Brief inhalation of low-dose carbon monoxide protects rodents and swine from postoperative ileus

Objective: Carbon monoxide (CO), an endogenous byproduct of heme metabolism, is produced at high levels in injured tissue via induction of heme-oxygenase-1 activity, where it contributes to the modulation of proinflammatory processes. Alone, CO has potent anti-inflammatory effects in models of acute and chronic inflammation. In rodents, inhalation of low concentrations of CO (250 ppm) for 24 hrs protects against postoperative gastrointestinal ileus. The current study determined whether shorter exposures and lower concentrations were equally protective and whether CO treatment would be effective in a large animal species (swine) managed under conditions approximating the clinical setting. Design: Dosing studies were first performed in rats by exposing them to CO (30-250 ppm) or air by inhalation for 1 or 3 hrs before anesthesia. An effective dosing regimen was then selected for testing in swine. Postoperative ileus in both species was induced by laparotomy and mild compression (running) of the small intestine. Measurements and Main Results: In rats, inhalation of 75 ppm CO for 3 hrs before anesthesia and surgery ameliorated the surgically induced delay in gastrointestinal transit to levels achieved using 250 ppm for 24 hrs. Swine treated with 250 ppm CO for the same time period exhibited significantly improved postoperative intestinal circular muscle contractility in vitro and gastrointestinal transit in vivo. Carboxyhemoglobin concentrations measured after termination of CO exposure averaged 5.8% (baseline, 1.5%). No deleterious effects on heart rate, oxygen saturation, blood chemistries, and serum electrolytes were observed. Conclusions: These findings demonstrate that inhalation of a low concentration of CO before surgery attenuates postoperative ileus in rodents and, more importantly, in a large animal species without risk to well-being during surgery or perioperatively. Exposures need not be prolonged, with significant benefit occurring with a 3-hr pretreatment.