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SGEM#150: Hypertonic Saline for Traumatic Brain Injury

SGEM#150: Hypertonic Saline for Traumatic Brain Injury

Podcast Link: SGEM150

Date: March 24th, 2016

Guest Skeptic: Dr. Chris Bond. Chris is an emergency physician and clinical lecturer at the University of Calgary. He is currently the host of CAEP Casts, which highlights educational innovations from emergency medicine residency programs across Canada. Chris also has his own #FOAMed blog called Standing on the Corner Minding My Own Business (SOCMOB).

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Dr. Elyse Pelletier

Lead Author: Dr. Elyse Pelletier. Elyse works at the Centre de Recherche CHU de Québec, Population Health and optimal Health Practices Unit. She is also in the Department of Family and Emergency Medicine, Université Laval, Québec, QC, Canada.

Case: A 21-year-old male is standing on the corner, minding his own business (SOCMOB) when he is hit in the head with a bat and suffers a severe traumatic brain injury. He is brought into the trauma room and appears to have an isolated head injury. He does not open his eyes to pain, does not speak, and he withdraws to painful stimuli. His Glasgow Coma Score is 6 and after intubating him, his left pupil is sluggish and 5 mm while his right is 3 mm and reactive. You decide to give a hyperosmolar solution for his suspected increased intracranial pressure (ICP) while he is being transported to the CT scanner. You ask for a bag of mannitol, but someone asks whether hypertonic saline will be more effective for this patient?

Background: Severe traumatic brain injury (TBI) is associated with a high morbidity and mortality and is a common injury seen in Canada (Turgeon et al and Zygun et al). In severe cases, increased intracranial pressure (ICP) may happen and generate secondary cerebral injuries following decreased cerebral perfusion pressure and ischemia. Increased ICP is strongly associated with mortality and unfavorable neurological outcomes (Giulioni and Ursino).

  • Several interventions have been proposed to manage ICP:
    • Cerebrospinal Fluid Drainage (Bullock et al) – This is basically where an external ventricular drain is inserted into one of the ventricles of the brain to drain off CSF when the ICP is increasing.
    • Decompressive Craniectomy (Bullock et al) –  This removes a piece of skull to allow the swollen brain to expand and thus reduce ICP.
    • Barbiturate Coma (Guidelines) – This is a last ditch effort when all other medical and surgical therapies have failed. Barbiturates are postulated to decrease ICP by a number of mechanisms such as lowering vascular tone and cerebral metabolism. Unfortunately, the RCTs of barbiturate comas were all done in the 80s, when standard care was prolonged hyperventilation, fluid restriction and steroids.

One therapeutic intervention to treat increased ICP is the use of hyperosmolar solutions. Mannitol is the most frequently administered hyperosmolar solutions and is the solution recommended by the clinical practice guidelines (Guidelines). Mannitol is considered the gold standard for hyperosmolar therapy in the treatment of ICP (Guidelines, Brown et al,  and Sakowitz et al).

Recently, hypertonic saline solutions have been receiving support in treatment of increased ICP in TBI because of their volume expansion properties and osmotic effect (Mattox et al).

Clinical Question: What are the clinical benefits and harms associated with the use of hypertonic saline when compared to any alternative solution in patients with severe traumatic brain injury?

Reference: Pelletier et al. Hypertonic saline in severe traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials. CJEM March 2016

  • Population: Adults (aged 18 years and older) suffering from severe traumatic brain injury (Glasgow Coma Scale ≤ 8)
    • Exclusions: For case-mix population studies, those with less than 80% adult patients were excluded
  • Intervention: Hypertonic saline
  • Comparison: Any other type of solution (e.g. Mannitol or normal saline)
  • Outcome:
    • Primary outcome: Death and control of intracranial pressure
    • Secondary outcomes Neurological outcomes at discharge, length of stay in the intensive care unit and hospital, and the occurrence of adverse events (including plasmatic osmolality and natremia).

Authors Conclusions: We observed no mortality benefit or effect on the control of intracranial pressure with the use of hypertonic saline when compared to other solutions. Based on current level of evidence pertaining to mortality or control of intracranial pressure, hypertonic saline could thus not be recommended as a first line agent for managing patients with severe traumatic brain injury”.

Quality Checklist for Therapeutic Systematic Reviews:checklist

  1. The clinical question is sensible and answerable. Yes
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. No. High risk of bias in most studies, small sample sizes and inconsistent outcomes.
  4. The assessment of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Yes
  6. There was low statistical heterogeneity for the primary outcomes. Yes for mortality and no for ICP.
  7. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: Eleven studies were included in the systematic review for a total of 1,820 patients.

