key: cord-0966815-q91h510l
authors: Tzoulis, Ploutarchos; Waung, Julian A; Bagkeris, Emmanouil; Hussein, Ziad; Biddanda, Aiyappa; Cousins, John; Dewsnip, Alice; Falayi, Kanoyin; McCaughran, Will; Mullins, Chloe; Naeem, Ammara; Nwokolo, Muna; Quah, Helen; Bitat, Syed; Deyab, Eithar; Ponnampalam, Swarupini; Bouloux, Pierre-Marc; Montgomery, Hugh; Baldeweg, Stephanie E
title: Dysnatremia is a predictor for morbidity and mortality in hospitalized patients with COVID-19
date: 2021-02-24
journal: J Clin Endocrinol Metab
DOI: 10.1210/clinem/dgab107
sha: 2f90e89f8834690cbbb47a3ecf10058f101d9da2
doc_id: 966815
cord_uid: q91h510l

BACKGROUND: Dysnatremia is an independent predictor of mortality in patients with bacterial pneumonia. There is paucity of data about the incidence and prognostic impact of abnormal sodium concentration in patients with coronavirus disease 19 (COVID-19). METHODS: This retrospective longitudinal cohort study, including all adult patients who presented with COVID-19 to two hospitals in London over an 8-week period, evaluated the association of dysnatremia (serum sodium < 135 or > 145 mmol/L, hyponatremia and hypernatremia, respectively) at several timepoints with inpatient mortality, need for advanced ventilatory support and acute kidney injury (AKI). RESULTS: The study included 488 patients (median age 68 years). At presentation, 24.6% of patients were hyponatremic, mainly due to hypovolemia, and 5.3% hypernatremic. Hypernatremia two days after admission and exposure to hypernatremia at any timepoint during hospitalization were associated with a 2.34-fold (95% CI 1.08 – 5.05, p=0.0014) and 3.05-fold (95% CI 1.69 – 5.49, p<0.0001), respectively, increased risk of death compared to normonatremia. Hyponatremia at admission was linked with a 2.18-fold increase in the likelihood of needing ventilatory support (95% CI 1.34-3.45, p= 0.0011). Hyponatremia was not a risk factor for in-hospital mortality, except for the subgroup of hypovolemic hyponatremia. Sodium values were not associated with the risk for AKI and length of hospital stay. CONCLUSION: Abnormal sodium levels during hospitalization are risk factors for poor prognosis, with hypernatremia and hyponatremia being associated with a greater risk of death and respiratory failure, respectively. Serum sodium values could be used for risk stratification in patients with COVID-19.

The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represents the greatest global public health crisis of this generation 1 . Risk stratification at the time of hospital presentation is essential in order to allow early identification of patients at high risk of death and effective allocation of health resources 2 3 4 5 . Older age, male sex, Black or Asian ethnicity, and the presence of diabetes mellitus, obesity or ischemic heart disease (IHD) are well-established risk factors for excess mortality in COVID-19 6 7 8 9 . Elevated biomarkers, such as white cell count, neutrophil count, C-reactive protein (CRP), urea, creatinine, transaminases, cardiac troponin I and D-dimer, as well as low lymphocyte count and hypoalbuminemia are associated with excess in-hospital mortality 10 11 12 . Recent studies have added elevated serum cortisol 13 and hyperglycemia 14 at admission as independent predictors of mortality in patients with Hypernatremia (serum sodium > 145 mmol/L) and hyponatremia (serum sodium < 135 mmol/L) are independent risk factors for excess mortality in hospitalized patients 15 16 17 18 19 20 . Hypernatremia is rare among patients with communityacquired pneumonia (CAP), but can occur when significant renal water loss is corrected with too little water or relatively hypertonic fluids 15 and is independently associated with mortality 21 . Hyponatremia is the most common electrolyte abnormality in patients with bacterial pneumonia, is usually attributed to the syndrome of inappropriate antidiuresis (SIAD) or hypovolemia, and predicts poor outcome 21 22 23 24 . Infection can cause excess release of pro-inflammatory A c c e p t e d M a n u s c r i p t 6 cytokines, such as interleukin-1β (IL-1β) and interleukin-6 (IL-6), which induce nonosmotic release of arginine vasopressin (AVP), causing hyponatremia due to SIAD 25 26 . Therefore, hyponatremia is a good surrogate marker of the degree of inflammatory response, reflecting the severity of various infections 27 . Neither the extent to which the relationship between hyponatremia and poor outcome is causal, nor the impact of correcting serum sodium, are known 28 29 .

