Cyclwxygenase inhibition (with ibuprofen) combined with histamine (HI, 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 inhiiit 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 (O;, 133 per cent) and hypochlorous acid (HOCI, 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 (0;) and 47 per cent (HOCI), equivalent to that in untreated septic animals. This coincided with a significant deterioration in pulmo~ry compliance (P< 005) 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 300min versus baseline. Histamine receptor antagonism may inadvertently enhance microvascular injury in sepsis.
Antihistamines (H ,and H,-receptor antagomsts) have been used in multidrug regimens to counteract the fluid and protein leakage that results from microvascular permeability injury in sepsis syndromes l. Current evidence2 suggests that sepsis-induced microvascular injury is linked to polymorphonuclear neutrophil (PMN )-derived toxic oxygen radicals. PMN-mediated host injury may be the final common pathway for tissue injury in sepsis syndromes such as adult respiratory distress and extrapulmonary multiple organ failure. This event represents a complex interaction of numerous humoral and cellular mediators and there are many stages at which this injury sequence can be modified using pharmacological agents3. Combined intravenous administration of the cyclo-oxygenase inhibitor ibuprofen and the antihistamines cimetidine and diphenhydramine has been shown to be effective in a porcine septic shock model l. This combination reverses most of the experimental physiological derangements, including microvascular permeability injury I. Ibuprofen produces direct inhibition of the vasoactive properties of thromboxanes and attenuates the priming of PMNs for enhanced superoxide anion ( 0 ; ) and hypochlorous acid (HOC1) generation. This effect results in the protection of experimental septic animals from oxygen radical-induced endothelial cell i n j ~r y ~~~.
Histamine, acting through H, receptors, mediates endothelial cell contraction and this results in increased permeability of the microvascular endothelium to fluid, protein and eventually inflammatory cells, with subsequent impairment of normal lung mechanics6-i0. The role of H, antagonism is less well defined and recent in vitro evidence demonstrates that histamine inhibits the production of the superoxide anion from activated PMNs, an action reversed by cimetidine11s*2.