Hyperchloremia, not Concomitant Hypernatremia, Independently Predicts Early Mortality in Critically Ill Moderate–Severe Traumatic Brain Injury Patients



Hypernatremia has been associated with mortality in neurocritically ill patients, with and without traumatic brain injury (TBI). These studies, however, lack concomitant adjustment for hyperchloremia as a physiologically co-occurring finding despite the associations with hyperchloremia and worse outcomes after trauma, sepsis, and intracerebral hemorrhage. The objective of our study was to examine the association of concomitant hypernatremia and hyperchloremia with in-hospital mortality in moderate–severe TBI (msTBI) patients.


We retrospectively analyzed prospectively collected data from the OPTIMISM-study and included all msTBI patients consecutively enrolled between 11/2009 and 1/2017. Time-weighted average (TWA) sodium and chloride values were calculated for all patients to examine the unadjusted mortality rates associated with the burden of hypernatremia and hyperchloremia over the entire duration of the intensive care unit stay. Multivariable logistic regression modeling predicting in-hospital mortality adjusted for validated confounders of msTBI mortality was applied to evaluate the concomitant effects of hypernatremia and hyperchloremia. Internal bootstrap validation was performed.


Of the 458 patients included for analysis, 202 (44%) died during the index hospitalization. Fifty-five patients (12%) were excluded due to missing data. Unadjusted mortality rates were nearly linearly increasing for both TWA sodium and TWA chloride, and were highest for patients with a TWA sodium > 160 mmol/L (100% mortality) and TWA chloride > 125 mmol/L (94% mortality). When evaluated separately in the multivariable analysis, TWA sodium (per 10 mmol/L change: adjusted OR 4.0 [95% CI 2.1–7.5]) and TWA chloride (per 10 mmol/L change: adjusted OR 3.9 [95% CI 2.2–7.1]) independently predicted in-hospital mortality. When evaluated in combination, TWA chloride remained independently associated with in-hospital mortality (per 10 mmol/L change: adjusted OR 2.9 [95% CI 1.1–7.8]), while this association was no longer observed with TWA sodium values (per 10 mmol/L change: adjusted OR 1.5 [95% CI 0.51–4.4]).


When concomitantly adjusting for the burden of hyperchloremia and hypernatremia, only hyperchloremia was independently associated with in-hospital mortality in our msTBI cohort. Pending validation, our findings may provide the rationale for future studies with targeted interventions to reduce hyperchloremia and improve outcomes in msTBI patients.

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We thank our research patients and families for their participation in the OPTIMISM-study. We also thank Dr. Wiley Hall, Dr. Raphael Carandang, and Ms. Irina Mechikow for the assistance in the data collection of the OPTIMISM patients.


This study was supported by: NIH/NICHD 5K23HD080971 (PI: Muehlschlegel) and NIH UL1TR000161 (CTSA; PI: Luzuriaga). Dr. Muehlschlegel is supported by grants NIH/NICHD 5K23HD080971 (PI); UMass Memorial Medical Group PACE-Prize 2018 (co-PI); DARPA HR001117S0032-WASH-FP-031 (consultant).

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KLD, SM, and MLO were responsible for the study design, analysis, and interpretation of results. KLD was responsible for the writing of the manuscript. MLO, JMF and SM also contributed to writing the manuscript and critically revised the manuscript. AMW was responsible for the clinical data for patients and review of the manuscript. JMF was responsible for the statistical analysis of results. SM oversaw study design and provided expertise regarding analysis and interpretation of results. SM was responsible for the funding of the study.

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Correspondence to Kristen L. Ditch.

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This work was performed at the University of Massachusetts Medical School and its affiliated university hospital, UMass Memorial Medical Center (Worcester, MA).

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Crude mortality rates for time-weight average (TWA), peak, and mean serum sodium and chloride values. Panel A shows the crude mortality rates for TWA, peak and mean sodium values. Panel B shows the crude mortality rates for TWA, peak, and mean chloride values (TIFF 5088 kb)

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Ditch, K.L., Flahive, J.M., West, A.M. et al. Hyperchloremia, not Concomitant Hypernatremia, Independently Predicts Early Mortality in Critically Ill Moderate–Severe Traumatic Brain Injury Patients. Neurocrit Care 33, 533–541 (2020). https://doi.org/10.1007/s12028-020-00928-0

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  • Traumatic brain injury
  • Hyperchloremia
  • Hypernatremia
  • Neurocritical care
  • Mortality