Hyponatremia, Inflammation at Admission, and Mortality in Hospitalized COVID-19 Patients: A Prospective Cohort Study

Juan Carlos Ayus, Armando Luis Negri, Michael L Moritz, Kyung Min Lee, Daniel Caputo, Maria Elena Borda, Alan S Go, Carlos Eghi, Juan Carlos Ayus, Armando Luis Negri, Michael L Moritz, Kyung Min Lee, Daniel Caputo, Maria Elena Borda, Alan S Go, Carlos Eghi

Abstract

Background: Systemic inflammation has been associated with severe coronavirus disease 2019 (COVID-19) disease and mortality. Hyponatremia can result from inflammation due to non-osmotic stimuli for vasopressin production. Methods: We prospectively studied 799 patients hospitalized with COVID-19 between March 7 and November 7, 2020, at Hospital Posadas in Buenos Aires, Argentina in order to evaluate the association between hyponatremia, inflammation, and its impact on clinical outcomes. Admission biochemistries, high-sensitivity C-reactive protein (hsCRP), ferritin, patient demographics, and outcome data were recorded. Outcomes (within 30 days after symptoms) evaluated included ICU admission, mechanical ventilation, dialysis-requiring acute kidney injury (AKI), and in-hospital mortality. Length of hospital stay (in days) were evaluated using comprehensive data from the EHR. Results: Hyponatremia (median Na = 133 mmol/L) was present on admission in 366 (45.8%). Hyponatremic patients had higher hsCRP (median 10.3 [IR 4.8-18.4] mg/dl vs. 6.6 [IR 1.6-14.0] mg/dl, p < 0.01) and ferritin levels (median 649 [IQR 492-1,168] ng/dl vs. 393 [IQR 156-1,440] ng/dl, p = 0.02) than normonatremic patients. Hyponatremia was associated with higher odds of an abnormal hsCRP (unadjusted OR 5.03, 95%CI: 2.52-10.03), and remained significant after adjustment for potential confounders (adjusted OR 4.70 [95%CI: 2.33-9.49], p < 0.01). Hyponatremic patients had increased mortality on unadjusted (HR 3.05, 95%CI: 2.14-4.34) and adjusted (HR 2.76, 95%CI:1.88-4.06) in Cox proportional hazard models. Crude 30-day survival was lower for patients with hyponatremia at admission (mean [SD] survival 22.1 [0.70] days) compared with patients who were normonatremic (mean [SD] survival 27.2 [0.40] days, p < 0.01). Conclusion: Mild hyponatremia on admission is common, is associated with systemic inflammation and is an independent risk factor for hospital mortality. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT04493268.

Keywords: C-reactive protein; COVID-19; hyponatremia; inflammation; mortality.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Ayus, Negri, Moritz, Lee, Caputo, Borda, Go and Eghi.

Figures

Figure 1
Figure 1
Cohort assembly of eligible patients hospitalized for COVID-19.
Figure 2
Figure 2
Relationship between plasma sodium and the Charlson comorbidity index. (A) Scatterplot of the Charlson comorbidity index according to the plasma sodium (Spearman test: rho = 0.21; p < 0.01). (B) Boxplot of the Charlson comorbidity index according to severity of hyponatremia, group 1 ≤ 126 mEql/L, group 2 = 126–130 mEq/L and group 3 = 131–135 Eq/L (Kruskal-Wallis test: p < 0.01).
Figure 3
Figure 3
Thirty-day in-hospital mortality between COVID-19 patients at admission with or without hyponatremia.
Figure 4
Figure 4
Adjusted model by age and comorbidities.
Figure 5
Figure 5
Adjusted model by Charlson score and comorbidities.
Figure 6
Figure 6
Sensitivity analysis.

