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Effects of beta blockers upon gastric intramucosal pH and blood volume.
Why does the pHi rise when fluid balance is negative?
Reciprocal pH-dependence of myocardial protection and dysfunction.
pH dependence of carbonic anhydrase activity and blood flow
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Richard G Fiddian-Green, FRCS, FACS None
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richardfg{at}hotmail.com Richard G Fiddian-Green
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Dear Sir, I have been around the block several times trying to understand the findings in this most interesting of studies (1) and would appreciate your indulgence in permitting me yet another round. The changes in blood volume in this study were linearly related to the changes in gastric intramucosal pH, the correlation coefficient being 0.65 (Figure 3). There was no p value but with a n=20 it must be highly significiant. The authors observed that, "It is recognised that extracellular fluid (ECF) volume increases during open-heart surgery with CPB" and concluded that, "The increase in BVc observed..might be a result not only of postoperative transfusion but also of reabsorption of ECF into the vascular space". The rate of anaerobic glycolysis glycolysis and acccompanying generation of lactate from glucose is pH-dependent increasing linearly in tumour cell culture as the pH rises from 6.1 to 8.5 (2,3,4). It was estimated that about 70% of the pH effect on the rates of glucose consumption by the tumour cells, which had been depleted of their ATP, may be due to the effect on sugar transport and the remainder to the effect on the activities of glycolytic enzymes. The rate of ATP resynthesis by oxidative phosporylation should be inversely related to the pH for it should be upregulated by an increase in protonmotive force. As ATP resynthesis by anaerobic glycolysis is some 20 less efficient than that by oxidative phosporylation the degree to which ATP resynthesis is dependent upon nutrient delivery, and presumably capillary recruitment and blood volume, should also increase as the pH rises. If so the relationship in figure 3 might simply be a reflection of that. As Lionel Opie observes(5) myocytes are made oxygen hungry by fatty acids and the consumption of fatty acids and oxygen can be inhibited by beta blockade. Hence his conclusion that fatty acids are harmful the valueof beta blockers in protecting the myocardium from acute reductive stresses. The benefit is not surprising given that synaptic vesicles that concentrate and store catecholamines [600nM] also concentrate and store ATP [200nM] (6). Whilst beta blockade may conserve ATP stores within myocytes when studied in vitro and prevent surges in ATP utilization by myocytes during episodes of acute reductive stress beta blockade has adverse effects. By shifting nutrient consumption from fatty acids to glucose beta blockade should limit the capacity for ATP resynthesis by oxidative phosphorylation: hence the adverse effect of beta blockade upon exercise capacity. In so doing a marked increase in myocardial workload appears to be needed to deliver the nutrients rerquired to maintain the same level of ATP resynthesis (7). If so myocardial reserve is limited by beta blockers a limitation that may be particularly important when the extraction and utilization of oxygen is impaired by cytokine release during reperfusion, endotoxaemia and/or sepsis. The risks of myocardial infarction and death from myocardial infarction in the immediate postoperative period might be reduced but the risks might be greatly increased if shock or multiple organ failure develops. The results of outcome sudies that show beta blockers having little or no beneficial effect may, therefore, underestimate the degree of myocardial protection conferred and conceal the potentially harmful effects. In this study, "All patients were given a low dose of catecholamines (3 µg•kg–1•min–1 dopamine and 3 µg•kg–1•min–1 dobutamine), 1 µg•kg–1•min–1 diltiazem and 0.5-1 µg•kg–1•min–1 nitroglycerin after surgery. No patients received blood transfusion but each received 476 ± 96 ml albumin 4% solution, 1508 ± 160 ml lactated Ringer's solution and 1238 ± 121 ml of glucose 5% solution"(1). It is difficult if not impossible to anticpate the metabolic consequences of this combination of intyerventions. If ATP must be released with catecholamines for them to be effective might the inotropic action of the catecholamine drugs be enhanced and be less likely to induce an energy deficit, and hence do harm, by adding ATP -MgCl2 possibly delivered in red blood cells be they real or synthetic (8)? If so might administering adequate amounts of ATP-MgCl2 in either of these ways provide greater myocardial protection that beta blockers? Were any patients in this study on beta blockers before and/or during surgery? If