Strong Ions, Acid-base, and Crystalloid Design

Transcription

1 Strong Ions, Acid-base, and Crystalloid Design T. J. Morgan and B. Venkatesh I Introduction It is now generally accepted that whenever large volumes of saline are administered intravenously, metabolie acidosis can result [1-3]. Examples of at risk situations include acute normovolemic hemodilution, cardiopulmonary bypass, hypovolemic and septic shock, multi trauma, bums, liver transplantation, diabetic ketoacidosis and hyperosmolar non-ketotic coma. The conventional explanation is that there is simple dilution of extracellular bicarbonate (HCO;;) by large volumes of non-hco;; containing fluid [4-7]. However, Stewart's physical-chemical approach to acid-base analysis provides a different perspective. In this chapter, we will see how Stewart's concepts might assist in the design of crystalloid solutions with predetermined acid-base effects. We will begin by reviewing some important principles of acidbase analysis with an emphasis on the physical-chemical approach. I Acid-base Analysis: Fundamental Principles Usually, the first step in the laboratory evaluation of arterial acid-base status is to measure the arterial PaCOz and ph. The PaCOz/pH relationship then allows us to distinguish respiratory from metabolie (non-respiratory) acid-base perturbations, traditionally using offsets in bicarbonate concentration ([HCO;;]) (the Boston school) [8, 9] or standard base excess (the Copenhagen school) [10-12]. In acute respiratory acid-base disturbanees, PaCOz is abnormal but its relationship to ph is normal (Fig. 1). Here there is no [HCO;;] offset, and standard base excess lies in the normal range. If the PaCOz/pH relationship is shifted to the left, there is a metabolie acidosis, in which case [HCO;;] and standard base excess are low. If the PaCOz/pH relationship is shifted to the right, there is a metabolie alkalosis (Fig. 1), and [HCO;;] and standard base excess are elevated. I The Physical Chemical Approach [l3-15) The Stewart approach looks at acid-base analysis from a different perspective. Here [HCO;;] and ph are both seen as dependent variables determined by three independent variables. These are PCOl> strong ion difference ([SID]), and the total concentration of non-volatile weak acid buffer ([A TOT]). A TOT consists primarily of protein histidine residues. In plasma, A TOT is largely albumin (with a small contribution J.-L. Vincent (ed.), Yearbook of Intensive Care and Emergency Medicine 2002 Springer-Verlag Berlin Heidelberg 2002

2 428 T. J. Morgan and B. Venkatesh 100 c; I E Ö U ,----, ,----,----,---, ph Fig. 1. PaCOipH relationships. Illustrated are the normal relationship (N) and examples of metabolie aeidosis (Acid) and metabolie alkalosis (Alk) from inorganic phosphate). In whole blood the predominant contributor to ATOT is hemoglobin. The [SID] concept is based on the observation that certain ions such as Na+, K+, Cl- and lactate remain essentially fully ionized under all physiologic acid-base conditions, and do not bind to other molecules such as albumin. They are therefore termed 'strong ions': [SID] = [strong cations] - [strong anions]. In normal plasma, [SID] is approximately 40 meq/l. [SID] in whole blood is harder to quantify, but can be derived using expressions for intra-erythrocytic buffering and plasma/ erythrocyte distribution equations [16, 17]. In the Stewart analysis, as in all other 'schools' of acid-base analysis, respiratory acid-base disturbances arise because of primary alterations in PaC0 2 What is different about the physical-chemical approach is the contention that metabolic acidbase derangements can be caused only by alterations in one or both of [SID] and [ATOT]' To improve our understanding of this idea, we now need to explore the concept of 'buffer base'. I The 'Buffer Base' Concept To preserve electrical neutrality, the 'space' left by the surfeit of strong cations is filled passively by weak anions (i.e., anions that can bind protons to form their parent molecules in the physiological ph range) (Fig. 2). These are the buffer base anions, and consist of two basic types - the anions of non-volatile weak acids (the A component of A TOT where [A TOT] = [HA] + [A-]), and the weak anion HC03. Buffer base is, therefore, ([A-] + [HC03]), and is numerically the same as [SID]. [A-] is also numerically the same as the anion gap, provided no other unmeasured anions Buffer base ~ Cations An ions Fig. 2. Illustration of the mirror image relationship between strong ion differenee ([SID]) and the buffer base anions. The total coneentration of buffer base anions ([A -l + [HCOJ]) is determined by [SIDl in order to maintain eleetroneutrality. La- is the lactate anion

