Original Article

The Relationship Between Hypokalemia and Mortality in Hospitalized Patients With COVID-19 Pneumonia: A Prospective Study

Please cite this article as follows: Ozturk ES, Keskinler MV, Hussein AL-Janabi MA, Sargin M, Oguz A. The relationship between hypokalemia and mortality in hospitalized patients with COVID-19 pneumonia: a prospective study. Avicenna J Clin Microbiol Infect. 2024; 11(1):33-37. doi:10.34172/ajcmi.3536

Introduction

COVID-19 infection presents a spectrum of clinical manifestations, ranging from asymptomatic cases to severe pneumonia, respiratory distress, multiorgan dysfunction, sepsis, and even death (1,2). The prognosis of COVID-19 is influenced by various demographic and clinical factors, with laboratory parameters also playing a crucial role (3).

Hypokalemia, often associated with unfavorable outcomes, serves as an indicator of increased activity in the renin-angiotensin-aldosterone system among patients with COVID-19 pneumonia. In addition to reflecting disease progression, hypokalemia may independently elevate the risk of requiring invasive mechanical ventilation (4). Potassium, a vital intracellular electrolyte, holds pivotal roles in cardiovascular, musculoskeletal, gastrointestinal, respiratory, and neurological functions (5,6). Hypokalemia can lead to dysrhythmias and precipitate serious clinical complications (7). Numerous studies indicate that hypokalemia alters the disease trajectory in COVID-19 patients (8). This study seeks to contribute to the existing literature by exploring potential causes of hypokalemia and its impact on mortality rates among individuals with COVID-19 pneumonia.

Subjects and Methods

The study enrolled 300 patients aged 18 years and older, with a glomerular filtration rate of 60% or higher, who were admitted to Istanbul Medeniyet University Hospital with a diagnosis of COVID-19 pneumonia from March 2020 to September 2021.

All patients were provided with detailed information about the study and signed informed consent forms. The collected data were related to patients’ age, gender, presence of comorbidities (e.g., diabetes mellitus, hypertension, and cardiovascular disease), and medications (i.e., diuretics, corticosteroids, insulin, beta 2 agonists, and angiotensin-converting enzyme [ACE] inhibitors/angiotensin receptor blockers [ARBs], beta-blockers, digoxin, and antipsychotic drugs). The other data included the presence of vomiting/diarrhea, hypomagnesemia, and hypokalemia, length of hospital stay, and discharge/death outcomes.

Patients’ chronic diseases were documented by reviewing hospital records, while their regular medication usage was determined by examining hospital information management system records and Ministry of Health doctor’s data bank records.

Hypomagnesemia was diagnosed if at least one of the measured magnesium values between the first and fifth days of hospitalization was below 1.6 mmol/L. Similarly, hypokalemia was defined as occurring if at least three out of five measured potassium values between the first and fifth days of hospitalization were below 3.5 mmol/L.

Statistical Analysis

The data were analyzed using IBM SPSS Statistics 18 software (Copyright: SPSS Inc., 1989, 2010). The normal distribution of continuous variables was assessed using the Kolmogorov-Smirnov test. Categorical variables were presented as frequencies (n) and percentages (%), while parametric continuous variables were expressed as means ± standard deviations (SD), and non-parametric variables were represented by median (minimum and maximum) values.

For the analysis of categorical variables, the Pearson chi-square, Fisher’s exact, or Fisher-Freeman-Halton exact test was employed, with Yates and post hoc Bonferroni corrections applied where necessary. Considering that the assumptions for parametric tests were not met, the Mann-Whitney U test was utilized for comparing means between the two groups.

Univariate and multivariate logistic regression analyses were conducted to identify independent risk factors associated with dependent variables. Variables with P values less than 0.2 in the univariate analyses were included in the multivariate model. The results were reported as odds ratios (OR) with 95% confidence intervals.

Survival probabilities were estimated using the Kaplan-Meier method, and the log-rank test was performed to assess differences in survival probabilities between variable levels. A statistical significance level of 0.05 was considered for all analyses.

Results

The study encompassed 300 patients, with a mean age of 59.54 ± 15.70 years. Among them, 101 (33.7%) had diabetes mellitus, 161 (53.7%) had hypertension, and 111 (37.0%) had cardiovascular disease. Additionally, 50 patients (16.7%) experienced vomiting/diarrhea, 51 (17.0%) had hypomagnesemia, and 57 (19.0%) had hypokalemia. Ultimately, 284 patients (94.7%) were discharged, while 16 (5.3%) succumbed during hospitalization. The mean hospital stay was 10.10 ± 6.10 days, ranging from 5 to 43 days. The relationship between the presence of hypokalemia and independent variables was investigated, as detailed in Table 1.