so might the correlation between the changes in intramucosal pH and blood volume in figure 3 be improved by excluding these patients? More specifically might beta blockade eliminate the correlation between changes in intramucosal pH and blood volume or even reverse the direction of the slope? What if beta blockers were withheld and Intralipid, which consists largely of poly unsaturated fatty acids (PUFAs), were infused (9) preferrably with phosphate (10) to accomodate the anticipated increase in the rate of oxygen consumption and ATP resynthesis from endogenous ADP, H+ and Pi? Whilst the Intralipid might precipitate an energy defict in myocytes it might decrease myocardial workload enough to have a positive effect upon myocyte energy mertabolism by decreasing the cardiac output needed to deliver the nutrients needed to maintain ATP resynthesis in peripheral tissues. In exploring such possibilities it would be wise to clamp the arterial pH and preferably the gastric intramucosal pH, possibly at the lower limit of normality or just below that, using two Radiometer automatic titrators possibly one charged with HCl and the other with NaOH (11). Given the findings in this study both preventing a abnormally large fall in gastric intramucosal pH and accompanying blood volume and preventing an abnormally large rise would seem desirable. This is a really interesting study. The authors are to be commended for having done it. Yours, Richard G Fiddian-Green 1. Satoshi Ohki, Fumio Kunimoto, Yukitaka Isa, Hiroshi Tsukagoshi, Susumu Ishikawa, Akio Ohtaki, Toru Takahashi, Tetsuya Koyano, Noboru Oriuchi, and Yasuo Morishita Changes in gastric intramucosal pH and circulating blood volume following coronary artery bypass grafting Can J Anesth 2000; 47: 516-521 2. E Kaminskas The pH-dependence of sugar-transport and glycolysis in cultured Ehrlich ascites-tumour cells. Biochem J. 1978 August 15; 174(2): 453–459. 3. Cain SM. Oxygen delivery and utilization in hypoxic dogs made acidemic and alkalemic. Adv Exp Med Biol. 1976;75:483-9. 4. Cain SM. pH effects on lactate and excess lactate in relation to O2 deficit in hypoxic dogs. J Appl Physiol. 1977 Jan;42(1):44-9. 5. Lionel H. Opie, MD, DPhiL, DSc, FRCP and Bernard J. Gersh, MB, ChB, DPhil, FACC. Drugs for the Heart, 6th Edition Elsevier, 2005. 6. Bear, MF; BW Connors, and MA Paradiso (2001). Neuroscience: Exploring the Brain. Baltimore: Lippincott. 7. Richard G Fiddian-Green Successful evolutionary adaptation to environmental stress? http://www.heartjnl.com/cgi/eletters/90/4/381#343, 14 Jul 2004 8. Robinson DA, Wang P, Chaudry IH. Administration of ATP-MgCl2 after trauma-hemorrhage and resuscitation restores the depressed cardiac performance. J Surg Res. 1997 Apr;69(1):159-65. 9. Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia. 2006 Aug;61(8):800-1. 10. Storm TL. Severe hypophosphataemia during recovery from acute respiratory acidosis. Br Med J (Clin Res Ed). 1984 Aug 25;289(6443):456-7. 11. Fiddian-Green RG, Silen W. Mechanisms of disposal of acid and alkali in rabbit duodenum. Am J Physiol. 1975 Dec;229(6):1641-8. |
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Richard G Fiddian-Green, FRCS, FACS None
Send letter to journal:
richardfg{at}hotmail.com Richard G Fiddian-Green
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"The pHi increased in patients whose BVc increased by > 300 ml. Mean fluid balance was negative in this period (–386 ± 667 ml; range, –1786 - + 423 ml)"(1). What does this mean? How could the pHi go up if the blood volume has increased but the fluid balance has become negative? The authors concluded that, "improvement of pHi, an indicator of splanchnic perfusion, appears to be related to systemic vasodilatation and an increase in BVc". If the blood volume has increased, and the method is not perturbed by alterations in tissue pH, and the fluid balance is negative the intravascular compartment must have expanded. If so it must have expanded because of dilatation of arterioles and/or of splanchnic venous capacitance vessels as the authors imply and/or because of capillary recruitment. How then might the pHi have increased? Might it have risen because tissue perfusion had increased and reduced the tissue pCO2 by improving tissue washout? In other words might the rise in pHi have been a reflection of an increase in tissue blood flow in excess of tissue needs? Unlikely. In our studies in anaesthetised dogs we observed that the pHi fell from a seemingly abnormally elevated level as DO2 was decreased even though DO2(crit) [i.e. oxygen supply-dependency] had not been reached (2). This raised the possibility that the fall in pHi above DO2(crit) might be indicative of nutrient supply-dependency possibly induced by an anabolic drive(3). If, however, the pHi is primarily a reflection of the balance between proton accumulation from ATP hydrolysis and proton consumption by oxidative