Electrolyte imbalances as poor prognostic markers in COVID-19: a systemic review and meta-analysis

Abstract

Purpose: Serum electrolyte imbalances are highly prevalent in COVID-19 patients. However, their associations with COVID-19 outcomes are inconsistent, and of unknown prognostic value. We aim to systematically clarify the associations and prognostic accuracy of electrolyte imbalances (sodium, calcium, potassium, magnesium, chloride and phosphate) in predicting poor COVID-19 clinical outcome.

Methods: PubMed, Embase and Cochrane Library were searched. Odds of poor clinical outcome (a composite of mortality, intensive-care unit (ICU) admission, need for respiratory support and acute respiratory distress syndrome) were pooled using mixed-effects models. The associated prognostic sensitivity, positive and negative likelihood ratios (LR + , LR-) and predictive values (PPV, NPV; assuming 25% pre-test probability), and area under the curve (AUC) were computed.

Results: We included 28 observational studies from 953 records with low to moderate risk-of-bias. Hyponatremia (OR = 2.08, 95% CI = 1.48-2.94, I² = 93%, N = 8), hypernatremia (OR = 4.32, 95% CI = 3.17-5.88, I² = 45%, N = 7) and hypocalcemia (OR = 3.31, 95% CI = 2.24-4.88, I² = 25%, N = 6) were associated with poor COVID-19 outcome. These associations remained significant on adjustment for covariates such as demographics and comorbidities. Hypernatremia was 97% specific in predicting poor outcome (LR + 4.0, PPV = 55%, AUC = 0.80) despite no differences in CRP and IL-6 levels between hypernatremic and normonatremic patients. Hypocalcemia was 76% sensitive in predicting poor outcome (LR- 0.44, NPV = 87%, AUC = 0.71). Overall quality of evidence ranged from very low to moderate.

Conclusion: Hyponatremia, hypernatremia and hypocalcemia are associated with poor COVID-19 clinical outcome. Hypernatremia is 97% specific for a poor outcome, and the association is independent of inflammatory marker levels. Further studies should evaluate if correcting these imbalances help improve clinical outcome.

Keywords: Death risk; Electrolytes; Hypernatremia; Intensive care; Respiratory medicine; Severe acute respiratory syndrome.

Fig. 1

PRISMA flow diagram of the study selection process

Fig. 2

Forest plot showing the (a) unadjusted and (b) adjusted association between electrolyte imbalances with poor outcome*, stratified by the type of electrolyte imbalance. Black diamonds are the estimated pooled odds ratios for each random-effects meta-analysis; red boxes reflect the relative weight apportioned to studies in the meta-analysis.*Poor outcome Is defined as a composite of mortality, ICU admission, respiratory support and acute respiratory distress syndrome

Fig. 3

Forest plot showing the pooled unadjusted odds ratios (a) and adjusted odds ratios (b) of the association between electrolyte imbalances and mortality, stratified by the type of electrolyte imbalance. Black diamonds are the estimated pooled odds ratios for each random-effects meta-analysis; blue/red boxes reflect the relative weight apportioned to studies in the meta-analysis

Fig. 4

Forest plot showing the unadjusted association between electrolyte imbalances with ICU admission, stratified by the type of electrolyte imbalance. Black diamonds are the estimated pooled odds ratios for each random-effects meta-analysis; blue boxes reflect the relative weight apportioned to studies in the meta-analysis

Fig. 5

Forest plot showing the a unadjusted and b adjusted association between electrolyte imbalances and respiratory support, stratified by the type of electrolyte imbalance. Black diamonds are the estimated pooled odds ratios for each random-effects meta-analysis; red boxes reflect the relative weight apportioned to studies in the meta-analysis

Fig. 6

a Summary receiver operator characteristic curve, b Fagan plot and c Coupled funnel plot of hypernatremia in predicting poor outcome

Fig. 7

a Summary receiver operator characteristic curve, b Fagan plot and c Coupled funnel plot of hypocalcemia in predicting poor outcome