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General Anesthesia: Luc Massicotte, Marie-Pascale Sassine, Serge Lenis, Robert F. Seal, and André Roy Survival rate changes with transfusion of blood products during liver transplantation: [Le taux de survie change avec la transfusion de produits sanguins pendant la transplantation hépatique] Can J Anesth 2005; 52: 148-155 [Abstract] [Full text] [PDF]

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Steering the course beween systemic organ dysfunction and graft rejection.

Richard G Fiddia-Green   (6 March 2005)

Steering the course beween systemic organ dysfunction and graft rejection. 6 March 2005
Richard G Fiddia-Green, FRCS, FACS None Send letter to journal: Re: Steering the course beween systemic organ dysfunction and graft rejection. richardfg{at}hotmail.com Richard G Fiddia-Green	The demonstration that the one-year survival rate following liver transplantation decreased significantly with the intraoperative transfusion of any amount of plasma or more than four units of RBCs is consistent with the hypothesis that shock, defined as a gastric intramucosal acidosis, was the cause (1). The damage appears to occur during reperfusion rather than during the antecedent ischemia, or perhaps more accurately decline in Daniel Atkinson energy charge (2) of which the gastric intramucosal pH is a clinicallly validated stochiometic surrogate (3). In a recent study of 989 patients mechanically ventilated for >48 hr, differences in hospital mortality between patients who received haloperidol within 2 days of initiation of mechanical ventilation and those who never received haloperidol were examined. Despite similar baseline characteristics, patients treated with haloperidol had significantly lower hospital mortality compared with those who never received haloperidol (20.5% vs. 36.1%; p =0.004)(4). Haloperidol inhibits electron transfer activity at respiratory complex I (5) and tends to increase body temperature, on occasion malignantly. Inhibiting electron transfer should reduce the rate of isothermic ATP resynthesis by oxidative phosphorylation and increase that from anaerobic glycolysis, unless offset by a compensatory lipid shift. If accompanied by a rise in body temperature, net ATP yield should be increased by an increase in the rate of glycolytic turnover, metabolic rate and oxygen consumption [Q10 effect] just as thyroxine does. The proportion of ATP being resynthesised by oxidative phosphorylation should, logically, be decreased if the rise in temperature is prevented by cooling. Haloperidol might shift substrate utilisation from oxygen to glucose. If so, the isothermic generation of free radicals by complex I should be decreased. Restricting access to nutrient substrate, which incrases longevity in animal models, is said to have a similar effect(6). If anaerobic glycolysis is exothermic, and oxidative phosphorylation endothermic, the effect might be the product of a reversed Q10 effect. Free radical scavenging inhibits the decrease in oxygen consumption induced by cytokines in isothermic cultured enterocytes by depleting their intracellular levels of NAD(+)/NADH by activating the nuclear enzyme poly(ADP-ribose) polymerase (PARP) (7). The appearance of free radicals may, therefore, operate a negative feedback control on oxygen consumption and free radical release, and a positive feedback on thermogenesis. This should protect cells from free radical injury but might place an unacceptable workload on the heart by increasing the need for nutrient dispatch to meet the greatly increased tissue needs even to maintain the same leve of ATP resynthesis(8). The intraoperative transfusion of any amount of plasma or more than four units of RBCs might exert their adverse effects by these means. Should free radical release be excessive, cytochrome C may be released from mitochondria further deceasing their ability to consume oxygen but precipitating apoptosis (9). Indeed the release of cytochrome C is widely used as a marker of apoptosis. Apoptosis, an ATP-dependent process, does not induce an inflammatory response and might even be the penultmate cytoptrotective response hypotheticaly being a stimulus for orderly cell renewal (10). In the absence of adequate ATP, necrosis is inevitable and an inflammatory response and healing with fibrosis and no cell renewal can be expected. Opening of the mitochondrial permeability transition pore (MPTP) is a critical event in the evolution of reperfusion injury in the heart (11). Inhibitors of the MPTP, notably Cyclosporin A in transplantation, protect the heart against reperfusion injury possibly by limiting metabolic rate. Other protective agents include free radical scavengers, pyruvate and ischemic preconditioning. All of these treatments are said to inhibit MPTP opening at reperfusion and enhance subsequent pore closure, but their effect on the MPTP is indirect. Pyruvate might additonally or alteratively owe its benefical action to an increase in nutrient density in plasma. Considered from a stochiometric perspective, as in the case of a lipd shift, this should limit the increase and even decrease myocardial workload. What is not known is whether temperature and thermogenesis might be critical variables. Haloperidol might, therefore, have impoved outcome in ventilated patients by preventing the opening the MPTP by free radicals and thereby preserving ATP yield from oxidative phosphorylation. If so, there is a risk that haloperidol