High-dose steroids tame post-EVAR inflammation

BOSTON – Preoperative high-dose methylprednisolone dramatically reduced inflammation and enhanced recovery after endovascular aortic repair without increased morbidity in a prospective, double-blinded randomized study.

The primary outcome of modified systemic inflammatory response syndrome (SIRS) developed in 92% on placebo and 27% given methylprednisolone (relative risk, 0.29; P less than .001).

The effect was particularly striking in patients with three or more SIRS criteria, with an overall number needed to treat of 1.5, Dr. Henrik Kehlet said at the annual meeting of the American Surgical Association.

Tempering the postoperative inflammatory response with methylprednisolone also significantly trimmed hospital stays from 3 to 2 days (P less than .001) and morphine requirements from 10 mg to 0 mg (P less than .001).

Medical morbidity was reduced in the methylprednisolone group, but not significantly (23% vs. 36%; P = .1), as was surgical morbidity (20% vs. 21%; P = 1.0).

Importantly, there was no sign of an increase in diagnosed (23% vs. 17%) or treated (1% vs. 3%) endoleaks on computed tomography scan among 146 patients evaluable at 3 months’ follow-up, said Dr. Kehlet, professor of perioperative therapy and head of the surgical pathophysiology section at Rigshospitalet, Copenhagen University, and the oft-described "father" of rapid recovery.

Patrice Wendling/Frontline Medical News

About 40%-60% of patients undergoing endovascular aortic repair (EVAR) will develop postoperative SIRS. Although there is limited surgical injury with the minimally invasive procedure, there is still a stress response because the prosthesis releases proinflammatory mediators from the thrombus in the aortic aneurysm, he explained.

Invited discussant Dr. Basil Pruitt of the division of trauma at the University of Texas Health Science Center, San Antonio, observed that the findings take on added import in light of a 7,500-patient study presented at the recent American College of Cardiology meeting showing that methylprednisolone conferred no significant benefit and was associated with a 15% increased risk of postoperative heart attack plus death when given during cardiac surgery with cardiopulmonary bypass. He also questioned whether the glucocorticosteroid lowered the metabolic rate, as this would impair wound healing, or induced hypoglycemia or glucose intolerance.

"Do those findings and the concerns noted above simply define patient groups in whom methylprednisolone should not be infused preoperatively or, alternatively, do they define a threshold of physiologic or operative insult beyond which the effect of methylprednisolone is outweighed by the magnitude of injury and the associated systemic inflammatory response syndrome?" he asked.

Dr. Kehlet responded that he was unable to determine why that particular abstract found increased morbidity, but noted that the same authors previously published a systematic review (Eur. Heart J. 2008;29:2592-600) supporting reduced morbidity with steroid use in cardiopulmonary bypass.

He added, "The effect may depend on the type of injury, as you mention; cardiopulmonary bypass [is] a very special injury with many mediators of the stress response, compared to other surgical operations. We need more studies. And, finally, if you want to find out about the real outcomes, you must integrate the pharmacologic intervention with an optimized, fast-track setup."

Dr. Kehlet said they did not measure metabolic rate, but that no clinical problem was observed in the limited number of diabetics (n = 22) in their study. This finding is also supported by a huge, multicenter Dutch trial, in which intraoperative high-dose dexamethasone was associated with higher postoperative glucose levels in cardiopulmonary bypass patients, but had no effect on diabetes in subgroup analyses or on the primary endpoint of major morbidity at 30 days (JAMA 2012;308:1761-7).

For Dr. Kehlet's single-center, double-blinded study, 153 patients undergoing EVAR for abdominal aortic aneurysm were randomly assigned to receive a preoperative single dose of placebo or what was described as a single "old-fashioned sepsis dose of methylprednisolone" at 30 mg/kg. The two groups were similar at baseline with respect to age, comorbidities, aneurysm size, thrombus volume, EVAR procedures, and blood loss.

