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J Intensive Care Med 2013 Hinson 3 11
J Intensive Care Med 2013 Hinson 3 11
Care Medicine
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Analytic Reviews
Abstract
Osmotic agents play a vital role in the reduction of elevated intracranial pressure and treatment of cerebral edema in Neurologic
critical care. Both mannitol and hypertonic saline reduce cerebral edema in many clinical syndromes, yet there is controversy over
agent selection, timing, and dosing regimens. Despite the lack of randomized, controlled trials, our knowledge base on the
appropriate clinical use of osmotic agents continues to expand. This review will summarize the evidence for the use of
mannitol and hypertonic saline in a variety of disease states causing cerebral edema, as well as outlining monitoring and safety
considerations.
Keywords
mannitol, hypertonic saline, osmotic therapy, cerebral edema
Received July 7, 2010, and in revised form September 20, 2010. Accepted for publication October 12, 2010.
Introduction
Although osmotic agents have been utilized to reduce cerebral
edema for nearly 5 decades, significant controversy regarding
choice of agent and dosing exists. While a variety of agents
have been investigated including hypertonic urea, glycerol, and
sorbitol,1-3 this review will focus on the 2 main agents used in
adult clinical practice today: mannitol and hypertonic saline
(HS). This review will summarize the evidence for the use of
these 2 agents in a variety of disease states causing cerebral
edema, as well as outlining monitoring and safety considerations.
Pharmacologic Properties
Mannitol
Mannitol has long been recognized for its ability to reduce
intracranial pressure (ICP) in animals and entered the clinical
realm in 1960s.4 It is a freely filtered, nonmetabolized solute
that decreases the reabsorption of water and, to a lesser extent,
sodium, across the renal tubule, creating diuresis. Mannitol
works in a biphasic fashion to reduce ICP. Initially, it alters
blood dynamics (rheology), specifically by reducing the
viscosity of blood. Mannitol has been shown to reduce blood
viscosity by reducing red cell rigidity, thereby easing the passage of the red cell through small blood vessels independent
of hematocrit.5 This effect disappears 4 hours after administration. Mannitol also increases intravascular volume due to
increased plasma osmolality, as well as increasing cardiac output.6 In response to reduced viscosity and intravascular volume
expansion, there is compensatory cerebral vasoconstriction
1
Neurosciences Critical Care, Johns Hopkins Medical Institutions, Baltimore,
MD, USA
2
Department of Surgery, University of Maryland School of Medicine,
Baltimore, MD, USA
3
Division of Stroke and Neuro-Critical Care, Departments of Neurology,
Surgery, Neurosurgery, and Anesthesiology, University of Maryland School
of Medicine, Baltimore, MD, USA
Corresponding Author:
Kevin N. Sheth, Division of Neuro-Critical Care & Stroke, Neurology/Neurosurgery/Emergency Med/Anesthesiology, University of Maryland School of
Medicine, University of Maryland Medical Center, Adams Cowley Shock
Trauma Center, 110 South Paca Street, 3rd floor, Baltimore, MD 21201, USA
Email: ksheth@som.umaryland.edu
Sodium Concentration
(mEq/L)
Osmolarity
(mOsm/L)
Ringers lactate
0.009
0.02
0.03
Mannitol 20%
Mannitol 25%
0.075
0.234
130
154
242
513
n/a
n/a
1283
4004
275
308
684
1062
1098
1375
2566
8008
Hypertonic Saline
Hypertonic saline gained popularity initially as a volume
expander in acute resuscitation, particularly in hemorrhagic
shock.14 Investigators noted that among patients sustaining
TBI, there was an improved survival rate,15 which was attributed to reduction in cerebral edema and validated in animal
models.16,17 As a result, HS evolved over time as an alternative
to mannitol in treating cerebral edema. Hypertonic saline has
been shown in animal models to produce a biphasic reduction
in ICP, first by way of rheology followed by osmotic activity
across the blood-brain barrier.18,19 Hypertonic saline has the
additional theoretical benefit of being less permeable than
mannitol across the blood-brain barrier due to its higher reflection coefficient. As a consequence, the theoretical potential for
water to follow the solute into the brain worsening cerebral
edema is reduced.20
The majority of inquiry regarding HS has occurred in TBI,
although literature in other forms of cerebral edema exists.