Recent observational data suggest that hyponatremia is common in COVID-19 patients on hospital admission and associated with poor clinical outcome 30 31 32 .

However, longitudinal data such as ours remain lacking. Our primary objective was to examine the association of serum sodium during hospitalization with key clinical outcomes, including mortality, need for advanced respiratory support and Acute Kidney Injury (AKI). Our secondary objective was to explore the role of serum sodium as a marker of inflammatory response in COVID-19, by evaluating the longitudinal relationship between sodium and CRP concentration.

This retrospective longitudinal cohort study was undertaken in two inner city hospitals in London, the Whittington Hospital (hospital A) and University College London Hospital NHS Foundation Trust, UCLH (hospital B). The study was approved by the governance team and institutional ethics board of hospitals A and B, respectively. The study included all consecutive patients aged 16 years or older who were admitted to hospitals A and B between February and May 2020 and who had a A c c e p t e d M a n u s c r i p t 7 positive real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 on nasopharyngeal swab or other specimen.

Data were obtained from electronic medical records, pathology records and discharge summaries. Demographic characteristics, comorbidities, hematological and biochemical laboratory results on admission, radiological findings, and data relating to respiratory, cardiological and renal complications was collected. Results of four biochemical variables (serum sodium, urea, creatinine and CRP) were collected longitudinally on the day of presentation (day 1), on day 3 (± 24 hours), on day 6 (± 24 hours), on day 11 (± 48 hours), on day 18 (± 48 hours), as well as on the day of admission to intensive care unit (ICU), the day of lowest and highest serum sodium concentration, and on the day of the last sodium measurement within 48 hours prior to discharge or death. The change in serum sodium between day 6 and day 1 was defined as 5-day delta sodium and was divided into four groups (≤ -3, -2 to +2, +3 to +7 and ≥ +8 mmol/L), according to the magnitude of change. Main outcome measures were inpatient mortality, need for advanced respiratory support, defined as continuous positive airway pressure (CPAP) or intubation and invasive mechanical ventilation (IMV), and AKI.

When blood glucose exceeded 10 mmol/L on presentation, serum sodium concentration was corrected for hyperglycemia. For glucose values between 10-22.1 mmol/L or ≥ 22.2 mmol/L, we used a correction factor of a 1.6 or 2.4 mmol/L, respectively, decrease in sodium concentration per 5.6 mmol/L increase in glucose value above 10 mmol/L 33 . Serum sodium was measured on days 1, 3, 6, 11, 18 to A c c e p t e d M a n u s c r i p t 8 determine changes to sodium status longitudinally. Accordingly, serum sodium status was stratified into 3 categories: 135-145 mmol/L, normal as per the laboratory reference ranges; <135 mmol/L (hyponatremia) and >145 mmol/L (hypernatremia).

Hyponatremia was further classified into mild (130-134 mmol/L) and moderate to severe (<130 mmol/L) 34 .

Chronic kidney disease (CKD) prior to admission was defined as the most recent estimated glomerular filtration rate (eGFR) within 12 months pre-admission at <60 ml/min. A diagnosis of chronic hyponatremia was established if the last sodium value within 12 months pre-admission was <135 mmol/L. AKI was diagnosed and classified based on Kidney Disease: Improving Global Outcomes (KDIGO) definitions using the peak creatinine during hospitalization and last creatinine value pre-admission 35 . The etiology of hyponatremia was ascertained through the results of laboratory investigations, including serum osmolality, spot urinary osmolality and sodium, serum cortisol and thyrotropin 36 . In the absence of those data, plasma urea was used to discriminate euvolemic from hypovolemic hyponatremia since plasma urea value > 5 mmol/L has a predictive power of 80% for hypovolemic hyponatremia, while urea < 5 mmol/L indicates euvolemic hyponatremia in 80% of patients 37 .

