Elsevier

The Lancet

Volume 351, Issue 9107, 28 March 1998, Pages 929-933
The Lancet

Articles
Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock*

https://doi.org/10.1016/S0140-6736(05)60602-2Get rights and content

Summary

Background

Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40–70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor α (TNF α MAb) in the treatment of septic shock.

Methods

In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7·5 mg/kg TNFα MAb (n=949) or placebo (0·25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days.

Findings

382 (40·3%) of 948 patients who received TNFα MAb and 398 (42·8%) of 930 who received placebo had died at 28 days (95% CI −0·02 to 0·07, p=0·27). We found no association between therapy with TNFα MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNFα MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNFα MAb group compared with placebo (day 7, p<0·001; day 28, p=0·005). Serious adverse events were reported in 55·2% of patients given placebo and 54·1% in the TNFα MAb group.

Interpretation

We did not find an improvement in survival after septic shock with TNFα MAb. Therapy not solely dependent on TNFα blockade may be required to improve survival.

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.

Section snippets

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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