Hypokalemia and Clinical Implications in Patients With Coronavirus Disease 2019 (COVID-19)

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Hypokalemia and Clinical Implications in Patients with Coronavirus
Disease 2019 (COVID-19)
Dong Chen1*, Xiaokun Li2*, Qifa Song3†, Chenchan Hu1, Feifei Su1, Jianyi Dai1,
Yinghai Ye1, Jianping Huang1, Xiaoming Zhang4
1
Departments of Infectious Diseases, Wenzhou Central Hospital and Sixth People’s
Hospital of Wenzhou, Wenzhou, Zhejiang Province, China

2
Wenzhou Medical University, Wenzhou, Zhejiang Province, China
3
Department of Microbiology, Ningbo Municipal Centre for Disease Control and
Prevention, Ningbo, Zhejiang Province, China

4
Department of Microbiology, Wenzhou Municipal Centre for Disease Control and
Prevention, Wenzhou, Zhejiang Province, China
*Dong Chen and Xiaokun Li contribute equally.
†Corresponding author: qifasong@126.com

medRxiv preprint doi: https://doi.org/10.1101/2020.02.27.20028530.this version posted February 29, 2020. The copyright holder for this
perpetuity.
BACKGROUND
SARS-CoV-2 has caused a series of COVID-19 globally. SARS-CoV-2 binds
angiotensin I converting enzyme 2 (ACE2) of renin–angiotensin system (RAS) and
causes prevalent hypokalemia
METHODS
The patients with COVID-19 were classified into severe hypokalemia, hypokalemia,
and normokalemia group. The study aimed to determine the relationship between
hypokalemia and clinical features, the underlying causes and clinical implications of
hypokalemia.
RESULTS
By Feb 15, 2020, 175 patients with COVID-19 (92 women and 83 men; median age,
46 [IQR, 34–54] years) were admitted to hospital in Wenzhou, China, consisting 39
severe hypokalemia-, 69 hypokalemia-, and 67 normokalemia patients.
Gastrointestinal symptoms were not associated with hypokalemia among 108
hypokalemia patients (P>0.05). Body temperature, CK, CK-MB, LDH, and CRP
were significantly associated with the severity of hypokalemia (P<0.01). 93% of
severe and critically ill patients had hypokalemia which was most common among
elevated CK, CK-MB, LDH, and CRP. Urine K+ loss was the primary cause of
hypokalemia. 1 severe hypokalemia patients was given 3 g/day, adding up to an
average of 34 (SD=4) g potassium during hospital stay. The exciting finding was that
patients responded well to K+ supplements when they were inclined to recovery.
CONCLUSIONS
Hypokalemia is prevailing in patients with COVID-19. The correction of
hypokalemia is challenging because of continuous renal K+ loss resulting from the