A modified version of SIRS was assessed during the first 4 days after surgery and defined by two or more of the following criteria: fever of more than 38° C (100.4° F) or less than 36° C (96.8° F), heart rate of more than 90 beats per minute, respiratory rate of more than 20 breaths per minute or arterial carbon dioxide tension of less than 4.3 kPa (32.25 mm Hg), and a C-reactive protein (CRP) level of more than 75 mg/L. The traditional fourth SIRS criterion of leukocytosis was replaced with CRP level because glucocorticoids always lead to leukocytosis, Dr. Kehlet noted.

Among 150 evaluable patients, high-dose methylprednisolone almost completely eliminated the proinflammatory activities of interleukin (IL)-6 (186 pg/mL vs. 20 mg/dL; P less than .001), IL-8, and CRP.

Among other inflammatory parameters, methylprednisolone reduced soluble tumor necrosis factor receptor 1 levels, but did not modify the d-dimer response, metalloproteinase-9, or myeloperoxidase, he said.

By 3 months, mortality was similar at 3% in the methylprednisolone group and 1% in the placebo group (P less than .5).

"What we don’t know is what the optimal dose-response relationship is because we used a very high dose and, of course, this was only 150 patients, so the safety issues cannot be answered based on this study, but the results are promising for future large-scale studies in this interesting operation," Dr. Kehlet concluded.

Dr. Kehlet and his coauthors reported no financial disclosures.

The complete manuscript of this study and its presentation at the American Surgical Association’s 134th annual meeting, April 2014, in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.

pwendling@frontlinemedcom.com

BOSTON – Preoperative high-dose methylprednisolone dramatically reduced inflammation and enhanced recovery after endovascular aortic repair without increased morbidity in a prospective, double-blinded randomized study.

The primary outcome of modified systemic inflammatory response syndrome (SIRS) developed in 92% on placebo and 27% given methylprednisolone (relative risk, 0.29; P less than .001).

The effect was particularly striking in patients with three or more SIRS criteria, with an overall number needed to treat of 1.5, Dr. Henrik Kehlet said at the annual meeting of the American Surgical Association.

Tempering the postoperative inflammatory response with methylprednisolone also significantly trimmed hospital stays from 3 to 2 days (P less than .001) and morphine requirements from 10 mg to 0 mg (P less than .001).

Medical morbidity was reduced in the methylprednisolone group, but not significantly (23% vs. 36%; P = .1), as was surgical morbidity (20% vs. 21%; P = 1.0).

Importantly, there was no sign of an increase in diagnosed (23% vs. 17%) or treated (1% vs. 3%) endoleaks on computed tomography scan among 146 patients evaluable at 3 months’ follow-up, said Dr. Kehlet, professor of perioperative therapy and head of the surgical pathophysiology section at Rigshospitalet, Copenhagen University, and the oft-described "father" of rapid recovery.

Patrice Wendling/Frontline Medical News

About 40%-60% of patients undergoing endovascular aortic repair (EVAR) will develop postoperative SIRS. Although there is limited surgical injury with the minimally invasive procedure, there is still a stress response because the prosthesis releases proinflammatory mediators from the thrombus in the aortic aneurysm, he explained.

Invited discussant Dr. Basil Pruitt of the division of trauma at the University of Texas Health Science Center, San Antonio, observed that the findings take on added import in light of a 7,500-patient study presented at the recent American College of Cardiology meeting showing that methylprednisolone conferred no significant benefit and was associated with a 15% increased risk of postoperative heart attack plus death when given during cardiac surgery with cardiopulmonary bypass. He also questioned whether the glucocorticosteroid lowered the metabolic rate, as this would impair wound healing, or induced hypoglycemia or glucose intolerance.

"Do those findings and the concerns noted above simply define patient groups in whom methylprednisolone should not be infused preoperatively or, alternatively, do they define a threshold of physiologic or operative insult beyond which the effect of methylprednisolone is outweighed by the magnitude of injury and the associated systemic inflammatory response syndrome?" he asked.

Dr. Kehlet responded that he was unable to determine why that particular abstract found increased morbidity, but noted that the same authors previously published a systematic review (Eur. Heart J. 2008;29:2592-600) supporting reduced morbidity with steroid use in cardiopulmonary bypass.

