Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

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

Abstract

Background

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.

Methods

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.

Results

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]).

Conclusions

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    Aiyagari V, Deibert E, Diringer MN. Hypernatremia in the neurologic intensive care unit: How high is too high? J Crit Care. 2006;21:163–72.

  2. 2.

    Kolmodin L, Sekhon MS, Henderson WR, et al. Hypernatremia in patients with severe traumatic brain injury: a systematic review. Ann Intensive Care. 2013;3:35.

  3. 3.

    Vedantam A, Robertson CS, Gopinath SP. Morbidity and mortality associated with hypernatremia in patients with severe traumatic brain injury. Neurosurg Focus. 2017;43:E2.

  4. 4.

    Fang L, You H, Xu Z, et al. Mannitol is an independent risk factor of acute kidney injury after cerebral trauma: a case-control study. Ren Fail. 2010;32:673–9.

  5. 5.

    Yang B, Xu J, Xu F, et al. Intravascular administration of mannitol for acute kidney injury prevention: a systematic review and meta-analysis. PLoS ONE. 2014;9:e85029.

  6. 6.

    Kim MY, Park JH, Kang NR, et al. Increased risk of acute kidney injury associated with higher infusion rate of mannitol in patients with intracranial hemorrhage. J Neurosurg. 2014;120:1340–8.

  7. 7.

    Riha HM, Erdman MJ, Vandigo JE, et al. Impact of moderate hyperchloremia on clinical outcomes in intracerebral hemorrhage patients treated with continuous infusion hypertonic saline: a pilot study. Crit Care Med. 2017;45:e947–53.

  8. 8.

    Lee JY, Hong TH, Lee KW, et al. Hyperchloremia is associated with 30-day mortality in major trauma patients: a retrospective observational study. Scand J Trauma Resusc Emerg Med. 2016;24:117.

  9. 9.

    Neyra JA, Canepa-Escaro F, Li X, et al. Association of Hyperchloremia with hospital mortality in critically ill septic patients. Crit Care Med. 2015;43:1938–44.

  10. 10.

    De Vasconcellos K, Skinner DL. Hyperchloraemia is associated with acute kidney injury and mortality in the critically ill: a retrospective observational study in a multidisciplinary intensive care unit. J Crit Care. 2018;45:45–51.

  11. 11.

    Sadan O, Singbartl K, Kandiah PA, et al. Hyperchloremia is associated with acute kidney injury in patients with subarachnoid hemorrhage. Crit Care Med. 2017;45:1382–8.

  12. 12.

    Badawi O, Yeung SY, Rosenfeld BA. Evaluation of glycemic control metrics for intensive care unit populations. Am J Med Qual. 2009;24:310–20.

  13. 13.

    Muehlschlegel S, Carandang R, Ouillette C, et al. Frequency and impact of intensive care unit complications on moderate-severe traumatic brain injury: early results of the Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study. Neurocrit Care. 2013;18:318–31.

  14. 14.

    Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap): a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81.

  15. 15.

    Brain Trauma Foundation. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24:S1–106.

  16. 16.

    Carney N, Totten AM, O’Reilly C, et al. Brain trauma foundation, american association of neurological surgeons joint section on neurotrauma and critical care: guidelines for the management of severe trauma brain injury, fourth Edition. Neurosurgery. 2017;80:6–15.

  17. 17.

    Darmon M, Diconne E, Souweine B, et al. Prognostic consequences of borderline dysnatremia: pay attention to minimal serum sodium change. Crit Care. 2013;17(1):R12.

  18. 18.

    Tsipotis E, Price LL, Jaber BL, et al. Hospital-associated hypernatremia spectrum and clinical outcomes in an unselected cohort. Am J Med. 2018;131(1):72–82.

  19. 19.

    Kellum JA, Lameire N, Aspelin P, et al. Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2012;2:1–138.

  20. 20.

    Lopes JA, Jorge S. The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review. Clin Kidney J. 2013;6(1):8–14.

  21. 21.

    Steyerberg EW, Mushkudiani N, Perel P, et al. Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med. 2008;5:e165.

  22. 22.

    Austin PC, Steyerberg EW. Events per variable (EPV) and the relative performance of different strategies for estimating the out-of-sample validity of logistic regression models. Stat Methods Med Res. 2017;26:796–808.

  23. 23.

    Gönen M. Analyzing Receiver Operating Characteristic Curves with SAS®. SAS Institute Inc., 2007. https://epdf.pub/analyzing-receiver-operating-characteristic-curves-with-sasc627d717a106b83b202f0dc5f73caff182822.html.