3 Strong Ions, Acid-base, and Crystalloid Design 429 are present. Protons generated in biologieal fluids are buffered exclusively by either or both of these anions in the following manner: H+ + A- +-+ HA (1) (2) It is eertainly true that [SID] is the independent variable whieh defines, eontrols and is numerieally identieal to the buffer base anion coneentration [l2]_ However, in the final analysis it is buffer base which determines metabolie acid-base status, despite its being the dependent variable. As we will see, buffer base also plays an important buffering role in respiratory acid-base alterations. I Metabolie Acid-base Disturbanees and Buffer Base We have stated that metabolie acid-base disturbances are due to alterations in either [SID] or [ATOT]. [SID] reduetions oeeur when strong anions such as lactate or beta-hydroxybutyrate appear in the plasma unaeeompanied by strong eations (thus eausing a raised anion gap aeidosis), or when [Cn and [Na+] simply move closer together (eausing a normal anion gap aeidosis). An isolated reduetion in [SID] by either meehanism reduees the total buffer base eoneentration, with both [HC03] and [A -] participating in the buffering proeess. Sinee PC0 2 also remains eonstant, the fall in [HC03] shifts the fundamental PC0 2/pH relationship to the left (via the Henderson-Hasselbaleh equation), ereating a metabolie aeidosis (Fig. 1). The effeet of [A TOT] is more eomplieated. Studies performed in vitro confirm that isolated [A TOT] elevations eause a metabolie acidosis, and reduetions eause a metabolie alkalosis [18]. The meehanism ean be thought of as follows: An isolated inerease in [A TOT] inereases the A - eomponent of buffer base. However, the total buffer base eoneentration ([A-] + [HC03]) eannot alter, sinee it is eonstrained by [SID]. As a result [HC03] is redueed by an equal amount. Sinee PC0 2 remains unehanged, this shifts the PC0 2/pH relationship to the left and ereates a metabolie acidosis (Fig. 1). In similar manner, an isolated fall in [A TOT] ereates a metabolie alkalosis. The situation in vivo is probably different, in that alterations in [A TOT] take days rather than hours to appear (in the absence of hemodilution), and seem to stimulate eompensatory ehanges in [SID] via alterations in [Cn [19]. Under these cireumstanees [A TOT] is better thought of as setting the normal range for [SID] rather than eausing primary metabolie acid-base disturbanees. However, during erystalloid fluid loading the [SID] ehanges aeeompanying dilutional [A TOT] reduetions are governed solely by the [SID] of the diluting erystalloid. As a result, appropriate [SID] eompensation for aeute A TOT dilution ean only oeeur if the diluent erystalloid [SID] is ealibrated for this purpose. Thus, in summary, isolated deereases in [SID] or uneompensated inereases in [A TOT] eause a metabolie aeidosis, whereas inereases in [SID] or deereases in A TOT eause a metabolie alkalosis. All such disturbances are mediated by alterations in the eomponents of buffer base. The metabolie effeets of ehronie in vivo [A TOT] reductions are probably eompensated by redueed [SID].