perpetuity.
degradation of ACE2. The end of urine K+ loss indicates a good prognosis and may be
a reliable, in-time, and sensitive biomarker directly reflecting the end of adverse effect
on RAS system.
KEYWORDS: Hypokalemia; severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2); Coronavirus Disease 2019 (COVID-19); Clinical Implication;
biomarker
Since December 2019, a life-threatening coronavirus was recognized as the
etiological factor of a series of severe pneumonia cases arising in the city Wuhan of
China 1. This virus was named severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) by the International Committee on Taxonomy of Viruses. The disease
was named Coronavirus Disease 2019 (COVID-19) by World Health
Organization(WHO). SARS-CoV-2 invades human cells through binding angiotensin
I converting enzyme 2 (ACE2) on the cell membrane 2. ACE2 is widely distributed in
many types of human tissues, especially in the vital organs, such as heart, liver,
kidney, and lungs 3. ACE2 is viewed as the principal counter-regulatory mechanism
for the main axis of renin–angiotensin system (RAS) that is an essential player in the
control of blood pressure and electrolyte balance. 4. SARS-CoV-2 binds ACE2 and
enhances the degradation of ACE2, and thus decreases the counter-act of ACE2 on
RAS. The final effect is to increase reabsorption of sodium and water, and thereafter
increase blood pressure and excretion of potassium (K+) 5. Besides, patients with
COVID-19 often had gastrointestinal symptoms such as diarrhea and vomiting 6.
Collectively, the impacts on RAS and gastrointestinal system by COVID-19 probably
lead to disruptions of homeostasis of electrolytes and pH. One of the disruptions that
perpetuity.
may reflect the progression of COVID-19 and should be closely monitored is
hypokalemia. K+ ions are the predominant intracellular cations and influence
membrane polarization of cells. Hypokalemia results in cellular hyperpolarity,
increases resting potential, and hastens depolarization in cardiac cells and lung cells 7.
Severe hypokalemia of under 3 mmol/L plasma K+ can trigger ventricular arrhythmia
and respiratory muscle dysfunction, both conditions being life-threatening in patients
in severe COVID-19 condition. This knowledge implies that hypokalemia may have a
consuderable impact on the treatment outcome of patients with COVID-19 and should
be seriously tackled as these patients have a high prevalence of dysfunction in heart,
lungs, and other vital organs.
As little is known about the prevalence of hypokalemia and its adverse effects on
the treatment outcomes of patients with COVID-19, here we reported the high
prevalence of hypokalemia in such patients and investigated the relevant causes and
clinical meaning. We also aimed to determine the possible relationship between
hypokalemia and the treatment outcomes of these patients.
METHODS
STUDY POPULATION
This study included patients with COVID-19 who were admitted to the hospital for
infectious diseases in the city Wenzhou of China from Jan 11 to Feb 15, 2020. All
patients were aged ≥14 years old and were diagnosed to have COVID-19 according to
the criteria issued by the National Health and Health Commission of the People's
Republic of China 8. All cases were screened with the presence of cough, fever, and
radiographic presentations and confirmed by the real-time PCR on the respiratory
tract samples or blood samples to test for a sequence of SARS-CoV-2. Based on
disease severity, four types of cases were specified according to the criteria mentioned
perpetuity.
above, i.e., mild cases that showed mild clinical manifestations and no pneumonia;
moderate cases that showed respiratory symptoms and mild pneumonia; severe cases
that showed pneumonia and any of acute respiratory distress syndrome (ARDS) with
respiratory rate of over 30 times/min and oxygen saturation of less than 93%; and
critical cases that showed pneumonia and any of shock, respiratory failure, and
failures in other organs.
STUDY DESIGN
This retrospective study was conducted during the COVID-19 outbreak. A trained
team of medical staff reviewed and collected the recorded demographic,
epidemiological, clinical, and laboratory data in a standardized data collection form
modified from electronic medical records. The patients were classified into three
groups according to three levels of plasma K+, i.e., severe hypokalemia group (under
3 mmol/L), hypokalemia group (3–3.5 mmol/L), and normokalemia group (over 3.5
mmol/L). The clinical features, therapy, and treatment outcomes were compared
between three groups, aiming to specify the relationship between hypokalemia and
clinical features, and to determine the underlying causes and clinical implications of
hypokalemia. To elucidate the mechanisms of hypokalemia, an experimental group of
20 patients with hypokalemia and a control group of 20 patients with normokalemia
were established and their K+ in point urine sample was measured and compared. In
addition, among the patients with COVID-19, plasma K+ concentrations were
compared between the patients with and without gastrointestinal symptoms. We also
randomly selected several clinically mild and severe cases with hypokalemia to trace
the treatment effect of K+ supplements.
This study was approved by the Ethics Committee of Wenzhou Central Hospital
perpetuity.
and Sixth People’s Hospital of Wenzhou and followed the Declaration of Helsinki.
Written consent was acquired for all patients.
DATA COLLECTION
The epidemiological investigation was focused on the transmission mode through
the history of travel or residence in Wuhan and the close contact with confirmed
patients within 14 days according to the WHO interim surveillance recommendations
for human infection with novel coronavirus 9. The etiological examinations included
real-time PCR assays that detected SARS-CoV-2, influenza, respiratory syncytial
virus, adenovirus, and para-influenza virus in respiratory specimens. The
immunological responses and possible sepsis were evaluated by measuring white
blood cells, erythrocyte sedimentation rate, procalcitonin, and C-reactive protein.
Lungs, liver, cardiovascular, and renal functions were evaluated using laboratory tests,
including coagulation profile, plasma assays (creatinine, blood urea nitrogen, alanine
aminotransferase, aspartate transferase, creatine kinase, lactate dehydrogenase, and
electrolytes), arterial blood gas examination, and electrocardiogram (ECG). K+ in spot
urine samples was measured and reported in mmol/gram of creatinine.
Additionally, computed tomography (CT) was used to diagnose infection in the
lungs. Therapeutic data and treatment outcomes were also retrieved. The therapeutic
principles included general support, monitoring of lungs, liver, kidney and myocardial
functions, active control over the high fever, oxygen uptake and K+ supplements if
necessary, and antiviral therapy with interferon-α and lopinavir/ritonavir. Treatment

