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General Anesthesia: Michelle Duggan, Doreen Engelberts, Robert P. Jankov, Jordan M. A. Worrall, Rong Qu, Gregory M. T. Hare, A. Keith Tanswell, J. Brendan Mullen, and Brian P. Kavanagh Hypocapnia attenuates mesenteric ischemia-reperfusion injury in a rat model: [L’hypocapnie atténue la lésion mésentérique d’ischémie-reperfusion chez un modèle rat] Can J Anesth 2005; 52: 262-268 [Abstract] [Full text] [PDF]

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Might hypocapnia up-regulate ATP resynthesis and down-regulate free radical generation?

Richard G Fiddian-Green   (3 April 2005)

Might hypocapnia up-regulate ATP resynthesis and down-regulate free radical generation? 3 April 2005
Richard G Fiddian-Green, FRCS, FACS None Send letter to journal: Re: Might hypocapnia up-regulate ATP resynthesis and down-regulate free radical generation? richardfg{at}hotmail.com Richard G Fiddian-Green	Figure 2 in a complementary study of hemorrhagic shock and resuscitation in rats shows the changes in sublingual and intragastric pCO2 and arterial lactate (1). The lactate was a linear function of pCO2 corresponding most closely with the sublingual pCO2 during shock and with gastric pCO2 with resuscitation. One interpretation of these findings is that they reveal the inhibitory effect the mass action effect of a rise in tissue pCO2 is expected to have on oxidative phosporylation (2). If so the inhibitory effect on oxidative phosporylation was evident in the oropharynx an hour before it was evident in the gastric mucosa and lagged more than one hour behind the gastric pCO2 in returning to baseline levels with resuscitation. [The findings are intriguing for they raise the possibility that sublingual pCO2 might improve the sensitivity and clinical utility of tonometeric monitoring]. How might these data be reconciled with hypocapnia/tissue-hypocarbia being injurious to the liver in this animal study (3) and yet attenuating ischemia-reperfusion induced lipid peroxidation in the bowel? The difference between the two studies is that the effect of hemorrhage was systemic, even though the gut might have been selectively affected by the endogenous vasipressors released, and that of mesenteric ischemia regional. Mesenteric ischemia induced by vascular occlusion would have elevated intramucosal pCO2 but not necessarily intrahepatic pCO2, for hepatic artery flow was preserved. Mesenteric ischemia might, therefore, have inhibited oxidative phosporylation in gut mucosa but not in the liver. Any conversion of xanthine dehydrogenase to xanthine oxidase might, therefore, have been greatest in, or even confined to the gut. In which case free radical injury was more likely to have occurred in the gut than in the liver. This interpretation would suggest that the hypocapnia in the present study might have attenuated ischemia-reperfusion induced lipid peroxidation in the bowel by attenuating the release of free radicals, upon which the lipid peroxidation presumably depended. In which case the beneficial effect must have occurred during reperfusion, raising the possibility that the release of free radicals durng reperfusion might be a function of tissue pCO2 at the time. The laser-Doppler flow studies of bowel showed that hypocapnia attenuated reperfusion and so the beneficial effect could not have been caused by an enhancement of gut blood flow. Might the beneficial effect of hypocarbia on the gut have been due to the upregulation of ATP resynthesis and an attenuation of free radical release during reperfusion caused by a mass action? Free radical generation depends upon the degradation of ATP into AMP. Why then the harmful effect of hypocarbia on the liver? As free radicals uncouple oxidative phosporylation they might have graeatly increased the demand for hepatic blood flow when released from ischemic gut. Perhaps the adverse effect of hypocarbia on the liver was caused by restricting the fulfillment of the demand for an increased blood flow from the portal vein and hepatic artery. In dogs, restricting blood flow has an additive effect on the effects of an intramucosal acidosis induced