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Acidosis, phosphofructokinase and diabetic coma
- Jonathan M Handy, Neil Soni (3 November 2008)
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Acidosis is detrimental
- Viktor Rosival (24 October 2008)
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Physiology is not teleology!
- Nick Barnett (27 August 2008)
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The semantics of normal
- YURI ZELENIN, USA (11 August 2008)
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Jonathan M Handy, Consultant Intensivist / Anaesthetist Chelsea & Westminster Hospital, London, Neil Soni
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Sir: Dr Rosival highlights an extremely pertinent point in his response to our article(1) however we disagree with the conclusions to which he has arrived from the quoted evidence. The study by Edge(2) eloquently highlights the association of acidosis with worse neurological effects during diabetic ketoacidosis in children. However they provide no mechanism of causation and highlight in their discussion that the pathophysiological mechanism behind such neurological changes remains elusive. As stated in our article; association does not imply (or preclude) causation. It is of little surprise that patients with poorer clinical (neurological) presentation had worse metabolic derangement. Dr Rosival implies that the studies of Umpierrez(3) and Fiordalisi(4) showed improved outcomes using alkalinising agents during management of diabetic ketoacidosis (DKA). The former study was a prospective non- interventional study not designed to elucidate the mechanisms of coma in DKA. The central tenet of the latter was a fluid resuscitation and management regime for patients with DKA which used a physiological approach in which both bicarbonate and acetate were used as part of anion replacement (rather than as alkalinising therapy) and as a part of a complicated fluid management regime. It cannot be concluded from this that one part of a complicated regime is solely responsible for the overall outcome from that regime. Indeed this is not the conclusion of the original authors in either study. Nevertheless, the role of acidosis in the inhibition of phosphofructokinase (PFK) is an interesting (and complex) one. Acidosis has a complex association with insulin resistance possibly through its effects on PFK(5) or through alterations in cortisol metabolism(6). During insulin deficiency cellular uptake of glucose is impaired, effectively depriving the cell of substrate for glycolysis. During this phase, the effects of cytosolic acidosis on PFK cannot be of significance as there is no or little glucose entering the pathway. On administration of insulin, however, it is possible that this cytosolic PFK inhibition may impair the ability to utilise glucose and thus delay cellular ATP production. The return of pyruvate as substrate for the Kreb’s cycle leads to increased Kreb’s metabolites which include malonyl-CoA. This is an important inhibitor of ketogenesis in the liver. Thus if acidosis delays the return to aerobic metabolism in these circumstances, ketogenesis and ATP deficiency could theoretically persist. Such a mechanism has not, however been mechanistically proven and (as we stated in our article), the results of experiments in cell lines, isolated organs and differing species should be interpreted with caution when extrapolated to the clinical situation. Returning to our original article; it is our view that mild to moderate acidoses are commonly encountered physiological and pathophysiological phenomena for which there is little evidence of direct causative detriment and which we tolerate relatively well. It is also our view that severe acidosis almost certainly does have detrimental effects: DKA is certainly such a state with severe metabolic derangement where the effects of acidosis could theoretically have direct detrimental effects. However such effects remain to be proven. 1. Handy JM, Soni N. Physiological effects of hyperchloraemia and acidosis. Br J Anaesth 2008;101:141-50. 2. Edge JA, Roy Y, Bergomi A et al. Conscious level in children with diabetic ketoacidosis is related to severity of acidosis and not to blood glucose concentration. Pediatr Diabetes 2006;7:11-5. 3. Umpierrez GE, Kelly JP, Navarrete JE et al. Hyperglycemic crises in urban blacks. Arch Intern Med 1997;157:669-75. 4. Fiordalisi I, Novotny WE, Holbert D et al. An 18-yr prospective study of pediatric diabetic ketoacidosis: an approach to minimizing the risk of brain herniation during treatment. Pediatr Diabetes 2007;8:142-9. 5. Inoue Y, Kaneko T. [Effects of pH on the endocrine system and metabolism]. Nippon Rinsho 1992;50:2124-8. 6. McCarty MF. Acid-base balance may influence risk for insulin resistance syndrome by modulating cortisol output. Med Hypotheses 2005;64:380-4. Conflict of Interest:None declared |
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Viktor Rosival
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To the Editor of "British Journal of Anaesthesia" In their recent paper(1), Handy and Soni write on p 142 "With regard to acidosis, the clinical literature is remarkable in its lack of conclusive evidence to support the perception that the acidosis itself is a detrimental state in need of direct correction". However, they have omitted the paper of Edge et al(2) which has shown that low blood pH is the immediate cause of coma: the glycolytic enzyme phosphofructokinase is pH dependent(3) as its activity is decreasing with decreasing pH. Thus, the utilisation of glucose in brain cells is impaired and, therefore, the clinical consequences of decreasing blood pH are drowsiness - stupor - coma - death in coma. On p 145, they have also discussed diabetic ketoacidosis. In diabetic ketoacidosis, life threatening is only its most severe stage, coma. Several authors have reports zero lethality of coma in patients with diabetic ketoacidosis, e g Umpierrez et al(4) and Fiordalisi et al(5); their treatment included also infusions of alkalising solutions. Where are published reports on zero lethality in similar comatose patients without infusions of alkalising solutions? Dr. Viktor Rosival, Synlab Department of Laboratory Medicine, Dérer's Hospital, Bratislava, Slovakia. e-mail: rosivalv@hotmail.com References 1. Handy JM, Soni N. Physiological effects of hyperchloraemia and acidosis. Brit J Anaesthesia 2008; 101: 141-50 2. Edge JA, Roy Y, Bergomi A et al. Conscious level in children with diabetic ketoacidosis is related to severity of acidosis and not to blood glucose concentration. Pediatr Diabetes 2006; 7: 11-5 3. Trivedi B, Danforth WH. Effect of pH on the Kinetics of Frog Muscle Phosphofructokinase. J biol Chem 1966; 241: 4110-2 4. Umpierrez GE, Kelly JF, Navarrete JS et al. Hyperglycemic crises in urban blacks. Arch Intern Med 1997; 157: 669-75 5. Fiordalisi I, Novotny WE, Holbert D et al. An 18-yr prospective study of pediatric diabetic ketoacidosis: an approach to minimizing the risk of brain herniation during treatment, Pediatr Diabetes 2007; 8: 142-9 Conflict of Interest:None declared |
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Nick Barnett, SpR Anaeesthesia National hospital for neurology and neurosurgery
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The Editor In an otherwise meticulously researched editorial on the "Physiological effects of hyperchloraemia and acidosis" (1) the paragraph the authors devote to teleology is somewhat incongruent. Teleology in the biological sciences is a contentious notion disputed by philosophers of science and biologists alike. Bekoff (2) and Allen (2,3) state that teleologic notions are controversial because i. they are vitalistic (positing some special life force) ii. require backward causation iii. incompatible with mechanistic explanation (that is cause precedes effect - because of i.+ii.) iv. mentalistic (attributing the action of mind where there is none) v. empirically untestable (because of the above). One might add to this list that many of the statements made in the paragraph cannot be disproved according to Popper's criterion of falsifiability and are therefore unscientific. The situation that obtained on the African Savannah facing primordial mammals is not one we can rightly have any claim to know so the statement that acidosis "..would be disastrous for the hunting or hunted animal" is not only unknoweable but also impossible to falsify. Furthermore the physiology of predator and prey could be assumed to have very different characteristics. The statement that if "acidosis had a major impact on contractility humans would never have evolved the ability to perform high-intensity exercise" is a clear instance of backward causation (2). The effect or ability to perform high-intensity exerice is cited as a reason (or cause) why acidosis might have minimal impact on the exercising myocardium. Another central difficulty with a teleological approach is that it commits the naturalistic fallacy - that is to say that it ascribes normative value (good or bad) to an agent-neutral description. To say that acidosis is 'disastrous' or even 'lethal' is to impute moral value or badness to a scientifc observation that is without any prima facie moral value. It may well not be conducive to survival under current paradigms but also may well be if an organism adapted in a different manner. A strategy that avoids reference to design, backward causation and naturalistic fallacy is to consider function and natural selection. Accounts of function are themselves fraught (2) but essentially align a given trait and its maintenance in the population say the ability to withstand acidosis with a given function - the ability to perform high intensity exercise - via the process of natural selection. It might be therefore that the ability to withstand prolonged periods of acidosis is a trait that favoured natural selection in humans and mammals more generally. However mammals differ quite widely in their development of acidosis and in their anaerobic thresholds. This might suggest that for various mammals eg equidae, acidosis is offset at all costs rather than the development of a permissive reaction to developing acidosis as the editorial seems to suggest. The point or purpose (if you like) of teleogically-invoked explanations of biological functions is that they are extremely complex and the lines of argument extremely subtle and much debated. Teleology in this context is thus at best an entertaining thought-experiment at worst pure conjecture. In an excellent editorial that sets out to examine the body of evidence ('the literature') on acidosis, teleology is perhaps worthy of a few lines but certainly not an entire unreferenced paragraph. Nick Barnett BSc,MRCP, FRCA References: 1 Handy JM, Soni N. Physiological effects of Hyperchloraemia and acidosis. Br J Anaesth 2008; 101: 141-50. 2. Bekoff M, Allen C. Teleology, function, design, and the evolution of animal behavior. Trends in Ecology and Evolution 1995;10(6): 253-55. 3. Allen C. Teleological notions in biology. Stanford Encyclopedia of Philosophy 2003 http: //plato.stanford.edu/entries/teleology-biology/ Conflict of Interest:None declared |
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YURI ZELENIN, ANESTHESIOLOGIST Bloomington, Indiana, USA
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Sir, The authors state that normal saline is "neither normal nor physiological". This assertion is not accurate, simply because "normal" refers to the osmolarity and not to being somehow natural to the body. Normal here implies normality as a matter of physical chemistry, not normalcy as a matter of physiology. Likewise, 0.45% NaCl is nicknamed "half-normal" because of its lower osmolarity, not because it is half as good as 0.9% NaCl. Conflict of Interest:None declared |
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