perpetuity.
outcomes were referred to as improved, cured, and failed, and the number of hospital
days and the days for patients to have SARS-CoV-2-PCR-negative results. The
patients who were discharged from the hospital were required to be quarantined for
two weeks.
STATISTICAL ANALYSIS
Continuous measurements with normal distribution were described in mean and
standard deviation (SD), while those that were not normally distributed were
described in median and interquartile range (IQR). Categorical variables, such as
onsets of abnormal laboratory values, were described in counts of events and
percentages. The comparison between groups was conducted using Fisher’s exact test
for categorical variables when the numbers of events in both groups were over five,
and student test for normally distributed continuous measurements. P <0.05 was used
as the significance threshold value. All analyses were conducete by SPSS (version
20.0).
RESULTS
During the study period, 175 patients with COVID-19 were included, consisting of
92 women and 83 men (Table 1). The median age was 46 (IQR, 34–54) years.
Fifty-seven (33%) patients had a history of exposure to the epidemic area. The
patients consisted of 39 patients with severe hypokalemia (<3 mmol/L), 69 patients
with hypokalemia (3–3.5 mmol/L), and 67 patients with normokalemia (>3.5

perpetuity.
mmol/L). Only 10 patients had a plasma K+ concentration of >4 mmol/L. No
statistical difference was identified in demographic features and the prevalence of a
history of exposure to the epidemic area between three groups. Seventy-one patients
had underlying diseases, including 28 patients with hypertension, 12 patients with
diabetes, and 31 patients with other conditions. The prevalence of underlying diseases
was associated with the severity of hypokalemia (P<0.05).
Table 1. Epidemiological and clinical symptoms of patients stratified by three

different levels of plasma potassium
Plasma potassium range (mmol/L) P value a
Severe Normaka-
Attribute Total Hypokalemia
hypokale lemia P1 P2 P3
(3–3.5)
mia(<3) (>3.5)
No. of patients 175 39 (22%) 69 (40%) 67 (38%) – – –
Age, median (IQR), year 46 (34–54) 48(43–57) 46(38–56) 41(30–53) – – –
0.8 0.7 0.4

Female 92 (53%) 21 (54%) 39 (56%) 32 (48%)
Male 0.8 0.7 0.4

83 (47%) 18 (46%) 30 (43%) 35 (52%)
History of exposure to
57 (33%) 16 (41%) 20 (29%) 21 (31%) 0.2 0.4 0.9
epidemic area
Underlying disease 71 (41%) 25 (64%) 29 (42%) 17 (25%) 0.04* <0.01** 0.05*
Respiratory symptoms
Dry cough 109 (62%) 25 (64%) 39 (56%) 45 (67%) 0.5 0.8 0.2
Dyspnea or tachypnea 23 (13%) 10 (26%) 8 (12%) 5 (7%) 0.1 0.02* 0.6
Runny nose 8 (5%) 1 (3%) 3 (4%) 4 (6%) – – –
Sore throat 13 (7%) 2 (5%) 7 (10%) 4 (6%) – – –

Gastrointestinal symptoms
Diarrhea 34 (19%) 12 (31%) 16 (23%) 6 (9%) 0.5 0.01** 0.03*
Vomiting 7 (4%) 2 (5%) 4 (6%) 1 (1%) – – –
Abdominal pain 5 (3%) 3 (8%) 2 (3%) – – – –

Other symptoms
Patient’s temperature at 37.2 ±0.6 37.6±0.5 37.2±0.5 37.1±0.5 <0.01** <0.01** 0.12
perpetuity.
admission ℃
Highest patient’s
38.2±0.6 38.6±0.6 38.1±0.5 38.1±0.5 <0.01** <0.01** 1
temperature ℃
Myalgia 0.6 – –
22 (13%) 8 (21%) 11 (16%) 3 (4%)
Heart rate 0.33 0.02* 0.07

90±12 92±12 91±11 88±10
Respiratory rate 21±2 22±3 21±2 21±2 0.02* 0.02* 1
Abbreviations: SD, standard deviation; IQR, interquartile range.

Note: Continuous variables are described in mean±SD. The categorical variables are described in
counts (%).
a
P 1 value difference indicates that between the severe hypokalemia group the hypokalemia
group.
P 2 value difference indicates that between the severe hypokalemia group and the normakalemia
group.
P 3 value difference indicates that between the hypokalemia group and the normakalemia group.
* Statistically significant (P<0.05).
** Statistically significant (P<0.01).
Concerning the presenting symptoms (Table 1), except that the patients with severe
hypokalemia had a statistically higher prevalence of dyspnea or tachypnea, no
association was observed between the severity of hypokalemia and the prevalence of
common respiratory symptoms, such as cough and running nose. As to the
gastrointestinal symptoms that might cause hypokalemia, 34 (19%) patients had
diarrhea with an average of 6 onset times per day and often ended within 1–4 days,
dominantly in the patients with hypokalemia (P<0.05). Few patients had vomiting and
abdominal pain. The patients with severe hypokalemia had statistically higher body
temperature (mean, 37.6℃; SD, 0.5 ℃) than the patients with hypokalemia
(mean=37.2℃, SD=0.5 ℃, and P<0.0) and the patients with normokalemia
(mean=37.1℃, SD=0.5℃, and P<0.01). Similar difference was also observed in the
highest patient’s temperature during the hospital stay. The patients with severe
perpetuity.
hypokalemia also had a higher heart rate and respiratory rate than the remaining
patients (P<0.05).
Table 2. Laboratory examinations of patients stratified by three levels of plasma

potassium
Severe Hypokale Normaka-
Attribute Total
hypokale mia lemia P1 P2 P3
mia(<3) (3–3.5) (>3.5)
No. of patients 175 39 (22%) 69 (40%) 67 (38%) – – –
WBC (×109/L) 0.16 0.05* 0.17

