key: cord-1001568-8t8trp75
authors: Moreno-Pérez, Oscar; Leon-Ramirez, Jose-Manuel; Fuertes-Kenneally, Laura; Perdiguero, Miguel; Andres, Mariano; Garcia-Navarro, Mar; Ruiz-Torregrosa, Paloma; Boix, Vicente; Gil, Joan; Merino, Esperanza
title: Hypokalemia as a sensitive biomarker of disease severity and invasive mechanical ventilation requirement in COVID-19 pneumonia: a case series of 306 Mediterranean patients
date: 2020-09-17
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.09.033
sha: c3d3222185e5bee45822eff4e182200a3339e6f0
doc_id: 1001568
cord_uid: 8t8trp75

Objectives Serum levels of potassium (K+) seem significantly lower in severe SARS-CoV-2 infection, with an unknown clinical translation. The objective was to investigate whether hypokalemia acts as a biomarker of severity in COVID-19 pneumonia, and associates with major clinical outcomes. Methods Retrospective cohort study of inpatients with COVID-19 pneumonia (March 3 - May 2, 2020). Patients were categorized according to nadir levels of K + in the first 72 hours of admission: hypokalemia (K+ ≤3.5 mmol/L) and normokalemia (>3.5 mmol/L). Main outcomes were all-cause mortality and need of invasive mechanical ventilation (IMV), analyzed by multiple logistic regression (OR; 95%CI). Results 306 patients were enrolled. Ninety-four patients (30.7%) had hypokalemia, showing at baseline significantly higher comorbidity (Charlson index ≥3, 30.0% vs. 16.3%)(p = 0.02), CURB65 scores (1.5(0.0-3.0) vs. 1.0(0.0-2.0))(p = 0.04), and some inflammatory parameters. After adjustment for confounders, hypokalemia was independently associated with requiring IMV during the admission (OR 8.98; 95%CI 2.54-31.74). Mortality was 15.0% (n = 46) and was not influenced by low K + . Hypokalemia was associated with longer hospital and ICU stay. Conclusions Hypokalemia is prevalent in patients with COVID-19 pneumonia. Hypokalemia is an independent predictor of IMV requirement and seems to be a sensitive biomarker of severe progression of COVID-19.

Early studies reported various electrolyte abnormalities at admission in patients who later presented the severe form of coronavirus disease 2019 . Electrolyte imbalance may not only affect patient care, but could provide insights into the COVID-19 pathophysiology.

Serum levels of potassium were reported to be significantly lower in COVID-19 patients with severe disease, in a pooled analysis of five studies with a total sample size of 1415 patients (-0.12 mmol/L; 95% CI -0.18 to -0.07 mmol/L) (Lippi et al. 2020) .

Recently, Chen and colleagues have published, for the first time, a high prevalence of hypokalemia among patients with COVID-19, suggesting the presence of a disordered in the renin-angiotensin system (RAS) activity, which is altered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and may be associated with treatment outcomes, in a cohort of Wenzhou, China (D. . Unfortunately, the authors limited the analysis to the description of the correlation between hypokalemia and clinical and laboratory parameters, without evaluating outcomes.

To provide insights into this issue, we have examined retrospectively the prevalence of hypokalemia during hospitalization and its impact on major outcomes, in hospitalized patients with COVID-19 from Alicante, Spain, one of the European countries most affected by the SARS-CoV-2 outbreak.

This is a retrospective cohort study of patients with COVID-19 pneumonia hospitalized in an academic center of Spain. The study period was from the 3 rd of March until the 2 nd of May 2020.

HGUA-ISABIAL ethics committee approved the study; as the study was retrospective, obtaining informed consent from participants was waived. The research was conducted according to the principles of the World Medical Association Declaration of Helsinki.

COVID-19 diagnosis required a positive reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2, mainly in nasopharyngeal aspirates. Patients who did not undergo testing, this was unavailable or had a negative result, were not included in the present study.

For this study, only one positive test was necessary for the patient to be included in the analysis.

