February 21, 1997

New drug’s ability to reduce sepsis mortality studied

New drug's ability to reduce sepsis mortality studied

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Dr. Gordon Bernard

A new drug designed to combat sepsis has been found to significantly reduce mortality in patients with the gram-negative form of the infection.

In a study published last week in the Journal of the American Medical Association, investigators showed that the drug, deltibant, produced statistically significant improvement in 28-day survival, reducing mortality from 50 percent to 22.2 percent.

The drug did not, however, significantly impact mortality rates in patient groups not presenting gram-negative infection as the source of their systemic inflammatory response syndrome (SIRS) and sepsis, said Dr. Gordon R. Bernard, professor of Medicine, one of the study's principle investigators.

Gram-negative infections accounted for approximately 22 percent of patients with SIRS and sepsis in the study, Bernard said.

While the drug showed no significant impact on mortality in the overall study population, improvements recorded in the gram-negative subset are cause for further investigation, the study's authors wrote.

"Improved survival at 28 days in patients with gram-negative infection suggests that further trials extending the duration of treatment with the highest-dose regimen are warranted."

Sepsis syndrome and septic shock are important and persistent causes of death in critically ill patients. Approximately 500,000 cases occur each year in the United States, with increasing incidence attributable to an ever-aging and immunocompromised population. Despite significant advances in supportive care, mortality rates still approach 50 percent.

Septic shock is a highly dangerous condition in which there is tissue damage and a dramatic drop in blood pressure as a result of the multiplication of bacteria and the presence of their toxins in the blood. These toxins may cause leakage of fluid from blood vessels and a reduction of the vessels' ability to constrict, leading to a drop in blood pressure.

Severe sepsis was originally thought to result from the uncontrolled spread of infectious microorganisms. Recent studies, however, suggest that the septic response results from the body's release of inflammatory mediators to fight invading bacteria. When released in high quantities and at inappropriate times, these mediators initiate SIRS ‹ a progressively dysfunctional host response that contributes to organ failure and mortality.

The drug deltibant is a combination of two peptides that work to block a certain subclass of bradykinin receptors, a type of mediator. In animal models, deltibant enhanced survival in endotoxic and traumatic shock.

This study was a randomized, placebo-controlled phase II trial of the drug deltibant in the treatment of SIRS and sepsis involving a total of 504 patients at 47 hospitals across the country. While no statistically significant improvements in mortality for the overall group were achieved, investigators believe that further testing of deltibant may be clinically relevant.

"The possibility that a higher dose might have resulted in a greater survival improvement must be considered. Our data suggest that improved outcome might be dependent on the nature, duration and progression of an inflammatory response to a specific class of organism," the article reported.