by hypoxia (4). In a second complementary study done in a rabbit model, gut and hepatic ischaemia was induced by descending thoracic aorta occlusion with a 4-Fr Fogarty embolectomy catheter maintained for 40 mins and followed by 2 hrs of reperfusion (5). The ischaemia resulted in a significant decrease in gastric intramucosal pH as compared with sham-operated rabbits (p < .001). The change in gastric mucosal hydrogen ion concentration was significantly associated with plasma alanine aminotransferase activity (r2 = .48, p < .01) and bronchoalveolar protein content (r2 = .51, p < .01). Xanthine oxidase inactivation significantly improved gastric intramucosal pH after aortic occlusion and reperfusion (p < .001), with a concomitant attenuation of the release of plasma alanine aminotransferase (p < .05) and accumulation of bronchoalveolar protein (p < .05) during reperfusion. These findings confirm the importance of free radicals in the genesis of ischemia-reperfusion injury of the gut mucosa and liver. [In isolated heptaocytes mitochondrial oxygen radical formation by complex III is involved in cell killing during reductive stress (6)]. They imply that the degree of harmful free radical release in the gut and the liver during reperfusion after global causes of ischaemia, such as occlusion of the thoracic aorta and haemorrhage, might be a function of the degree of an antecedent fall in gastric intramucosal pH and rise in intramucosal [H+]. [The pulmonary consequences of ischemia-reperfusion injury also observed in this study add to the concern that measurements of sublingual pCO2 may not be as specific or as accurate as intramucosal pCO2 and particularly pH in predicting adverse outcomes in clinical practice]. Common assumptions in clincal practice are that a rise in pCO2 increases blood flow, and a fall decreases it, and that a therapeutic increase in blood flow [perfusion]is good and a fall bad for an anesthetized patient. The possibility that a rise in pCO2 might down regulate and a fall upregulate oxidative phoosphorylation in a dose- related manner, and even have reciprocal effects on free radical release, needs to be considered. The stochiometric reality is that the rise in blood flow [perfusion] seen with a rise in PCO2 may simply be a reflection of the need to increase nutrient dispatch and improved washout of anaerobic metabolites imposed by a decline in efficiency of ATP resynthesis and shift to dependence upon anaerobic glycolysis. So is it better to keep the pCO2 low, normal or high during anesthesia? The answer might be that it depends upon the tissue pH, for this appears to be the stochiometric surrogate of the energy charge upon which cellular function and viability ultimately depend. 1. Nakagawa Y, Weil MH, Tang W, Sun S, Yamaguchi H, Jin X, Bisera J. Sublingual capnometry for diagnosis and quantitation of circulatory shock. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1838-43. 2. pCO2, pH and the regulation of aerobic / anaerobic glycolysis. Richard G Fiddian-Green (15 March 2005) eLetter re: Jerry Yee and Irawan Susanto Sublingual Capnometry : In Search of Its Holy Grail Chest 2000; 118: 894-896 3. Michelle Duggan, Doreen Engelberts, Robert P. Jankov, Jordan M. A. Worrall, Rong Qu, Gregory M. T. Hare, A. Keith Tanswell, J. Brendan Mullen, and Brian P. Kavanagh Hypocapnia attenuates mesenteric ischemia-reperfusion injury in a rat model: [L’hypocapnie atténue la lésion mésentérique d’ischémie-reperfusion chez un modèle rat] Can J Anesth 2005; 52: 262-268 4. Grum CM, Fiddian-Green RG, Pittenger GL, Grant BJ, Rothman ED, Dantzker DR. Adequacy of tissue oxygenation in intact dog intestine. J Appl Physiol. 1984 Apr;56(4):1065-9. 5. Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ. Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol. 1993 Apr;264(4 Pt 1):C961-7. 6. Nielsen VG, Tan S, Baird MS, McCammon AT, Parks DA. Gastric intramucosal pH and multiple organ injury: impact of ischemia-reperfusion and xanthine oxidase. Crit Care Med. 1996 Aug;24(8):1339-44. 7. Horswill CA. Effects of bicarbonate, citrate, and phosphate loading on performance. Int J Sport Nutr. 1995 Jun;5 Suppl:S111-9.