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Hypernatremia and intracranial pressure: more questions than answers.
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PMID:  23294598     Owner:  NLM     Status:  Publisher    
ABSTRACT: The observational literature suggests that hypernatremia is associated with worse outcomes in patients with traumatic brain injury. In a previous issue of Critical Care, Wells and colleagues add to this literature by failing to show an association between hypernatremia and reduced intracranial pressure. However, we must bear in mind many limitations of observational methods before eliminating hyperosmolar therapy from our armamentarium.
Donald Eg Griesdale; Mypinder S Sekhon; William R Henderson
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-7
Journal Detail:
Title:  Critical care (London, England)     Volume:  17     ISSN:  1466-609X     ISO Abbreviation:  Crit Care     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9801902     Medline TA:  Crit Care     Country:  -    
Other Details:
Languages:  ENG     Pagination:  401     Citation Subset:  -    
Department of Medicine, Division of Critical Care Medicine, Vancouver General Hospital, University of British Columbia, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada.
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Journal ID (nlm-ta): Crit Care
Journal ID (iso-abbrev): Crit Care
ISSN: 1364-8535
ISSN: 1466-609X
Publisher: BioMed Central
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Copyright © 2013 BioMed Central Ltd
Print publication date: Year: 2012
Electronic publication date: Day: 7 Month: 1 Year: 2013
pmc-release publication date: Day: 7 Month: 1 Year: 2014
Volume: 17 Issue: 1
First Page: 401 Last Page: 401
PubMed Id: 23294598
ID: 4057414
Publisher Id: cc11888
DOI: 10.1186/cc11888

Hypernatremia and intracranial pressure: more questions than answers
Donald EG Griesdale123 Email:
Mypinder S Sekhon1 Email:
William R Henderson1 Email:
1Department of Medicine, Division of Critical Care Medicine, Vancouver General Hospital, University of British Columbia, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada
2Department of Anesthesia, Pharmacology and Therapeutics and Department of Medicine, Division of Critical Care Medicine, Vancouver General Hospital, University of British Columbia, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada
3Centre for Clinical Epidemiology and Evaluation, Vancouver Coastal Health Research Institute, 828 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada

In a previous issue of Critical Care, Wells and colleagues [1] report on their retrospective cohort study examining the relationship between serum sodium and intracranial pressure (ICP) with severe traumatic brain injury (TBI). This is an ongoing topic of interest to neurointensivists as hyperosmolar therapy remains a treatment option for elevated ICP [2]. We commend the authors for their contribution to a fundamentally important issue in neurocritical care; however, several issues deserve further discussion.

A critical limitation of observational methodology is confounding by indication, which exists when variables associated with exposure are also associated with outcomes in the study base [3]. Clinicians administer hyperosmolar therapy and induce hypernatremia on the basis of measured and unmeasured characteristics of patients. Lack of a formalized TBI protocol, including indications for hypertonic saline (HTS), can exacerbate this bias. For example, clinicians in the study by Wells and colleagues used both boluses and infusions of HTS with a range of administered concentrations (3% versus 7.5%). No attempt was made to adjust for differences in baseline characteristics of patients. Furthermore, although regression is an important method to help reduce bias, several assumptions must be met for the analysis to be valid. Linear regression is predicated upon independence of data. With 1,230 paired sodium and ICP measurements in 81 patients, there is likely to be marked within-subject correlation of data that is not taken into account by this analysis. Consequently, a linear mixed model or other analysis is warranted to specifically model and account for this correlation [4]. Failing to do so limits the interpretability of their results.

Authors' response

Diana L Wells, Joseph M Swanson, G Christopher Wood, Louis J Magnotti, Bradley A Boucher, Martin A Croce, Charles G Harrison, Michael S Muhlbauer and Timothy C Fabian

We thank Griesdale and colleagues for their thoughtful letter describing concerns with our study, specifically the retrospective design and statistical tests. Owing to the lack of literature supporting the benefits of HTS to induce hypernatremia in patients with TBI, we pragmatically evaluated this practice in one of the largest studies to date [1,5,6].

We agree with the limitations mentioned by Griesdale and colleagues in regard to the lack of a formalized TBI protocol and the inclusion of various doses of HTS, and we addressed this in our discussion. Importantly, patients in our study were treated with the same general approach to hyperosmolar therapy (84% of patients received 3% NaCl boluses) [1].

In regard to adjustment for baseline characteristics, we performed linear regression in important subgroups divided by baseline ICP and Glasgow Coma Scale score. Furthermore, to account for within-subject correlation of data, we conducted linear regression for each individual patient as described in Table 2 of the article. In none of the many analyses performed was there an indication of a general correlation between serum sodium and ICP [1]. Nonetheless, we agree that other statistical methods such as a linear mixed model could have possibly shed more light on these data.

Recognizing the limitations of our study is important and should serve as a call to the medical community for the need of a well-designed, prospective randomized controlled trial evaluating the use of HTS to induce hypernatremia in TBI. This is essential before we can truly include or limit this therapy as a valid option in our treatment armamentarium for these patients.


HTS: hypertonic saline; ICP: intracranial pressure; TBI: traumatic brain injury.

Competing interests

The authors declare that they have no competing interests.

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Mascha EJ,Sessler DI,Equivalence and noninferiority testing in regression models and repeated-measures designsAnesth AnalgYear: 20111767868710.1213/ANE.0b013e318206f87221304155
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