  • Primary Outcomes:
    • Four studies had data on mortality (n=1,638). There was no significant difference in mortality RR 0.96 (95% CI, 0.83 to 1.11) I2=0%.
    • Six studies had data on ICP which also showed no significant difference WMD -0.39 (95% CI -3.78 to 2.99) I2=79%. 

No significant mortality benefit or improved control of ICP compared to any other solution

  • Secondary outcomes: No difference
    • Glasgow Outcome Scales extended- Two studies: no statistical difference
    • Disability Rankin Scale – Two studies: could not be pooled, no effect of the intervention
    • Functional Independence Measure (FIM) – One study: no clinical and statistical difference
    • Cerebral Performance Category – One study: no clinical and statistical difference
    • Ventilator- Free Days – One study: no observed benefit
    • Days Alive Out of ICU – One study: no observed benefit
    • Days Alive Out of Hospital – One study: no observed benefit
  • Adverse Events: Hypernatremia was seen in all studies. No difference in seizures or nosocomial infections. Only one study reported on renal insufficiency.

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This is the largest systematic review on hypertonic saline for TBI to date and has strict methodological standards. In particular, we really liked how exhaustive the search strategy was to find the included articles. You searched multiple electronic databases, looked for the grey literature and reviewed the references of included studies.

  • Our team wanted to be thorough, we searched Medline, Embase, SCOPUS, Cochrane, Web of science, Biosis. There was no language restriction. We also contacted authors of studies that only the abstract was available to obtain additional unpublished data.

Now a few questions for Elyse to help us better understand the paper.

  1. Primary Outcomes: You had not one but two primary outcomes. They were death and intracranial pressure. Death is a very important patient oriented outcome but ICP is a disease-oriented outcome. Why the two primary outcomes?
    • Response: The decision to use two co-primary outcomes was based on the main reasons why clinicians justify their use of hyperosmolar therapies; death is a clinically relevant outcome while ICP control is the main mechanism behind a potential clinically significant benefit.
    • One of your secondary outcomes was good neurological outcome at discharge. Some may argue that that would be even more patient oriented. Why not have good neurological outcome as your primary outcome for the study?
    • Response: We agree that neurological functional outcome measures are the best outcome measures to use in severe TBI. When we designed the study, we feared that very little data were published using such outcome measures and that readers will consider ICP control and death as more relevant of their practice, for good or bad reasons.
  2. Compare to other Systematic Reviews: There have been six systematic reviews looking at the efficacy of hypertonic saline. How did your study compare to the other systematic reviews?
    • Response: Our study is the most recent and the largest systematic review. Most of the others reviews included studies that were not randomized or that included patients with a variety of pathologies that create intracranial hypertension (e.g. stroke, spontaneous hemorrhage). We included studies solely with severe TBI population and randomized design, as well as we did not restrict our comparators to mannitol.
    • Why do you think some of the other systematic reviews came to different conclusions?
    • Response: Mostly because positive systematic reviews included studies with various design (retrospective) and population (e.g. stroke, head injury, and tumor). Finally, they did not report clinically significant outcomes such as mortality, but rather used surrogate outcomes as their primary.
  3. High Risk of Bias: You used the Cochrane Collaboration’s Tool for assessing the risk of bias. Nine out of the eleven included studies were deemed to have high risk of bias. Only two of the included studies were felt to have low risk of bias based on the Cochrane Collaboration’s tool. What impact do you think the bias should have on our interpretation of the results?
    • Response:  The quality and the risk of bias of included studies in a systematic review may for sure have an impact on the quality of the evidence that is generated. Despite the conduction of a thorough systematic review following high methodological standards, we must deal with included studies of various methodological quality. In our review, the two studies (Bulger and Cooper) with low bias have a large part of all patients included in the meta-analysis (1511 patients).
  4. Concentrations of Hypertonic Saline Solutions? This varied in the different studies. Did it seem to make any difference depending on concentration used?
    • Response: We did not observe any impact on the concentration used. However, the small number of studies limited our ability to detect an effect.
  5. Sensitivity Analysis: There were only a few studies that could be pooled for analyses. What impact did that have on the systematic review?
    • Response: In our protocol, we planned a series of sensitivity analyses that could not be performed (e.g. different types of hypertonic saline concentrations) due to the limited number of studies. The absence of these sensitivity analyses did not impact the overall result of our systematic review, but precluded to generate hypotheses that could explain the findings.
  6. Difference in Management: What are the differences from a management perspective when using hypertonic saline solutions versus mannitol in terms of ongoing hour-to-hour treatment of the patient in the ICU (e.g. measuring serum osmolalities, urine output differences, etc.)?
    • Response: Both solutions are hyperosmolar solutions; management and monitoring following their administration are thus comparable regardless of the solution used.
  7. What about the Harm? Trials are usually powered to find benefit and often under report harms. You could not do a meta-analysis on adverse events due to lack of standardization. Can you expand and comment on the adverse events or harms observed in the included trials.
    • Response: Most studies measured variation in natremia and osmolality but reported it in various ways that were difficult to appropriately evaluate. More importantly, most studies did not report clinical adverse events (e.g. hypotension, dialysis, etc) nor if they monitored it at all. We can thus say that adverse events in relation with the use of hypertonic saline solutions are potentially underreported.

