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      The End of the Bicarbonate Era? A Therapeutic Application of the Stewart Approach

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          Abstract

          Critically ill patients frequently present with disorders of acid–base homeostasis (1), making arterial blood gas interpretation a cornerstone activity in the clinical assessment of patients by intensivists. Many of us are unaware that we’ve been taught to interpret acid–base homeostasis in the “bicarbonate era” (2), where a focus on the Henderson-Hasselbalch equation for dissociation of carbon dioxide has led us to believe that bicarbonate is a major determinant of acid–base status (3). However, when we try to understand some of the commonly encountered acid–base abnormalities in critical illness, such as hyperchloremia (4), the Henderson-Hasselbalch equation leaves us yearning for a better explanation. Forty years ago, the Canadian physiologist Peter Stewart provided a better explanation. He described an approach to understanding acid–base in which bicarbonate is not the major determinant of acid–base status (5). Although it is referred to as the “modern” approach (2), Stewart’s explanation incorporated time-tested concepts of physical chemistry, such as conservation of mass, dissociation of electrolytes, and electroneutrality, some of which date back to the 18th century (6). Therefore, it is perhaps more accurate to refer to Stewart’s work as the physicochemical approach. Stewart applied these physicochemical principles by using simple algebra to demonstrate that plasma pH (and bicarbonate concentration) is determined by the Pco 2, the strong ion difference, and the concentration of weak acids (primarily albumin and phosphate). The strong ion difference in plasma is determined by the relatively higher concentration of sodium compared with chloride, and the difference is typically about 40 mEq/L (5). The electroneutrality of plasma is maintained because the charge gap between these two strong ions is made up by the dissociation of weak acids into their respective anions, including the dissociation of dissolved carbon dioxide into bicarbonate. By showing that plasma proteins (weak acids) and dissolved strong ions also participate in acid–base homeostasis, the physicochemical approach provides an explanation for acid–base disorders commonly encountered in critical illness, such as hypoalbuminemia and hyperchloremia. However, although this approach is mathematically accurate (7), it oversimplifies some of the mechanistic insights (8), which is perhaps why reception has been mixed, ranging from full embracement at the bedside (9) to outright hostility (10). Unfortunately, the controversy has left many of us wondering whether it is truly important to learn the physicochemical approach. After all, intensivists really have access to only two tools for rapid manipulation of plasma pH in the setting of acidosis: 1) hyperventilation to lower Pco 2 and 2) administration of sodium bicarbonate. Nonetheless, our understanding of these interventions may be improved with the physicochemical approach. For example, although the Henderson-Hasselbalch equation predicts that hyperventilation will lower pH, it doesn’t allow us to understand that hyperventilation does this by removing carbon dioxide without changing the strong ion difference, and it doesn’t predict the effect that remaining weak acids will have on the final observed pH. Similarly, the physicochemical approach helps us understand that administration of sodium bicarbonate increases pH by increasing the concentration of plasma sodium relative to chloride, rather than simply by adding a bicarbonate buffer to the system. This is because sodium fully dissociates in solution, whereas bicarbonate exists in equilibrium with dissolved carbon dioxide (Pco 2) (i.e., it behaves like a weak acid). In fact, the physicochemical approach helps us understand the potential harmful effects of a rapid bolus of sodium bicarbonate, because it predicts an increase in the local Pco 2. This may rapidly increase intracellular Pco 2, worsening intracellular acidosis, because carbon dioxide rapidly diffuses across cellular membranes (11). In this issue of the Journal, Zanella and colleagues (pp. 799–813) report their ingenious alternative method for therapeutically increasing the strong ion difference in plasma (12). The authors used electrodialysis cell technology to defy the principles of electroneutrality and remove chloride ions from plasma while maintaining the concentration of sodium ions. As a result, they increased the strong ion difference and raised the pH back to normal levels. They tested this technology in animal models of both metabolic and respiratory acidosis and showed that the effect was maintained even after the electrodialysis was discontinued. Their work not only validates a direct therapeutic application of the physicochemical approach, it also provides fascinating insights into acid–base homeostasis. Before electrodialysis was initiated, renal chloride excretion was increased in response to both metabolic and respiratory acidosis. Once the pH was restored by lowering plasma chloride with electrodialysis, renal chloride excretion was reduced. Homeostatic mechanisms involving chloride shifts have previously been shown to play an important role in the maintenance of pH through mechanisms involving circulating red blood cells (13) as well as the kidney (14). This leads one to conclude that lowering plasma chloride with electrodialysis augments the natural homeostatic response to acidosis, unlike the administration of concentrated sodium bicarbonate, which also increases plasma sodium. However, we should be cautiously enthusiastic. Modifying pH by removing chloride and manipulating the strong ion difference will not treat the underlying cause of the acid–base disorder any more than lowering Pco 2 or administering sodium bicarbonate does, unless of course the primary derangement is hyperchloremia, elevated Pco 2, or hyponatremia. Although acidosis with hyperchloremia is quite common in critical illness (4), preventing hyperchloremia by using the physicochemical approach to guide the choice and composition of fluids is perhaps a simpler and wiser alternative. Furthermore, hyperventilation, sodium bicarbonate administration, and chloride electrodialysis do not directly treat elevated lactate levels, the most common cause of acidosis in critical illness (1). However, Zanella and colleagues make no such claims. They simply use the physicochemical approach to elegantly show that increasing the strong ion difference restores pH to normal levels. It’s conceivable that the same result could be more easily obtained by conventional dialysis, where the dialysate solutions are engineered to target a given strong ion difference. Either way, the manipulation of strong ion difference to achieve specific therapeutic effects is slowly gaining traction, and similar approaches have recently been shown to enhance respiratory support (15, 16). Whatever the future holds for these therapies, it behooves us to start teaching the physicochemical approach to our medical students and junior colleagues sooner rather than later.