He added, "The effect may depend on the type of injury, as you mention; cardiopulmonary bypass [is] a very special injury with many mediators of the stress response, compared to other surgical operations. We need more studies. And, finally, if you want to find out about the real outcomes, you must integrate the pharmacologic intervention with an optimized, fast-track setup."

Dr. Kehlet said they did not measure metabolic rate, but that no clinical problem was observed in the limited number of diabetics (n = 22) in their study. This finding is also supported by a huge, multicenter Dutch trial, in which intraoperative high-dose dexamethasone was associated with higher postoperative glucose levels in cardiopulmonary bypass patients, but had no effect on diabetes in subgroup analyses or on the primary endpoint of major morbidity at 30 days (JAMA 2012;308:1761-7).

For Dr. Kehlet's single-center, double-blinded study, 153 patients undergoing EVAR for abdominal aortic aneurysm were randomly assigned to receive a preoperative single dose of placebo or what was described as a single "old-fashioned sepsis dose of methylprednisolone" at 30 mg/kg. The two groups were similar at baseline with respect to age, comorbidities, aneurysm size, thrombus volume, EVAR procedures, and blood loss.

A modified version of SIRS was assessed during the first 4 days after surgery and defined by two or more of the following criteria: fever of more than 38° C (100.4° F) or less than 36° C (96.8° F), heart rate of more than 90 beats per minute, respiratory rate of more than 20 breaths per minute or arterial carbon dioxide tension of less than 4.3 kPa (32.25 mm Hg), and a C-reactive protein (CRP) level of more than 75 mg/L. The traditional fourth SIRS criterion of leukocytosis was replaced with CRP level because glucocorticoids always lead to leukocytosis, Dr. Kehlet noted.

Among 150 evaluable patients, high-dose methylprednisolone almost completely eliminated the proinflammatory activities of interleukin (IL)-6 (186 pg/mL vs. 20 mg/dL; P less than .001), IL-8, and CRP.

Among other inflammatory parameters, methylprednisolone reduced soluble tumor necrosis factor receptor 1 levels, but did not modify the d-dimer response, metalloproteinase-9, or myeloperoxidase, he said.

By 3 months, mortality was similar at 3% in the methylprednisolone group and 1% in the placebo group (P less than .5).

"What we don’t know is what the optimal dose-response relationship is because we used a very high dose and, of course, this was only 150 patients, so the safety issues cannot be answered based on this study, but the results are promising for future large-scale studies in this interesting operation," Dr. Kehlet concluded.

Dr. Kehlet and his coauthors reported no financial disclosures.

The complete manuscript of this study and its presentation at the American Surgical Association’s 134th annual meeting, April 2014, in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.

pwendling@frontlinemedcom.com

BOSTON – Preoperative high-dose methylprednisolone dramatically reduced inflammation and enhanced recovery after endovascular aortic repair without increased morbidity in a prospective, double-blinded randomized study.

The primary outcome of modified systemic inflammatory response syndrome (SIRS) developed in 92% on placebo and 27% given methylprednisolone (relative risk, 0.29; P less than .001).

The effect was particularly striking in patients with three or more SIRS criteria, with an overall number needed to treat of 1.5, Dr. Henrik Kehlet said at the annual meeting of the American Surgical Association.

Tempering the postoperative inflammatory response with methylprednisolone also significantly trimmed hospital stays from 3 to 2 days (P less than .001) and morphine requirements from 10 mg to 0 mg (P less than .001).

Medical morbidity was reduced in the methylprednisolone group, but not significantly (23% vs. 36%; P = .1), as was surgical morbidity (20% vs. 21%; P = 1.0).

Importantly, there was no sign of an increase in diagnosed (23% vs. 17%) or treated (1% vs. 3%) endoleaks on computed tomography scan among 146 patients evaluable at 3 months’ follow-up, said Dr. Kehlet, professor of perioperative therapy and head of the surgical pathophysiology section at Rigshospitalet, Copenhagen University, and the oft-described "father" of rapid recovery.