Comment on authors conclusion compared to SGEM Conclusion: We agree with the author’s conclusion.

SGEM Bottom Line: Hypertonic saline as a first line treatment for patients with severe traumatic brain injury cannot be recommended at this time.

Case Resolution: You give the patient mannitol en route to the CT scanner and his pupil remains sluggish but does not dilate further. He has a large epidural hemorrhage and is taken directly to the operating room for drainage.

Dr. Chris Bond

Dr. Chris Bond

Clinical Application: Chris will continue to use mannitol for the management of elevated ICP in traumatic brain injury patients

What do I tell my patient? In this case we’d likely be speaking to the family members. I would tell them the patient had sustained a serious life threatening brain injury. We are doing everything we can to help. The CT scan shows a serious bleed in the brain. The neurosurgeons are taking him for emergency surgery now. They will be able to explain more once he is out of surgery.

Keener Kontest: There was no winner last week. The answer was Salgo v. Leland Stanford Jr. University Board of Trustees. This was the medical legal case from 1957 that introduced the term “informed consent” for the first time?

Screen Shot 2015-11-29 at 3.19.26 PMListen to the podcast for this weeks’ question. Sent your answer to and the 1st correct answer will receive a cool skeptical prize.

Now it is time for the SGEMers to join the conversation. What do you think about this #SGEMHOP episode? What questions do you have for Elyse and her team? Reach out to us on Twitter, Facebook or the SGEM blog. The best social media feedback will be published in CJEM.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

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  • Elyse B. Pelletier

    I would be glad to answer any comment or question.
    Thank you Ken and Chris for this opportunity!

    • Thanks for taking part in this CJEM-SGEM collaboration @@elysebpelletier:disqus!

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  • Brent Thoma

    Ken, Chris & Elyse,

    Thanks for putting this together.

    I’m wondering what the evidence made Mannitol the gold standard for this treatment in the first place? A quick lit search found this Cochrane review on Mannitol in TBI from 2013 ( which really did not provide convincing evidence that it impacts any patient oriented outcomes. The one RCT it included that compared Mannitol to ‘Standard Care’ showed a RR for mortality of 0.83 (95% CI 0.47 to 1.46). That is not a particularly compelling evidence base for a ‘gold standard’ treatment.

    Given that the gold standard has not been shown to impact the primary outcome (mortality), does it make sense to demand that hypertonic saline meets this standard before it is endorsed for use? As noted in the article, there are concerns over the use of Mannitol due to its potential for volume depletion and hypotension which could lead to decreased CPP. Hypotension is one thing that HAS been shown to lead to worsening morbidity and mortality in these patients. Is the ongoing use of Mannitol instead of hypertonic saline justified based on the literature, or solely used because “it’s what we’ve always done”?

    I agree with your conclusions that this systematic review does not provide a compelling reason to change practice. My question is, do we have any compelling evidence to support what we currently do? It’s unfortunate that the data reported on adverse events was so limited because, I think, given the lack of literature supporting improved outcomes for mannitol, literature finding decrease adverse events with the use of hypertonic saline would potentially support a change in practice.

    Look forward to your thoughts!


    • Elyse B. Pelletier

      Dear Brent,

      Thank you very much for your question. Actually, I did my master degree about mannitol and hypertonic saline treatment, I would be glad to share my memoir with you! I must agree with your comments, mannitol is the gold standard mostly on practice. First studies were published in 50′ and were animals studies or observational studies during neurosurgery! “Good” randomized controlled studies have never been published on the effect on mannitol on mortality or other outcomes. But I must wonder why hypertonic saline gained so much popularity lately…The first study that made that “trend” was the 1991 Mattox study (USA multicenter trial). On field use of HSS in combat. There was a subgroup analyses that showed benefit from severe head injury patients. But there was never another study that clearly supported that finding. Still, there are concerns with adverse effects with both treatment. A lot of what we do in our day to day practice are based on “what we have always done”, as you said. Is that the right thing to do? I let you decide!

      • Juan Pablo Peña Diaz

        Firstly, congratulations for this new SGEM post and Dr. Pelletier.