might precipitate a systemic energy deficit and hence organ dysfuntions and failure. Haloperidol is known to have induced cardiotoxicty in the critically ill (12) in whom a decline in systemic energy charge is often present and reflected in a gastric intramucosal acidosis. The risk in patients having elective surgery, who do not usually have an antecedent energy deficit but might develop one during surgery, is relatively small (13) but still significant. Ischaemic colitis does not occur after abdominal aortic surgery unless the intramucosal pH falls below 6.9, a very abormally low level pH (14,15). Furthermore, myocyte apoptosis does not occur unless intramyocardial pH falls below the same level (10). It is possible, therefore, that the beneficial effects of haloperidol were restricted to those patients in whom the intramucosal pH had fallen to very abnormally low levels. Those in whom it had not fallen to these levels might even have been adversely affected by a decline in energy charge. The reverse might apply in the cytokine release induced by blood products, low degrees of release being beneficial and high degrees harmful. Graft rejection might be similarly effected; survival, dysfunction, apoptosis, necrosis, acute rejection and fibrosis being different manifestations of the same process. Transplanters should be thinking beyond witholding plasma and restricting RBCs during transplantation, which can also increase graft survival, and thinking more about tissue energetics. Metabolic monitorng provides them with the opportunity to steer a more rational and precise course between the rocks of inducing systemic organ dysfunctions and preventing graft failure and/or rejection. The graft, rather than gastric mucosa, is likely to be the canary of the body (16) in these circmstances. Knowing the tissue pH both in the graft and in gastric mucosa would be essential in achieving this objective. In either case preventing an excessive degree of free radical release and preventing an unacceptably large increase in myocardial workload might be the most desirable objectives in the short and long term(17). Giving haloperidol to inhibit free radical release, if that is how it exerts its beneficial actions, might eliminate the difference in outcome observed in this study if administered in optimal regional and systemic doses. Haloperidol is but one of a host of ways in which these objectives might be achieved. 1. Fiddian-Green RG. Open versus laparoscopy assisted colectomy. Lancet. 2003 Jan 4;361(9351):74; author reply 75-6. 2. Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001 Dec;23(12):1112-9. 3. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-base balance. Br J Anaesth. 1995 May;74(5):591-606. 4. Milbrandt EB, Kersten A, Kong L, Weissfeld LA, Clermont G, Fink MP, Angus DC Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. 2005 Jan;33(1):226-9 5. Modica-Napolitano JS, Lagace CJ, Brennan WA, Aprille JR Differential effects of typical and atypical neuroleptics on mitochondrial function in vitro. Arch Pharm Res. 2003 Nov;26(11):951-9. 6. Barja G. Free radicals and aging. Trends Neurosci. 2004 Oct;27(10):595-600. 7. Khan AU, Delude RL, Han YY, Sappington PL, Han X, Carcillo JA, Fink MP. Liposomal NAD(+) prevents diminished O(2) consumption by immunostimulated Caco-2 cells. Am J Physiol Lung Cell Mol Physiol. 2002 May;282(5):L1082-91. 8. Successful evolutionary adaptation to environmental stress? Richard G Fiddian-Green Heart Online, 14 Jul 2004 eLetter re: D A Lawlor, G Davey Smith, R Mitchell, and S Ebrahim Temperature at birth, coronary heart disease, and insulin resistance: cross sectional analyses of the British women’s heart and health study Heart 2004; 90: 381-388 9. Chen Q, Chai YC, Mazumder S, Jiang C, Macklis RM, Chisolm GM, Almasan A. The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. Cell Death Differ. 2003 Mar;10(3):323-34. 10. A myocyte buddy system in stressed myocardium? Richard G Fiddian-Green (6 August 2004) eLeter re: T B Lindhardt, N Gadsbøll, H Kelbæk, K Saunamäki, J K Madsen, P Clemmensen, B Hesse, and S Haunsø Pharmacological modulation of the ATP sensitive potassium channels during repeated coronary occlusions: no effect on myocardial ischaemia or function Heart 2004; 90: 425-430 11. Halestrap AP. The mitochondrial permeability transition pore in reperfusion injury and cardioprotection. Cardiovasc J S Afr. 2004 Jul;15(4 Suppl 1):S5. 12. Akers WS, Flynn JD, Davis GA, Green AE, Winstead PS, Strobel G Prolonged cardiac repolarization after tacrolimus and haloperidol administration in the critically ill patient. Pharmacotherapy. 2004 Mar;24(3):404-8. 13. Harrigan EP, Miceli JJ, Anziano R, Watsky E, Reeves KR, Cutler NR, Sramek J, Shiovitz T, Middle M A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol. 2004 Feb;24(1):62-9. 14. Fiddian-Green RG, Amelin PM, Herrmann JB, Arous E, Cutler BS, Schiedler M, Wheeler HB, Baker S Prediction of the development of sigmoid ischemia on the day of aortic operations. Indirect measurements of intramural pH in the colon. Arch Surg. 1986 Jun;121(6):654-60. 15. Schiedler MG, Cutler BS, Fiddian-Green RG Sigmoid intramural pH for prediction of ischemic colitis during aortic surgery. A comparison with risk factors and inferior mesenteric artery stump pressures. Arch Surg. 1987 Aug;122(8):881-6. 16. Dantzker DR. The gastrointestinal tract. The canary of the body? JAMA. 1993 Sep 8;270(10):1247-8. 17. 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.