4 430 T. J. Morgan and B. Venkatesh I Respiratory Acid-base Disturbances and Buffer Base In respiratory acid-base disturbances, A - alone participates in the buffering process, since protons generated by changes in PCOz cannot be buffered by the system in which they are produced. Total buffer base concentration is fixed as always by [SID], so that any alteration in [HC03'l is mirrored by an equal and opposite alteration in [A -]. Thus, as changes in PCOz cause HC03' (and H+) to be generated or consumed, the total concentration of buffer base does not change, merely the ratio of [HC03'] to [A-]. In respiratory acidosis, [HC03'] increases and [A-] decreases by the same amount, and the converse applies in respiratory alkalosis. Hence, it can be seen that the buffer base anions are vital determinants of the acid-base status of biological fluids, even though in the Stewart analysis they are dependent variables. Knowledge of how [SID], [A TOT] and PaCOz interact with buffer base anions improves our understanding of the Stewart approach, and how physical chemical principles can improve our understanding of crystalloid acidbase effects. I Interpreting Crystalloid-induced Acid-base Effects Using this model, crystalloid infusions can have two separate effects on metabolic (non-respiratory) acid-base balance. There will always be a tendency to reduce [ATOT] by simple dilution, since crystalloid solutions by definition contain no hemo globin or albumin. Such [A TOT] reductions must produce a metabolic alkalosis as we have discussed [18]. However, there is a simultaneous effect on [SID], the specifics of which depend on the [SID] of the crystalloid fluid [20]. If the [SID] of the diluting crystalloid is lower than that of the extracellular space, there will be a tendency to reduce extracellular [SID] and thus buffer base, creating a co-existent metabolic acidosis. Conversely, fluids with high [SID] (such as sodium bicarbonate solutions) increase extracellular [SID] and, therefore, buffer base concentrations, superimposing a further metabolic alkalosis on that of A TOT dilution. With any large volume crystalloid infusion, the final acid-base outcome is thus a summation of the effects of alte red extracellular [SID] and the metabolic alkalosis of reduced [A TOT]. All NaCI solutions have a zero [SID], since Na+ and cr are present in equimolar concentrations. This is also true of dextrose in saline solutions. The [SID] of water, dextrose solutions and mannitol is also zero, since no strong ions are present in these fluids. Infusion of large volumes of this group of fluids will thus have a tendency to reduce extracellular [SID], pushing acid-base balance in the direction of a metabolic acidosis [21, 22]. Importantly, although this type of acidosis is commonly hyperchloremic, the same phenomenon can occur with areduction in chloride concentrations depending on the fluid infused [23]. Either way the anion gap will not be elevated. In fact, as A TOT is diluted the anion gap will be reduced (since the anion gap is really [A -], provided no other unmeasured anions are present).

5 Strong Ions, Acid-base, and Crystalloid Design 431 I Determining the 'Neutral' Crystalloid [SIDJ For a crystalloid not to produce acid-base disturbances during large volume infusion, some [SID] reduction must be necessary to offset the metabolic alkalosis of A TOT dilution, but the two processes should balance exactly. However, theoretical determination of the crystalloid [SID] required to create this balance is difficult. This is because infused strong ions are distributed amongst plasma, erythrocytes and interstitial fluid in complex ways governed by Gibbs-Donnan equilibria, and the laws of electroneutrality and of chemical equilibrium. In contrast, ATOT (especially hemoglobin) is concentrated primarily in the intravascular space and remains so during crystalloid infusions. We recently performed an in vitra experiment to gain a more exact picture of the relationship between crystalloid [SID] and its acid-base effects [24]. We found that there was a linear relations hip between crystalloid [SID] and the rate of change (slope) of base excess as hemoglobin concentration fell during hemodilution of normal blood. If this relationship also holds true in vivo, the [SID] of any given crystalloid might perform as a simple descriptor of its potential acid-base effects. From our in vitro data, a crystalloid [SID] of 24 meq/1 exactly balances the metabolic alkalosis of A TOT dilution [24]. An [SID] of 24 meq/1 is very similar to the effective in vivo [SID] of Hartmann's solution (Table 1), assuming that all contained lactate is metabolized on infusion. Dr Alexis Hartmann hirnself considered his modification of Ringer's injection to be alkalinizing rather than neutral in its effects. In fact his intention was to create a solution less severely alkalinizing than sodium bicarbonate solutions [25] by adding lactate in its slowly metabolized racemic form to Ringer's solution [26]. Most of the resultant metabolic delay in his original preparation was due to the d-iactate component of the racemic mixture. üf interest, for some years, preparations of Hartmann's solution used in Australia have contained only the I-lactate form (personal communication, Bill Houghton, Baxter, Australia). This isomer should disappear quite rapidly after infusion by the process of oxidation or by undergoing gluconeogenesis. Although our in vitro data indicate that once the exogenous lactate is metabolized, Hartmann's solution should be neither alkalinizing nor acidifying (i.e., it should be neutral in its effects), confirmatory in vivo experimentation is required. I Does Infusion-Related Metabolie Acidosis Really Matter? There have been calls for a simple resuscitation crystalloid which does not cause acid-base disturbances [27]. However, whether an infusion-related metabolic acidosis is likely to cause harm remains uncertain. There is even a theoretical potential benefit - areduction in hemoglobin-oxygen affinity due to the Bohr effect, which increases tissue oxygen availability [28]. However, this affinity shift is rapidly corrected by a ph-induced fall in 2,3-diphosphoglycerate (2,3-DPG) levels [29]. The detrimental effects of acidosis are mediated via reduced ph within the cell, a milieu with its own specific buffering mechanisms [30]. Severe acidemia reduces myocardial contractility and can stimulate tachy- and bradydysrhythmias, systemic arteriolar dilatation, venoconstriction, and pulmonary vasoconstriction. There is an increased respiratory drive combined with depressed diaphragmatic function, and there are other adverse effects on brain, liver, and the musculoskeletal system [30].