        Secondly, as i see with this new light, we can think that HS is the prefered treatment in patients with shock + severe TBI during firsts minutes of resuscitation and mannitol for the isolated TBI which are hemodynamic stable ?

        Viva la #FOAMed !

        @juanpaesculapio / @UrgenciasCol

        • Elyse B. Pelletier

          Dear Juan,

          Thank you for your comment. Most emergency physicians think exactly as you stated, but, with the articles I reviewed, population as you described were included and again, no benefit in mortality. I let you judge!

          • Juan Pablo Peña Diaz

            I surprisingly see!.

            Probably not better, but in shock TBI pts, HSS could be associated with less hypotension or was the same than mannytol?

            Best regards!

            @juanpaesculapio / @UrgenciasCol

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  • Nadim Lalani

    Great post guys. I feel that the fact of the matter is that [If i remember correctly] almost 50% mortality in this patient population – there’s not going to be any intervention that will dramatically alter that. no?

    • Elyse B. Pelletier

      Thank you. You are right, that’s why we prefer nowadays “good neurological outcome” as outcomes studied…Unfortunately, as I said in the podcast, a lot of the studies in the review didn’t have this outcome measured or had different scales to measure it

  • Justin Morgenstern

    Another great episode of the SGEM, which made me question a belief that had been slowly developing over the last few years.
    With so many clinical decisions to make in a normal shift, it is incredibly difficult to know the evidence for everything. It seems like I have been hearing about hypertonic saline for intracranial hypertension everywhere since leaving residency – every conference, every blog, every podcast. I was beginning to worry that I was in a group of late-adopters, as I have continued to use mannitol. Of course, most of the excitement seemed to have been based on physiologic outcomes. This review is an incredibly important publication in that it reminds us to continue looking at patient oriented outcomes when deciding to change practice. However, one of the great difficulties of evidence based practice is that newer therapies are scrutinized through the EBM lens, but our traditional therapies are just grandfathered in. Hypertonic saline may not be better than mannitol, but are we sure we are helping patients with mannitol? For me, this study is a reminder of the continued need to examine our beliefs, and the need for more high quality research in this area.

    • Elyse B. Pelletier

      What can I answer to your comment?!! I totally agree…amen!

  • Ryan Deedo

    I think one of the points that isn’t discussed by this paper is the use of prehospital osmotic agents. I work for a HEMS service and I can tell you that mannitol is a serious pain prehospital as it will crystallize if it gets cold and must be stored at warmer temperatures. Hypertonic saline is not nearly as temperature sensitive and it is okay to use it even if its cold (of course we would use a fluid warmer before it hits the patient). I view this as there not being a significant difference between the two fluids so why not use the one that is easier/safer to handle.

  • Kirsty Challen

    Thanks Elyse, Ken & Chris for a very interesting discussion. Here is the #paperinapic

  • Simon Carley

    Excellent review Ken. I’ve been away and missed this and in the interim put together a post for St.Emlyn’s. I’ll add the links back here as to be honest yours is a fabulous review.

    The one question we considered was that in many of these studies they have measured ICP, yet in the ED that’s unusual for us and we are ‘flying blind’.

    I wondered what your thoughts were on this as it applies to all osmotic agents.



    • Chris Bond

      Hey Simon,

      Great to hear from you. I read your post and you make a very good point about us “flying blind”. I like your idea of an ocular US that is continuous and real time from a monitoring point of view. That would be very cool and non-invasive. Alas, we don’t have this yet.

      To me, if we are having to re-dose HTS or mannitol multiple times in the ED, we aren’t really getting the patient to the definitive care that they likely need. Are you keeping patients with blown pupils in the ED that long before they get to OR/ICU if that is what they need?

      I think that ultimately HTS and mannitol are likely close and more study is indeed needed. For me, long term neuro outcomes really would be the most patient oriented outcome, but there is so little data on this. ICP as an outcome is disease oriented, and who knows what it really means.



      • Simon Carley

        Thanks Chris.

        We don’t keep our patients any longer than necessary so not usually redosing in the ED. Sorry if we gave that impression. Several of my colleagues are ED Intensivists and so they see the continuation of care through to ICU. It was they who raised the question.

        I totally agree about long term outcomes. That is where we might see a difference and to be honest it would not need to be a particularly large study owing to the severe nature of the disease and the high adverse outcome rate.



        • Chris Bond

          Ah, that makes a lot more sense.



          • Elyse B. Pelletier

            Dear Simon,

            Merci beaucoup for your comments. I read your blog and I thank you for the review!
            I agree with you, intracranial hypertension in the ED is difficult to evaluate. Indeed, I published two years ago a small survey about the utilisation of hypertonic saline in the ED. It could worth a look to help you think about it!



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