Multi-agent therapy in the treatment of sepsis-induced microvascular injury

Cyclo-oxygenase inhibition (with ibuprofen) combined with histamine (H1, H2) receptor antagonism (with diphenhydramine and cimetidine) attenuates microvascular leak injury in sepsis syndromes. Ibuprofen reduces microvascular injury by limiting oxygen radical production by neutrophils. Histamine is known to inhibit this oxygen radical production, an effect antagonized by cimetidine. In the present study neutrophils isolated from pigs made septic with Pseudomonas organisms exhibited a significant (P < 0.05) increase in the production of the oxygen radicals, superoxide anion (O2-, 133 per cent) and hypochlorous acid (HOCl, 38 per cent). Ibuprofen used alone attenuated this sepsis-stimulated overproduction. Addition of the antihistamines cimetidine and diphenhydramine produced a significant increase in oxygen radical production (P < 0.05), by 122 per cent (O2-) and 47 per cent (HOCl), equivalent to that in untreated septic animals. This coincided with a significant deterioration in pulmonary compliance (P < 0.05) compared with that found in control animals and those treated with ibuprofen alone, and a significant accumulation of extravascular lung water (P < 0.05) at 240 and 300 min versus baseline. Histamine receptor antagonism may inadvertently enhance microvascular injury in sepsis.