Characteristics of the patients were expressed in frequencies and percentages when categorical and in median and interquartile range (IQRs) when continuous. Kaplan Meier survival curves were produced for serum sodium on day 3 of hospitalization as well as for exposure to abnormal sodium at any point during hospitalization.

Pearson's Chi-square test was used to compare mortality rates between 5-day delta sodium groups as well as rates of death, respiratory support and AKI between A c c e p t e d M a n u s c r i p t 9 longitudinal sodium status groups. Mann Whitney test was used to study the association of serum sodium concentrations on day 1, 3, 6, 11 or 18 with survival rate, need for advanced respiratory support, and AKI. Mann Whitney test with Bonferroni correction was used to study the association between laboratory results at presentation with survival. Cox proportional hazard models with time varying covariates were used to assess the association of sodium concentrations at day 1, 3 and 6 with in-hospital death. A-priori confounders considered in the multivariable analysis were: age, gender, ethnicity, smoking status, number of comorbidities, urea and CRP levels. The Friedman test was used to assess the change of sodium and urea over time and the Pearson correlation coefficient assessed their relationship.

Univariable linear mixed effect models were used to explore whether the levels of sodium and urea during hospitalization were significantly different between the group of survivors and non-survivors. P-value < 0.05 was considered statistically 

This study included 488 patients, 277 males (56.8%) and 211 females (43.2%), with a median age of 68 years ( Table 1 ). The commonest comorbidities were hypertension (45.7%), diabetes mellitus (25%), CKD (16.4%), asthma (11.9%), IHD (11.3%), cerebrovascular disease (8.6%), arrhythmia (8.6%), active cancer (8%), and chronic obstructive pulmonary disease (COPD) (8%). According to the most recent sodium levels preceding hospital admission, 5.1% of individuals had pre-A c c e p t e d M a n u s c r i p t 10 existing hyponatremia. Increased mortality was associated with advanced age, male gender, smoking, pre-existing CKD, chronic hyponatremia and the presence of active malignancy. Non-survivors had significantly higher concentrations of BUN, creatinine, CRP and troponin, but lower concentrations of lymphocyte count and albumin compared to survivors.

At hospital presentation, 26 individuals (5.3%) had hypernatremia with a median plasma urea value of 12.4 mmol/L. The incidence of hyponatremia at the time of hospital presentation was higher at 24.6%, including 18.4% with mild and 6.2% moderate to severe hyponatremia, with a median urea concentration of 5.6 mmol/L.

Only 19% of patients with serum sodium < 130 mmol/L underwent appropriate laboratory work-up for the etiology of hyponatremia. Of those, based on urinary sodium cut-off of 30 mmol/L, three quarters were classified as hypovolemic hyponatremia and one quarter as non-hypovolemic hyponatremia. For the remaining hyponatremic cases, using the cut-off value of 5 mmol/L for urea concentration, 55.7% were classified as probable hypovolemic and 44.3% non-hypovolemic hyponatremia.

Serum sodium at presentation did not differ between survivors (median, IQR) (137, 135-140 mmol/L) and non-survivors (138, 134-141 mmol/L). Stratified by sodium status at admission, the mortality rate for normonatremic, hyponatremic and hypernatremic patients was 28.4%, 30.8% and 46.1%, respectively. Those results indicated a strong trend towards higher mortality rate in patients with baseline A c c e p t e d M a n u s c r i p t 11 hypernatremia, despite the difference not being statistically significant (p=0.07).

Among 120 patients who presented with hyponatremia, 31 individuals who either had only one measurement of serum sodium or developed at any stage hypernatremia were excluded in order to assess the impact of normalization of hyponatremia on patient outcomes. Comparison of 54 hyponatremic patients who had their sodium corrected with 35 patients who remained persistently hyponatremic did not show a significant difference in the in-hospital mortality rate (25.9 % versus 31.4 %, p=0.57).

