ArticlesDouble-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock*
Introduction
In the USA there are about 500 000 cases of sepsis due to gram-negative, gram-positive, and fungal organisms every year, and about half of these develop hypotension (shock) refractory to fluid resuscitation.1 Septic shock is the most common cause of death in intensive-care units in the USA;2 mortality rates are estimated at 40–70%, despite the availability of potent antibiotics and intensive supportive care.3, 4, 5, 6, 7
Therapies that can be used early, irrespective of the infecting organism or organisms, are of particular interest in the treatment of sepsis, since prediction of the infecting organisms can be difficult based on clinical presentation in critically ill septic-shock patients.4 Blood cultures are positive in about 45% of patients with sepsis.8 In studies of sepsis, at least a third of all patients with positive cultures had gram-positive infections and about 40–50% had gram-negative infections.9, 10 However, gram-positive organisms are predominant in patients with positive blood cultures.6
Although the pathophysiology of systemic inflammation and organ dysfunction is complex, tumour necrosis factor α (TNFα) seems to be a principal mediator that can cause the manifestations of sepsis and septic shock, including hypotension, activation of the clotting cascade, and organ or system dysfunction.11, 12, 13, 14 Anti-TNFα antibodies protect, animals from death caused by endotoxins, gram-negative bacteria such as Escherichia coli, and gram-positive bacteria such as Staphylococcus aureus.15, 16, 17, 18, 19 Two large clinical trials9, 20 that used murine monoclonal antibodies to human TNFα (TNFα MAb) showed a decrease in mortality among patients with shock and organ dysfunction who were treated with TNFα MAb. We aimed, in a randomised, placebo-controlled, double-blind, clinical trial with a prospectively defined analytical plan, to further assess the efficacy and safety of TNFα MAb therapy in patients with septic shock.
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Methods
The protocol was approved and carried out in accordance with the guidelines of institutional review boards at each participating centre.
Adults older than 18 years admitted to hospital with shock due to sepsis within 12 h before and present at the time of randomisation were eligible for enrolment. All the enrolment criteria had to be filled. The criteria were: clinical evidence of acute infection; hyperthermia (rectal, core, oral, or axillary temperature >38·3°C [101°F]) or hypothermia (rectal
Results
1916 patients were enrolled and 1879 patients received treatment (n=949) or placebo (n=930). Ten patients died and the investigator withdrew 27 before infusion (figure 1). At the time of infusion, 930 (98·0%) TNFα MAb and 905 (97·3%) placebo patients were in septic shock. Four (0·4%) TNFα MAb and five (0·5%) placebo patients were lost to follow-up by day 28 and their survival was unknown. In addition, the local institutional review board excluded one patient in the TNFα MAb group from the
Discussion
We found no survival benefit among patients with septic shock treated with TNFα MAb and no evidence that TNFα MAb therapy shortened the length of the shock episode or hastened the resolution of sepsis-induced organ failure. Although there were significantly fewer episodes of subsequent coagulopathy among patients given TNFα MAb, no other organ or system failures seemed to be prevented. Even in the subgroup of patients with raised baseline plasma TNFα concentrations, TNFα MAb did not
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