phosphorylation then a rise in pHi must indicate that the rate of ATP resynthesis has exceeded the rate of ATP hydrolysis. Under what circumstances might the rate of ATP resynthesis be expected to exceed the rate of ATP hydrolysis? During the repayment of an oxygen debt? This is unlikely to have been present in these circumstances. Is it possible that the induction of anaesthesia caused a rise in pHi by inducing an anticipatory increase in ATP pool size possibly by triggering the release of stress hormones? Might anaesthesia have also reduced myocardial workload by increasing nutrient energy density per unit volume of flowing blood (4) and even induced a bradycardia (5)? If it did the metabolic stress of inducing anaesthesia has been underestimated. If a lipid shift were induced by the induction of anaesthesia it might in theory have reduced the cardiac output to less than 2l/min without impairing tissue energetics were it not for adverse metabolic effects of the anaesthesia. The inference is that a lipid shift might eliminate the need for a compensatory capillary recruitment and the vasodilatory increase in blood volume observed in this study. There are physiological reasons for believing that circulating blood volume might also have been decreased without compromising tissue energetics for there may be benefits to be derived from restricting fluids and keeping cardiac filling pressures much lower than they usually are in common practice(6). The conclusion that, "improvement of pHi, an indicator of splanchnic perfusion, appears to be related to systemic vasodilatation and an increase in BVc" (1) is meaningless in this metabolic context. The continued focus of attention by upon haemodynamics and perfusion to the exclusion of sensitive and objective measures of metabolic activity would appear to be a serious impediment to further reductions in the risks of perioperative morbidity and mortality especially in emergencies. 1. Satoshi Ohki, Fumio Kunimoto, Yukitaka Isa, Hiroshi Tsukagoshi, Susumu Ishikawa, Akio Ohtaki, Toru Takahashi, Tetsuya Koyano, Noboru Oriuchi, and Yasuo Morishita Changes in gastric intramucosal pH and circulating blood volume following coronary artery bypass grafting Can J Anesth 2000; 47: 516-521 2. 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. 3. Nutrient supply dependency and the lactate shuttle hypothesis Richard G Fiddian-Green Chest Online, 3 Jul 2004 eLetter re: David Roy Dantzker Monitoring Tissue Oxygenation : The Quest Continues Chest 2001; 120: 701-702 4. 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 5. Bradycardia in haemorrhagic shock: a cytoprotective response to free radicals? Richard G Fiddian-Green (23 February 2004) eLetter re: Ian Thomas and John Dixon Bradycardia in acute haemorrhage BMJ 2004; 328: 451-453 6. Dehydration may benefit marathon runners. Richard G Fiddian-Green (19 July 2003), The need to go back to the basics. Richard G Fiddian-Green bmj.com, 16 Aug 2003 eLetters re: Timothy David Noakes Overconsumption of fluids by athletes BMJ 2003; 327: 113-114 |
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Richard G Fiddian-Green, FRCS, FACS None
Send letter to journal:
richardfg{at}hotmail.com Richard G Fiddian-Green
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The popularity with the measurements of gastric intramucosal pH (pHi) used in this study has unfortunately been largely replaced by measurements of intramucosal pCO2 (1,2). One reason for this appears to be the discrepancy between measurements of pH measured directly in the submucosal space and those measured indirectly by the tonometric method, the direct measurements being lower than the indirect measurements in low-flow and especially no-flow states (3). What has not been considered in this contentious issue (4,5,6) is the effect of pH upon carbonic anhydrase activity and the pivotal importance of pH in the regulation of tissue energetics. The pH in a closed system, such as a no-flow state, falls with the addition of protons almost entirely because of a rise in pCO2. In an open system, such as the volume resuscitated hyperdynamic state in sepsis, the pH falls largely because the[HCO3-] falls there being degrees of change between these two extremes. If pH falls below pH 7.0 and especially if it approaches pH 6.0, and cytosolic pH is lower than and usually falls in parallel with the interstitial pH, carbonic anhydrase (CA) will be inhibited (7). That means that the buffering of protons by HCO3-, which depends upon the generation of CO2 catalysed by CA, will also be inhibited. The very limited fall in [HCO3-] that occurs with the addition of protons to a closed sytem should also be restricted and with it the ability to increase tissue pCO2 in rsponse to aan accumulation of unbuffered protons. The progressive freezing of the bicarbonate buffer system in vivo that in effect occurs with a fall in pH from pH 7.0 