4.9±1.5 4.6±1.4 4.9±1.6 5.2±2.1
No. of leukopenia (<4×109/L) 44 (25%) 11 (28%) 16 (23%) 17(25%) 0.6 0.8 0.8
Lymphocyte (×109/L) 1.28±0.6 1.12±0.5 1.24±0.6 1.39±0.6 0.14 0.01** 0.07
No. of hypolymphocytemia
61 (35%) 16 (41%) 27 (39%) 18 (27%) 1 0.1 0.1
(<1.1×109/L)
CRP (0–8 mg/L) 19±21 28±23 19±20 13±18 0.4 0.1 0.06
ESR (0–20 mm/h) 26±16 34±15 26±16 22±15 <0.01** <0.01** 0.07
CK (U/L) 96±188 131±188 95±84 78±51 0.02* 0.08 0.08
No. of elevated CK (>170 U/L) 24 (14%) 15 (38%) 5 (7%) 4 (6%) <0.01** <0.01** 1
CK-MB (U/L) 20±13 35±18 21±14 17±12 <0.01** <0.01** 0.04*
No. of elevated CK-MB (>18 U/L) 39 (22%) 25 (64%) 7 (10%) 7 (10%) <0.01** <0.01** 1
LDH (U/L) 216±66 256±81 213±60 196±60 <0.01** <0.01** 0.05*
No. of elevated LDH (>240 U/L) 57 (33%) 23 (59%) 18 (26%) 16(24%) <0.01** <0.01** 0.8
ALT (<40 U/L) 31±28 37±35 30±30 28±30 0.14 0.08 0.35
AST (<40U/L) 31±18 41±20 30±19 26±14 <0.01** <0.01** 0.08
Creatinine (25–70 umol/L) 68±31 71±17 69±31 65±33 0.35 0.14 0.27
BUN (3–7 mmol/L) 3.7±1.2 3.9±1.3 3.7±1.3 3.6±1.4 0.22 0.14 0.33
pH 7.42±0.04 7.43±0.04 7.42±0.03 7.41±0.03 0.07 <0.01** 0.03
No. of pH>7.45 19 (11%) 11 (28%) 5 (7%) 3 (4%) <0.01** – –
pCO2 5.4±0.8 5.5±0.7 5.4±0.9 5.3±0.8 0.27 0.10 0.24
Oxygen saturation (93–100%) 96.6±2.2 96.3±2.4 96.6±2.0 96.8 ±2.1 0.24 0.13 0.28
Potassium (3.5–5.5 mmol/L) 3.4±0.4 2.9±0.2 3.4±0.2 3.8±0.3 <0.01** <0.01** <0.01**
Sodium (135–145 mmol/L) 138±3 136±3 138±3 138±3 <0.01** <0.01** 1
Computed tomography (CT) and electrocardiogram ( ECG) examinations
Pulmonary ground-glass opacities 174 (100%) 39(100%) 68(100%) 67 (100%) 1 1 1
ECG 63 (36%) 30 (77%) 23 (33%) 10 (15%) <0.01** <0.01** <0.02*
Abbreviations: CK, creatine kinase; LDH, lactate dehydrogenase; ESR, erythrocyte sedimentation
rate; CRP, C-reactive protein; ALT, alanine aminotransferase; AST, aspartate transferase; BUN,
perpetuity.
blood urea nitrogen.
Note: See Table 1.
Among a series of laboratory examinations (Table 2), creatine kinase (CK),
CK-MB, lactate dehydrogenase, aspartate transferase, and erythrocyte sedimentation
rate were significantly associated with the severity of hypokalemia (P<0.01).
Collectively, these attributes with elevated values were generally related to
myocardial injury. A total of 108 patients with hypokalemia exhibited moderate
decreases in sodium, white blood cells, and lymphocyte than the 67 patients with
normokalemia. Among these 108 patients, 39 patients exhibiting gastrointestinal
symptoms had a mean plasma K+ of 3.22 (SD, 0.22) mmol/L, which was not
statistically different from the mean value of 3.26 (SD, 0.28) mmol/L in 69 patients
without gastrointestinal symptoms. Regarding the urine K+ output, 20 patients with
hypokalemia had a mean K+ concentration of 32 (SD, 11) mmol/gram of creatinine,
which was statistically higher than the corresponding mean of 18 (SD, 7) mmol/gram
of creatinine for 20 patients with normokalemia (P<0.01).
In the part of CT and ECG examinations, nearly all patients had pulmonary
ground-glass opacities, in trast, abnormal ECG results were significantly correlated
with the severity of hypokalemia (P<0.01) as the prevalence of abnormal ECG results
was 77%, 33%, and 15% for patients with severe hypokalemia, hypokalemia, and
normokalemia, respectively.
perpetuity.
In terms of severity, there were 37 severe cases and 3 critically cases (Table 1
and Table 4). Severe and critically ill patients had higher occurrence of severe
hypokalemia, hypokalemia, abnormal ECG presentations, as well as elevated CK,
CK-MB, LDH, and CRP (all P<0.01). Among these abnormal indices, hypokalemia
was most common as 93% of severe and critically ill patients had hypokalemia. In
contrast, elevated BUN and creatinine were rare. Abnormal ECG presentations were
usually representative of hypokalemia and improved with K+ supplement treatment.
Elevated CK, CK-MB, and LDH often came to normal level within 3–6 days (Figure
1). Elevated ALT and AST were generally mild and came to normal level after liver
support therapy (Table 2 and Table 4). Most patients with intermittent abnormal
oxygen saturation were improved after oxygen inhalation except for three critically ill
patients who were given invasive mechanical ventilation.
Table 3. Therapy and outcomes of patients stratified by three levels of plasma

