Osmotic Therapy for Treatment of Intracranial Hypertension for Traumatic Brain Injury

Osmotic therapy is a mainstay in the treatment of intracranial hypertension after traumatic
brain injury. Despite sparse concrete evidence of beneficial effects on patient outcome, it
has been widely accepted by treating physicians that osmotic therapy is effective, at least
in helping control elevated intracranial pressure (ICP), and control of ICP has been shown
to improve outcome. Mannitol is the most commonly utilized agent. It is widely available,
effective, and has a low side-effect profile. Large doses for long term periods have been
shown to be safe, but its usefulness is limited by elevation of serum osmolarity and
potential alteration in renal function, and its efficacy seems to diminish with repeated
doses. Rebound intracranial hypertension has been reported after discontinuation of large
doses. Other hypertonic agents such as urea and glycerol are no longer used.

More recently, hypertonic saline (HTS) solutions of various concentrations have become
available, and have been shown in several animal research studies and small human trials to
be safe and effective in the management of intracranial hypertension. HTS does not cross
the blood-brain barrier, and has the ability to improve intravascular volume without the
osmotic diuresis effect of mannitol. Several institutions routinely use HTS solutions in
the management of traumatic brain injuries, and the use of both mannitol and HTS is common.
Additionally longer-term use of HTS is not as restricted by plasma osmolarity. There have
been several small trials comparing the two agents, but these studies have been relatively
poorly controlled and therefore reached limited conclusions. At our institution both agents
(in the forms of 20% mannitol and 3% sodium chloride) are used routinely, with no particular
rationale for one over the other. There is suggestion that one agent may be better than the
other, but this has not been explicitly tested in humans.

It is our hypothesis that HTS and mannitol both adequately treat intracranial hypertension,
but that HTS may have additional benefits of allowing more frequent and/or longer-term
dosing, and volume expansion without osmotic diuresis (thereby improving the patient's
overall fluid state, potentially decreasing morbidity).

We propose a study of patients with acute traumatic brain injury requiring osmotic therapy
to control elevated ICP, comparing the use of 20% mannitol to 3% sodium chloride (NaCl).

Specific Aims:

Primary Goal:

Assess efficacy of 20% mannitol versus 3% NaCl in controlling elevated ICP in acute
traumatic brain injury

Secondary Goals:

Assess effects on hemodynamic parameters (mean arterial pressure, cerebral perfusion
pressure, central venous pressure and volume status) Assess effects on serum sodium and
osmolarity Assess effects on patient outcomes at discharge

Inclusion Criteria:

- All hemodynamically stable patients aged 18-65 presenting with acute traumatic brain
injury requiring monitoring of intracranial pressure (ICP) will be screened for
randomization.

Exclusion Criteria:

- Patients with known pre-existing renal abnormalities or serum creatinine greater than
or equal to 2.0mg/dl will be excluded.