There are insufficient data to support a Level I recommendation for this topic.

Mannitol is effective for control of raised intracranial pressure (ICP) at doses of 0.25 gm/kg to 1 g/kg body weight. Arterial hypotension (systolic blood pressure < 90 mm Hg) should be avoided

Restrict mannitol use prior to ICP monitoring to patients with signs of transtentorial herniation or progressive neurological deterioration not attributable to extracranial causes.

Hyperosmolar agents currently in clinical use for traumatic brain injury (TBI) are mannitol and hypertonic saline (HS) (Table 1).

Mannitol is widely used in the control of raised ICP following TBI. Its use is advocated in two circumstances. First, a single administration can have short term beneficial effects, during which further diagnostic procedures (e.g., CT scan) and interventions (e.g., evacuation of intracranial mass lesions) can be accomplished. Second, mannitol has been used as a prolonged therapy for raised ICP. There is, however, a lack of evidence to recommend repeated, regular administration of mannitol over several days. Although there are data regarding its basic mechanism of action, there are few human studies that validate different regimens of mannitol administration.

Current therapies used for ICP control (mannitol, barbiturates) bear the risk of further reducing perfusion to the brain either by lowering blood pressure and cerebral perfusion pressure (CPP) or by causing cerebral vasoconstriction (hyperventilation). Ideally, a therapeutic intervention should effectively reduce ICP while preserving or improving CPP.

The use of HS for ICP control was discovered from studies on "small volume resuscitation." Hypertonic saline solutions were tested in poly-traumatized patients with hemorrhagic shock. The subgroup with accompanying TBI showed the greatest benefit in terms of survival and hemodynamic parameters were restored effectively. The findings that HS may benefit patients with TBI while preserving or even improving hemodynamic parameters stimulated further research on the effects of HS solutions on increased intracranial pressure in patients with TBI subarachnoid hemorrhage, stroke and other pathologies.

This chapter combines information from the previous guideline about mannitol with new information about hypertonic saline. For this topic, Medline was searched from 1966 through April of 2006 (see Appendix B for search strategy), and results were supplemented with literature recommended by peers or identified from reference lists. Of 42 potentially relevant studies, no new studies were added to the existing table for mannitol (Evidence Table I) and 2 were included as evidence for the use of hypertonic saline (Evidence Table II).

Three publications about mannitol were identified in the literature research that were not included as evidence due to questions about the integrity of the trial data.

Over the last three decades, mannitol has replaced other osmotic diuretics for the treatment of raised ICP. Its beneficial effects on ICP, CPP, CBF, and brain metabolism, and its short-term beneficial effect on neurological outcome are widely accepted as a result of many mechanistic studies performed in humans and in animal models. There is still controversy regarding the exact mechanisms by which it exerts its beneficial effect, and it is possible that it has two distinct effects in the brain.

1. One effect may be an immediate plasma expanding effect, which reduces the hematocrit, increases the deformability of erythrocytes, and thereby reduces blood viscosity, increases CBF, and increases cerebral oxygen delivery. These rheological effects may explain why mannitol reduces ICP within a few minutes of its administration, and why its effect on ICP is most marked in patients with low CPP (<70).
2. The osmotic effect of mannitol is delayed for 15-30 min while gradients are established between plasma and cells. Its effects persist for a variable period of 90 min to 6 or more h, depending upon the clinical conditions. Arterial hypotension, sepsis, nephrotoxic drugs, or preexisting renal disease place patients at increased risk for renal failure with hyperosmotic therapy.

Relatively little is known regarding the risks of mannitol when given in combination with hypertonic saline, or when used for longer periods (>24 h). The last edition of these guidelines provided a Level III recommendation that intermittent boluses may be more effective than continuous infusion. However, recent analysis concluded that there are insufficient data to support one form of mannitol infusion over another.

The administration of mannitol has become common practice in the management of TBI with suspected or actual raised intracranial pressure. In a randomized controlled trial (RCT) comparing mannitol with barbiturates for control of high ICP after TBI, mannitol was superior to barbiturates, improving CPP, ICP, and mortality. However, the evidence from this study is Class III.