Table 1 compares the concentration and osmolality of several
commonly utilized formulations. As there is no universally
agreed-upon concentration or schedule for administering HS,
comparison between studies is difficult. Additionally, higher
concentrations of HS, particularly 23.4% saline, must be given
via central venous access, making its administration less feasible for patients without a central line catheter.
Continuous infusions as well as bolus dosing of varying
concentrations of HS have been investigated as alternatives
Clinical Applications
Mannitol Versus HS
Limited head-to-head comparisons exist comparing the
efficacy of mannitol to HS in reduction of ICP. Table 2 lists
5 recent prospective trials comparing the 2 agents. Vialet
et al prospectively examined a series of patients with severe
TBI and elevated ICP, comparing 7.5% saline with 20% mannitol.25 The authors found their patient cohort had fewer episodes and shorter durations of elevated ICP with 2 mL/kg of
7.5% saline compared with 2 mL/kg of body weight of 20%
mannitol. Additionally, episodes of elevated ICP requiring
external ventricular drainage and total CSF drained were fewer
in the saline group.25 However, it is critical to assure that
osmolar loads are dosed in a similar fashion to make a valid
comparison. In the Vialet study, the mannitol group received
a much smaller osmolar load, potentially driving the better
result in the saline group.25 Francony et al compared the effectiveness of a single eqimolar infusion of 20% mannitol with
7.45% HS for ICP reduction in a group of patients with a variety of neurologic injuries. They found that both agents were
equally effective at reducing ICP.24 However, only mannitol
increased cerebral perfusion pressure (CPP) and CBF velocities. Based on these results, the authors recommend mannitol
to be first line in patients with poor cerebral perfusion, and
HS to be considered in patients with hypovolemia or hyponatremia.24 The authors allude to an important clinical concern
when choosing mannitol: vigilant attention to volume status
is essential in order to not disrupt hemodynamics. If not
addressed, this point can be a potential confounder in studies
comparing mannitol with HS. Most recently, Ichai et al
compared 3% sodium lactate with 20% mannitol, both dosed at
1.5 mL/kg in a population of patients with TBI.23 Sodium lactate
Hinson et al
Type of
Prospective Trial Agent
Ichai et al
(2009)23
Francony et al
(2008)24
Battison
(2005)25
Harutjunyan
(2005)26
Vialet et al
(2003)27
Randomized
controlled
Randomized
controlled
Randomized
controlled
Randomized
controlled
Randomized
controlled
Condition(s)
Treated
TBI Stroke
Number of
Patients?
Outcome
34
20
40
20
Abbreviations: CBF, cerebral blood flow; CPP, cerebral profusion pressure; GOS, Glascow Outcome Score; HES, hydroxyethyl starch; HS, hypertonic saline; ICP,
intracranial pressure; NS, normal saline; TBI, traumatic brain injury; SAH, subarchnoid hemorrhage
Mannitol
Hypertonic Saline
Renal Failure
Rebound
Metabolic Acidosis
Hypokalemia
Hypovolemia
Ischemic Stroke
Unlike TBI, controversy exists regarding the utility of hyperosmolar agents in ischemic stroke. First, the lack of intact bloodbrain barrier in ischemic stroke is worrisome, based on the fear
that osmotic agents may leak across the compromised
membrane bringing water with the solute. This phenomenon
has been reported in animals, but may not apply to humans.41
Second, mannitol seems to reduce the water content of the
uninjured hemisphere,11 which could worsen midline shift if
present. To address these concerns, Manno et al examined a
group of patients with complete middle cerebral artery (MCA)
infarctions with cerebral edema and administered boluses of
mannitol. They found that a single, large dose of mannitol
(1.5 g/kg of body weight) did not worsen midline shift nor
precipitate neurologic decline in the first hour after administration.9 From a global outcomes perspective, a large retrospective observational study failed to find any effect of routine
mannitol use on outcome at 1 month or 1 year. Of greater concern, depending on the variables entered into the authors
regression model, mannitol appeared either to have no effect
or to be harmful, rendering the authors unable to make any recommendation on the use of mannitol in ischemic stroke.42
However, it is difficult to interpret these results as the treatment
groups were not homogenous enough to be directly comparable, and routine mannitol use is not a common clinical practiceits use usually being reserved for malignant cerebral
edema. The literature does suggest bolus dosing of mannitol
and HS can reduce ICP, but long-term outcomes in these studies were not addressed.43,44 It may be appropriate not to address
long-term outcomes, as patients requiring osmotic therapy for
cerebral edema are usually critically ill. Critical illness entails
many confounders affecting outcome such as ICU-acquired
infections, requiring large numbers of patients to account for
these confounders. Thus, ICP may be the more appropriate
measure of efficacy.
