a b s t r a c t

Background: Hyperkalemia is an Electrolyte disorder commonly encountered in the emergency department that can result in significant morbidity and mortality. While sodium bicarbonate is often used for acute lowering of serum potassium, its efficacy is not well established. The purpose of this study was to evaluate and quantify the amount of potassium reduction in emergency department patients who received intravenous sodium bicar- bonate as part of treatment for hyperkalemia compared with those who did not.

Methods: A Retrospective electronic chart review was conducted on adult patients who presented to the emer- gency department with initial potassium concentration greater than or equal to 5.4 mMol/L and received intra- venous insulin as part of hyperkalemia treatment. Patients who received intravenous sodium bicarbonate in addition to Intravenous insulin were included in the sodium bicarbonate group. The control group included patients who did not receive intravenous sodium bicarbonate. The primary objective of this study was to com- pare the absolute reduction in serum potassium between initial and second concentrations in patients from the sodium bicarbonate group and those in the control group.

Results: A total of 106 patients were included in this study with 38 patients in the sodium bicarbonate group and 68 patients in the control group. Median initial potassium concentration was 6.6 mMol/L in the sodium bicarbon- ate group and 6.1 mMol/L in the control group (P = 0.009). Absolute reduction of potassium at first repeat was 1 and 0.9 mMol/L in sodium bicarbonate group and control group respectively (P = 0.976).

Conclusions: The addition of sodium bicarbonate therapy to intravenous insulin in the treatment of hyperkalemia did not offer statistically significant added efficacy in potassium lowering. Larger studies are needed to further validate the result findings.

(C) 2021

1. Introduction

Potassium is an electrolyte required for normal transmembrane gra- dient potential and normal body physiology. Its regulation is achieved mostly through the renal system with a normal physiological range often defined as 3.5-5 mMol/L [1,2]. Potassium disorders are commonly encountered in the inpatient setting and the emergency department (ED) with incidences ranging from 1 to 10% in hospitalized patients and 0.36-2.6% in ED patients [3]. Common etiologies of hyperkalemia include pseudohyperkalemia, transmembrane shift of potassium, cell

* Corresponding author.

E-mail address: [email protected] (S. Geng).

¹ Shiyi Geng’s affiliation has changed since the completion of this work. The previous af- filiation was with the Department of Pharmacy, University of Alabama at Birmingham Hospital.

lysis, and decrease in Potassium excretion [1]. Pseudohyperkalemia is an in-vitro phenomenon that occurs with cell lysis (e.g., mechanical trauma with phlebotomy, hematological disorders with increased cell fragility) or with potassium contamination in blood samples, and this condition should be considered prior to treatment in patients without risk factors for hyperkalemia [4]. Causes of decrease in potassium excre- tion can occur in the settings of renal failure, from effects of certain med- ications (e.g., potassium-sparing diuretics, renin-angiotensin- aldosterone inhibitors), or in conditions with decreased response to or impaired production of aldosterone [1,5]. Other common etiologies of hyperkalemia encountered in the ED may include those with acidemia and diabetic ketoacidosis or in tissue trauma with rhabdomyolysis [1,6]. Symptoms of hyperkalemia include weakness, depressed deep tendon reflexes, arrhythmias, and cardiopulmonary arrest [7]. Acute hyperkalemia associated with myocardial conduction destabilization and electrocardiogram changes can lead to fatal deterioration if left

https://doi.org/10.1016/j.ajem.2021.07.032

0735-6757/(C) 2021

untreated [1,2]. rapid identification and correction of hyperkalemia is es- sential as prolonged duration of hyperkalemia is associated with higher in-hospital mortality and normalization of serum potassium during the ED stay has been associated with decreased mortality [8,9]. Unfortu- nately, evidence guiding the optimal use of several pharmacological agents in the acute management of hyperkalemia is lacking. The main pharmacological agents involved in the treatment of acute hyperkalemia have not changed over the past several decades, but there is not a univer- sal standardized treatment protocol in EDs across the United States [10]. Overall management modalities target stabilization of cardiac cellular membranes, redistribution of extracellular potassium into cells, and/or elimination of potassium from the body [1].