potassium
Severe Normaka-
Attribute Total Hypokalem
hypokale lemia P1 P2 P3
ia (3–3.5)
mia(<3) (>3.5)
No. of patients 175 39 (22%) 69 (40%) 67 (38%) – – –
Oxygen inhalation 51 (29%) 16 (41%) 24 (35%) 11 (16%) 0.5 0.01** 0.02*

Interferon-α 170 (97%) 39(100%) 67 (97%) 64 (96%) 1 1 1
Lopinavir/ritonavir 151 (86%) 39(100%) 62 (90%) 50 (75%) 0.05* <0.01** <0.01**
Arbidol 151 (86%) 36 (92%) 62 (90%) 53 (79%) 1 0.10 0.10
Hormone 12 (7%) 7 (18%) 5 (7%) – 0.1 – –
Complication 11 (6%) 6 (15%) 3 (4%) 2(3%) – – –
Severe cases 37 (21%) 17 (44%) 14 (20%) 6 (9%) 0.01* <0.01** 0.2
Critically ill cases 3 (2%) 3 (8%) – – – – –
No. of discharged patients 52 (30%) 12 (31%) 22 (32%) 18 (27%) 1 0.7 0.6
Days of hospital stay b 16±6 19±8 16±6 15±5 0.01 <0.01** 0.14
perpetuity.
Days to turn PCR-negative b 13±7 14±6 13±7 11±5 0.22 <0.01** 0.03*
Note: See Table 1.

b
The values are calculated according to the number of the patients who were cured
and discharged.
Table 4. Occurrence of abnormal biomarkers between the group of severe and

critically ill cases and the group of moderate and mild cases
Severe and Moderate and
Attribute Total P value
critically ill mild
No. of patients 175 40 135 –

+
K (mean±SD) 3.4±0.4 3.1±0.3 3.5±0.4 <0.01**
+
K (<3 mmol/L) 19 (11%) 15 (38%) 4 (3%) <0.01**
+
K (<3.5 mmol/L 78 (44%) 22 (55%) 56 (41%) 0.1
CK (>170 U/L) 24 (14%) 11 (28%) 13 (10%) <0.01**
CK-MB (>18 U/L) 39 (22%) 24 (60%) 15 (11%) <0.01**
LDH (>240U/L) 57 (33%) 26 (65%) 31 (23%) <0.01**
BUN (>7 mmol/L) 1 (1%) 1 (2%) – –
Creatinine (>110 umol/L) 1 (1%) 1 (2%) – –
Oxygen saturation (<93%) 8 (5%) 8 (20%) – –
CRP (0–8 mg/L) 85 (49%) 32 (80%) 53 (39%) <0.01**
ALT (<40 U/L) 34 (19%) 13 (33%) 21 (16%) 0.02*
AST (<40U/L) 28 (16%) 12 (30%) 16 (12%) 0.01**
9
No. of leukopenia (<4×10 /L) 44 (25%) 14 (35%) 30 (22%) 0.1
ECG 63 (36%) 25 (62%) 38 (28%) <0.01**
Note: See Table 1.
Turning to the therapy and treatment outcomes (Table 3), the severity of
hypokalemia meant a higher prevalence of severe cases (P<0.01) and necessitated
more frequent usage of antiviral drugs such as lopinavir/ritonavir (P<0.01) and
arbidol, as well as oxygen inhalation (P<0.05) besides interferon-α. Till the time when
the manuscript was written, 62 (35%) patients were cured and discharged from the
hospital. The severity of hypokalemia led to substantially more days of hospital stay
perpetuity.
(P<0.05) and more days needed for patients to have PCR-negative results (P<0.05).
As to the K+ supplements treatment, the average amount of K+ supplements for 21
discharged patients with severe hypokalemia was 3 g/day, adding up to an average of
34 (SD, 4) g during the whole hospital stay for each patient.