References

    1. Renn LL, Wang YM, Wu ZQ, Xiang ZC, Guo L, Xu T, et al. . Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study. Chin Med J. (2020) 133:1015–24. 10.1097/CM9.0000000000000722
    1. Ye Q, Wang B, Mao J. The pathogenesis and treatment of cytokine storm in covid 19. J Infect. (2020) 80:607–13. 10.1016/j.jinf.2020.03.037
    1. Li H, Liu L, Zhang D, Xu J, Dai H, Tang N, et al. . SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. (2020) 395:1517–20. 10.1016/S0140-6736(20)30920-X
    1. Mustafa MI, Abdelmoneim AH, Mahmoud EM, Makhawi AM. Cytokine storm in COVID-19 patients, its impact on organs and potential treatment by QTY code-designed detergent-free chemokine receptors. Mediat Inflamm. (2020) 2020:1–7. 10.1155/2020/8198963
    1. He L, Ding Y, Zhang Q, Che X, He Y, Shen H, et al. . Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE21 cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J Pathol. (2006) 210:288–97. 10.1002/path.2067
    1. Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, et al. . Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically ill patients with coronavirus disease 2019. Clin Infect Dis. (2020). 71:1937–42. 10.1093/cid/ciaa449
    1. Potasso L, Sailer CO, Blum CA, Cesana-Nigro N, Schuetz P, Mueller B, et al. . Mild to moderate hyponatrtemia at discharge is associated with increased risk of recurrence in patients with community-acquired pneumonia. Eur J intern Med. (2020) 75:44–9. 10.1016/j.ejim.2019.12.009
    1. Nair V, Niederman MS, Masani N, Fishbane S. Hyponatremia in community-acquired pneumonia. Am J Nephrol. (2007) 27:184–90. 10.1159/000100866
    1. Swart RM, Hoorn EJ, Betjes MG, Zietse R. Hyponatremia and inflammation: the emerging role of interleukin-6 in osmoregulation. Nephron Physiol. (2011) 118:45–51. 10.1159/000322238
    1. Corona G, Giuliani C, Parenti G, Norello D, Verbalis JG, Fortu G, et al. . Moderate hiponatremia is associated with increased risk of mortality: evidence of a meta-analysis. PLoS ONE. (2013) 8:e80451. 10.1371/journal.pone.0080451
    1. Akbar MR, Pranata R, Wibowo A. Irvan, Shite TA, Martha JW. Prognostic value of Hyponatremia for predicting poor outcomes in patients with COVID-19: a systematic review and meta-analysis. Front Med. (2021) 8:6669–49. 10.3389/fmed.2021.666949
    1. Ruiz-Sanchez JG, Nuñez-Gil IJ, Cuesta M, Rubio MA, Maroun-Eid C, Arroyo-Espliguero R, et al. . Prognostic impact of hiponatremia and hipernatremia in COVID-19 pneumonia. A HOPE-COVID-19 (health outcome predictive evaluation for COVID-19) registry analysis. Front Endocrinol. (2020) 11:599255. 10.3389/fendo.2020.599255
    1. De Carvalho H, Letellier T, Karakachoff M, Desvaux G, Caillon H, Papuchon E, et al. . Hyponatremia is associated with poor outcome in COVID-19. J Nephrol. (2021). 34:991–8. 10.1007/s40620-021-01036-8
    1. Hirsch JS, Uppal NN, Sharma P, Khanin Y, Shah HH, Malieckal DA, et al. . Prevalence and outcomes of hyponatremia and hypernatremia in patients hospitalized with COVID-19. Nephrol Dial Transplant. (2021) 36:1135–8. 10.1093/ndt/gfab067
    1. Berni A, Malandrino D, Corona G, Maggi M, Parenti G, Fibbi B, et al. . Serum sodium alterations in SARS CoV-2 (COVID 19) infection: impact on patient outcome. Eur J Endocrinol. (2021) 185:137–44. 10.1530/EJE-20-1447
    1. Duan J, Wang X, Chi J, Chen H, Bai L, Hu Q, et al. . Correlation between the variables collected at admission and progression to severe cases during hospitalization among patients with COVID-19 in Chongqing. J Med Virol. (2020) 92:2616–22. 10.1002/jmv.26082
    1. Ruuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia. Lancet. (2011) 377:1264–75. 10.1016/S0140-6736(10)61459-6
    1. Viasus D, Marinescu C, Villoslada A, Cordero E. Gálvez- Acebal J, et al. Community-acquired pneumonia during the first post-pandemic influenza season. A prospective, multicentre cohort study. J Infect. (2013) 67:185–93. 10.1016/j.jinf.2013.05.006
    1. Karki L, Thapa B, Sah MK. Hyponatremia in patients with community acquired pneumonia. J Nepal Med Assoc. (2016) 54:67–71. 10.31729/jnma.2821
    1. Oliveira DB, Durigon EL, Carvalho AC, Leal AL, Souza TS, Thomazelli LM, et al. . Epidemiology and genetic variability of human metapneumovirus during a 4-year long study in southeastern Brazil. J Med Virol. (2009) 81:915–21. 10.1002/jmv.21436
    1. Xu X, Sun Z, Liu J, Zhang J, Liu T, Mu X, et al. . Analysis and clinical features and early warning indicators of death from severe fever with thrombocytopenia syndrome. Int J Infect Dis. (2018) 73:43–8. 10.1016/j.ijid.2018.05.013
    1. Basaran S, Yavuz SS, Sakurai M, Kato J, Tokoyama T, Koda Y, et al. . Hyponatremia is predictive of HSV-1 encephalitis among patients with viral encephalitis. Tohoku J Exp Med. (2018) 247:198–195. 10.1620/tjem.247.189
    1. Van Griensen J, Bah El, Haba N, Delamou A, Camara BS, Olivier KJ-J, et al. . Electrolyte and metabolic disturbances in Ebola patients during a clinical trial guinea. Emerg Infect Dis. (2015) 22:2120. 10.3201/eid2212.161136
    1. Caputo D, Negri AL, Eghi C, Ayus JC. Prevalence of hyponatremia in dengue infected patients. In: Abstract TH-PO1116. American Society of Nephrology Kidney Week. New Orleans, LA (2017).

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner