{"id":5221,"date":"2011-07-14T20:24:32","date_gmt":"2011-07-14T20:24:32","guid":{"rendered":"http:\/\/crashtext.org\/misc\/alpha-stat-vs-ph-stat.htm\/"},"modified":"2014-07-15T18:15:30","modified_gmt":"2014-07-15T22:15:30","slug":"alpha-stat-vs-ph-stat","status":"publish","type":"post","link":"https:\/\/crashingpatient.com\/intensive-care\/alpha-stat-vs-ph-stat.htm\/","title":{"rendered":"Alpha-Stat vs. pH-Stat"},"content":{"rendered":"

<\/span>Beyond Davis : the Alpha-stat Hypothesis<\/span><\/h2>\n

Reeves (1972) and Rahn extended the conclusions reached by Davis by considering the dissociation constants (pK) for these metabolic intermediates. They found that the pK for all the acid intermediates was less than 4.6 and the pK of all the basic intermediates was greater than 9.2 . The degree of dissociation of all these compounds at a pH around neutrality was 1.0 (ie fully ionised). The intermediates are all charged and trapped within the lipid cell membrane. They suggested looking at acid-base physiology from the point of view of the intracellular<\/em> environment instead of the usual clinical extracellular approach. They first posed the following question: <\/p>\n

What is the ideal intracellular pH?<\/h4>\n

The work of Davis and their findings concerning pK values suggested that the ideal state for intermediary metabolism is the state of neutrality<\/strong> because maximal ionisation with consequent intracellular trapping of metabolic intermediates occurs at this pH. <\/p>\n

First Hypothesis: pH(ICF) = pN<\/h5>\n

If theoretically it is clear that the ideal ICF pH should be the pH of neutrality (pN), then the next step is to ask the question: <\/p>\n

Is the actual intracellular pH as predicted?<\/h4>\n

According to Rahn, measurements confirmed that the mean intracellular pH of man is 6.8 at 37\u00b0C which is indeed the pH of neutrality (pN) at that temperature! Before going further we need to understand: <\/p>\n

What is meant by “neutrality”?<\/h4>\n

Neutrality is defined, for aqueous systems, as the state when [H+] = [OH-]. (This definition derives from the Arrhenius acid-base theory and it is noted in passing that a criticism of the Bronsted-Lowry theory is that it has no definition of neutrality.) By the Law of Mass Action applied to the dissociation of water (see Section 10.4<\/a>), then: pN = 0.5 x pKw\u0092 (where pKw\u0092 is the ion product for water. ) Consideration of this equation is important as it provides us with a way to test the Davis, Reeves and Rahn hypothesis that intracellular pH equals pN (with consequent biological advantage of intracellular trapping of metabolic intermediates. The clue is that pKw’is very temperature dependent<\/em>. So pN is temperature dependent and if the hypothesis (ICF pH = pN) is correct then intracellular pH should change with change in temperature to maintain the predicted relationship. An intracellular pH at about pN must surely apply to other animals (with body temperatures other than 37C) as there is no reason to believe that humans at 37\u00b0C alone should be in a unique position. If this predicted change with temperature does occur, it would lend very strong support to the theory. So, the next question is: <\/p>\n

Does intracellular pH change with temperature in order to remain equal to pN at each temperature? (And if so: How does this happen?)<\/h4>\n

Measurements of intracellular pH in skeletal muscles have been carried out in several ectothermic animals which have been acclimatised at temperatures ranging from 5\u00b0C to 31\u00b0C. These all show the expected pH change: intracellular pH is maintained at about pN with change in temperature!!<\/strong> It has been calculated that for the body to have this temperature-pH relationship requires certain things. There must be a buffer system with a pK which is approximately one-half that of water (because a buffer is most effective close to its pK) and which changes its pK so that it maintains this relationship as temperature changes. The buffer must be present in sufficient concentration and have certain chemical properties (eg delta H\u00b0 = 7 kcals per mole). For this system to work optimally, it also requires a constant CO2 content. Experimental work has shown that protein buffering, largely due to the imidazole group of histidine is responsible for maintaining this temperature-pH relationship (aided by phosphate and bicarbonate buffering). Of all the protein-dissociable groups that are available, it is only the imidazole of histidine that has the correct pK and whose pK changes with temperature in the appropriate way.<\/strong> The imidazole has a degree of dissociation (referred to as alpha) of 0.55 in the intracellular compartment and this remains constant despite changes in temperature (ie the pK is changing with change in temperature). This theory about the constancy of the imidazole alpha value as proposed by Reeves and Rahn has been termed the imidazole alphastat hypothesis. Alphastat Hypothesis The degree of ionisation (alpha) of the imidazole groups of intracellular proteins remains constant despite change in temperature. The other necessary condition for maintaining imidazole alpha constant is that the CO2 content in blood must be kept constant at different body temperatures. This means that ventilation must be regulated to maintain the imidazole alpha in the blood. It has been found experimentally that this regulation to maintain imidazole alpha constant in blood will result in imidazole alpha being maintained in other compartments (eg intracellular fluid) as well. The respiratory control that adjusts ventilation probably involves proteins whose activity is altered in an appropriate direction by an alphastat mechanism. Adjustment of ECF pCO2 is necessary as this maintains a constant relative alkalinity of the ECF relative to the ICF so there is constancy of the gradient for H+ across the cell membrane. In reality this does not mean that ventilation has to increase markedly with decrease in temperature because the reduced metabolic rate will automatically result in decreased CO2 production. Important Note:<\/strong> Many people have an almost unshakeable belief that a pH of 7.0 is the ‘neutral pH’ and consequently have trouble understanding how the change in pN with temperature can be possible. A solution to this is to understand that the definition of neutrality is the pH when [H+] = [OH-]. At a temperature of 25C, this condition does indeed occur in pure water when pH is 7.0 and this is the basis of the common high-school teaching. But, as indicated in the calculations in Section 10.4<\/a>, this condition of [H+] = [OH-] occurs when pH = 0.5 x pKw\u0092. This pH (the pN) is dependent only<\/em> on the ion product of water (pKw’)- and this term is very temperature dependent. So the required condition of [H+] = [OH-] occurs at different pH values at different temperatures. Effectively, this means that the dissociation of water is temperature dependent. <\/p>\n

<\/span>1.6.2 Alpha-stat versus pH-stat<\/span><\/h2>\n

The alternative theory is the pH-stat hypothesis<\/strong>: <\/p>\n

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this argues that the pH should be kept constant despite changes in temperature. This is the same as saying that ECF pH should be kept at 7.4 whether the temperature is 20C or 25C or whatever it is. Blood gas results: To temperature correct or not? The pH-stat approach<\/strong> is also implicitly the approach used by anyone who temperature corrects blood gas results to the patient\u0092s temperature but interprets the values against the reference range relevant to 37\u00b0C. No reference range is available for temperatures other than 37\u00b0C but the pH-stat approach is that the reference range for 37\u00b0C is valid at all temperatures. The alpha-stat approach is to never temperature correct blood gas results. Do not report the patient’s temperature on the request form, or if doing the gases yourself, only enter the temperature as 37\u00b0C no matter what the patient’s actual temperature. The results from the blood gas machine must then be those as measured in the machine at 37\u00b0C. The reference range for 37\u00b0C is obviously the correct one to apply when assessing these results. You should be careful because if you or a colleague indicate the patient’s actual temperature on the blood-gas request form, the lab technician will enter this temperature into the blood-gas machine and the printed report will have the values calculated for this patient temperature (i.e. the ‘corrected’ values). Note that whatever the actual patient temperature, the machine is always thermostatted to 37\u00b0C and all measurements are consequently performed at 37\u00b0C. For other patient temperatures, the computer in the machine uses various correction formulae to calculate what the values for the parameters would be at the patient’s actual temperature. The pH correction used in most machines is the Rosenthal correction factor<\/a>. The manual for the blood gas machine has a complete listing of the formulae it uses for all calculated values. This controversy over whether the alpha-stat or the pH-stat theory is correct<\/em> does have practical anaesthetic relevance in patients who are rendered hypothermic (eg while on cardiopulmonary bypass). What is the pH level to aim for in these patients? It seems that the alpha-stat theory is now widely accepted. This is probably related to the intellectual attraction of the theoretical arguments because major differences in outcome between groups of patients managed by the pH-stat or the alpha-stat technique have not been clear. Cells are capable of functioning despite the presence of a certain level of perturbation. Clinical studies have concentrated on which approach is best for the heart (myocardial outcome) and\/or which approach is best for the brain (neurological outcome). The pH-stat aim to maintain a pH of 7.4 at the lower temperatures of hypothermic cardiac bypass is achieved by having a pCO2 level which is higher than that required for alpha-stat management. This means that from the alphastat point of view, pH-stat management results in a respiratory acidosis at the lower temperature. One effect is that the cerebral blood flow is higher at a given temperature with pH-stat management than it is with alphastat management. (See section 1.6.3<\/a>) The alphastat hypothesis is about maintaining alpha which means that the net charge on all proteins is kept constant despite changes in temperature. This ensures that all proteins can function optimally despite temperature changes. The importance of pH is not just about intracellular trapping of metabolic intermediates (small molecule effect) but also about protein function (large molecule effect). This affects all proteins, though enzymes usually figure prominently as examples. So, to answer the question about why pH is so important in metabolism involves these two reasons. Summary: The two reasons why pH is so important for metabolism <\/p>\n