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

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AJRCCM Articles in Press. Published on 28-October-
Matthew Cove MBChB1, John A. Kellum MD2

Addresses: – 1 –

2 –

Department of Medicine, National University Health System, NUHS Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore. Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA.

Corresponding author: –

Matthew Cove
Department of Medicine, National University Health System, NUHS Tower Block, Level 10, 1E Kent Ridge Road, Singapore 119228.
Email. mdcmec@nus.edu.sg
Tel. +65 6772 7678

Conflict of interest: – MEC has received honorariums and travel support from Medtronic and Baxter. JAK, is a paid consultant for Baxter and NXStage Medical

Word Count: – Title characters Main text

References

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Copyright © 2019 by the American Thoracic Society

AJRCCM Articles in Press. Published on 28-October-2019 as 10.1164/rccm.201910-2003ED

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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 we’ve been taught to interpret acid-base homeostasis in the “bicarbonate era” (2), where focus on the Henderson-Hasselbach equation for dissociation of carbon dioxide has led us to beleive 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- Hasselbach 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 where bicarbonate is not the major determinant of acid-base status (5). Although 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 partial pressure of carbon dioxide (PCO2), 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 to 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, as well as 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

Copyright © 2019 by the American Thoracic Society

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AJRCCM Articles in Press. Published on 28-October-2019 as 10.1164/rccm.201910-2003ED

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 only have access to two tools for rapid manipulation of plasma pH in the setting of acidosis- hyperventilation to lower partial pressure of carbon dioxide or administration of sodium bicarbonate. Nonetheless, the understanding of these interventions may be improved with the physicochemical approach. For example, although the Henderson-Hasselbach equation predicts hyperventilation lowers pH, it doesn’t allow us to understand it does this by removing carbon dioxide without changing the strong ion difference and doesn’t predict the effect 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 adding bicarbonate buffer to the system. This is because sodium fully dissociates in solution, whereas bicarbonate exists in equilibrium with dissolved carbon dioxide (PCO2) 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 PCO2. Since carbon dioxide rapidly diffuses across cellular membranes, this may rapidly increase intracellular PCO2, worsening intracellular acidosis (11).

Copyright © 2019 by the American Thoracic Society

AJRCCM Articles in Press. Published on 28-October-2019 as 10.1164/rccm.201910-2003ED

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Here, Zanella et al report their ingenious alternative method of 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 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 discontinuing the electrodialysis. Their work not only validates a direct therapeutic application of the physicochemical approach, it provides fascinating insights into acid-base homeostasis. Prior to initiation of electrodialysis, renal chloride excretion was increased in response to both metabolic and respiratory acidosis. Once pH was restored by lowering plasma chloride with electrodialysis, renal chloride excretion was reduced. Homeostatic mechanisms involving chloride shifts have been previously 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 PCO2 or administering bicarbonate does, unless of course the primary derangement is hyperchloremia, elevated PCO2, or hyponatremia. While acidosis with hyperchloremia is quite common in critical illness (4), prevention of hyperchloremia by using the physicochemical approach to guide fluid choice and composition 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 et al make no such

Copyright © 2019 by the American Thoracic Society

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AJRCCM Articles in Press. Published on 28-October-2019 as 10.1164/rccm.201910-2003ED

claims. They simply use the physicochemical approach to elegantly show that increasing the strong ion difference restores pH to normal levels. It’s conceivable 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.

Copyright © 2019 by the American Thoracic Society

References

AJRCCM Articles in Press. Published on 28-October-2019 as 10.1164/rccm.201910-2003ED

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1. Gunnerson KJ, Saul M, He S, Kellum JA. Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients. Crit Care 2006;10:R22–9.

2. Kishen R, Honore PM, Jacobs R, Joannes-Boyau O, De Waele E, De Regt J, Van Gorp V, Boer W, Spapen H. Facing acid-base disorders in the third millennium – the Stewart approach revisited. Int J Nephrol Renovasc Dis 2014;7:209–217.

3. Story DA. Bench-to-bedside review: A brief history of clinical acid–base. Critical Care 2004;8:253–6.

4. Yunos NM, Bellomo R, Story D, Kellum J. Bench-to-bedside review: Chloride in critical illness. Crit Care 2010;14:226.

5. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983;61:1444–1461.

6. Whitaker RD. An historical note on the conservation of mass. J Chem Educ 1975;52:658.

7. Ring T, Kellum JA. Strong Relationships in Acid-Base Chemistry – Modeling Protons Based on Predictable Concentrations of Strong Ions, Total Weak Acid Concentrations, and pCO2. In: Wang Y-T, editor. PLoS ONE 2016;11:e0162872–21.

8. Doberer D, Funk G-C, Kirchner K, Schneeweiss B. A critique of Stewart’s approach: the chemical mechanism of dilutional acidosis. Intensive Care Med 2009;35:2173– 2180.

9. Story DA. Stewart Acid-Base: A Simplified Bedside Approach. Anesthesia & Analgesia 2016;123:511–515.

Copyright © 2019 by the American Thoracic Society

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AJRCCM Articles in Press. Published on 28-October-2019 as 10.1164/rccm.201910-2003ED

10. Siggaard-Andersen O, Fogh-Andersen N. Base excess or buffer base (strong ion difference) as measure of a non-respiratory acid-base disturbance. Acta Anaesthesiol Scand Suppl 1995;107:123–128.

11. Aschner JL, Poland RL. Sodium bicarbonate: basically useless therapy. Pediatrics 2008;122:831–835.

12. Zanella A, Caironi P, Castagna L, Rezoagli E, Salemo D, Scotti E, Scaravilli V, Deab SA, Langer T, Mauri T, Ferrari M, Dondossola D, Chiodi M, Zadek F, Magni F, Gatti S, Gattinoni L, Pesenti AM. Extracorporeal Chloride Removal by Electrodialysis (CRe-ED): A Novel Approach to Correct Acidemia. Am J Respir Crit Care Med [online ahead of print] 25 September 2019; https://www.atsjournals.org/doi/abs/10.1164/rccm.201903-0538OC.

13. Langer T, Scotti E, Carlesso E, Protti A, Zani L, Chierichetti M, Caironi P, Gattinoni L. Electrolyte shifts across the artificial lung in patients on extracorporeal membrane oxygenation: interdependence between partial pressure of carbon dioxide and strong ion difference. Journal of Critical Care 2015;30:2–6.

14. Ramadoss J, Stewart RH, Cudd TA. Acute renal response to rapid onset respiratory acidosis. Can J Physiol Pharmacol 2011;89:227–231.

15. Cove ME, Vu LH, Ring T, May AG, Federspiel WJ, Kellum JA. A Proof of Concept Study, Demonstrating Extracorporeal Carbon Dioxide Removal Using Hemodialysis with a Low Bicarbonate Dialysate. ASAIO J 2019;65:605–613.

16. Zanella A, Castagna L, Salerno D, Scaravilli V, Abd El Aziz El Sayed Deab S, Magni F, Giani M, Mazzola S, Albertini M, Patroniti N, Mantegazza F, Pesenti A. Respiratory Electrodialysis. A Novel, Highly Efficient Extracorporeal CO2 Removal Technique. Am J Respir Crit Care Med 2015;192:719–726.

Copyright © 2019 by the American Thoracic Society

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