# Adding Hyponatremia to the “Rule-of-6” Prediction Tool Improves Performance in Identifying Hospitalised Patients with COVID-19 at Risk of Adverse Clinical Outcomes

## TL;DR

Adding low sodium levels to a prediction tool improves identifying high-risk hospitalized COVID-19 patients.

## Contribution

Adding hyponatremia improves the 'rule-of-6' tool for predicting adverse outcomes in hospitalized COVID-19 patients.

## Key findings

- Hyponatremia is independently associated with adverse outcomes in hospitalized COVID-19 patients.
- Adding hyponatremia to the 'rule-of-6' increases the tool's predictive accuracy (AUC from 0.72 to 0.76).
- Hyponatremic patients had higher rates of pneumonia and adverse outcomes regardless of virus variants.

## Abstract

The ‘rule-of-6’ prediction tool was shown to be able to identify COVID-19 patients at risk of adverse outcomes. During the pandemic, we frequently observed hyponatremia at presentation. We sought to evaluate if adding hyponatremia at presentation could improve the ‘rule-of-6’ prediction tool. We retrospectively analysed 1781 consecutive patients admitted to a single tertiary academic institution in Singapore with COVID-19 infection from February 2020 to October 2021. A total of 161 (9.0%) patients had hyponatremia. These patients were significantly older, with more co-morbidities and more likely to be admitted during the Delta wave (2021). They were more likely to have radiographic evidence of pneumonia (46.0% versus 13.0%, p < 0.001) and more adverse outcomes (25.5% vs. 4.1%, p < 0.001). Hyponatremia remained independently associated with adverse outcomes after adjusting for age, lack of medical co-morbidities, vaccination status, year of admission, CRP, LDH, and ferritin. The optimised cut-off for serum sodium in predicting adverse outcomes was approximately <135 mmol/L as determined by the Youden index. Although derived in early 2020, the ‘rule-of-6’ prediction tool continued to perform well in our later cohort (AUC: 0.72, 95%CI: 0.66–0.78). Adding hyponatremia to the ‘rule-of-6’ improved its performance (AUC: 0.76, 95%CI: 0.71–0.82). Patients with hyponatremia at presentation for COVID-19 had poorer outcomes even as new variants emerged.