To be noteworthy, the most significant adverse effect of hypokalemia is a
myocardial injury that can be well reflected by ECG, CK, and CK-MB. A careful
check identified a noticeable jump of increase in the prevalence of abnormal ECG
results and elevated CK and particularly elevated CK-MB in the patients with severe
hypokalemia (Table 2).
Figure 1. Trend in plasma K+ and pH in COVID-19 progression and the patient’s response to K+
supplement
Patient #1: The figure shows CK and LDH fall into the normal range in a few days. The relapse of
elevated loss of urinary K+ leads to the failure in K+ supplements.
perpetuity.
Time point A–C: CK, 530, 365, 40 U/L; CK-MB, 65, 45, 11 U/L; LDH, 357, 270, 212 U/L,
respectively. Time point D–F: Urine K+, 41, 50, 38 umol/gram of creatinine, respectively.
Patient #2: The figure shows CK and LDH fall into the normal range in a few days. The loss of
urine K+ is alleviated, which ensures the effective treatment of K+ supplements.
Time point A–C: CK, 258, 132, 62 U/L; CK-MB, 35, 26, 12 U/L; LDH, 355, 238, 220 U/L,
respectively. Time point D–F: Urine K+, 32, 21, 9 umol/gram of creatinine, respectively.
DISCUSSION
The current study illustrated the high prevalence of hypokalemia in the patients
with COVID-19 and the positive association between the degree of hypokalemia and
the severity of COVID-19. The study also proved that hypokalemia was more
attributable to renal loss of K+ than gastrointestinal loss.
Previous literature has proved that sufficient and appropriate levels of plasma K+
have a protective role in preventing myocardial failure through weakening cellular
hyperpolarity and depolarization 10,11. SARS-CoV-2 can result in heart dysfunction
due to the intensively expressed ACE2 in the patients’ myocardial cells that act as
receptors for this virus. Therefore, it is beneficial to patients that plasma K+ levels be
frequently checked and maintained between 4.0 and 5.5 mmol/L or 4.5 and 5.5
mmol/L for serum K+ as serum generally has more K+ than plasma 12. In the present
study, hypokalemia was prevailing among the patients with COVID-19, up to 62%
(108/175) patients having plasma K+ that was under 3 mmol/L. Among 175 patients,
only 10 patients had plasma K+ of 4 mmol/L recommended for patients with
myocardial dysfunction. That strikingly low prevalence of optimal concentration of
plasma K+ implied a massive risk for the patients’ heart to be affected by both
hypokalemia and the virus. As an emerging infectious disease, the available data on
serum K+ levels is scanty. Only one previous study on 41 patients reported 4.2
mmol/L as the mean serum K+, as well as higher K+ in the ICU patients (mean, 4.6
perpetuity.
mmol/L) than non-ICU patients (mean, 4.1 mmol/L), suggesting that the elevated
serum K+ was associated with severity of illness 13. However, our findings that were
derived from more patients were contrary to this previous study. Considering the
implications of serum K+ concentrations in this disease, further investigation is
necessary.
The present study also proved that the degree of hypokalemia was correlated with
several clinical features reflecting the severity of the disease. These features included
the underlying conditions, high body temperature, and notably, the elevated
laboratory indices related to myocardial injury, such as CK, CK-MB, lactate
dehydrogenase, aspartate transferase, and erythrocyte sedimentation rate, as well as
abnormal ECG results. The other indices, including WBC, lymphocyte, CRP, ALT,
were correlated with hypokalemia with less strength than the attributes mentioned
above. Regarding the blood gas results, the higher prevalence (28%) of pH of over
7.45 was seen in the patients with severe hypokalemia because severe hypokalemia
led to alkalosis due to H+-K+ exchange between intracellular and extracellular fluid 14.
Nevertheless, the prevalence of abnormal oxygen saturation and CO2 pressure were
not sensitive enough to identify the difference between patients with different K+
levels. The patients showing renal dysfunction were rare according to a generally
normal concentration of blood urea nitrogen and creatinine, as well as sufficient urine
output. The globally normal renal function ensured the safe application of K+
supplements. Notably, because of the variety in different laboratories and assays that
may produce various reference values, it is not recommended to compare results
directly. The current study also listed the number and percentage of several abnormal
laboratory results, such as WBC, CK, CK-MB, etc, which were considered to be
perpetuity.
important indices for hypokalemia, myocardial injury, and evaluation of disease. We
expected these arrangements of results might facilitate future studies.
Seeing that hypokalemia was prevalent among patients with COVID-19 and
associated with the severity of the disease, elucidation of the mechanisms for
hypokalemia was elementary for understanding and treatment of COVID-19. In the
current situation, two probable causes of hypokalemia are increased gastrointestinal
loss and increased urinary loss 15. Both causes can find their way in the patients with
COVID-19, as mentioned in the introduction section. However, the present findings
indicated that gastrointestinal loss might not contribute much to hypokalemia as based
on the following reasons: only a small proportion of patients with hypokalemia
showing gastrointestinal symptoms, e.g., 31% of patients with severe hypokalemia
having diarrhea; among the patients with hypokalemia, no significant difference
between those with and those without diarrhea; the average number of diarrhea onsets
being 5 times/day and diarrhea ending in a short time, meaning that the diarrhea was
mild. Therefore, hypokalemia might principally result from increased urine loss. This
was proved in this study by the dramatically increased urine K+ output in the
hypokalemia group than the control group with normokalemia. This finding that
increased urine K+ was the primary cause of hypokalemia was consistent with the
pathogenesis of SARS-CoV-2. This virus drives RAS towards enhanced ACE–Ang II
(angiotensin II)–Ang II type 1 receptor (AT1) axis by degrading ACE2 that is the
principal counter-regulatory mechanism for the central axis of the RAS4. The final
effect of this disturbance of RAS is the increased distal delivery of sodium and water
perpetuity.
to collecting tubule of the kidney and enhanced potassium secretion. This effect is
similar to the effect of aldosterone that stimulates water and sodium reabsorption and
potassium excretion and thus increases body water and blood pressure 16.
As hypokalemia has an adverse effect on myocardial functions, in-time treatment is
required for achieving good outcomes. However, the mechanism of hypokalemia in
the present study hinted that it was challenging to achieve normokalemia in the
presence of continuous renal loss of K+. This worry was proved by the elevated
amount of urine K+ measured in umol/gram of creatinine (Figure 1). The continual K+
supplements had very little effect on the return of normokalemia when the urine loss
of K+ persisted in the severe cases. Interestingly, we found a noteworthy phenomenon
in most patients who were cured of COVID-19. As shown in Figure 1, when patients
were inclined to recovery, they responded well to K+ supplement treatment and
steadily returned to normokalemia. This phenomenon indicated the end of urine loss
of K+ due to disordered RAS balance; in other words, the ACE2 function began to
return. This exciting finding suggested that return of normokalemia might be a
reliable biomarker for monitoring ACE2 function.
Although COVID-19 causes injury to lungs, heart, liver, and kidney, our study
showed the occurrence of abnormal indices related to heart, liver, and kidney was low,
and oxygen saturation often returned to normal level upon oxygen inhalation in most
patients (Table 2 and Table 4). Several laboratory indices, such as elevated CK,
CK-MB, LDH, ALT and AST were usually came to normal level or substantially
improved after relevant treatment. The superficial mildness contradicted with the
sudden progression of disease in some patients. This contradiction might result from
the fact that the biomarkers were not sensitive to reflect the whole progression of this
disease. Therefore, a more sensitive biomarker to monitor the ongoing condition is