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          Most cited references 13

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          Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients

          Introduction Acid–base abnormalities are common in the intensive care unit (ICU). Differences in outcome exist between respiratory and metabolic acidosis in similar pH ranges. Some forms of metabolic acidosis (for example, lactate) seem to have worse outcomes than others (for example, chloride). The relative incidence of each type of disorder is unknown. We therefore designed this study to determine the nature and clinical significance of metabolic acidosis in critically ill patients. Methods An observational, cohort study of critically ill patients was performed in a tertiary care hospital. Critically ill patients were selected on the clinical suspicion of the presence of lactic acidosis. The inpatient mortality of the entire group was 14%, with a length of stay in hospital of 12 days and a length of stay in the ICU of 5.8 days. Results We reviewed records of 9,799 patients admitted to the ICUs at our institution between 1 January 2001 and 30 June 2002. We selected a cohort in which clinicians caring for patients ordered a measurement of arterial lactate level. We excluded patients in which any necessary variable required to characterize an acid–base disorder was absent. A total of 851 patients (9% of ICU admissions) met our criteria. Of these, 548 patients (64%) had a metabolic acidosis (standard base excess < -2 mEq/l) and these patients had a 45% mortality, compared with 25% for those with no metabolic acidosis (p < 0.001). We then subclassified metabolic acidosis cases on the basis of the predominant anion present (lactate, chloride, or all other anions). The mortality rate was highest for lactic acidosis (56%); for strong ion gap (SIG) acidosis it was 39% and for hyperchloremic acidosis 29% (p < 0.001). A stepwise logistic regression model identified serum lactate, SIG, phosphate, and age as independent predictors of mortality. Conclusion In critically ill patients in which a measurement of lactate level was ordered, lactate and SIG were strong independent predictors of mortality when they were the major source of metabolic acidosis. Overall, patients with metabolic acidosis were nearly twice as likely to die as patients without metabolic acidosis.
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            Respiratory Electrodialysis. A Novel, Highly Efficient Extracorporeal CO2 Removal Technique.

            We developed an innovative, minimally invasive, highly efficient extracorporeal CO2 removal (ECCO2R) technique called respiratory electrodialysis (R-ED).
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              Base excess or buffer base (strong ion difference) as measure of a non-respiratory acid-base disturbance.

              Stewart in 1983 (Can J Physiol Pharmacol 1983: 61: 1444) reintroduced plasma buffer base under the name "strong ion difference" (SID). Buffer base was originally introduced by Singer and Hastings in 1948 (Medicine (Baltimore) 1948: 27: 223). Plasma buffer base, which is practically equal to the sum of bicarbonate and albuminate anions, may be increased due to an excess of base or due to an increased albumin concentration. Singer and Hastings did not consider changes in albumin as acid-base disorders and therefore used the base excess, i.e., the actual buffer base minus the buffer base at normal pH and pCO2, as measure of a non-respiratory acid-base disturbance. Stewart and followers, however, consider changes in albumin concentration to be acid-base disturbances: a patient with normal pH, pCO2, and base excess but with increased plasma buffer base due to increased plasma albumin concentration get the diagnoses metabolic (strong ion) alkalosis (because plasma buffer base is increased) combined with metabolic hyperalbuminaemic acidosis. Extrapolating to whole blood, anaemia and polycytaemia should represent types of metabolic alkalosis and acidosis, respectively. This reveals that the Stewart approach is absurd and anachronistic in the sense that an increase or decrease in any anion is interpreted as indicating an excess or deficit of a specific acid. In other words, a return to the archaic definitions of acids and bases as being the same as anions and cations. We conclude that the acid-base status (the hydrogen ion status) of blood and extracellular fluid is described in terms of the arterial pH, the arterial pCO2, and the extracellular base excess. It is measured with a modern pH-blood gas analyser. The electrolyte status of the plasma is a description of the most important electrolytes, usually measured in venous blood with a dedicated electrolyte analyser, i.e., Na+, Cl-, HCO3-, and K+. Albumin anions contribute significantly to the anions, but calculation requires measurement of pH in addition to albumin and is usually irrelevant. The bicarbonate concentration may be used as a screening parameter of a nonrespiratory acid-base disturbance when respiratory disturbances are taken into account. A disturbance in the hydrogen ion status automatically involves a disturbance in the electrolyte status, whereas the opposite need not be the case.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                1 April 2020
                1 April 2020
                1 April 2020
                1 April 2020
                : 201
                : 7
                : 757-758
                Affiliations
                [ 1 ]Department of Medicine

                National University Health System

                Singapore, Singapore

                and
                [ 2 ]Department of Critical Care Medicine

                University of Pittsburgh

                Pittsburgh, Pennsylvania
                Article
                201910-2003ED
                10.1164/rccm.201910-2003ED
                7124708
                31658424
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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                Figures: 0, Tables: 0, Pages: 2
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