Sodium bicarbonate may assist in the lowering of serum potassium in hyperkalemia by alkalinizing systemic blood volume and causing the intracellular shift of potassium via hydrogen and potassium ex- change [1,2]. Despite routine use in the clinical setting, the efficacy of sodium bicarbonate for acute hyperkalemia is not well established. One of the original studies recommending sodium bicarbonate for hyperkalemia treatment administered a continuous infusion to a small number of patients with metabolic acidosis [11]. Several subsequent studies evaluating sodium bicarbonate also utilized a continuous infu- sion rather than bolus administration typical in most EDs today and often only included limited numbers of end-stage renal disease patients [12-16]. When used as monotherapy, intravenous sodium bicarbonate has been shown to be less efficacious compared to intravenous insulin or nebulized salbutamol in lowering serum potassium [14,15]. Further- more, combination therapies with sodium bicarbonate have resulted in mixed findings posing questions surrounding any added benefit [14,17]. In one study conducted in eight hemodialysis patients, sodium bicarbonate alone or with other agents did not lead to a significant de- crease in potassium concentrations following its administration com- pared to those similar agents with saline [17]. Current clinical practice guidelines suggest the consideration of sodium bicarbonate in patients with concomitant metabolic acidemia, but also emphasize the risk of so- dium and fluid overload without literature supported benefits associ- ated with its addition to other treatment options [18,19]. Despite the paucity of robust literature, its routine use in clinical practice is still common. A recent study across multiple EDs in the United States found sodium bicarbonate was used in 29% of the hyperkalemia treat- ments [10]. In addition, multiple supply shortages of prepared intrave- nous sodium bicarbonate in the recent years have further sparked renewed interest in defining the efficacy of sodium bicarbonate in the management of hyperkalemia.

The purpose of this study was to evaluate and quantify the amount

of potassium reduction in ED patients who received intravenous sodium bicarbonate as part of their treatment for hyperkalemia compared with those who did not.

1. Methods

This study was approved by the institutional review board at the University of Alabama at Birmingham (UAB). A retrospective electronic chart review was conducted on adult patients who presented to either UAB ED or UAB Highlands ED from August 1, 2010 to August 31, 2018.

receiving more than one round of hyperkalemia treatment prior to a re- peat potassium concentration being obtained, mechanical ventilation, or any patient with missing data points affecting the primary outcome. Hemolyzed serum potassium blood samples were excluded. Every sixth patient with ICD code for hyperkalemia who received intravenous insu- lin in the ED was reviewed systematically based on chronological order of ED presentation date and time to ensure even distribution of patient sample extraction throughout the entirety of the study period. For pa- tients who had multiple ED visits during the study period, only the First visit was included. A total of 252 patients were reviewed for the in- clusion in this study. Thirty-eight patients were excluded due to initial potassium at presentation was less than 5.4 mMol/L, and 108 patients were excluded due to meeting one or more of the exclusion criteria.

Patients who received intravenous sodium bicarbonate in addition to intravenous regular insulin comprised the sodium bicarbonate group, and patients who received intravenous regular insulin without sodium bicarbonate were included in the control group. There were no restrictions on the type or amount of other pharmacological agents for hyperkalemia management.

The primary objective of this study was to compare absolute reduc- tion in serum potassium between initial and second concentrations in the sodium bicarbonate group and the control group. The secondary endpoints were to compare absolute reduction in repeat serum potas- sium concentrations at two hour intervals, up to eight hours from the initial potassium concentration.

Due to the pilot nature of this study and the paucity of published lit- erature, no formal sample size calculation was performed. Statistical analysis was performed with P < 0.05 considered statistically signifi- cant. Two-tailed Student’s t-test was used for parametric data, Mann- Whitney Rank Sum for nonparametric data, and Chi-Square test for nominal data. SigmaSTAT (Version 3.5; San Jose, California) was utilized for the analysis of data.

1. Results

A total of 106 patients were included in this study. Thirty-eight pa- tients were included in the sodium bicarbonate group and 68 patients were included in the control group. Both sodium bicarbonate and insulin were administered as an Intravenous bolus in this study population. Baseline demographics were similar between the two groups (Table 1). Documented chronic kidney disease or end stage renal disease on presentation and the initial serum creatinine on presentation were not statistically different between the two groups. Concomitant pharmaco- logical interventions that may be used in the acute treatment of hyperkalemia were similar between the two groups with the exception

Table 1

Baseline demographics.
	Sodium bicarbonate (n = 38)	Control group (n = 68)	P value
Age, median (years)	62	59	0.742
Percentage of males, n [%]	25 [66%]	35 [51%]	0.222

