or younger routinely undergo lumbar puncture at our institution, regardless of illness severity, and patients diagnosed with conditions known or suspected to increase CSF protein concentrations were excluded. Second, infants with aseptic meningitisa condition that can be associated with elevated CSF protein concentrationsmay have been misclassified as uninfected. Though we excluded patients with positive CSF enteroviral PCR tests, some infants were not tested and other viruses (eg, parechoviruses)34 not detected by the enterovirus PCR may also cause aseptic meningitis. Third, certain antibiotics including ampicillin and vancomycin are known to interfere with the CSF protein assay used in our laboratory.24 Forty‐two of the 375 subjects included in our final analysis received antibiotics prior to lumbar puncture. When receiving antibiotics prior to lumbar puncture were excluded from analysis, the CSF protein concentrations were within 1% of the overall study population, suggesting that antibiotic administration before lumbar puncture did not influence our results in any meaningful way. We would not expect any of these limitations to disproportionately affect patients in 1 particular age category.

In conclusion, the CSF protein concentration values reported here represent the largest series to‐date for this young age group. Our study quantifies the age‐related decline in CSF protein concentration from birth to 56 days of life. Our work designing this study, specifically the exclusion criteria, refines the approach to defining normal CSF protein values in children. As CSF protein values decline steadily with increasing age, the selection of reference values is a balance of accuracy and convenience. Age‐specific reference values by 2‐week increments would be most accurate. However, considering reference values by month of age, as is the convention for CSF WBCs, is far more practical. The 95th percentile values by age category in our study were as follows: ages 014 days, 132 mg/dL; ages 1528 days, 100 mg/dL; ages 2942 days, 89 mg/dL; and ages 4356 days, 83 mg/dL. The 95th percentile values were 115 mg/dL for infants 28 days and 89 mg/dL for infants 2956 days. We feel that either approach is reasonable. These values can be used to accurately interpret the results of CSF studies in neonates and young infants.

Communication among hospital care providers is critically important to provide safe and effective care.15 Yet, studies in operating rooms, intensive care units (ICUs), and general medical units have revealed widely discrepant views on the quality of collaboration and communication between physicians and nurses.68 Although physicians consistently gave high ratings to the quality of collaboration with nurses, nurses rated the quality of collaboration with physicians relatively poorly.

A significant barrier to communication among providers on patient care units is the fluidity and geographic dispersion of team members.8 Physicians, nurses, and other hospital care providers have difficulty finding a way to discuss the care of their patients in person. Research has shown that nurses and physicians on patient care units do not communicate consistently and frequently are not in agreement about their patients' plans of care9, 10

Interdisciplinary Rounds (IDR) have been used as a means to assemble patient care unit team members and improve collaboration on the plan of care.1114 Prior research has demonstrated improved ratings of collaboration on the part of physicians,13, 14 but the effect of IDR on nurses' ratings of collaboration and teamwork has not been adequately assessed. One IDR study did not assess nurses' perceptions,13 while others used instruments not previously described and/or validated in the literature.12, 14 Regarding more concrete outcomes, research indicates variable effects of IDR on length of stay (LOS) and cost. Although 2 studies documented a reduction in LOS and cost with the use of IDR,12, 13 another study showed no effect.15 Furthermore, prior studies evaluated the use of IDR on resident‐covered teaching services. The effect IDR has on collaboration, LOS, and cost in a nonteaching hospitalist service setting is not known.

This study had 3 aims. The first was to assess the impact of an intervention, Structured Inter‐Disciplinary Rounds (SIDR), on nurses' ratings of collaboration and teamwork. The second was to assess the feasibility and sustainability of the intervention. The third was to assess the impact of the intervention on hospital LOS and cost.

Methods

Results

Ratings of Teamwork and Perceptions of SIDR

As shown in Figure 1, a larger percentage of nurses rated the quality of communication and collaboration with hospitalists as high or very high on the intervention unit compared to the control unit (80% vs. 54%; P = 0.05).

Figure 1

Nurses' ratings of the teamwork and safety climate are summarized in Table 2. The median teamwork climate score was 85.7 (interquartile range [IQR], 75.092.9) for the intervention unit as compared to 61.6 (IQR, 48.283.9) for the control unit (P = 0.008). The median safety climate score was 75.0 (IQR, 70.581.3) for the intervention unit as compared to 61.1 (IQR, 30.281.3) for the control unit (P = 0.03).

