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).
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)
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).
Author’s 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:
The clinical question is sensible and answerable. Yes
The search for studies was detailed and exhaustive. Yes
The primary studies were of high methodological quality. No. High risk of bias in most studies, small sample sizes and inconsistent outcomes.
The assessment of studies were reproducible. Yes
The outcomes were clinically relevant. Yes
There was low statistical heterogeneity for the primary outcomes. Yes for mortality and no for ICP.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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 author’s 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
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. Thiswas the medical legal case from 1957 that introduced the term “informed consent”for the first time?
Listen to the podcast for this weeks’ question. Sent your answer to TheSGEM@gmail.com 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.