Consider the following case scenario: A 42-year-old man is brought to the Emergency Department following a car crash. He has a GCS of 6 and is intubated and ventilated. The CT scan shows acute subdural hemorrhage with a midline shift of 3 cm and cerebral edema. He needs urgent evacuation of the subdural hematoma; in the meanwhile, you consider osmotherapy to reduce the intracranial pressure. Would you choose 20% mannitol or hypertonic saline?
Nearly a century ago, Weed and Mckibben serendipitously demonstrated a reduction in ICP following intravenous administration of hypertonic saline in cats.1 Following this seminal study, clinicians were quick to adopt this practice in their patients; a variety of osmotic agents were used, including glycerol and urea. From the 1960s, mannitol became firmly entrenched in clinical practice as standard osmotic therapy. This practice continued until there was an upsurge of interest with the use of hypertonic saline in the past two decades.
Hypertonic saline has several potential advantages over mannitol. It expands the intravascular compartment and may better maintain cardiac output and blood pressure; in contrast, mannitol may lead to excessive diuresis and hypovolemia. Mannitol may cause renal dysfunction in higher doses; besides, it may lead to a hyperglycemic, hyperosmolar state and cause encephalopathy. Other theoretical advantages of hypertonic saline include immunomodulatory and anti-inflammatory effects. It may also prevent the accumulation of the excitatory amino acid, glutamine, and prevent neuronal damage.2
In the light of these putative advantages, how does hypertonic saline compare with mannitol in the real word? Several randomized controlled studies have been performed that compared mannitol with boluses of hypertonic saline in different strengths to evaluate the effect on ICP. While some studies have demonstrated a more profound and sustained ICP reduction with hypertonic saline,3,4 others have not shown a significant difference.5,6 Importantly, no study has demonstrated a difference in clinical outcomes, including mortality. In the most exhaustive meta-analysis that compared both treatments, including 11 randomized controlled trials, no difference was seen in the degree of ICP reduction or on mortality in patients with severe traumatic brain injury.7
Hypertonic saline is available in solutions of different strengths, including 3%, 7.5%, and 23.4%. The bolus volume required to achieve the desired osmolality varies from 30 ml for 23.4% saline to 150 ml for 3%. It is interesting to note that nearly all the randomized controlled trials with hypertonic saline used it as intermittent boluses in response to raised ICP. Many of us use continuous infusions of hypertonic saline, often without ICP monitoring. It remains unclear whether continuous infusions are as effective in reducing ICP compared to bolus doses. This is particularly relevant when the intracranial pressure is not monitored. A sodium level of 145–150 mmol/l is often recommended when hypertonic saline is used; however, this target level may be little more than just a ballpark number. The brain trauma foundation (BTF) continues to recommend mannitol for ICP reduction, considering the lack of firm evidence to support the use of hypertonic saline.8
Coming back to our patient, our practice until a couple of years ago would have been to use hypertonic saline, as a combination of boluses and a continuous infusion targeting a sodium level of around 150 mmol/l. The turnaround time to obtain sodium levels and diligent titration to reasonably precise levels often turned out to be time and labor-intensive. Several recent studies suggest that the difference in ICP reduction is at best, modest, and clinical outcomes including mortality are unchanged with the use of hypertonic saline, compared to mannitol. Hence, we have gone back to our previous practice of using mannitol, unless there is a concern with inducing hemodynamic instability or renal dysfunction. In spite of the many theoretic advantages, hypertonic saline may cause significant volume overload in patients with poor heart function; besides, the possibility of central pontine demyelination cannot be entirely ruled out with a rapid increase in sodium levels.
At the end of the day, osmotic therapy is at best, only intended to buy time before a definitive intervention is carried out, as in our gentleman with the acute subdural hematoma. A transient, modest difference in ICP, even if it may assume statistical significance, may not translate to a perceptible change in clinical outcomes. What would be your choice of osmotic agent in the case we discussed?
- Weed LH, Mckibben PS. Pressure changes in the cerebrospinal fluid following intravenous injection of solutions of various concentrations. Am J Physiol 48, 512–30 (1919).
- Relationship between excitatory amino acid release and outcome after severe human head injury. – PubMed – NCBI. Available at: https://www.ncbi.nlm.nih.gov/pubmed/?term=Relationship+between+excitatory+amino+acid+release+and+outcome+after+severe+human+head+injury. (Accessed: 15th December 2018)
- Ichai, C. et al.Sodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain-injured patients. Intensive Care Med. 35, 471–479 (2009).
- Battison, C., Andrews, P. J. D., Graham, C. & Petty, T. Randomized, controlled trial on the effect of a 20% mannitol solution and a 7.5% saline/6% dextran solution on increased intracranial pressure after brain injury. Crit. Care Med. 33, 196–202; discussion 257-258 (2005).
- Cottenceau, V. et al.Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J. Neurotrauma 28, 2003–2012 (2011).
- Sakellaridis, N. et al.Comparison of mannitol and hypertonic saline in the treatment of severe brain injuries. J. Neurosurg. 114, 545–548 (2011).
- Berger-Pelleiter, E., Émond, M., Lauzier, F., Shields, J.-F. & Turgeon, A. F. Hypertonic saline in severe traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials. CJEM 18, 112–120 (2016).
- Carney, N. et al.Guidelines for the Management of Severe Traumatic Brain Injury. 4th edition 244 (2016)