Cases & Commentaries
The Forgotten Drip
A 45-year-old man was brought to the emergency
department by his friends because of a 1-day history of a severe
headache and "bizarre behavior." A computed tomography (CT) scan of
his brain revealed acute intracranial hemorrhage with cerebral
edema, evidence of midline shift, and increased intracranial
pressure (Figure). The patient was admitted to the
intensive care unit (ICU).
Multiple therapies were initiated to reduce the
intracranial pressure and swelling, including intubation and
mechanical ventilation, intravenous steroids, and an infusion of
mannitol. In addition, intravenous fluids were withheld, to prevent
worsening of the cerebral edema. Over the next 24 hours, the
patient showed minimal improvement and remained unresponsive and
comatose. Repeat CT scanning showed a stable hemorrhage but
persistent cerebral edema.
On hospital day 2, another CT scan showed that
the hemorrhage was unchanged, but there was significant improvement
in the cerebral edema. Based on these results, the physicians
expected the patient's mental status to be improved; however, he
remained in a coma. A review of that day's laboratory data revealed
that the patient had developed severe hypernatremia (high enough to
explain his continued altered mental status) and new acute renal
failure since admission. Nephrology was consulted to help determine
the etiology of the hypernatremia and renal failure and to make
recommendations about management.
In reviewing the records, consultants realized
that the mannitol infusion had been continued for more than 24
hours at a very high dose. The mannitol, as expected, had induced a
profound osmotic diuresis. Because the patient had not received any
additional intravenous or enteral fluids, he had become severely
dehydrated. Although the hemorrhage and cerebral edema were
improved, the patient remained unresponsive and comatose because of
the hypernatremia and acute renal failure. He had a prolonged
hospitalization and ultimately died from complications related to
Spontaneous intracerebral hemorrhage (ICH) is
the etiology of 10%–20% of new strokes each year in the
United States. It is a tremendously morbid disease, with one third
to one half of patients dying within 30 days of their hemorrhage.
There are currently no approved therapies specifically targeting
ICH, and evidence-based acute management focuses on mitigating the
effects of cerebral edema, managing hydrocephalus, controlling
hypertension, and preventing hospital-acquired
Elevated intracerebral pressure (ICP) is found
in many cases of ICH, and its prompt treatment likely improves
outcome. Two general pathophysiologic approaches toward elevated
ICP have been touted in the literature. The "Lund protocol,"
derived in patients with elevated ICP in the setting of head
trauma, assumes that the normal blood-brain barrier is disrupted
and focuses on procedures designed to maintain fluid within the
intravascular compartment in order to avoid increasing brain
parenchymal edema.(2) A
second, potentially complementary approach is driven by the concept
of the cerebral perfusion pressure (CPP, calculated as mean
arterial pressure [MAP] – ICP).(3) This CPP-driven strategy emphasizes
measures designed to minimize cerebral ischemia by keeping CPP
greater than 70 mm Hg, either by lowering ICP or raising MAP. In
ICH, this CPP-driven goal must be balanced against the potential
danger of hematoma expansion that can result if MAP remains
Management of increased ICP in patients with
ICH should always begin with simple but effective measures
including raising the head of the bed to 30 degrees, which
decreases ICP by increasing venous return from the brain, and
avoidance of hypotonic fluids (solutions with lower tonicity than
blood, such as half normal saline [1/2NS] or dextrose in water
[D5W]). Isotonic solutions, such as normal saline (NS), should
indeed be administered to ICH patients in order to maintain
euvolemia. Intravascular hypovolemia can lead to cerebral
hypoperfusion and possibly ischemia. Moreover, infusion of isotonic
fluid and maintenance of euvolemia can prevent the systemic effects
of dehydration that occurred in this case. In addition, adequate
sedation and analgesia in ICH patients will prevent spikes in ICP
associated with agitation and pain and should be an integral part
of initial ICH management.
If ICP remains elevated clinically despite
these simple measures, a more aggressive approach is indicated.
Although no randomized data exist, many experts recommend placement
of an ICP monitor in order to be able to objectively titrate these
interventions once a more aggressive approach is warranted. ICP
monitoring devices are small plastic catheters that are inserted
into the brain to measure ICP. If increased ICP is secondary to
hydrocephalus from either intraventricular blood or obstruction of
cerebral spinal fluid (CSF) outflow, placing a ventriculostomy in
order to reduce ICP via CSF drainage is a must and may be
life-saving for some patients. Most ventriculostomy devices also
allow for accurate intermittent measurement of ICP in addition to
drainage. Classic teaching has suggested that hyperventilation is
fundamental in the management of ICP. However, although
hyperventilation is a rapidly effective method of reducing ICP, its
utility is limited by its very transient effect and simultaneous
lowering of cerebral blood flow; as a result, it should be used
only on a very temporary basis in patients with elevated
Osmotic therapy remains the basis of most
aggressive ICP management protocols. Mannitol and infusions of
hypertonic saline are the most common agents used for this purpose.
Mannitol induces a brisk osmotic diuresis since it is not absorbed
in the renal tubule and will pull fluid into the urine. Mannitol
should almost always be used intermittently in bolus fashion, based
on clinical neurologic deterioration or elevations in ICP
measurements, rather than via a continuous intravenous drip. In
order to avoid renal failure and volume depletion (5,6), a strict institutional protocol
should involve monitoring plasma osmolality and serum sodium every
4–6 hours whenever mannitol is used. Mannitol should be
withheld if the plasma osmolality exceeds 320 mOsm/kg or if the
patient becomes hypernatremic. Dosing should be limited to less
than 250 mg/kg every 4 hours to reduce the chances of renal
patients with preexisting oliguric or anuric renal failure,
including patients on dialysis, mannitol should be avoided.
In patients whose ICP remains refractory after
the initial simple measures outlined above and osmotic therapy, a
variety of third-line approaches are used including neuromuscular
blockade, barbiturate coma, and induced hypothermia.(1) Rigorous evidence-based
comparisons of these third-line techniques do not exist, and
therefore institutional and individual preference guides therapy at
this point in ICP management.
In this case, intravenous corticosteroids were
also used in an attempt to reduce cerebral edema in a patient with
ICH. While corticosteroids are likely effective in reducing edema
in some settings such as with intracranial neoplasms, they have no
role in ICH as proven by randomized trials and should be avoided in
this setting as their use may even be associated with worse
This case brings up several key points
regarding the management of elevated ICP in ICH.
- All centers should develop a
step-wise protocol that guides the management of elevated ICP in
- Use of neuromonitoring to objectively
assess ICP in a patient whose clinical examination is poor remains
useful to gauge the effects of these interventions. By the time
osmotic therapy is instituted, most patients should have ICP
monitoring in place.
- Ventriculostomy with CSF drainage
allows for reduction of ICP as well as ICP monitoring in patients
with obstructive hydrocephalus or intraventricular
- Mannitol should always be used in a
bolus fashion and should never be administered without frequent
strict monitoring of serum sodium and plasma osmolality in order to
prevent the complications that occurred in this case.
Andrew Josephson, MD
Assistant Clinical Professor of Neurology
Director, Neurohospitalist Program
Department of Neurology
University of California,
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Hyperosmolality with hyponatremia, caused by inappropriate
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Dorman HR, Sondheimer JH, Cadnapaphornchai P. Mannitol-induced
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Figure. Example CT scan (not from this case)
showing acute intracranial hemorrhage with cerebral edema, evidence
of midline shift, and increased intracranial pressure.