Table 2.Nurses' Ratings of Teamwork and Patient Safety Climate by Unit

	Control Unit, n = 24	Intervention Unit, n = 25	P Value
Abbreviation: IQR, interquartile range.
Median Teamwork Climate Score (IQR)	75.0 (70.581.3)	61.6 (48.283.9)	0.008
Median Safety Climate Score (IQR)	85.7 (75.092.9)	61.1 (30.281.3)	0.03

Sixty‐five of 88 (74%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved the efficiency of their work day. Eighty of 88 (91%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved team collaboration. Seventy‐six of 88 (86%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved patient care. Sixty‐seven of 88 (76%) hospitalists and 22 of 25 (88%) nurses indicated that they wanted SIDR to continue indefinitely.

Discussion

We found that nurses working on a unit using SIDR rated the quality of communication and collaboration with hospitalists significantly higher as compared to a control unit. Notably, because hospitalists worked on both the intervention and control unit during their weeks on service, nurses on each unit were rating the quality of collaboration with the same hospitalists. Nurses also rated the teamwork and safety climate higher on the intervention unit. These findings are important because prior research has shown that nurses are often dissatisfied with the quality of collaboration and teamwork with physicians.68 Potential explanations include fundamental differences between nurses and physicians with regard to status/authority, gender, training, and patient care responsibilities.6 Unfortunately, a culture of poor teamwork may lead to a workplace in which team members feel unable to approach certain individuals and uncomfortable raising concerns. Not surprisingly, higher ratings of teamwork culture have been associated with nurse retention.22, 23 SIDR provided a facilitated forum for interdisciplinary discussion, exchange of critical clinical information, and collaboration on the plan of care.

Our findings are also important because poor communication represents a major etiology of preventable adverse events in hospitals.15 Higher ratings of collaboration and teamwork have been associated with better patient outcomes in observational studies.2426 Further research should evaluate the impact of improved interdisciplinary collaboration as a result of SIDR on the safety of care delivered on inpatient medical units.

The majority of providers agreed that SIDR improved patient care and that SIDR should continue indefinitely. Importantly, providers also felt that SIDR improved the efficiency of their workday and attendance was high among all disciplines. Prior studies on IDR either did not report attendance or struggled with attendance.11 Incorporating the input of frontline providers into the design of SIDR allowed us to create a sustainable intervention which fit into daily workflow.

Our bivariate analyses found significant patient case‐mix differences between the intervention and control unit, limiting our ability to perform direct comparisons in LOS and cost. Pre‐post analyses of LOS and cost may be affected by cyclical or secular trends. Because each approach has its own limitations, we felt that analyses using both an historic as well as a concurrent control would provide a more complete assessment of the effect of the intervention. We included case mix, among other variables, in out multivariable regression analyses and found no benefit to SIDR with regard to LOS and cost. Two prior studies have shown a reduction in LOS and cost with the use of IDR.12, 13 However, one study was conducted approximately 15 years ago and included patients with a longer mean LOS.12 The second study used a pre‐post study design which may not have accounted for unmeasured confounders affecting LOS and cost.13 A third, smaller study showed no effect on LOS and cost with the use of IDR.15 No prior study has evaluated the effect of IDR on LOS and cost in a nonteaching hospitalist service setting.

Our study has several limitations. First, our study reflects the experience of an intervention unit compared to a control unit in a single hospital. Larger studies will be required to test the reproducibility and generalizability of our findings. Second, we did not conduct preintervention provider surveys for comparison ratings of collaboration and teamwork. A prior study, conducted by our research group, found that nurses gave low ratings to the teamwork climate and the quality of collaboration with hospitalists.8 Because this baseline study showed consistently low nurse ratings of collaboration and teamwork across all medical units, and because the units in the current study were identical in size, structure, and staffing of nonphysician personnel, we did not repeat nurse surveys prior to the intervention. Third, as previously mentioned, our study did not directly assess the effect of improved teamwork and collaboration on patient safety. Further study is needed to evaluate this. Although we are not aware of any other interventions to improve interdisciplinary communication on the intervention unit, it is possible that other unknown factors contributed to our findings. We believe this is unlikely due to the magnitude of the improvement in collaboration and the high ratings of SIDR by nurses and physicians on the intervention unit.

In summary, SIDR had a positive effect on nurses' ratings of collaboration and teamwork on a nonteaching hospitalist unit. Future research efforts should assess whether improved teamwork as a result of SIDR also translates into safer patient care.