This study was not funded.	Height, mean (cm)	170.6	171.5	0.692
Adult patients at least 18 years of age with an International Classifi-	Weight, median (kg)	74.6	77.1	0.220
cation of Diseases (ICD) code for hyperkalemia (ICD-9: 276.7; ICD-10:	Body mass index, median (kg/m2)	24.5	26.2	0.177
E87.5) and initial potassium of 5.4 mMol/L or greater were included. All patients must have received intravenous regular insulin as part of	Documented chronic kidney disease/end stage renal disease on presentation, n [%] Documented electrocardiogram changes on	20 [53%] 18 [47%]	34 [50%] 34 [50%]	0.954 0.954
hyperkalemia treatment while in the ED. Exclusion criteria included	presentationa, n [%]
those who were pregnant, incarcerated, had experienced cardiac arrest prior to or immediately upon their ED arrival, those with concomitant	Serum creatinine on presentation, median (mg/dL)	3.05	2.85	0.683

conditions requiring treatment with continuous administration of intra- venous insulin (e.g., diabetic ketoacidosis, hyperosmolar hyperglycemic state, beta-blocker or calcium channel blocker toxicity), patients requir- ing emergent dialysis, transfers from outside institutions, patients

^a Electrocardiogram changes were defined as any physician documentation explicitly stating electrocardiogram changes were observed due to hyperkalemia or documentation of the common changes associated with hyperkalemia (e.g., prolonged PR interval, broad QRS complexes, peaked T waves).

Table 2

Pharmacological agents administered.

Sodium

Control

Table 4 Absolute potassium reduction from baseline levels at given time points, shown as median (mMol/L).

P value

bicarbonate (n = 38)

group

(n = 68)

Sodium bicarbonate

Control group P value

Sodium bicarbonate dose in mEq,	50 [50-100]	0	-		First 2 h	n = 17	1	n = 17	1.1	0.704
median [range]					Between 2 and 4 h	n = 14	0.85	n = 29	1	0.575
Insulin dose in units, median [range]	10 [5-10]	10 [5-20]	0.463		Between 4 and 6 h	n = 18	1.2	n = 23	0.7	0.080
Inhaled albuterol, n [%]	15 [39%]	34 [50%]	0.401		Between 6 and 8 h	n = 6	0.15	n = 20	1.05	0.106
intravenous calcium, n [%]	36 [95%]	50 [74%]	0.016
Intravenous glucose, n [%]	38 [100%]	66 [97%]	0.747
Loop diuretics, n [%]	4 [11%]	8 [12%]	0.899

Sodium polystyrene sulfonate, n [%] 15 [39%] 22 [32%] 0.600

of intravenous calcium (Table 2). A higher percentage of patients in the sodium bicarbonate group received intravenous calcium as part of their initial hyperkalemia treatment than those in the control group (95% vs. 74% [P = 0.016]).

The median initial potassium concentration was statistically higher in the patients who received sodium bicarbonate as part of their hyperkalemia treatment than the patients in the control group (6.6 mMol/L vs. 6.1 mMol/L [P = 0.009]). Absolute reduction of potassium at first repeat was 1 and 0.9 mMol/L in the sodium bicarbonate group and control group, respectively [P = 0.976]. The median time to the first repeated Serum potassium concentration check was 3 h in the so- dium bicarbonate group and 4 h in the control group [P = 0.077]. No dif- ferences were detected between the two groups in regards to the absolute potassium reduction at different time intervals within the first eight hours following the initial concentration nor in the lowest po- tassium concentration achieved (Tables 3 and 4). A baseline pH at pre- sentation was only available from six of 38 patients in the sodium bicarbonate group and eight of 68 patients in the control group. The mean baseline pH was 7.16 in the sodium bicarbonate group compared to 7.28 in the control group [P = 0.053], and no statistical differences in initial serum potassium nor in potassium reduction were found be- tween these patients (Table 5). However, the significance of this finding is limited due to a baseline pH being unavailable from a majority of the patients included in the evaluation of this study.

1. Discussion

The pharmacotherapy involved in the acute management of hyperkalemia has not changed in the past several decades. Sodium bi- carbonate is often used as part of the treatment for hyperkalemia to as- sist in the intracellular shift of potassium. Although evidence for the use of sodium bicarbonate is limited and heterogeneous, its use remains common in clinical practice. Several intravenous sodium bicarbonate shortages in varying severity occurred during the study period, affecting prescribing patterns at those times and providing the opportunity for

Table 3

Serum potassium reduction in the eight hours following initial level.