6 432 T.J. Morgan and B. Venkatesh However, most significant adverse responses occur only in acidemia of a severity seldom seen after crystalloid infusions. Furthermore, intracellular ph is much more resistant to metabolic than respiratory acidosis. At this time it, therefore, remains to be determined whether fluids with neutral acid-base effects produce better results in terms of tissue oxygenation, organ function or survival. Nevertheless, the onset of an infusion-related metabolic acidosis introduces a risk of incorrect diagnoses such as unresolved ketoacidosis or persistent tissue dysoxia. In the face of persisting metabolic acidosis despite resuscitation, clinicians may overlook the fact that the anion gap or concentrations of beta-hydroxybutyrate or lactate are inconsistent with these diagnoses. Inappropriate and perhaps harmful therapies such as further aggressive insulin therapy or fluid loading might then follow. I Altering Crystalloid [SID]: Practical Considerations To increase the [SID] of fluids such as saline above zero it is necessary to replace some Cl- ions (strong anions) with weak anions such as HCO:3. HC0:3 in solution equilibrates with dissolved carbon dioxide (COz), a highly diffusible gas. Such solutions must be stored in glass and infused promptly to prevent COz loss. Because HC0:3 ions are unstable, commercially produced balanced salt solutions are manufactured with organic acid anions (lactate, acetate, or gluconate) as stable surrogates for HCO:3 (Table 1). Although these anions are actually strong ions with pka values of approximately 3.5, they are metabolized in vivo following infusion. Provided their metabolic clearance is rapid, the effective in vivo [SID] of these solutions can be calculated as though the contained organic anions are weak ions (Table 1). Of note, in all [SID] determinations we take the view of Schlichtig and colleagues that Ca ++ and Mg ++ are not strong ions, since they bind reversibly to albumin in a ph dependent mann er [17]. This is contrary to the more widely held opinion that they are strong ions [14]. Available evidence indicates that fluid replacement using balanced salt solutions can reduce the incidence of infusion related metabolic acidosis [2, 31]. In fact some Table 1. Three balanced salt solutions (electrolyte concentrations in mmol/i) Hartmann's Plasmalyte Plasmalyte R Sodium Chloride Potassium S 5 10 Calcium 2 5 Magnesium l.s 3 lactate 29 8 Acetate Gluconate 23 Effective [SIDI b a Baxter, Australia; b meq/1