to pH 6.0 should not be reflected in the other body buffer systems. There may, therefore, be a systematic error in calculating pH from pCO2 and [HCO3-] at very low pHs, the actual pH being progresively lower than the derived pH. This possibility does not appear to have been considered previously (8). It is not, however, an issue that would ever have been of clinical relevance to blood gas analysis for an arterial pH lower than pH 7.0 and certainly pH 6.90 is invariably incompatible with life. That the tonometric method underestimates the severity of a tissue acidosis should not be of clinical concern possibly unless the measurement is used as an index of the adequacy of tissue perfusion in low-flow states. Although the pCO2 of luminal contents is more likely to be in equilibrium with that in the superfical layers of mucosa than the deeper layers of the gut wall the DO2(crit) for the mucosa appears to be the same as that for the serosa even in a larger animal model(9). My concern that the measurements of pHi might not accurately reflect the pH in deepers layers of the gut is not supported by these findings. The use of DO2(crit) to define that point at which oxygen supply dependency occurs is of limited value if nutritional supply dependency can occur when the pHi is still normal or even abnormally elevated and precedes the development of oxygen supply dependency(6). Indeed an abnormal elevation in pHi is a potent stimulus for anaerobic glycolysis (10), probably because it eliminates the protonmotive force needed to drive ATP resynthesis by oxidative phosphorylation and shifts the need to meet tissue energy needs to anaerobic glycolysis. Conversely the rate of ATP resynthesis by oxidative phosphorylation increases as the pH falls and the magnitude of the protonmotive force driving ATP resynthesis increases. A fall in tissue pH appears, therefore, to be a cytoprotective (11) metabolic response to metabolic stress, which is accompanied by the down regulation of ATP-dependent cellular activity in accordance with the Daniel Atkinson energy charge hypothesis. The net effect is an improvement in tissue energy supply/demand balance. There is a functional price to be paid for the cytoprotective effect of tissue acidosis. In the myocardium, for example, the fall in pH is accompanied by opening of the K+(ATP) channel and a decrease in myocardial contractility, a fall in cytolic pH of just 0.2 of a pH unit being sufficient to decrease contractility 50% (12). Whilst this may be cytoprotective to the heart during open heart surgery it may of have catastrophic systemic consequences if the low cardiac output syndrome develops as often occurs with cardiac surgery. A major feature of a systemic anerobic shift may be a geometric increase in myocardial workload. To replenish 1 mole ATP by anaerobic glycolysis 20 times more glucose has to be delivered than that required to replenish 1 mole ATP by oxidative phosphorylation. Whilst much of this increase in demand for glucose is probably met by an increase in glycogenolysis, hyperglycaemia increasing the delivery gradient, and an increase in glucose uptake and utilisation induced by the release of the stress hormones the remainer has to be met by an increase in blood flow. The increase in demand for glucose delivery may exceed the functional capacity of the heart, expecially if that capacity is already compromised, and precipitate acute heart failure by imposing an overwhelming workload on the heart. The acute heart failure might even precede any fall in pHi in the gut as with extreme hypoxaemia induced in anaesthetised dogs(13). Viewed in this context the increase in DO2 and VO2 that accompanied the fall in pHi in this study (14) may be interpreted as an anaerobic shift wholly or partially induced by hypovolaemia which triggered the need to limit the increase in myocardial workload by increasing ATP resynthesis by oxidative phosporylation. Hence the correlation between pHi and circulating blood volume. The benefits of a pH-stat protocol relative to the alpha-stat protocol, which include being less likely to cause a lactic acidosis and develop brain and cardiac damage (15), may be similarly explained. There is another possibility. The fall in pHi might have been triggered by an increase in demand for nutrient delivery induced by an anaerobic shift caused by the anaesthetic agents (16) being used rather than by the hypovolaemia. In which case the beneficial effects of inceasing cardiac output by increasing circulating blood volume may have been due to the elimination of the hypothetical need for a compensatory increase in protonmotive force by eliminating a nutrient supply dependency. It is an important consideration for it raises the possibility that the induction of anesthesia alone might increase myocardial workload. In which case the increase in workload might be eliminated by a more liberal and aggressive use of the pH-stat protocol as previously considered (3,6). 