	Sodium bicarbonate	Control group	P value
	(n = 38)	(n = 68)
Initial serum potassium, median (mMol/L)	6.6	6.1	0.009
Absolute reduction of potassium at first	1	0.9	0.976

this investigation. An eight-year study period design with patients sys- tematically extracted across the time period was chosen to avoid the in- fluence of any particular transient practice changes in response to drug shortages. In our patient population, the addition of intravenous sodium bicarbonate provided no statistical differences in the absolute reduction of serum potassium at the first repeat. Similarly, no differences were de- tected between the groups at each two hour interval within eight hours following the initial serum potassium concentration. The study results also highlight that patients who presented to the ED with higher serum potassium concentrations were more likely to receive intrave- nous sodium bicarbonate as part of the Treatment regimen. Those pa- tients who received sodium bicarbonate also had a higher incidence of receiving intravenous calcium. These findings are in agreement with a recent published study showing ED patients who presented with higher serum potassium concentrations were more likely to receive combina- tion pharmacological therapies [10]. However, this study may not have an adequate sample size to detect a significant difference in abso- lute reduction of potassium at the first repeat serum potassium. Future larger studies may allow further exploration into the efficacy of intrave- nous sodium bicarbonate in this patient population and help establish its place in hyperkalemia management.

There were several limitations to this study inherent to its retrospec- tive design. First and foremost, insulin administration was required for inclusion. This may have limited our overall sample being investigated, but it does provide some degree of standardization between groups. Furthermore, the insulin dose used in this study was not weight-based and the majority of the patients received a fixed dose of 10 units regular insulin intravenously. This is likely due to an institutional hyperkalemia order set containing built-in selectable options for intravenous insulin and sodium bicarbonate that defaulted to doses of 10 units and 50 mEq, respectively. Additionally, there was no systematic or protocolized pattern on when repeated serum potassium concentrations were ob- tained in the patients included in the study. The aforementioned order set did not include a scheduled repeat serum potassium, thus a wide range of time frames were encountered. Other pharmacological thera- pies utilized in the treatment of hyperkalemia outside of sodium bicar- bonate or insulin were not controlled. However, the only difference noted amongst concomitant agents was with intravenous calcium, which is utilized to stabilize myocardium and would not be expected to affect the primary outcome of the study. Mechanically ventilated pa- tients were initially chosen to be excluded from this study to limit any confounding acid-base status adjustments achieved by the ventilator

Table 5

Analysis of potassium concentration changes in patients with initial pH available at presentation.

repeat, median (mMol/L)

Time to first repeat potassium concentration, median (hours)

Lowest potassium concentration reached	5.35	5.157	0.255
within first 8 h period, mean (mMol/L)				Initial pH, mean	7.16	7.28	0.053
Time to reach lowest recorded potassium	4.5	4	0.792	Initial serum potassium, mean (mMol/L)	7.4	6.9	0.371
concentration within first 8 h period,				Absolute reduction of potassium at first	0.7	1.5	0.229
median (hours)				repeat, mean (mMol/L)

3 4 0.077

Sodium bicarbonate (n = 6)

Control group (n = 8)

P value

and possibly influencing the primary outcome of serum potassium re- duction outside of the effects of pharmacotherapies provided. However, because these patients were excluded, limited information on initial acid-base status was available. Due to the severely underpowered na- ture of the analysis in this subset group of patients in this study, how so- dium bicarbonate would impact serum potassium reduction in patients presenting with acidemia cannot be evaluated from the results in this study. Another limitation of this study was that the results were not stratified based on degrees of Renal impairment, other past medical his- tory, or medication use prior to admission. While the patient population included in this study was a real-world patient population generalizable to other large tertiary referral centers in the United States, studies focus- ing on specific population subsets would provide further guidance in defining the role of sodium bicarbonate in the treatment of acute hyperkalemia. Lastly, the objectives in this current study focused on the changes in serum potassium concentrations, not clinical outcomes (e.g., hospital length of stay, requirement for future dialysis sessions, mortality). More studies may be needed to assist in defining the corre- lation of this surrogate endpoint to meaningful clinical benefits.

1. Conclusions

This study did not detect statistical differences in the absolute reduc- tion of serum potassium in patients who received sodium bicarbonate as part of hyperkalemia treatment and those who did not. These data support the need for randomized controlled trials to better understand the role and clinical efficacy of intravenous sodium bicarbonate in the acute management of hyperkalemia.

Contributors

Shiyi Geng: Methodology, Validation, Formal analysis, Investigation, Writing - original draft.

Emily Green: Conceptualization, Methodology, Writing - review & editing, Resources.

Michael Kurz: Methodology, Writing - review & editing.

