Question normal

Fotios Barkas, MD, PhD, Sebastien Filippas-Ntekouan, MD, Angelos Liontos, MD, Maria Kosmidou, MD, PhD, George Kalambokis, MD, PhD, Haralampos Milionis*, MD, PhD

Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece

* Address for correspondence:
Haralampos Milionis, MD, PhD, Professor of Internal Medicine, Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Stavrou Niarchou Avenue, 45500, Ioannina, Greece, e-mail: hmilioni@uoi.gr, tel: +302651007500

Case report
A 69-year-old woman with a 2-day history of fever, dry cough, sore throat, fatigue and diarrhea a was admitted in the Infectious Disease Unit in University Hospital of Ioannina in Greece after being confirmed positive for SARS-CoV-2. Previous medical history was unremarkable. On physical examination, temperature was 38.5 oC, blood pressure 135/80 mm Hg, pulse rate 99 beats/min, respiratory rate 20 per min and oxygen saturation of 85% while the patient was breathing ambient air. Bilateral crackles were evident on auscultation; chest x-ray showed basilar streaky opacities in both lungs. The patient was supplied with oxygen at a flow rate of 10 liter per minute with a Venturi face mask (FiO2=50%) and treated with ceftriaxone (2 gr q.d), azithromycin (500 mg q.d) and hydroxychloroquine (400 mg b.i.d for the 1st day and 200 mg b.i.d afterwards), as proposed by Hellenic National Public Health Organization.
Laboratory evaluation on Day 1 showed increased inflammatory markers and persisting hypokalemia (Table 1). Arterial blood gas test was consistent of both metabolic and respiratory alkalosis. Further assessment indicated increased renal excretion of potassium: urine potassium 60 mmol/L and urine potassium-to-creatinine ratio 38 mmol/g. For the treatment of hypokalemia, potassium was administered intravenously via a peripheral line at a daily dosage of 80 mEq.
The following days, the patient remained febrile and stable without any signs of respiratory improvement, whereas she reported 1-2 diarrheas daily. After administering 400 mg tocilizumab on Day 5, symptom and laboratory improvement was noticed.

Discussion
We were prompted to present this case by the results of a preprinted retrospective study including 175 Covid-19 patients showing that 62% were diagnosed with hypokalemia during their hospitalization.(1) However, these findings were not confirmed by another study reporting mean potassium levels of 3.8 mmol/l (interquartile range: 3.5-4.2).(2) Considering the life-threatening risk of electrolyte abnormalities and especially hypokalemia, it is useful to consider potential factors contributing to hypokalemia in Covid-19 patients. Delays regarding the handling of blood specimens might result in pseudohypokalemia, especially in warm environments.(3) Long hospitalizations (~10 days) of SARS-CoV-2 patients might adversely affect potassium intake and lead to a negative imbalance.(2, 3) Covid-19 symptoms, such as cough, dyspnea, and tachypnea, could lead to respiratory alkalosis which lowers serum potassium by its intracellular shift , whereas diarrheas could increase potassium losses.(2, 3) Cardiovascular complications of Covid-19, such as myocardial infarction or myocarditis, along with the infection-induced stress could increase intracellular potassium shift due to beta2-adrenergic stimulation.(2-4) Although septic shock is infrequent among patients with Covid-19 (~1%), it could be associated with extracellular volume depletion and metabolic alkalosis which increase both intracellular shift of potassium and renal loss.(3) Drug-induced hypokalemia should always be considered in SARS-CoV-2 patients.(3) Inhaled beta2-adrenergic agonists and vasopressors, usually administered in those with respiratory infections and septic shock, increase beta2-adrenergic stimulation.(3) Chloroquine, used in treatment protocols against SARS-CoV-2 , may be associated with severe hypokalemia in case of intoxication.(3, 5) Hypokalemia induced by diuretics should be considered in hypertensive patients, while renal losses of potassium may be increased due to osmotic diuresis in those with poorly controlled diabetes.(3) Antibiotics, in particular piperacillin and ticarcillin, and nucleoside analogues may increase renal potassium losses.(3) However, remdesivir, a novel nucleotide analogue with in vitro activity against SARS-CoV-2 used as compassionate therapy, has not been connected with the development of hypokalemia.(5) Finally, it has been proposed that after the initial engagement of SARS-CoV-2 spike protein, there is subsequent down-regulation of ACE2 abundance on cell surfaces, leading to angiotensin II accumulation.(6) The latter could induce the secretion of aldosterone by the adrenal cortex, resulting in sodium reabsorption and potassium excretion from the collecting duct in kidney.
Although our patient presented with alkalosis and diarrhea upon her admission, the analysis of her urine sample strongly indicated ‘inappropriate’ renal potassium losses. According to the diagnostic approach described above, the ACE2 theory supported her persistent hypokalemia. It has been proposed that hypokalemia could be a prognostic marker of the viral load and Covid-19 severity.(1) Of note, the variations of our patient’s partialoxygen pressure paralleled those of potassium (Table 1). A keen eye and further investigation may confirm this relationship.
All things considered, hypokalemia is of multifactorial origin in SARS-CoV-2 patients and may adversely affect outcome especially in those with pre-existing cardiovascular disease. Therefore, potassium levels should be monitored and restored to normal, especially in severely affected SARS-CoV-2 patients.

References
1. chen d, Li X, song q, et al. Hypokalemia and Clinical Implications in Patients with Coronavirus Disease 2019 (COVID-19). 2020.
2. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020.
3. Palmer BF, Clegg DJ. Physiology and Pathophysiology of Potassium Homeostasis: Core Curriculum 2019. Am J Kidney Dis. 2019;74(5):682-95.
4. Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259-60.
5. Sanders JM, Monogue ML, Jodlowski TZ, et al. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020.
6. Vaduganathan M, Vardeny O, Michel T, et al. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020.