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Effects of ibuprofen on the physiology and survival of hypothermic sepsis

Arons, Murray M. MD; Wheeler, Arthur P. MD; Bernard, Gordon R. MD; Christman, Brian W. MD; Russell, James A. MD; Schein, Roland MD; Summer, Warren R. MD; Steinberg, Kenneth P. MD; Fulkerson, William MD; Wright, Patrick MD; Dupont, William D. MD; Swindell, Bridgett B. RN

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Objectives The objective was to compare the clinical and physiologic characteristics of febrile septic patients with hypothermic septic patients; and to examine plasma levels of cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) and the lipid mediators thromboxane B2 (TxB2) and prostacyclin in hypothermic septic patients in comparison with febrile patients. Most importantly, we wanted to report the effect of ibuprofen treatment on vital signs, organ failure, and mortality in hypothermic sepsis.

Setting The study was performed in the intensive care units (ICUs) of seven clinical centers in the United States and Canada.

Patients Four hundred fifty-five patients admitted to the ICU who met defined criteria for severe sepsis and were suspected of having a serious infection.

Intervention Ibuprofen at a dose of 10 mg/kg (maximum 800 mg) was administered intravenously over 30 to 60 mins every 6 hrs for eight doses vs. placebo (glycine buffer vehicle).

Measurements and Main Results Forty-four (10%) septic patients met criteria for hypothermia and 409 were febrile. The mortality rate was significantly higher in hypothermic patients, 70% vs. 35% for febrile patients. At study entry, urinary metabolites of TxB2, prostacyclin, and serum levels of TNF-alpha and IL-6 were significantly elevated in hypothermic patients compared with febrile patients. In hypothermic patients treated with ibuprofen, there was a trend toward an increased number of days free of major organ system failures and a significant reduction in the 30-day mortality rate from 90% (18/20 placebo-treated patients) to 54% (13/24 ibuprofen-treated patients).

Conclusions Hypothermic sepsis has an incidence of [similar]10% and an untreated mortality twice that of severe sepsis presenting with fever. When compared with febrile patients, the hypothermic group has an amplified response with respect to cytokines TNF-alpha and IL-6 and lipid mediators TxB2 and prostacyclin. Treatment with ibuprofen may decrease mortality in this select group of septic patients. (Crit Care Med 1999; 27:699-707)

For the Ibuprofen in Sepsis Study Group.

From the Center For Lung Research (Study Coordinating Center), Departments of Medicine, Preventive Medicine and Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, TN.

Supported by National Institutes of Health, National Heart Lung and Blood Institutes, grants HL 43167 (Cardiopulmonary Effects of Ibuprofen in Human Sepsis), HL 19153 (Specialized Center of Research in Acute Lung Injury), HL 07123 (Training Grant in Pulmonary Diseases); and the Bernard Werthan, Sr. Fund for Pulmonary Research, Nashville, TN. The authors thank The Upjohn Co. for supplying the intravenous ibuprofen and for providing support for the measurement of ibuprofen plasma levels.

The Ibuprofen in Sepsis Study Group: The Department of Pulmonary Medicine, St. Paul's Hospital, Vancouver, Canada (James A. Russell, MD; and Alana Drummond, RN); the University of Miami School of Medicine, Department of Veterans Affairs Medical Center, Miami, FL (Roland Schein, MD; and Maria Pena, RN); The Department of Pulmonary/Critical Care Medicine, School of Medicine in New Orleans, Louisiana State University Medical Center, New Orleans, LA (Warren R. Summer, MD; Bennett deBoisblanc, MD; Brenda Everett, RN; Chris Glenn, RN; and Denise Tebbe, RN); the Divisions of Pulmonary and Critical Care Medicine (Gordon R. Bernard, MD; Arthur P. Wheeler, MD; Brian W. Christman, MD; Bridgett B. Swindell, RN; Laurence C. Carmichael, MD; and Mary J. Stroud, RN), Biomedical Engineering and Computing (Stanley B. Higgins and Keyuan Jiang, PhD), Biostatistics (William D. Dupont, MD; and Walton D. Plummer, Jr, MS), and Radiological Sciences (Frank E. Carroll, MD), Vanderbilt University Medical Center, Nashville, TN; the Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, WA (Leonard D. Hudson, MD, Kenneth P. Steinberg, MD; and Doreen Anardi, RN); the Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC (William J. Fulkerson, Mary Jo Abernathy, RN, Lee Mallatratt, RN, and Pat Weston, RN); and the Division of Pulmonary Medicine, Methodist Hospital, Indianapolis, IN (Patrick E. Wright and Kelly Colvin, RN).

Address requests for reprints to: Gordon Bernard, MD, Center for Lung Research, T-1217 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2650.

© 1999 Lippincott Williams & Wilkins, Inc.