Jessica Rivera: Conceptualization, Methodology, Writing - review & editing, Resources.

Funding sources

This research did not receive any specific grants from funding agen- cies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

Shiyi Geng: none. Emily Green: none. Jessica Rivera: none.

Michael Kurz: funded by NIH 5U01DK096037 (Site PI); K23AG038548 (Site PI); R01GM101197 (Site PI); R01GM103799

(Site PI), American Heart Association, Society for Critical Care Medicine, Emergency Medicine Foundation, Rapid Pathogen Screening Inc, Boehringer-Ingelheim, Abbott, Zoll Medical Corporation, and Stryker Corporation to the University of Alabama at Birmingham.

Acknowledgement

None.

References

1. Long B, Warix JR, Koyfman A. Controversies in management of hyperkalemia. J Emerg Med. 2018;55:192-205.
2. Rossignol P, Legrand M, Kosiborod M, et al. Emergency management of severe hyperkalemia: guideline for best practice and opportunities for the future. Pharmacol Res. 2016;113:585-91.
3. Singer AJ, Thode Jr HC, Peacock WF. A retrospective study of emergency department potassium disturbances: severity, treatment, and outcomes. Clin Exp Emerg Med. 2017;4:73-9.
4. Meng QH, Wagar EA. Pseudohyperkalemia: a new twist on an old phenomenon. Crit Rev Clin Lab Sci. 2015;52:45-55.
5. Ravioli S, Pluess E, Funk GC, et al. Dyskalemias in patients with acute kidney injury presenting to the emergency department are common and independent predictors of adverse outcome. Int J Clin Pract. 2021;75:e13653.
6. Lindner G, Burdmann EA, Clase CM, et al. Acute hyperkalemia in the emergency de- partment: a summary from a kidney disease: improving global outcomes confer- ence. Eur J Emerg Med. 2020;27:329-37.
7. Alfonzo AV, Isles C, Geddes C, Deighan C. Potassium disorders-clinical spectrum and emergency management. Resuscitation. 2006;70:10-25.
8. Singer AJ, Thode Jr HC, Peacock WF. rapid correction of hyperkalemia is associated with reduced mortality in ED patients. Am J Emerg Med. 2020;38(11):2361-4.
9. Khanagavi J, Gupta T, Aronow WS, et al. Hyperkalemia among hospitalized patients and association between duration of hyperkalemia and outcomes. Arch Med Sci. 2014;10:251-7.
10. Peacock WF, Rafique Z, Clark CL, et al. Real world evidence for treatment of hyperkalemia in the emergency department (REVEAL-ED): a multicenter, prospec- tive, observational study. J Emerg Med. 2018;55:741-50.
11. Schwarz KC, Cohen BD, Lubash GD, Rubin AL. Severe acidosis and hyperpotassemia treated with sodium bicarbonate infusion. Circulation. 1959;19:215-20.
12. Mahoney BA, Smith WA, Lo DS, Tsoi K, Tonelli M, Clase CM. emergency interventions for hyperkalaemia. Cochrane Database Syst Rev. 2005(2):CD003235 https:// pubmed.ncbi.nlm.nih.gov/15846652/.
13. Ngugi NN, McLigeyo SO, Kayima JK. Treatment of hyperkalaemia by altering the transcellular gradient in patients with renal failure: effect of various therapeutic approaches. East Afr Med J. 1997;74:503-9.
14. Kim HJ. Combined effect of bicarbonate and insulin with glucose in acute therapy of hyperkalemia in end-stage renal disease patients. Nephron. 1996;72:476-82.
15. Kim HJ. Acute therapy for hyperkalemia with the combined regimen of bicarbonate and beta(2)-adrenergic agonist (salbutamol) in chronic renal failure patients. J Korean Med Sci. 1997;12:111-6.
16. Blumberg A, Weidmann P, Ferrari P. Effect of prolonged bicarbonate administration on plasma potassium in terminal renal failure. Kidney Int. 1992;41:369-74.
17. Allon M, Shanklin N. Effect of bicarbonate administration on plasma potassium in di- alysis patients: interactions with insulin and albuterol. Am J Kidney Dis. 1996;28: 508-14.
18. Clase CM, Carrero JJ, Ellison DH, et al. Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a kidney disease: improving global outcomes (KDIGO) controversies conference. Kidney Int. 2020;97:42-61.
19. Alfonzo A, Harrison A, Baines R, Chu A, Mann S, MacRury M. Clinical practice guide- lines treatment of acute hyperkalaemia in adults. The Renal Association; 2020.