Effects of mannitol and hypertonic saline on cerebral oxygenation and metabolism in patients with posttraumatic intracranial hypertension.

Traumatic brain injury (TBI) is the leading cause of death in patients under
the age of 45. The prognosis of the TBI is determined by the primary insult to
the brain and by a cascade of events leading to secondary brain injury.
Cerebral swelling is a key mechanism associated with this secondary brain
injury and contributes to intracranial hypertension, secondary ischemia and, if
uncontrolled, to brain herniation. Hyperosmolar therapy is one of the main
treatments for cerebral edema following TBI. Mannitol and hypertonic saline
(HS) are hyperosmolar agents that are routinely used in patients with cerebral
swelling. On theoretical grounds, HS is likely to have more favourable effects
on cerebral oxygenation, cerebral blood flow and metabolism compared to
mannitol. So far, a direct comparison between these agents has not been made.

Aim of this study is to compare the effects of mannitol and HS in equimolar
concentrations on cerebral blood flow, cerebral oxygenation, metabolism and
inflammation in patients with severe TBI.

Randomized single blind prospective intervention study

Patients are randomized to treatment with 250 mOsm HS or mannitol via a central
venous catheter over 5 minutes. The treatment will be administered if the
intracranial pressure is > 25 mm Hg for at least 5 minutes and not related to a
transient external noxious stimulus or systemic derangement. In this trial
patients will be randomized to receive either mannitol or HS. If necessary,
additional boluses of the same drug may be administered to the patient in case
of persistent intracranial hypertension. If the patient fails to respond to the
study drug, the other drug may be used to lower intracranial pressure. In all
cases analysis of the results will be performed on an *intention-to treat*
basis.

Both mannitol and HS are routinely used in the treatment of cerebral swelling,
randomisation for one of these drugs is therefore without additional risk for
the patients. Intensive monitoring of these patients is part of routine
neurological intensive care. This includes monitoring of intracranial pressure,
jugular bulb oxygen saturation, and transcranial doppler. Extra procedures
related to the study include the following:
For the measurement of components of the inflammatory response and for the
measurement of jugular bulb oxygen saturation blood samples will be drawn from
the arterial and jugular bulb catheter Total amount of blood drawn from the
patients will be approximately 100 ml over a period of 2 days.
Instead of a single lumen transcranial bolt a 3 lumen transcranial bolt will be
threaded and tapped into the cranium under local anaesthesia. Introduction of a
bolt into the cranium is part of standard care of these patients and serves to
hold a catheter measuring intracranial pressure. The bolt will also be used to
grip and immobilize a microdialysis catheter (CMA Microdialysis, Sweden). After
insertion of the microdialysis catheter, dialysis is a semi-automatic process,
with no adverse events reported in the literature (29). Brain oxygen tension
will be measured continuously, through the 3th lumen of the bolt.
Measurement of cerebral blood flow with transcranial doppler is a noninvasive
procedure with no risks and minimal burden to the patient.
The risks of this study are negligible and the burden minimal, mostly because
treatment and monitoring are to a large extent part of routine care. The study
can only be carried out in incapacitated patients since it concerns comatose
patients in the acute phase after TBI injury.