enalaprilat-anhydrous and Multiple-Organ-Failure

Inadequate splanchnic perfusion, detected as a low gastric intramucosal pH (pHi), in the face of normal systemic perfusion predicts an increased risk for multiple organ failure after trauma. Although the exact etiology of this low pHi is unknown, angiotensin II is thought to be an important regulator of gut perfusion during and after resuscitation from shock. The purpose of this study is to determine whether enalaprilat, an angiotensin-converting enzyme inhibitor, improves gut perfusion in critically injured patients. To test this hypothesis, 18 trauma patients monitored with a nasogastric tonometer and a pulmonary artery catheter were enrolled in a prospective study. A single dose of enalaprilat, .625 mg, was given as an i.v. bolus or a 4 h infusion following systemic resuscitation. Pre- and postdrug tonometric and hemodynamic data, including cardiac index, mean arterial pressure, right ventricular end-diastolic volume index, systemic vascular resistance index, and oxygen transport variables were compared using the paired t test. Results demonstrate that pHi was significantly improved after 4 h (7.13 +/- .04 to 7.19 +/- .03, p = .03) and after 24 h compared with baseline (7.14 +/- .04 to 7.25 +/- .04, p = .04). Overall, pHi increased in 12 of 18 patients. No significant differences were observed in any of the studied hemodynamic or systemic perfusion variables including mean arterial pressure (92 +/- 4 to 87 +/- 4, p = .24) and oxygen delivery (669 +/- 33 to 675 +/- 32, p = .82). In examining the determinants of pHi, the intramucosal-arterial PCO2 difference was improved after enalaprilat administration (27 +/- 6 to 17 +/- 3 mmHg, p = .04) while no difference was observed in arterial bicarbonate (19.5 +/- .7 to 19.7 +/- .8, p = .90). Additionally, the change in pHi observed with enalaprilat correlated with predrug intramucosal-arterial PCO2 difference (r = .74, r2 = .55, p = .0005). These results demonstrate that enalaprilat improves gut perfusion as measured by gastric tonometry in critically injured patients, and that this effect appears to be independent of changes in systemic perfusion.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Digestive System; Enalaprilat; Female; Gastric Mucosa; Hemodynamics; Humans; Hydrogen-Ion Concentration; Lactic Acid; Male; Middle Aged; Multiple Organ Failure; Oxygen; Resuscitation; Shock, Traumatic; Splanchnic Circulation

Sympathetic and angiotensinergic activation reduce splanchnic oxygen delivery during hypovolemia, which may lead to failure of the intestinal mucosal barrier and eventually multiple organ dysfunction. This study integrates sympathetic and angiotensinergic responses with splanchnic hemodynamics and duodenal mucosal function during hypovolemia and evaluates pharmacologic blockade of either system to ameliorate the impact of acute hypovolemia. Chloralose-anesthetized pigs subjected to 20 and 40% blood volume reductions were randomized to controls or administered guanethidine or enalaprilate to block sympathetic and angiotensinergic activation, as assessed by plasma norepinephrine spillover and angiotensin II levels, respectively. Mesenteric and hepatic oxygen delivery/consumption as well as duodenal mucosal alkaline secretion and potential difference were determined. Hypovolemia preferentially increased mesenteric sympathetic outflow and caused a vigorous angiotensinergic activation. Guanethidine and enalaprilate blocked effectively the sympathetic and angiotensinergic responses. Treatment with enalaprilate, but not guanethidine, prevented the reduction of mesenteric oxygenation and duodenal mucosal alkaline secretion and potential difference observed in control animals. The down-regulation of mesenteric oxygenation and duodenal mucosal function during hypovolemia can be prevented by administration of enalaprilate, whereas guanethidine is uneffective in this respect. Interference with the reninangiotensin system might be of clinical interest to support mesenteric perfusion and organ function in hypovolemia.

Topics: Angiotensin II; Animals; Bicarbonates; Duodenum; Enalaprilat; Guanethidine; Hemodynamics; Intestinal Mucosa; Membrane Potentials; Multiple Organ Failure; Norepinephrine; Renin-Angiotensin System; Shock; Splanchnic Circulation; Swine; Sympathetic Nervous System; Sympatholytics