Multivariable analysis identified three independent risk factors for higher in-hospital mortality; older age (adjusted hazard ratio=1.04, 95% CI 1.01 -1.07, p=0.007), higher CRP concentrations (adjusted hazard ratio=1.10 per 20 mg/l, 95% CI 1.04 -1.17, p<0.001), and hypernatremia at any time point during the first five days of hospitalization (adjusted hazard ratio=2.74, 95% CI 1.16 -6.40), p=0.02) ( Table 2) .

Hypernatremia on day 3 and on day 6 predicted mortality with an estimated hazard ratio of 2.34 (95% CI 1.08 -5.05, p=0.0014) and 2.40 (95% CI 1.18 -4.85, p=0.0011), respectively, whereas hyponatremia was not associated with death ( Figure 1) .

A longitudinal analysis of sodium data during hospital stay classified patients into four groups; 37.9% of patients remained normonatremic throughout hospitalization, 36 .9% had exposure to hyponatremia, 10.9% were exposed to hypernatremia, and 14.3% experienced both hypernatremia and hyponatremia. The in-hospital mortality rate of patients who remained continuously normonatremic was 21.1%. Exposure to hypernatremia or both hypernatremia and hyponatremia were associated with significantly increased mortality rate of 56.6% (p<0.0001, odds ratio 3.05, 95% CI 1.69-5.49) and 45.7% (p=0.0038, odds ratio 2.25, 95% CI 1.33-3.82) respectively, A c c e p t e d M a n u s c r i p t 12 compared to normonatremia ( Figure 2 ). Finally, patients exposed to hyponatremia had a mortality rate of 28.3% which was not significantly different compared to that of normonatremic individuals (p=0. 16 

There was a progressive rise in median (IQR) serum sodium levels during highest mortality rate was observed in patients with the largest 5-day increase in sodium (≤ -3 mmol/L, 34.5%; -2 to +2 mmol/L, 17.5%; +3 to +7 mmol/L, 26.3%; ≥ 8 mmol/L, 54.8%; p <0.005). The value of the last serum sodium measurement prior to discharge or death was significantly higher in non-survivors compared to survivors (141 vs 139 mmol/L, p < 0.005), with a 29.6% rate of hypernatremia in non-survivors compared to 5.2% in survivors.

Hyponatremia is a prognostic factor for respiratory support, but not for length of stay and AKI Among 120 patients with hyponatremia at admission, 31.7% received advanced respiratory support compared to 17.5% and 7.7% of those with normonatremia or hypernatremia, respectively. Therefore, hyponatremia at admission is linked with a 2fold increase in the likelihood of needing ventilatory support (p= 0.0011, odds ratio 2.18, 95% CI 1.34-3.46). The median serum sodium on presentation was significantly lower in patients who required CPAP or IMV (136 mmol/L) than in those who did not (138 mmol/L); p < 0.01. Of note, hypernatremia was not associated with an increased likelihood to need respiratory support, since the percentage of patients 

This retrospective longitudinal cohort study of 488 inpatients with COVID-19 demonstrated a high prevalence for abnormal sodium of 29.9% at admission and 62.1% at any stage during hospitalization. Admission hyponatremia was common with an incidence of 24.6% and was usually classified as hypovolemic hyponatremia.

Both hypernatremia and hyponatremia were risk factors for poor prognosis.

Hypernatremia at any timepoint during hospitalization was a predictor of excess inpatient mortality. All types of hyponatremia were associated with significantly A c c e p t e d M a n u s c r i p t 15 increased risk for needing advanced ventilatory support, with hypovolemic hyponatremia also being a risk factor for in-hospital mortality.