perpetuity.
urgently needed for these patients. As discussed above, 93% severe and critically ill
patients had hypokalemia, showing that depletion of K+ was prevailing. Based on
analysis of the trend in plasma K+ and urine output of K+, the end of the depletion
often suggested a good prognosis (Figure 1). Therefore, comprehensive analysis of K+
depletion can be achieved by monitoring urine K+ loss, plasma K+, and the response
to K+ supplement treatment. Importantly, the information from this analysis related to
hypokalemia directly reflects the very basis of the pathogenesis of SARS-CoV-2 and
might be a reliable, int-time and sensitive biomarker to reflect the progression of
COVID-19.
The present study had some limitations. Most patients were still hospitalized.
Only a small proportion of cases were used to evaluate the treatment outcomes.
However, from several patients who had been cured, the principal results related to
hypokalemia treatment were consistent, which could provide reliable information.
Since this life-threatening disease is still ongoing in China and is developing in
several countries, we expect our findings can provide timely information about better
understanding and treatment of COVID-19.
To summarize, the present study has identified the prevailing hypokalemia in
patients with COVID-19. The correction of hypokalemia is challenging because of
continuous renal loss of potassium resulting from the degradation of ACE2 by the
binding of SAR-CoV-2. The end of loss of K+ often indicates a good prognosis and
may be a reliable, in-time, and sensitive biomarker that reflects the end of adverse
effect on the RAS system by SAR-CoV-2. Due to the possible injury to
cardiovascular functions, neurohormonal activation, and other vital organs by
hypokalemia, clinicians should pay great attention to hypokalemia and the patients’
response to K+ supplements.
perpetuity.
ACKNOWLEDGMENTS
This study was supported by Key scientific and technological innovation projects
of Wenzhou (ZY202004) and Natural Science Foundation of Ningbo (2017A610273).
All authors declare no interest.
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Hypokalemia and Clinical Implications in Patients With Coronavirus Disease 2019 (COVID-19)