  24. 24.

    Gönen M. SAS macro: bootstrapping validation. Accessed 26 Nov 2019. https://www.listendata.com/2015/01/model-validation-in-logistic-regression.html.

  25. 25.

    Berry WD, Feldman S. Quantitative applications in the social sciences: multiple regression in practice. Thousand Oaks, CA: SAGE Publications Inc.; 1985.

  26. 26.

    Suetrong B, Pisitsak C, Boyd JH, et al. Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients. Crit Care. 2016;20:315.

  27. 27.

    Boniatti MM, Cardoso PR, Castilho RK, et al. Is hyperchloremia associated with mortality in critically ill patients? A prospective cohort study. J Crit Care. 2011;26:175–9.

  28. 28.

    McCluskey SA, Karkouti K, Wijeysundera D, et al. Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg. 2013;117:412–21.

  29. 29.

    Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71:726–35.

  30. 30.

    Todd SR, Malinoski D, Muller PJ, et al. Lactated Ringer’s is superior to normal saline in the resuscitation of uncontrolled hemorrhagic shock. J Trauma. 2007;62:636–9.

  31. 31.

    Kiraly LN, Differding JA, Enomoto TM, et al. Resuscitation with normal saline (NS) vs. lactated ringers (LR) modulates hypercoagulability and leads to increased blood loss in an uncontrolled hemorrhagic shock swine model. J Trauma. 2006;61:57–64.

  32. 32.

    Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308:1566–72.

  33. 33.

    Williams EL, Hildebrand KL, McCormick SA, et al. The effect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg. 1999;88:999–1003.

  34. 34.

    Scheingraber S, Rehm M, Sehmisch C, et al. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology. 1999;90:1265–70.

  35. 35.

    Grinnon ST, Miller K, Marler JR, et al. National Institute of Neurological Disorders and Stroke Common Data Element Project: approach and methods. Clin Trials. 2012;9(3):322–9.

  36. 36.

    Clifton GL, Miller ER, Choi SC. Fluid thresholds and outcome from severe brain injury. Crit Care Med. 2002;30:739–45.

  37. 37.

    Fletcher JJ, Bergman K, Blostein PA, et al. Fluid balance, complications, and brain tissue oxygen tension monitoring following severe traumatic brain injury. Neurocrit Care. 2010;13:47–56.

  38. 38.

    Jeremitsky E, Omert LA, Dunham CM, et al. The impact of hyperglycemia on patients with severe brain injury. J Trauma. 2005;58:47–50.

  39. 39.

    Coester A, Neumann CR, Schmidt MI. Intensive insulin therapy in severe traumatic brain injury: a randomized trial. J Trauma. 2010;68:904–11.

  40. 40.

    Oddo M, Schmidt JM, Carrera E, et al. Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study. Crit Care Med. 2008;36:3233–8.

  41. 41.

    Jacobi J, Bircher N, Krinsley J, et al. Guidelines for the use of an insulin infusion for the management of hyperglycemia in critical ill patients. Crit Care Med. 2012;40:3251–76.

  42. 42.

    Mukaka M, White SA, Terlouw DJ, et al. Is using multiple imputation better than complete case analysis for estimating a prevalence (risk) difference in randomized controlled trials when binary outcome observations are missing? Trials. 2016;17:341.

  43. 43.

    Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials: a practical guide with flowcharts. BMC Med Res Methodol. 2017;17:162.

  44. 44.

    Groenwold RH, Moons KG, Vandenbroucke JP. Randomized trials with missing outcome data: how to analyze and what to report. CMAJ. 2014;186:1153–7.

  45. 45.

    National Research Council. The prevention and treatment of missing data in clinical trials. Washington, D.C.: The National Academies Press; 2010.

  46. 46.

    Hadjizacharia P, Beale EO, Inaba K, et al. Acute diabetes insipidus in severe head injury: a prospective study. J Am Coll Surg. 2006;207:477–84.

Download references

Acknowledgments

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.

Funding

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).

Author information

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.

Correspondence to Kristen L. Ditch.

Ethics declarations

Conflict of Interest

The remaining authors have disclosed that they do not have any conflicts of interest.

Ethical approval/Informed consent

This work was performed in adherence to ethical guidelines and was approved by UMass Memorial Medical Center IRB.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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 (2020). https://doi.org/10.1007/s12028-020-00928-0

Download citation

Keywords

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