The key novel finding of our study was that hospital-acquired hypernatremia, rather than hypernatremia at admission, was a predictor for in-hospital mortality, with the worst prognosis being reported in patients with the largest increase in serum sodium in the first 5 days of hospitalization. Hypernatremia reflects a deficit of total body water relative to total body sodium and is often accompanied by reduced extracellular fluid volume 38 With respect to the prognostic impact of low serum sodium in COVID-19, this study showed that hyponatremia at hospital presentation was related to an increased likelihood to require advanced ventilatory support, consistent with the findings in other COVID-19 studies 30 31 and studies in patients with CAP 39 . The prognostic value A c c e p t e d M a n u s c r i p t 16 of hyponatremia might reflect a direct pathogenic impact, or association with increasing disease severity. Contrary to the independent association of hyponatremia with mortality in CAP 21 23 24 , our study did not identify hyponatremia as a predictor of mortality in patients with COVID-19. However, in agreement with recent studies in general hospital populations 40 41 , our data confirmed hypovolemic hyponatremia as a risk factor for excess mortality. This might be mediated through more severe disease in the former group, for instance, affecting salt-water loss through sweat or decreased dietary sodium intake in the context of insufficient water intake, or through the impacts of hypovolemia on circulatory homeostasis and endorgan function.

Interestingly, occurrence at hypernatremia at any time point during hospitalization was not associated with the need for advanced respiratory support. The contradictory findings in our cohort that patients with hypernatremia were more likely to die without greater use of advanced ventilatory support, while those with hyponatremia required more often respiratory support without having increased mortality, might be explained by selection bias. Hypernatremic patients might include the oldest and most frail who were not eligible for advanced ventilatory support. In contrast, patients with hyponatremia might be critically ill, but younger and with fewer comorbidities, and therefore responded to ventilatory support and survived.

Our study confirmed that AKI is common in inpatients with COVID-19, with a recorded prevalence of 36.9% prevalence, similar to the 36.6% in a large New York cohort 42 . Since hypovolemia often contributes to development of AKI, it is surprising that abnormal serum sodium value was not a risk factor for AKI. Contrary to the wellestablished association of dysnatremia with length of hospitalization in CAP 21 43 , our A c c e p t e d M a n u s c r i p t 17 study did not find any association between sodium levels and length of stay in COVID-19 patients.

Our longitudinal analysis of the potential link between sodium status and CRP levels did not find the inverse association which was observed in other inflammatory conditions 25 26 44 . Two recent studies in patients with COVID-19 showed a significant relationship between elevated IL-6 levels and hyponatremia 30 The main strength of this study is its longitudinal design, while all other observational studies have reported only admission data 30 31 32 . Furthermore, this is the only study A c c e p t e d M a n u s c r i p t 18 which has evaluated the role of both hyponatremia and hypernatremia and has also collected data about the trajectory of natremia in combination with hydration status and inflammatory markers in order to explore their complex interaction. This study has several limitations. Firstly, the lack of electronic health records did not allow the authors to have detailed knowledge of medical treatment and fluid resuscitation strategies during hospitalization. Secondly, the lack of information about volume status and inadequate laboratory work-up did not allow us to accurately ascertain the etiology of hyponatremia. Thus, our population was heterogeneous, not allowing us to evaluate separately the impact of each subtype of hyponatremia on outcomes, which can differ substantially 40 . In addition, our study did not include a control group of non-COVID-19 patients presenting with pneumonia, not allowing a direct comparison of the impact of hyponatremia between patients with and without COVID-19. Finally, the generalizability of some findings might be limited by the fact that our study took place in a time period characterized by unprecedented pressure on healthcare resources and little available knowledge about COVID-19.

Hypernatremia at any timepoint during hospital stay is related to excess in-hospital mortality, while hyponatremia at presentation is associated with a higher likelihood to require advanced ventilatory support. Hyponatremia was not a risk factor for inhospital mortality, except for the subgroup of hypovolemic hyponatremia. Therefore, serum sodium values could be used in clinical practice to identify patients with COVID-19 at high risk of poor outcomes who would benefit from more intensive monitoring and judicious rehydration. M a n u s c r i p t 23 Tables   Table 1 -Patient characteristics at presentation   Table 2 Values for survivors are colored in green and for non-survivors in red.

The blue dotted lines show the upper and the lower reference limit for each parameter.

The magnitude of serum sodium increase was larger in non-survivors than in survivors.

The trajectory of serum urea was similar in survivors and non-survivors.

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