Criteria for hospital admission included advanced age, significant comorbidities, severe symptoms or poor clinical status, hypoxemia at room air (oximetry <94%, PaO2:FiO2 <300mmHg) and/or significant radiological pulmonary opacities. Antivirals, anti-inflammatories, and non-invasive ventilation were administered according to individual assessment under hospital protocol. Intravenous tocilizumab (TCZ) was reserved for severe cases at admission or in case of progressive clinical deterioration.

Explanatory variables -associated factors Data on patients' demographic characteristics, coexisting conditions (based on codes from the International Classification of Diseases, 10th Revision, Clinical Modification) were included in this analysis. Clinical information included age, sex, underlying coexisting conditions as noted in either the inpatient or the outpatient electronic health record, and Charlson index. Coexisting conditions included chronic obstructive pulmonary disease (COPD), an immunosuppressed condition, and a history of hypertension, diabetes mellitus, or underlying cardiovascular disease (including coronary artery disease, stroke or peripheral vascular disease). Drug therapy for high blood pressure recorded at the time of hospital admission i.e. ARBs, and ACE inhibitors, was also included.

Signs and symptoms at admission, extension of opacities of lung surface on X-rays or computed tomography, laboratory data (including C-reactive protein, Procalcitonin, Ferritin, Interleukin-6, Lactate dehydrogenase, D-dimers, Troponin T and Brain natriuretic peptide) and treatments used, including diuretics, were obtained from electronic medical records during admission.

According to the usual procedure in our center, the determination of potassium in the emergency laboratory was carried out in plasma, while the determination of potassium during hospital admission was carried out in serum. We classified the patients into groups according to the nadir of potassium levels (K+) in the first 72 hours of hospital admission: hypokalemia K+ ≤3.5 mmol/L (which includes severe hypokalemia (<3 mmol/L) and mild hypokalemia (3-3.5 mmol/L)) and normokalemia (>3.5 mmol/L) (D. .

The primary outcome of interest was the association between explanatory variables with the endpoint of all-cause in-hospital mortality. The secondary outcome of interest was the association between explanatory variables and the requirement of invasive mechanical ventilation (IMV) in the intensive care unit (ICU).

We compared the clinical features among the three groups; categorical and continuous variables are given as frequencies (percentages) and as median [interquartile range], respectively. Mann-Whitney's U and Chi square tests were used for group comparisons. Correlation between K+ nadir levels and K+ at admission was analyzed by Spearman´s Rho.

The study population was categorized into two groups: maximum care (ICU and intubation as needed) and patients with limited therapeutic effort (LTE). The attending team agreed with the families the suitable approach for each individual, considering patients and disease characteristics. Since patients with LTE were not candidates for ICU, or for invasive measures, only maximum care population was included in logistic regression models for IMV.

Multiple logistic regression models were built to explore the association between hypokalemia and clinical outcomes (all-cause mortality, ICU admission and invasive mechanical ventilation (IMV)), estimating odds ratios (OR; 95%CI). Variables were included as covariates if shown significant associations in simple models. Continuous variables were categorized on their 75percentiles within each population, to show the impact of severe, extreme values in the outcomes -except for those in which severity is defined by lowest levels, such as lymphocyte counts, where 25-percentiles were used. For the following variables, standard categorizations were followed: age ≥65years, Charlson comorbidity index ≥3, estimated glomerular filtration rate <60ml/min/1.73m2 (by CKD-EPI formula), oximetry <94% and PaO2: 

Three hundred and six patients were enrolled, median age 65.0 years (51.0-77.0), 57.8% males, 53.3% with Charlson index ≥3), see Table 1 . Regarding concomitant comorbidity, 46.2% were hypertensive, 38.8% were obese, and 21.1% had diabetes. The median evolution of the disease at the time of the first consultation was 7.0 days (IQR 4.0-11.0), with fever (72.1%) and dry cough Median length of stay and follow-up were 9 (5-14) and 105 days (100-109), respectively.

Characteristics of the study population according to the K+ levels are represented in table 1.

Patients with hypokalemia (ie. K+ ≤3.5 mmol/l) had at baseline significantly higher comorbidity rates, CURB65 Severity Score for Community-Acquired Pneumonia, serum levels of ferritin, IL-6, 

The patients with hypokalemia also required the administration of tocilizumab (TCZ) (44.1% (41 TCZ / 93 hypokalemia) vs 19.5% (41 TCZ / 210 non-hypokalemia), p=0.001) and corticosteroids (44.3% (39 corticosteroids / 88 hypokalemia) vs 25.9% (53 corticosteroids / 205 nonhypokalemia), p=0.002) in a higher percentage.

Of the 94 patients with hypokalemia, 50% received K+ supplements, with a maximum daily dosage of 40 mmol (30-60) and an accumulated dose of 172 mmol (80-390).

In patients who were candidates for ICU (not limitation of therapeutic effort)(238/306), severe hypokalemia and mild hypokalemia (combined or not) were associated with ICU admission and IMV requirement (OR 4.48 (95%CI 2.35-8.53) and OR 5.49 (95%CI 2.66-11.33), for hypokalemia, respectively). After adjustment (Figure 1) , only hypokalemia was independently associated with requiring IMV during the admission. Whereas, age ≥ 65 years, lymphocyte count <790/mm 3 and extensive pulmonary opacities on chest X ray showed a trend toward significance.

Mortality was 15.0% (n=46) and was not influenced by low potassium levels.

Severe hypokalemia and hypokalemia were associated with longer length of hospital and ICU stay.

Hypokalemia in emergency area was not associated with clinical outcomes.

Final outcomes as ICU admission, IMV requirement or fatal outcome, were not influenced by K+ replacement.

The present study confirmed the high prevalence of hypokalemia (one-third) in patients with COVID-19, highlighting its association with critically ill patients -IMV requirement (two-thirds) and longer length of hospital and ICU stay. The degree of hypokalemia was associated with some clinical features that reflected the severity of the disease, such as CURB65 index and inflammatory markers at admission. These associations, together with the fact that nadir hypokalemia in the first 72 hours of hospital admission was the only predictor of IMV requirement after adjusting for confounders, establish K+ levels as a sensitive dynamic biomarker of severe COVID-19 and suggested the disruption on the RAS system by SAR-CoV-2 (Kunutsor and Laukkanen 2020).

Three notable aspects reinforced the development of hypokalemia as an independent early marker of an unfavorable evolution of COVID-19, without an etiopathogenic role. First, hypokalemia in emergency area was not associated with clinical outcomes. Thus, K+ levels seem to have a dynamic behavior parallel to the evolution of the disease. Second, the therapeutic approaches initiated at admission did not influence the appearance of hypokalemia. The greater use of corticosteroids in patients with low K+ levels was conditioned by the severity of the underlying condition; of the 39 patients with hypokalemia who received corticosteroids, 26 (67%) received them after 72 hours of admission, without differences in the prevalence of hypokalemia with those who received them in the first 72 hours of admission (p=0.24). Also, use of diuretics (neither as a group or focusing on loop diuretics) showed no impact in the appearance of hypokalemia or severe hypokalemia. Lastly, final outcomes as ICU admission, IMV requirement or fatal outcome, were not influenced by K+ replacement. In non-COVID-19 populations, hypokalemia prevalence at admission in hospitalized patients is not common. Neither is in cases of severe bacterial pneumonia. Thongprayoon et al (2019) studied 73,983 hospitalized patients (without end-stage kidney disease), the mean admission K+ level was 4.2±0.5 mmol/L, 0.9% had K+ <2.9 mmol/L and 5% had K+ 3.0-3.4 mmol/L. Regardless of the main diagnosis, both hypo-and hyperkalemia were associated with an increased one-year mortality rate when compared to the normokalemia group, and this mortality risk increased in accordance with the severity of the hypo-and hyperkalemia.

This U-shaped risk relationship between potassium levels and all-cause and cardiovascular mortality is maintained in ambulatory patients across the range of kidney function (Kovesdy et al. 2018) . In a meta-analysis of 27 international cohorts, at the individual data, , compared with a reference K+ level of 4.2 mmol/L, the adjusted hazard ratio for all-cause mortality was 1.22

[95%CI 1.15-1.29] at 5.5 mmol/L and 1.49 (95%CI 1.26-1.76) at 3.0 mmol/L. Patient risks were similar regardless of eGFR, use of RAS inhibitors, and across cohorts and pointed in the same direction as our data.

The primary hypothesis is that hypokalemia is likely linked to a decreased activity of receptor angiotensin-converting enzyme 2 (ACE2) (Guo et al. 2020) . SARS-CoV-2 is thought to infect host cells through ACE2 to cause COVID-19 (Hoffmann et al. 2020) , promoting ACE2 depletion and an J o u r n a l P r e -p r o o f imbalance of the RAS and ACE2/angiotensin 1-7 axis with marked elevations of deleterious angiotensin-II levels. These changes would promote vasoconstriction, proinflammatoryprofibrotic effects, and lead to an increased reabsorption of sodium and water, thereby increasing blood pressure and potassium excretion (K+) (Weir and Rolfe 2010) .

The lower prevalence of dry cough in patients with hypokalemia and severe hypokalemia, in turn, support the role of ACE2 compromised activity; whether this is a true or random relation should be explored in future research. ACE2 is involved in the synthesis of bradykinins; in fact, patients with angiotensin-converting-enzyme inhibitors and activated ACE2 have higher concentrations of angiotensin 1-7 and bradykinins, what therefore contributes to dry cough (Nicolau et al. 2020) . Thus, the low frequency of dry cough in patients with hypokalemia, could translate a low ACE2 activity, mediated by SARS-CoV-2.

The role of gastrointestinal symptoms in hypokalemia development is not supported by our results, according with China cohort data (D. .

Aside from being a marker of severity, the clinical relevance of hypokalemia in this clinical setting lies in the fact that it would potentially contribute to myocardial dysfunction, ventricular arrhythmia (Bielecka-Dabrowa et al. 2012) , and respiratory muscle dysfunction. Nonetheless, the impact of hypokalemia on myocardial and respiratory function in COVID-19 patients is not clear, and direct evidence demonstrating that SARS-CoV-2 infects the human heart and decreases the ACE2 expression is currently lacking. In these regard, Shi et al. (Shi et al. 2020 ), reported no differences in median potassium levels in patients with and without cardiac injury, in a cohort of 416 hospitalized patients with COVID-19.

Regarding the limitations of our study, this is an observational, retrospective, single-center study, and collection of data was not standardized in advance. Long follow-up and no losses reinforce the present data. Multiple factors can condition changes in K+ during hospitalization, including the use of beta-lactam antibiotics and hydroxychloroquine (Heijden et al. 2019; Clemessy et al. 1995) . Nonetheless, the prevalence of hypokalemia in patients who received ceftriaxone (the main prescribed b-lactam in our series) was like the reported in the whole cohort (36% vs 30%), and patients who received hydroxychloroquine (94%), the prescribed dose (200 mg every 12 hours) was inferior than 10 mg / kg / day described in the literature of causing hypokalemia (Clemessy et al. 1995) . Finally, the absence of acid-base metabolism data, hampers interpreting our results.

In summary, the high prevalence of hypokalemia among patients with COVID-19 in this Mediterranean cohort suggests the presence of a disorder in the renin-angiotensin system activity, which is linked to severe SARS-COV-2 infection. Besides, this sensitive biomarker may reflect the progression of COVID-19, it is independently associated with IMV requirement after adjusting by confounders, and should be closely monitored to guide timely treatment.

Considering the implications of serum K+ concentrations in this disease, further investigation is necessary. Data shown as %, median (IQR) unless specified otherwise. In bold, statistically significant differences. Severe hypokalemia (K+ <3 mmol/L), mild hypokalemia (K+ 3-3.5 mmol/L), and normokalemia (K+ >3.5 mmol/L). We defined hypokalemia as K+ ≤3.5 mmol/L (i.e. severe hypokalemia plus mild hypokalemia Numbers and percentages of patients with each risk factor who had the outcomes (risk factor present) and of patients without each risk factor with favorable evolution (risk factor absent) are shown. The 95% confidence intervals (CIs) of the odds ratios have been adjusted for multiple testing. R 2 models: 0,51 for invasive mechanical ventilation. J o u r n a l P r e -p r o o f

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors have no conflicts of interest to declare.

This research work lacks funding sources.

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