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medRxiv preprint doi: https://doi.org/10.1101/2020.02.27.20028530.this version posted February 29, 2020.

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Hypokalemia and Clinical Implications in Patients with Coronavirus

Disease 2019 (COVID-19)

Yinghai Ye1, Jianping Huang1, Xiaoming Zhang4

Hospital of Wenzhou, Wenzhou, Zhejiang Province, China

Prevention, Ningbo, Zhejiang Province, China

Prevention, Wenzhou, Zhejiang Province, China

*Dong Chen and Xiaokun Li contribute equally.

†Corresponding author: qifasong@126.com

SARS-CoV-2 has caused a series of COVID-19 globally. SARS-CoV-2 binds

angiotensin I converting enzyme 2 (ACE2) of renin–angiotensin system (RAS) and

causes prevalent hypokalemia

46 [IQR, 34–54] years) were admitted to hospital in Wenzhou, China, consisting 39

severe hypokalemia-, 69 hypokalemia-, and 67 normokalemia patients.

Gastrointestinal symptoms were not associated with hypokalemia among 108

were significantly associated with the severity of hypokalemia (P<0.01). 93% of

hypokalemia. 1 severe hypokalemia patients was given 3 g/day, adding up to an

patients responded well to K+ supplements when they were inclined to recovery.

hypokalemia is challenging because of continuous renal K+ loss resulting from the

KEYWORDS: Hypokalemia; severe acute respiratory syndrome coronavirus 2

(SARS-CoV-2); Coronavirus Disease 2019 (COVID-19); Clinical Implication;

Since December 2019, a life-threatening coronavirus was recognized as the

(SARS-CoV-2) by the International Committee on Taxonomy of Viruses. The disease

was named Coronavirus Disease 2019 (COVID-19) by World Health

Organization(WHO). SARS-CoV-2 invades human cells through binding angiotensin

I converting enzyme 2 (ACE2) on the cell membrane 2. ACE2 is widely distributed in

kidney, and lungs 3. ACE2 is viewed as the principal counter-regulatory mechanism

COVID-19 often had gastrointestinal symptoms such as diarrhea and vomiting 6.

Collectively, the impacts on RAS and gastrointestinal system by COVID-19 probably

may reflect the progression of COVID-19 and should be closely monitored is

hypokalemia. K+ ions are the predominant intracellular cations and influence

membrane polarization of cells. Hypokalemia results in cellular hyperpolarity,

Severe hypokalemia of under 3 mmol/L plasma K+ can trigger ventricular arrhythmia

and respiratory muscle dysfunction, both conditions being life-threatening in patients

be seriously tackled as these patients have a high prevalence of dysfunction in heart,

lungs, and other vital organs.

clinical meaning. We also aimed to determine the possible relationship between

hypokalemia and the treatment outcomes of these patients.

radiographic presentations and confirmed by the real-time PCR on the respiratory

tract samples or blood samples to test for a sequence of SARS-CoV-2. Based on

failures in other organs.

team of medical staff reviewed and collected the recorded demographic,

epidemiological, clinical, and laboratory data in a standardized data collection form

hypokalemia. To elucidate the mechanisms of hypokalemia, an experimental group of

20 patients with hypokalemia and a control group of 20 patients with normokalemia

addition, among the patients with COVID-19, plasma K+ concentrations were

the treatment effect of K+ supplements.

Written consent was acquired for all patients.

The epidemiological investigation was focused on the transmission mode through

patients within 14 days according to the WHO interim surveillance recommendations

real-time PCR assays that detected SARS-CoV-2, influenza, respiratory syncytial

virus, adenovirus, and para-influenza virus in respiratory specimens. The

immunological responses and possible sepsis were evaluated by measuring white

blood cells, erythrocyte sedimentation rate, procalcitonin, and C-reactive protein.

aminotransferase, aspartate transferase, creatine kinase, lactate dehydrogenase, and

electrolytes), arterial blood gas examination, and electrocardiogram (ECG). K+ in spot

urine samples was measured and reported in mmol/gram of creatinine.

Additionally, computed tomography (CT) was used to diagnose infection in the