Mechanism of action. The principal effect on ICP is possibly due to osmotic mobilization of water across the intact blood-brain barrier (BBB) which reduces cerebral water content. While not applicable as evidence, in an animal study HS was shown to decrease water content, mainly of nontraumatized brain tissue, due to an osmotic effect after building up a gradient across the intact blood brain barrier. Effects on the icrocirculation may also play an important role: HS dehydrates endothelial cells and erythrocytes which increases the diameter of the vessels and deformability of erythrocytes and leads to plasma volume expansion with improved blood low. HS also reduces leukocyte adhesion in the traumatized brain.

Potential side effects. A rebound phenomenon as seen with mannitol has been reported after 3% saline administration for non-traumatic edema,40 but not after human TBI even with multiple use. Hypertonic saline infusion bears the risk of central pontine myelinolysis when given to patients with preexisting chronic hyponatremia. Hyponatremia should be excluded before administration of HS. In healthy individuals with normonatremia, central pontine myelinolysis was not reported with doses of hypertonic saline given for ICP reduction. In the pediatric population sustained hypernatremia and hyperosmolarity were generally well tolerated as long as there were no other conditions present, such as hypovolemia which may result in acute renal failure. Hypertonic saline also carries a risk of inducing or aggravating pulmonary edema in patients with underlying cardiac or pulmonary problems.

Continuous infusion. Shackford et al. conducted a RCT with 34 adult patients with a GCS of 13 and less after TBI. The hypertonic saline group received 1.6% saline titrated to treat hemodynamic instability with systolic blood pressures of <90 mm Hg during their pre and inhospital phase for up to 5 days. Maintenance fluid in these patients was normal saline. The other patient group received lactated Ringer's for hemodynamic instability and half normal saline as maintenance solution. The groups were not well matched and the HS group at baseline had higher ICPs and lower GCS scores. Despite these differences the ICP course was not different between groups. Outcome at discharge was also not different between groups. Serum sodium and osmolarity were higher in the HS group. Given the difference in study groups in terms of initial ICP and GCS, it is not possible to draw firm conclusions from this study. In addition, the concentration of HS tested (1.6%) was low compared to other trials.

In a retrospective study, Qureshi et al. reported the effects of a continuous 3% saline/acetate infusion in 36 patients with severe TBI compared to the continuous infusion of normal saline in 46 control patients. The incidence of cerebral mass lesions and penetrating TBI was higher in the HS group and ICP was not monitored in all patients. Given the mismatch of patients between groups this study does not help to clarify the role of continuous infusion of HS after TBI.

More studies regarding continuous administration of HS have been done in children with severe TBI. Three Class III studies showed beneficial effects of continuous HS infusion on ICP in pediatric TBI patients. Effective doses range between 0.1 and 1.0 mL/kg of body weight per hour, administered on a sliding scale. The choice of mannitol or hypertonic saline as first line hyperosmolar agent was left to the treating physician. The pediatric guidelines1 currently recommend continuous infusion of 3% saline for control of increased ICP as a Level III recommendation.

Bolus administration for treatment of intracranial hypertension. Four case series have been published evaluating bolus infusion of between 7.2% and 10% saline in patients after TBI.16,18,36,45 In a total of 32 patients, bolus infusion of HS reliably decreased ICP in all studies. HS effectively lowered ICP in patients that were refractory to mannitol. Repeated administration of HS in the same patient was always followed by a reduction in ICP and a rebound phenomenon was not observed. In a pilot RCT HS bolus infusion was compared to mannitol in nine patients, and HS was found to be equivalent or superior to mannitol for ICP reduction. Taken together, these studies suggest that HS as a bolus infusion may be an effective adjuvant or alternative to mannitol in the treatment of intracranial hypertension. However, the case series design, and the small sample of the trial, do not allow for conclusions.

Mannitol is effective in reducing ICP in the management of traumatic intracranial hypertension. Current evidence is not strong enough to make recommendations on the use, concentration and method of administration of hypertonic saline for the treatment of traumatic intracranial hypertension.

An RCT is required to determine the relative benefit of hypertonic saline versus mannitol.

• Research is needed to determine the optimal administration and concentration for hypertonic saline.
• The use of a single high dose of mannitol needs to be validated, preferably in a multicenter trial, as well as for the entire severe TBI population.
• Studies are required to determine the efficacy of prolonged hypertonic therapy for raised ICP, especially with respect to the effect of this therapy in relation to outcome.