1. Vincent JL, Creteur J. Gastric mucosal pH is definitely obsolete-- please tell us more about gastric mucosal PCO2. Crit Care Med. 1998 Sep;26(9):1479-81. 2. Fink, MP (1998) Tissue capnography as a monitoring strategy in critically ill patients: just about ready for prime time. Chest 114,667- 669 3. Fiddian-Green, RG (1995) Gastric intramucosal pH, tissue oxygenation and acid-base balance. Br J Anaesth 74,591-606. 4. Fiddian-Green RG. Monitoring of Tissue pH The Critical Measurement. Chest. 1999;116:1839-1841 5. Schlichtig, R.. 1996. Tissue-arterial PCO2 difference is a better marker of ischemia than intramural pH (pHi) or arterial pH-pHi difference. J. Crit. Care 11: 51-56 6. Fiddian-Green RG. Electronic letters re: David Roy Dantzker Monitoring Tissue Oxygenation : The Quest Continues Chest 2001; 120: 701-702 7. Berg JM,Tymoczko JL, Stryer L. Biochemistry. Fifth edition. WH Freeman and company, New York, 2002. 8. JOHN W. SEVERINGHAUS, POUL ASTRUP, and JOHN F. MURRAY. Blood Gas Analysis and Critical Care Medicine. Am. J. Respir. Crit. Care Med., Volume 157, Number 4, April 1998, S114-S122 9. Ranna A. Rozenfeld, Michael K. Dishart, Tor Inge Třnnessen, and Robert Schlichtig. Methods for detecting local intestinal ischemic anaerobic metabolic acidosis by PCO2. J Appl Physiol 81: 1834-1842, 1996 10. Cain SM. Oxygen delivery and utilization in hypoxic dogs made acidemic and alkalemic. Adv Exp Med Biol. 1976;75:483-9. 11. Gores GJ, Nieminen AL, Wray BE, Herman B, Lemasters JJ. Intracellular pH during "chemical hypoxia" in cultured rat hepatocytes. Protection by intracellular acidosis against the onset of cell death. J Clin Invest. 1989 Feb;83(2):386-96. 12. Levick JR. Cardiovascular physiology. Arnold, London, 2003. 13. 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. 14. Satoshi Ohki, Fumio Kunimoto, Yukitaka Isa, Hiroshi Tsukagoshi, Susumu Ishikawa, Akio Ohtaki, Toru Takahashi, Tetsuya Koyano, Noboru Oriuchi, and Yasuo Morishita Changes in gastric intramucosal pH and circulating blood volume following coronary artery bypass grafting Can J Anesth 2000; 47: 516-521 15. Fiddian-Green RG. Rapid responses to: Vipin Zamvar, David Williams, Judith Hall, Nicola Payne, Clare Cann, Karen Young, S Karthikeyan, and John Dunne Assessment of neurocognitive impairment after off-pump and on-pump techniques for coronary artery bypass graft surgery: prospective randomised controlled trial BMJ 2002; 325: 1268 16. Stevanato R, Momo F, Marian M, Rigobello MP, Bindoli A, Bragadin M, Vincenti E, Scutari G. Combined effect of propofol and GSNO on oxidative phosphorylation of isolated rat liver mitochondria. Nitric Oxide. 2001 Apr;5(2):158-65. |
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Richard G Fiddian-Green, FRCS, FACS None
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richardfg{at}hotmail.com Richard G Fiddian-Green
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Dear editor, May I make a comment about the interpretation of tonometric measurements? The conclusions drawn about the intramucoal pCO2 in so far as blood flow is concerned have not considered the inhibitory effect a fall in pH has on carbonic anhydrase(CA) activity. CA increases the rates of association and dissociation of carbonic acid some 5000 fold. CA activity is maximal at pH 8.0 and is sustained up to pH 9.0. At pH 7.0, just below normal cytosol pH but much lower than the interstitial pH usually measured tonometically, activity is half-maximal. Below 7.0 activity falls precipitously reaching near 0% at pH 6.0. This is the range encountered in dysoxia. [To calculate the cytosolic pH, which is normally around 7.10 to 7.20, using the tonometic method the cytosolic [HCO3-] must bee used. This is lower than interstitial [HCO3-]]. Inhibition of CA greatly limits the ability of cells to reverse an acidosis caused by unreversed ATP hydrolysis by loss of CO2 and increases reliance upon proton consumption by ATP resynthesis by oxidative phosporylation. [This effect may account for the unique state in gastric glands in which cells appear to be impermable to CO2 (1,2)]. The inference is that measurements of intramucosal pCO2 and pCO2-gap are less and less likely to reflect blood flow as cytosolic pH falls from pH 7.0 to pH 6.0. An abnormally increased intramucosal pCO2 or pCO2-gap might, therefore, conceivably exist at low cellular and tissue pH despite "normal" blood flow and be erroneously interpreted as a low-flow or no-flow sate.. 1. Boron WF, Waisbren SJ, Modlin IM, Geibel JP. Unique permeability barrier of the apical surface of parietal and chief cells in isolated perfused gastric glands. J Exp Biol. 1994 Nov;196:347-60. 2. Waisbren SJ, Geibel JP, Modlin IM, Boron WF. Unusual permeability properties of gastric gland cells. Nature. 1994 Mar 24;368(6469):332-5. |
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