The incidence of hypokalemia did not significantly differ between genders (P = 0.185). Patients with hypokalemia had a significantly higher median age compared to those without this disturbance (67 vs. 58 years, P = 0.012). Regarding comorbidities, no significant associations were found between diabetes mellitus (P = 0.999), hypertension (P = 0.193), cardiovascular disease (P = 0.781), and hypokalemia. However, the use of diuretics was significantly associated with hypokalemia (P = 0.035). Other medication usage and clinical findings did not exhibit significant differences between patients with and without hypokalemia (P > 0.05).

Furthermore, there was no significant difference in the incidence of vomiting/diarrhea (P = 0.236) or hypomagnesemia (P = 0.271) between patients with and without hypokalemia. However, patients with hypokalemia had a significantly higher mortality rate (14.0% vs. 3.3%, P = 0.003) and longer hospital stays (median 11 vs. 8 days, P < 0.001) compared to those without hypokalemia.

Univariate and multivariate logistic regression analyses revealed that age (OR: 1.023, P = 0.019), hospitalization days (OR: 1.112, P < 0.001), and diuretic usage (OR: 1.868, P = 0.036) were independent risk factors for hypokalemia. Additionally, hypokalemia significantly increased mortality (OR: 4.796, P = 0.003), along with prolonged hospitalization (OR: 1.147, P < 0.001). Multivariate analysis showed that hospitalization days were associated with both hypokalemia (OR: 1.108, P < 0.001) and mortality (OR: 1.131, P < 0.001), while the association between hypokalemia and mortality was not statistically significant (OR: 2.427, P = 0.153, Tables 2 and 3).

Discussion

The findings of this study demonstrated that hypokalemia is an independent risk factor associated with mortality and length of hospital stay. The homogeneous distribution in terms of gender, with the number of 150 female and 150 male patients, contributes to obtaining more objective results.

Due to the mean age of 59.54 ± 15.70 years, this study has a younger population compared to other studies (8,9), allowing us to independently evaluate the morbidity and mortality risk that increases with advanced age.

The frequency of hypokalemia in this study (19.0%) was similar to that of hypokalemia (15.8%) in the study performed by Mallow et al (10). It has been shown that hypokalemia is more common, especially in females aged 65 and over (11). In this study, no significant difference was found between gender and the development of hypokalemia. This situation can be explained by the fact that our patients were predominantly in the young age range.

It is known that the use of diuretics is a risk factor for the development of hypokalemia by causing renal potassium loss (12). Rodenburg et al reported that the risk of hypokalemia increased 11 times in patients using diuretics, especially the thiazide group (13). In this study, following the literature, the use of diuretics in patients with COVID-19 has been observed to be associated with hypokalemia. Potassium loss through the gastrointestinal tract is one of the causes of hypokalemia (12), and as a result, the presence of vomiting/diarrhea was found to be a risk factor for the development of hypokalemia. Studies have also demonstrated that hypokalemia may develop with vomiting/diarrhea due to drug-induced (lopinavir/ritonavir) or cytopathic effects of the virus (8–14).

Although the effect of beta-blockers on increasing potassium levels is known (15), no correlation was detected between hypokalemia and beta-blocker use in our study. Likewise, no significant correlation was observed between the development of hypokalemia in COVID-19 patients with and without using ACE-Is/ARBs. In their study, Alfano et al reported no correlation between the use of ACE-Is/ARBs and hypokalemia (8). Although we expected hypokalemia to be found less frequently in these patients, we could not reach this result; this can be attributed to the fact that the drugs used in the treatment of COVID-19 (corticosteroids, beta-2 agonists, or lopinavir/ritonavir) mostly have a potassium level-lowering effect.

While the mortality rate was 3.3% in patients without hypokalemia, this rate was 14.0% in patients with hypokalemia, and a significant correlation was observed between the number of deaths and the presence of hypokalemia. In addition, it was determined that mortality increased 4.79 times in the presence of hypokalemia. Hospitalization periods were longer in patients with hypokalemia than in patients without hypokalemia. In another study, it was revealed that patients with hypokalemia have a higher sequential organ failure assessment score and have a longer hospitalization period (8).

This study had some limitations. It is known that potassium plays an important role in blood pressure regulation. Nonetheless, retrospective blood pressure values followed during the hospitalization period of the patients could not be reached in this study.

The arrhythmia effect of hypokalemia could not be evaluated in patients because retrospective electrocardiogram records could not be accessed. There were no data regarding the body mass index, smoking, or blood lipid values, which could be used for evaluating the morbidity and mortality status of the patients more clearly.

Conclusion

Advanced age and the use of diuretics emerged as risk factors for hypokalemia in COVID-19 patients. The presence of hypokalemia was correlated with longer hospital stays and a higher mortality rate, underscoring the importance of vigilance regarding electrolyte imbalances in patient management.

