GASTRIC AND EXTRAGASTRIC ACTIONS OF THE HISTAMINE ANTAGONIST RANITIDINE DURING POSTTRAUMATIC SEPSIS

Background. Histamine H-2 antagonists (e.g., ranitidine) are generally thought to specifically reduce gastric acid secretion and are commonl y used for stress ulcer prophylaxis in critically ill patients because of their efficacy and safety profile. A few reports suggest that rani tidine might also bind to extragastric sites and/or act as an immunomo dulator. The potential effects on posttraumatic sepsis are unknown. Me thods. Mongrel pigs (n = 24) were anesthetized with fentanyl, injured by a 10 kg steel bar dropped from a height of 1 m onto the fleshy port ion of the posterior thigh, and then 35% of their blood volume was dra ined through the arterial catheter. All the shed blood plus two times the hemorrhage volume as lactated Ringer's solution was infused after a I-hour shock period. Either vehicle or ranitidine (1.5 mg/kg) was in travenously administered at the time of resuscitation and every 12 hou rs thereafter in a blinded fashion. After 72 hours a septic challenge was administered (15 mu g/kg Escherichia coli lipopolysaccharide [LPS] X 30 min). Serial gastroscopy, gastric pH, hemodynamics, leukocyte co unts, cortisol, and tumor necrosis factor were recorded for 180 minute s after LPS. Results. Immediately before LPS all hemodynamic variables were identical between treatments, but gastric PH was slightly higher and stress gastritis was marginally lower with ranitidine. LPS caused profound leukopenia and a hyperdynamic circulatory response (i.e., ta chycardia, increased cardiac output, and decreased peripheral vascular resistance at relatively constant blood pressure); these changes were not altered by ranitidine. Gastric pH remained elevated after LPS wit h ranitidine, but LPS-induced gastritis was not modified. Ranitidine d elayed the LPS-induced ventilation-perfusion imbalance and attenuated the peak increase in the proinflammatory cytokine, tumor necrosis fact or, without altering its antiinflammatory opponent, cortisol. Similar changes were observed in four additional animals treated with cimetidi ne. The proportion of circulating neutrophils and lymphocytes was slig htly altered 180 minutes after LPS, but there was no obvious effect on T lymphocytes in vivo, and no effect on the LPS-induced increase in n eutrophil CD18 expression in vitro was seen. Conclusions. (1) Ranitidi ne increased gastric pH, which blunted the stress gastritis caused by trauma but not that caused by LPS; (2) ranitidine delayed the early LP S-evoked pulmonary changes and reduced the tumor necrosis factor spike , which is consistent with a favorable immunomodulatory action that ha s been reported in patients who are critically ill or are undergoing a n elective abdominal surgical procedure; (3) the mechanism is probably related to H-2 receptor antagonism rather than to a nonspecific side effect of ranitidine, which suggests that histamine may have a previou sly unrecognized role in posttraumatic septic responses; and (4) the s ite of action is probably not in the heart or peripheral resistance ve ssels, but salutary effects on circulating lymphocytes or neutrophils cannot be excluded.