Communication among hospital care providers is critically important to provide safe and effective care.15 Yet, studies in operating rooms, intensive care units (ICUs), and general medical units have revealed widely discrepant views on the quality of collaboration and communication between physicians and nurses.68 Although physicians consistently gave high ratings to the quality of collaboration with nurses, nurses rated the quality of collaboration with physicians relatively poorly.

A significant barrier to communication among providers on patient care units is the fluidity and geographic dispersion of team members.8 Physicians, nurses, and other hospital care providers have difficulty finding a way to discuss the care of their patients in person. Research has shown that nurses and physicians on patient care units do not communicate consistently and frequently are not in agreement about their patients' plans of care9, 10

Interdisciplinary Rounds (IDR) have been used as a means to assemble patient care unit team members and improve collaboration on the plan of care.1114 Prior research has demonstrated improved ratings of collaboration on the part of physicians,13, 14 but the effect of IDR on nurses' ratings of collaboration and teamwork has not been adequately assessed. One IDR study did not assess nurses' perceptions,13 while others used instruments not previously described and/or validated in the literature.12, 14 Regarding more concrete outcomes, research indicates variable effects of IDR on length of stay (LOS) and cost. Although 2 studies documented a reduction in LOS and cost with the use of IDR,12, 13 another study showed no effect.15 Furthermore, prior studies evaluated the use of IDR on resident‐covered teaching services. The effect IDR has on collaboration, LOS, and cost in a nonteaching hospitalist service setting is not known.

This study had 3 aims. The first was to assess the impact of an intervention, Structured Inter‐Disciplinary Rounds (SIDR), on nurses' ratings of collaboration and teamwork. The second was to assess the feasibility and sustainability of the intervention. The third was to assess the impact of the intervention on hospital LOS and cost.

Methods

Results

Ratings of Teamwork and Perceptions of SIDR

As shown in Figure 1, a larger percentage of nurses rated the quality of communication and collaboration with hospitalists as high or very high on the intervention unit compared to the control unit (80% vs. 54%; P = 0.05).

Figure 1

Nurses' ratings of the teamwork and safety climate are summarized in Table 2. The median teamwork climate score was 85.7 (interquartile range [IQR], 75.092.9) for the intervention unit as compared to 61.6 (IQR, 48.283.9) for the control unit (P = 0.008). The median safety climate score was 75.0 (IQR, 70.581.3) for the intervention unit as compared to 61.1 (IQR, 30.281.3) for the control unit (P = 0.03).

Table 2.Nurses' Ratings of Teamwork and Patient Safety Climate by Unit

	Control Unit, n = 24	Intervention Unit, n = 25	P Value
Abbreviation: IQR, interquartile range.
Median Teamwork Climate Score (IQR)	75.0 (70.581.3)	61.6 (48.283.9)	0.008
Median Safety Climate Score (IQR)	85.7 (75.092.9)	61.1 (30.281.3)	0.03

Sixty‐five of 88 (74%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved the efficiency of their work day. Eighty of 88 (91%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved team collaboration. Seventy‐six of 88 (86%) hospitalists and 18 of 24 (75%) nurses agreed that SIDR improved patient care. Sixty‐seven of 88 (76%) hospitalists and 22 of 25 (88%) nurses indicated that they wanted SIDR to continue indefinitely.

Discussion

We found that nurses working on a unit using SIDR rated the quality of communication and collaboration with hospitalists significantly higher as compared to a control unit. Notably, because hospitalists worked on both the intervention and control unit during their weeks on service, nurses on each unit were rating the quality of collaboration with the same hospitalists. Nurses also rated the teamwork and safety climate higher on the intervention unit. These findings are important because prior research has shown that nurses are often dissatisfied with the quality of collaboration and teamwork with physicians.68 Potential explanations include fundamental differences between nurses and physicians with regard to status/authority, gender, training, and patient care responsibilities.6 Unfortunately, a culture of poor teamwork may lead to a workplace in which team members feel unable to approach certain individuals and uncomfortable raising concerns. Not surprisingly, higher ratings of teamwork culture have been associated with nurse retention.22, 23 SIDR provided a facilitated forum for interdisciplinary discussion, exchange of critical clinical information, and collaboration on the plan of care.