7 Strong Ions, Acid-base, and Crystalloid Design 433 balanced salt solutions are likely to cause metabolic alkalosis on large volume equilibration with the extracellular space, because of a high effective [SID]. For exampie, the effective [SID] of Plasmalyte (Baxter, Sydney, Australia) is 47 meq/l, assuming complete metabolism of the contained acetate and gluconate anions (Table 1). Data on its acid-base effects are limited, but if Plasmalyte is used to prime cardiopulmonary bypass circuits, arterial base excess becomes elevated by the end of bypass [32]. I Conclusion By applying Stewart's physical-chemical principles of acid-base it should be possible to design crystalloids with specific acid-base effects on large volume infusion. Our in vitra evidence suggests that a crystalloid [SID] of 24 meq/1 has neutral effects on acid-base balance in patients without pre-existing acid-base disturbances. Confirmation by in viva experimentation is required. Either way, it remains to be established that infusion-related metabolic acidosis causes significant harm. References 1. Scheingraber S, Rehm M, Sehmisch C, Finsterer U (1999) Rapid saline infusion pro duces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology 90: McFarlane C, Lee A (1994) A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia 49: Prough DS, Bidani A (1999) Hyperchloremic metabolic acidosis is a predictable consequence of intraoperative infusion of 0.9% saline. Anesthesiology 90: Mathes DD, Morell RC, Rohr MS (1997) Dilutional acidosis: Is it areal clinical entity? Anesthesiology 86: Goodkin DA, Raja RM, Saven A (1990) Dilutional acidosis. South Med J 83: Garella S, Chang BS, Kahn SI (1975) Dilutional acidosis and contraction alkalosis: Review of a concept. Kidney Int 8: Prough DS (2000) Acidosis associated with perioperative saline administration. Dilution or delusion? Anesthesiology 93: Schwartz WB, Relman AS (1963) A critique of the parameters used in the evaluation of acid-base disorders. N Engl J Med 268: Narins RB, Emmett M (1980) Simple and mixed acid-base dis orders: A practical approach. Medicine 59: Siggaard-Andersen 0, Engel K (1960) A micro method for determination of ph, carbon dioxide tension, base excess and standard bicarbonate in capillary blood. Scand J Clin Lab Invest 12: Astrup P, Jorgensen K, Siggaard-Andersen 0, et al (1960) Acid-base metabolism: New approach. Lancet 1: Siggaard-Andersen 0, Fogh-Andersen N (1995) Base excess or buffer base (strong ion difference) as measure of a non-respiratory acid-base disturbance. Acta Anesth Scand Suppl 107: Stewart PA (1981) How to understand acid-base. In: Stewart PA (ed) A Quantitative Acidbase Primer for Biology and Medicine. Elsevier, New York, pp Stewart PA (1983) Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 61: Story DA, Liskaser F, Bellomo R (2000) Saline infusion, acidosis and the Stewart approach. Anesthesiology 92: Schlichtig R (1997) [Base excessl vs [strong ion differencel: Which is more helpful? Adv Exp Med Biol 411:91-95

8 434 lj. Morgan and B. Venkatesh: Strong Ions, Acid-base, and Crystalloid Design 17. Schlichtig R, Grogono AW, Severinghaus JW (1998) Current status of acid-base quantitation in physiology and medicine. Anesthesiol Clin North Am 16: Rossing TH, Maffeo N, Fencl V (1986) Acid-base effects of altering plasma protein concentration in human blood in vitro. J Appl Physiol 61: Wilkes P (1998) Hypoproteinemia, strong-ion difference, and acid-base status in critically ill patients. J Appl Physiol 84: LeBlanc M, Kellum J (1998) Biochemical and biophysical principles of hydrogen ion regulation. In: Ronco C, Bellomo R (eds) Critical Care Nephrology. Kluwer Academic Publishers, Dordrecht, pp Miller LR, Waters JH (1997) Mechanism of hyperchloremic nonanion gap acidosis. Anesthesiology 87: Storey DA (1999) Intravenous fluid administration and controversies in acid-base. Crit Care Resuscitation 1: Makoff DL, da Silva JA, Rosenbaum BJ, Levy SE, Maxwell MH (1970) Hypertonie expansion: acid-base and electrolyte changes. Am J Physiol 218: Morgan TJ, Venkatesh B, Hall J (2002) Crystalloid strong ion difference determines metabolie acid-base change during in vitro hemodilution. Crit Care Med (in press) 25. White SA, GoldhilI DR (1997) Is Hartmann's the solution? Anaesthesia 52: Hartmann AF, Senn MJ (1932) Studies in the metabolism of sodium r-lactate. 1. Response of normal human subjects to the intravenous injection of sodium r-lactate. J Clin Invest 11: Dorje P, Adhikary G, Tempe DK (2000) Avoiding iatrogenic hyperchloremic acidosis - call for a new crystalloid fluid. Anesthesiology 92: Morgan TJ (1999) The significance of the P50. In: Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine. Springer-Verlag, Heidelberg pp Morgan TI, Koch D, Morris D, Clague A, Purdie DM (2001) Red cell 2,3-diphosphoglycerate concentrations are reduced in critical illness without net effect on in vivo P 50. Anaesth Intensive Care 29: Forrest DM, Walley KR, Russell JA (1998) Impact of acid-base disorders on individual organ systems In: Ronco C, Bellomo R (eds) Critical Care Nephrology. Kluwer Academic Publishers, Dordrecht, pp Traverso LW, Lee WP, Langford MJ (1986) Fluid resuscitation after an otherwise fatal hemorrhage: 1. Crystalloids solutions. J Trauma 26: Liskaser FI, Bellomo R, Hayhoe M, et al (2000) Role of pump prime in the etiology and pathogenesis of cardiopulmonary bypass-associated acidosis. Anesthesiology 93: