Gastric and extragastric actions of the histamine antagonist ranitidine during posttraumatic sepsis.
BACKGROUND
Histamine H2 antagonists (e.g., ranitidine) are generally thought to specifically reduce gastric acid secretion and are commonly used for stress ulcer prophylaxis in critically ill patients because of their efficacy and safety profile. A few reports suggest that ranitidine might also bind to extragastric sites and/or act as an immunomodulator. The potential effects on posttraumatic sepsis are unknown.


METHODS
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 portion of the posterior thigh, and then 35% of their blood volume was drained through the arterial catheter. All the shed blood plus two times the hemorrhage volume as lactated Ringer's solution was infused after a 1-hour shock period. Either vehicle or ranitidine (1.5 mg/kg) was intravenously administered at the time of resuscitation and every 12 hours thereafter in a blinded fashion. After 72 hours a septic challenge was administered (15 micrograms/kg Escherichia coli lipopolysaccharide [LPS] x 30 min). Serial gastroscopy, gastric pH, hemodynamics, leukocyte counts, cortisol, and tumor necrosis factor were recorded for 180 minutes 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., tachycardia, 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 with ranitidine, but LPS-induced gastritis was not modified. Ranitidine delayed the LPS-induced ventilation-perfusion imbalance and attenuated the peak increase in the proinflammatory cytokine, tumor necrosis factor, without altering its antiinflammatory opponent, cortisol. Similar changes were observed in four additional animals treated with cimetidine. The proportion of circulating neutrophils and lymphocytes was slightly 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 neutrophil CD18 expression in vitro was seen.


CONCLUSIONS
(1) Ranitidine increased gastric pH, which blunted the stress gastritis caused by trauma but not that caused by LPS; (2) ranitidine delayed the early LPS-evoked pulmonary changes and reduced the tumor necrosis factor spike, which is consistent with a favorable immunomodulatory action that has been reported in patients who are critically ill or are undergoing an elective abdominal surgical procedure; (3) the mechanism is probably related to H2 receptor antagonism rather than to a nonspecific side effect of ranitidine, which suggests that histamine may have a previously unrecognized role in posttraumatic septic responses; and (4) the site of action is probably not in the heart or peripheral resistance vessels, but salutary effects on circulating lymphocytes or neutrophils cannot be excluded.
Stewart
R M
RM
Department of Surgery (Trauma Division), University of Tennessee Health Science Center, Memphis 38163.
Fabian
T C
TC
Fabian
M J
MJ
Trenthem
L L
LL
Pritchard
F E
FE
Croce
M A
MA
Proctor
K G
KG
D000138:Acidosis / Q000188:drug therapy / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D004926:Escherichia coli; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D008070:Lipopolysaccharides / Q000633:toxicity; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D010100:Oxygen / Q000097:blood; D011899:Ranitidine / Q000494:pharmacology*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology; D013552:Swine; D014115:Toxemia / Q000188:drug therapy* / Q000503:physiopathology; D014947:Wounds and Injuries / Q000150:complications* / Q000503:physiopathology
D000276:Adjuvants, Immunologic; D008070:Lipopolysaccharides; D011899:Ranitidine; D010100:Oxygen