Ibuprofen for Hypothermic Patients with Sepsis?
Abstract & Commentary
Patients with sepsis syndrome, also called the systemic inflammatory response syndrome (SIRS), can be either febrile or hypothermic. This study, a spinoff of a much larger study, sought to determine whether hypothermic sepsis patients responded differently to the syndrome than those with fever, and also whether their response to the prostaglandin inhibitor prostaglandin was different from the responses of their febrile counterparts. For the parent study, Arons and colleagues enrolled 455 patients in seven intensive care units (ICUs) in the United States and Canada and randomized them to receive either ibuprofen, 10 mg/kg every six hours intravenously for eight doses, or placebo. All patients had to meet criteria for severe sepsis: core temperature higher than 38.2° or lower than 35.5°C; pulse at least 90 beats/min; respiratory rate of more than 20/min or minute ventilation of more than 10 L/min; and evidence of cardiovascular, renal, or pulmonary dysfunction in the setting of a known or suspected site of serious infection. Tumor necrosis factor alpha (TNF-a) and interleukin (IL) 6 levels were measured in the patients’ blood at study entry and again 20 hours later, and urine samples were obtained at study enrollment for measurement of thromboxane B2 and prostacyclin. All patients were followed for ultimate mortality and number of organ failure free days.
In the present paper, the study’s results for patients who were hypothermic at study entry (core temperature < 35.5°C or < 96°F) were compared to data from patients who were febrile (core temperature > 38.3°C or > 101°F). There were 44 hypothermic patients (9.6% of the total study group) and 409 hyperthermic patients; data from two initially normothermic patients were not used.
Hypothermic patients had significantly lower initial blood pressure, higher blood lactate levels, and higher APACHE II scores than their febrile counterparts. Mortality among hypothermic patients (70%) was higher than among febrile patients (35%), a difference that was described as statistically significant. At study entry, urinary levels of thromboxane B2 and prostacyclin, and serum levels of TNF-a and IL-6 were significantly higher in the hypothermic patients. Hypothermic patients who were randomized to receive ibuprofen were younger and had more positive blood cultures than those who received placebo. Mortality was not different between the two groups of hypothermic patients, although there was a nonsignificant trend toward an increased number of days free of major organ system failures in the ibuprofen-treated patients.
Arons et al conclude that the minority of patients with severe sepsis who are initially hypothermic (approximately 10%) have an amplified response with respect to the cytokines TNF-a and IL-6 and the lipid mediators thromboxane B2 and prostacyclin. They further conclude that treatment with ibuprofen in this subset of patients may decrease mortality. (Arons MM, et al. Crit Care Med 1999;27:699-707.)
COMMENT BY DAVID J. PIERSON, MD, FACP, FCCP
This study’s finding that hypothermia occurs in about 10% of patients with severe sepsis is consistent with the results of other large-scale studies of this syndrome (Clemmer TP, et al. Crit Care Med 1992;20:1395-1401). Also in keeping with previous studies is the observation that hypothermic sepsis patients do poorly—in this case, having twice the mortality of febrile sepsis patients. It is consistent with our present understanding of the pathogenesis and evolution of severe sepsis that hypothermic patients had an exaggerated response with respect to the cytokines TNF-a and IL-6 and the lipid mediators thromboxane B2 and prostacyclin in comparison with their febrile counterparts.
However, the conclusion that treatment with ibuprofen may improve survival in hypothermic sepsis seems to me to be less sound. This paper is a secondary publication generated by a large-scale randomized, controlled trial of ibuprofen in severe sepsis carried out between 1989 and 1995 in seven medical centers in the United States and Canada. The results of that trial (Bernard GR, et al. N Engl J Med 1997;336:912-918) showed no survival benefit from ibuprofen in patients with severe sepsis. As Arons et al acknowledge in their discussion, the present study suffers from the limitations of small sample size, significant differences in baseline characteristics between treated and placebo hypothermic patients, and the inherent problems of subgroup analysis of data not originally intended to address the question under consideration.
This paper’s results support the notion that hypothermic sepsis patients are biochemically distinct from their febrile counterparts, perhaps responding to ibuprofen differently. Arons et al call for a prospective trial to address the possibility of a survival benefit from ibuprofen in the small subset of septic patients who are hypothermic. Such a trial would be logistically and economically challenging to say the least, and in the meantime it seems hard to support a recommendation that any population of septic patients—even those with lower than normal body temperatures—be treated routinely with ibuprofen.
Compared to patients with severe sepsis who are febrile, hypothermic patients have:
a. half the overall mortality.
b. higher levels of thromboxane B2 and prostacyclin in the urine.
c. reduced serum levels of TNF-a and IL-6.
d. lower APACHE II scores.
e. All of the above
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