Acknowledgments

The authors wish to thank all study participants.

Authors’ Contribution

Conceptualization: Aytekin Oguz.

Data curation: Mehmet Sargin.

Formal analysis: Elif Sultan Ozturk.

Investigation: Elif Sultan Ozturk.

Methodology: Aytekin Oguz.

Project administration: Mehmet Sargin.

Resources: Elif Sultan Ozturk.

Software: Elif Sultan Ozturk.

Supervision: Aytekin Oguz.

Validation: Mirac Vural Keskinler.

Visualization: Mirac Vural Keskinler.

Writing–original draft: Maher Ali Hussein Al-Janabi.

Writing–review & editing: Mirac Vural Keskinler.

Ethical Approval

The study received approval from the local ethics committee on September 8, 2021, with decision number 2021/0454. The study adhered to the principles outlined in the Declaration of Helsinki. All patients were informed about the study, and their participation was voluntary, with each patient providing written informed consent prior to their inclusion in the study.

Funding

None.

References

1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18):1708-20. doi: 10.1056/NEJMoa2002032 [Crossref] [ Google Scholar]
2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223):497-506. doi: 10.1016/s0140-6736(20)30183-5 [Crossref] [ Google Scholar]
3. Gallo Marin B, Aghagoli G, Lavine K, Yang L, Siff EJ, Chiang SS. Predictors of COVID-19 severity: a literature review. Rev Med Virol 2021; 31(1):1-10. doi: 10.1002/rmv.2146 [Crossref] [ Google Scholar]
4. Beyerstedt S, Casaro EB, Rangel ÉB. COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis 2021; 40(5):905-19. doi: 10.1007/s10096-020-04138-6 [Crossref] [ Google Scholar]
5. Nomura N, Shoda W, Uchida S. Clinical importance of potassium intake and molecular mechanism of potassium regulation. Clin Exp Nephrol 2019; 23(10):1175-80. doi: 10.1007/s10157-019-01766-x [Crossref] [ Google Scholar]
6. Weaver CM. Potassium and health. Adv Nutr 2013; 4(3):368S-77S. doi: 10.3945/an.112.003533 [Crossref] [ Google Scholar]
7. Unwin RJ, Luft FC, Shirley DG. Pathophysiology and management of hypokalemia: a clinical perspective. Nat Rev Nephrol 2011; 7(2):75-84. doi: 10.1038/nrneph.2010.175 [Crossref] [ Google Scholar]
8. Alfano G, Ferrari A, Fontana F, Perrone R, Mori G, Ascione E. Hypokalemia in patients with COVID-19. Clin Exp Nephrol 2021; 25(4):401-9. doi: 10.1007/s10157-020-01996-4 [Crossref] [ Google Scholar]
9. Islam MK, Hasan P, Hossain MM, Hossain FS, Khan TD, Ratul RH. Prevalence of hypokalemia in COVID-19 and its association with clinical and common laboratory parameters. J Dhaka Med Coll 2020; 29(2):131-7. doi: 10.3329/jdmc.v29i2.51187 [Crossref] [ Google Scholar]
10. Mallow PJ, Belk KW, Topmiller M, Hooker EA. Outcomes of hospitalized COVID-19 patients by risk factors: results from a United States hospital claims database. J Health Econ Outcomes Res 2020; 7(2):165-74. doi: 10.36469/jheor.2020.17331 [Crossref] [ Google Scholar]
11. Kleinfeld M, Borra S, Gavani S, Corcoran A. Hypokalemia: are elderly females more vulnerable?. J Natl Med Assoc 1993; 85(11):961-4. [ Google Scholar]
12. Kardalas E, Paschou SA, Anagnostis P, Muscogiuri G, Siasos G, Vryonidou A. Hypokalemia: a clinical update. Endocr Connect 2018; 7(4):R135-46. doi: 10.1530/ec-18-0109 [Crossref] [ Google Scholar]
13. Rodenburg EM, Visser LE, Hoorn EJ, Ruiter R, Lous JJ, Hofman A. Thiazides and the risk of hypokalemia in the general population. J Hypertens 2014; 32(10):2092-7. doi: 10.1097/hjh.0000000000000299 [Crossref] [ Google Scholar]
14. Chen D, Li X, Song Q, Hu C, Su F, Dai J. Assessment of hypokalemia and clinical characteristics in patients with coronavirus disease 2019 in Wenzhou, China. JAMA Netw Open 2020; 3(6):e2011122. doi: 10.1001/jamanetworkopen.2020.11122 [Crossref] [ Google Scholar]
15. Ben Salem C, Badreddine A, Fathallah N, Slim R, Hmouda H. Drug-induced hyperkalemia. Drug Saf 2014; 37(9):677-92. doi: 10.1007/s40264-014-0196-1 [Crossref] [ Google Scholar]