Mannitol in head injuries

Journal Club

CJEM 1999;1(2):104-106

Clinical questions

In a head-injured patient with evidence of raised intracranial pressure (ICP), should mannitol be given? If so, in what dose and for what time period? How should patients receiving mannitol be monitored?

Article chosen

Schierhout G, Roberts I. Mannitol in acute traumatic brain injury [Systematic Review]. Cochrane Injuries Group. Cochrane Database of Systematic Reviews. Oxford; 1999. Issue 1.

Objectives

1. To compare the impact of dosing and duration on mannitol effectiveness.
2. To compare mannitol effectiveness to other ICP-lowering agents.
3. To quantify mannitol effectiveness at various stages following head injury.

Background

A 1995 survey by Ghajar¹ reported that 83% of US centres used osmotic diuretics in over half of severely head-injured patients. Authors of similar surveys report that 100% of neurosurgical centres in the UK use mannitol.^2,3 The 1995 Brain Trauma Foundation Guidelines⁴ recommend that mannitol be reserved for patients with signs of raised ICP or deteriorating neurological status. The effectiveness of mannitol is not well quantified.

The search

Studies were identified using the Cochrane Injuries Group (CIG) database, which is updated every 3 months. This database includes relevant articles published between 1966 and 1996 that were indexed as "randomized controlled trials" or "controlled clinical trials." In addition, 46 journals and 23 conference proceedings were hand searched. Reviewers contacted the authors of all identified studies to locate other published or unpublished trials.

Study selection

Trials were included in the review only if the subjects had suffered an acute traumatic brain injury and were assigned to mannitol treatment versus a control treatment. Control treatments included different doses of mannitol, other ICP-lowering agents, or standard care only. Crossover trials were excluded. Outcome measures included mortality and morbidity rates, and recovery comparisons between groups. Two independent reviewers evaluated the studies to determine whether they met review inclusion criteria. These reviewers corresponded with the trial authors to clarify questions and obtain additional data.

Main results

Of the studies identified, only 3 fulfilled review inclusion criteria. In these, death was the outcome measure chosen for comparison. One⁵ of the 3 studies compared ICP-directed mannitol therapy to "standard care" in 77 patients and reported a possible outcome improvement with mannitol (relative risk [RR] for death = 0.83; 95% CI, 0.47 to 1.46). The second study⁶ compared mannitol to pentobarbital in 59 patients and reported a similar outcome favouring mannitol (RR for death = 0.85; 95% CI, 0.52 to 1.38). The third study⁷ compared prehospital mannitol to placebo in 41 patients, finding no differences in systolic blood pressure during a 2-hour observation period, and a trend toward worse outcomes in the mannitol group (RR for death = 1.59; 95% CI, 0.44 to 5.79).

Conclusion

The authors concluded that mannitol therapy for raised ICP may reduce mortality rate more than pentobarbital, that ICP-directed mannitol treatment may be better than using clinical parameters alone, and that insufficient evidence exists to recommend one form of mannitol infusion over another. There are insufficient data to make any recommendations about prehospital mannitol use.

Source of funding

National Health Service Research and Development Program; Mother and Child Health, UK.

Commentary

Systematic reviews are often helpful in clarifying "best practice" when a number of studies, often with small sample sizes, provide conflicting evidence. They may be less helpful, however, when the majority of available literature is observational. This well-designed systematic review, which avoided selection and publication bias, is both interesting and thought provoking in that the authors were unable to find sufficient evidence to accomplish their stated objectives.

Trauma is the leading cause of death from ages 1 to 44. Head injury is an important determinant of outcome in half of all trauma deaths. Mannitol has been employed to reduce brain swelling for more than 40 years and is considered standard therapy for severely head-injured patients with elevated ICP; yet these authors found only two studies^6,7 that randomized head injury patients to mannitol vs. an alternate therapy (total n = 100 patients).

In this systematic review and another published in 1998,⁸ Schierhout and coworkers cite the lack of evidence that mannitol is effective, and suggest that this is an ideal opportunity to conduct randomized controlled trials to define the role of mannitol in head-injured patients. However, lack of evidence of effectiveness does not constitute evidence of ineffectiveness, and too many clinicians have witnessed dilated pupils normalize after a mannitol bolus; therefore it is unlikely that placebo controlled trials will be clinically or ethically acceptable. Moreover, unless new osmotic agents are developed that can be compared to mannitol, future randomized clinical trials should focus on determining the most effective dose of mannitol. Finally, future researchers will have to monitor intermediate outcomes and adverse effects, since it will be difficult to show statistically significant mortality differences without very large sample sizes.

References

1. Ghajar J, Hariri RJ, Narayan RK, Iacono LA, Firlik K, Patterson RH. Survey of critical care management of comatose, head-injured patients in the United States. Crit Care Med 1995;23:560-7.
2. Jeevaratnam DR, Menon DK. Survey of intensive care of severely head injured patients in the United Kingdom. BMJ 1996;312:944-7.
3. Matta B, Menon D. Severe head injury in the United Kingdom and Ireland: a survey of practice and implications for management. Crit Care Med 1996;24:1743-8.
4. Task Force of the American Association of Neurological Surgeons and Joint Section in Neurotrauma and Critical Care. Guidelines for the management of severe head injury. Brain Trauma Foundation; 1995.
5. Smith HP, Kelly DL Jr, McWhorter JM, Armstrong D, Johnson R, Transou C, Howard G. Comparison of mannitol regimes in patients with severe head injury undergoing intracranial monitoring. J Neurosurg 1986;65:820-4.
6. Schwartz ML, Tator CH, Rowed DW, Reid SR, Meguro K, Andrews DF. The University of Toronto head injury treatment study: a prospective, randomized comparison of pentobarbitol and mannitol. Can J Neurol Sci 1984;11:434-40.
7. Sayre MR, Daily SW, Stern SA, Storer DL, van Loveren HR, Hurst JM. Out of hospital administration of mannitol does not change systolic blood pressure. Acad Emerg Med 1996;3:840-8.
8. Roberts I, Schierhout G. Absence of evidence of five interventions routinely used in the intensive care management of severe head injury: a systemic review. J Neurol Neurosurg Psych 1998;65:729-33.