Our findings are also important because poor communication represents a major etiology of preventable adverse events in hospitals.15 Higher ratings of collaboration and teamwork have been associated with better patient outcomes in observational studies.2426 Further research should evaluate the impact of improved interdisciplinary collaboration as a result of SIDR on the safety of care delivered on inpatient medical units.

The majority of providers agreed that SIDR improved patient care and that SIDR should continue indefinitely. Importantly, providers also felt that SIDR improved the efficiency of their workday and attendance was high among all disciplines. Prior studies on IDR either did not report attendance or struggled with attendance.11 Incorporating the input of frontline providers into the design of SIDR allowed us to create a sustainable intervention which fit into daily workflow.

Our bivariate analyses found significant patient case‐mix differences between the intervention and control unit, limiting our ability to perform direct comparisons in LOS and cost. Pre‐post analyses of LOS and cost may be affected by cyclical or secular trends. Because each approach has its own limitations, we felt that analyses using both an historic as well as a concurrent control would provide a more complete assessment of the effect of the intervention. We included case mix, among other variables, in out multivariable regression analyses and found no benefit to SIDR with regard to LOS and cost. Two prior studies have shown a reduction in LOS and cost with the use of IDR.12, 13 However, one study was conducted approximately 15 years ago and included patients with a longer mean LOS.12 The second study used a pre‐post study design which may not have accounted for unmeasured confounders affecting LOS and cost.13 A third, smaller study showed no effect on LOS and cost with the use of IDR.15 No prior study has evaluated the effect of IDR on LOS and cost in a nonteaching hospitalist service setting.

Our study has several limitations. First, our study reflects the experience of an intervention unit compared to a control unit in a single hospital. Larger studies will be required to test the reproducibility and generalizability of our findings. Second, we did not conduct preintervention provider surveys for comparison ratings of collaboration and teamwork. A prior study, conducted by our research group, found that nurses gave low ratings to the teamwork climate and the quality of collaboration with hospitalists.8 Because this baseline study showed consistently low nurse ratings of collaboration and teamwork across all medical units, and because the units in the current study were identical in size, structure, and staffing of nonphysician personnel, we did not repeat nurse surveys prior to the intervention. Third, as previously mentioned, our study did not directly assess the effect of improved teamwork and collaboration on patient safety. Further study is needed to evaluate this. Although we are not aware of any other interventions to improve interdisciplinary communication on the intervention unit, it is possible that other unknown factors contributed to our findings. We believe this is unlikely due to the magnitude of the improvement in collaboration and the high ratings of SIDR by nurses and physicians on the intervention unit.

In summary, SIDR had a positive effect on nurses' ratings of collaboration and teamwork on a nonteaching hospitalist unit. Future research efforts should assess whether improved teamwork as a result of SIDR also translates into safer patient care.

Communication among hospital care providers is critically important to provide safe and effective care.15 Yet, studies in operating rooms, intensive care units (ICUs), and general medical units have revealed widely discrepant views on the quality of collaboration and communication between physicians and nurses.68 Although physicians consistently gave high ratings to the quality of collaboration with nurses, nurses rated the quality of collaboration with physicians relatively poorly.

A significant barrier to communication among providers on patient care units is the fluidity and geographic dispersion of team members.8 Physicians, nurses, and other hospital care providers have difficulty finding a way to discuss the care of their patients in person. Research has shown that nurses and physicians on patient care units do not communicate consistently and frequently are not in agreement about their patients' plans of care9, 10

Interdisciplinary Rounds (IDR) have been used as a means to assemble patient care unit team members and improve collaboration on the plan of care.1114 Prior research has demonstrated improved ratings of collaboration on the part of physicians,13, 14 but the effect of IDR on nurses' ratings of collaboration and teamwork has not been adequately assessed. One IDR study did not assess nurses' perceptions,13 while others used instruments not previously described and/or validated in the literature.12, 14 Regarding more concrete outcomes, research indicates variable effects of IDR on length of stay (LOS) and cost. Although 2 studies documented a reduction in LOS and cost with the use of IDR,12, 13 another study showed no effect.15 Furthermore, prior studies evaluated the use of IDR on resident‐covered teaching services. The effect IDR has on collaboration, LOS, and cost in a nonteaching hospitalist service setting is not known.

This study had 3 aims. The first was to assess the impact of an intervention, Structured Inter‐Disciplinary Rounds (SIDR), on nurses' ratings of collaboration and teamwork. The second was to assess the feasibility and sustainability of the intervention. The third was to assess the impact of the intervention on hospital LOS and cost.

Methods

Results