Patrice Wendling/Frontline Medical News

About 40%-60% of patients undergoing endovascular aortic repair (EVAR) will develop postoperative SIRS. Although there is limited surgical injury with the minimally invasive procedure, there is still a stress response because the prosthesis releases proinflammatory mediators from the thrombus in the aortic aneurysm, he explained.

Invited discussant Dr. Basil Pruitt of the division of trauma at the University of Texas Health Science Center, San Antonio, observed that the findings take on added import in light of a 7,500-patient study presented at the recent American College of Cardiology meeting showing that methylprednisolone conferred no significant benefit and was associated with a 15% increased risk of postoperative heart attack plus death when given during cardiac surgery with cardiopulmonary bypass. He also questioned whether the glucocorticosteroid lowered the metabolic rate, as this would impair wound healing, or induced hypoglycemia or glucose intolerance.

"Do those findings and the concerns noted above simply define patient groups in whom methylprednisolone should not be infused preoperatively or, alternatively, do they define a threshold of physiologic or operative insult beyond which the effect of methylprednisolone is outweighed by the magnitude of injury and the associated systemic inflammatory response syndrome?" he asked.

Dr. Kehlet responded that he was unable to determine why that particular abstract found increased morbidity, but noted that the same authors previously published a systematic review (Eur. Heart J. 2008;29:2592-600) supporting reduced morbidity with steroid use in cardiopulmonary bypass.

He added, "The effect may depend on the type of injury, as you mention; cardiopulmonary bypass [is] a very special injury with many mediators of the stress response, compared to other surgical operations. We need more studies. And, finally, if you want to find out about the real outcomes, you must integrate the pharmacologic intervention with an optimized, fast-track setup."

Dr. Kehlet said they did not measure metabolic rate, but that no clinical problem was observed in the limited number of diabetics (n = 22) in their study. This finding is also supported by a huge, multicenter Dutch trial, in which intraoperative high-dose dexamethasone was associated with higher postoperative glucose levels in cardiopulmonary bypass patients, but had no effect on diabetes in subgroup analyses or on the primary endpoint of major morbidity at 30 days (JAMA 2012;308:1761-7).

For Dr. Kehlet's single-center, double-blinded study, 153 patients undergoing EVAR for abdominal aortic aneurysm were randomly assigned to receive a preoperative single dose of placebo or what was described as a single "old-fashioned sepsis dose of methylprednisolone" at 30 mg/kg. The two groups were similar at baseline with respect to age, comorbidities, aneurysm size, thrombus volume, EVAR procedures, and blood loss.

A modified version of SIRS was assessed during the first 4 days after surgery and defined by two or more of the following criteria: fever of more than 38° C (100.4° F) or less than 36° C (96.8° F), heart rate of more than 90 beats per minute, respiratory rate of more than 20 breaths per minute or arterial carbon dioxide tension of less than 4.3 kPa (32.25 mm Hg), and a C-reactive protein (CRP) level of more than 75 mg/L. The traditional fourth SIRS criterion of leukocytosis was replaced with CRP level because glucocorticoids always lead to leukocytosis, Dr. Kehlet noted.

Among 150 evaluable patients, high-dose methylprednisolone almost completely eliminated the proinflammatory activities of interleukin (IL)-6 (186 pg/mL vs. 20 mg/dL; P less than .001), IL-8, and CRP.

Among other inflammatory parameters, methylprednisolone reduced soluble tumor necrosis factor receptor 1 levels, but did not modify the d-dimer response, metalloproteinase-9, or myeloperoxidase, he said.

By 3 months, mortality was similar at 3% in the methylprednisolone group and 1% in the placebo group (P less than .5).

"What we don’t know is what the optimal dose-response relationship is because we used a very high dose and, of course, this was only 150 patients, so the safety issues cannot be answered based on this study, but the results are promising for future large-scale studies in this interesting operation," Dr. Kehlet concluded.

Dr. Kehlet and his coauthors reported no financial disclosures.

The complete manuscript of this study and its presentation at the American Surgical Association’s 134th annual meeting, April 2014, in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.

pwendling@frontlinemedcom.com