Continuous infusions of osmotic agents have shown less
promise than bolus dosing. Bhardwaj et al found hypertonic
agents might actually increase infarct volume. Utilizing an
MCA occlusion model of stroke in rats, the investigators initiated osmolar therapy with 20% mannitol, 0.9% normal saline,
3% HS, or 7.5% HS at the onset of reperfusion. The group
Subarchnoid Hemorrhage
Both mannitol and HS significantly lower ICP in the animal
model of subarchnoid hemorrhage (SAH).47,48 A recent
Norwegian study compared 30-minute infusions of 2 mL/kg
of 7.2% HS or 0.9% saline (placebo) and measured ICP in
stable SAH patients. The group observed a reduction in ICP
of 3 mm Hg on average compared with 0.3 mm Hg in the
placebo group, as well as an increase in CPP of 5.6 mm Hg
compared with negligible change in CPP in the placebo group.
The authors favored HS over mannitol in the SAH patient population due to the risks of diuresis-induced hypovolemia and
the inherent risks of vasospasm. Additionally, the authors
hypothesize that SAH patients might be more suitable for the
osmotic effect of HS given a relatively intact blood-brain
barrier.49 Cerebral blood flow was of particular interest to
Tseng et al. Their group showed that infusions of 23.5% HS not
only reduced ICP but also increased CBF as evidenced by
continuous transcranial dopplar and Xenon-enhanced computed
tomography scans. Patients with the greatest increases in CBF in
response to HS seemed to also have the most favorable outcomes
as measured by discharge modified Rankin scores.50
Intracerebral Hemorrhage
Investigation of ICP management in intracerebral hemorrhage
with osmotic agents is less robust than in other disease states
like TBI. From the scant human clinical trials, it appears that
scheduled, low dose mannitol (100 mL of 20% dosed every
4 hours) did not improve outcome in ICH patients or change
CBF.51,52 While no clinical trials of HS in the setting of ICH
have been conducted, animal models suggest bolus dosing of
23.4% HS reverses transtentorial herniation and restores
regional CBF.53 In the same animal model, Quereshi et al also
compared bolus 20% mannitol, bolus 23.4% HS, and continuous 3% HS. While all 3 groups showed an initial drop in ICP
values, the investigators noted that only in the 3% group did
the animals have sustained lower ICP.54 This observation
Hinson et al
Liver Failure
Cerebral edema may occur as a consequence of acute,
fulminant liver failure. The presumed mechanism of cerebral
edema relates to ammonia and glutamine causing cytotoxic
injury combined with cerebral vasodilation from the loss of
autoregulation.55,56 Although the definitive therapy for fulminant hepatic failure is liver transplantation, the cerebral edema
may be imminently life-threatening. In the 1980s, mannitol
proved to be more effective than dexamethasone for reducing
cerebral edema and improving outcome in liver failure.57
More recently, interest has shifted to HS. Murphy et al induced
moderate hypernatremia (145-155 mmol/L) with a 24-hour
infusion of 30% saline at 10 mL/hour in a group of liver failure
patients with acute liver failure and Grade III or IV encephalopathy, and measured ICP. The group found that moderate
hypernatremia along with the standard of care interventions
significantly reduced ICP from baseline levels when compared
with standard of care alone. Standard of care was provided to
both patient groups, and included standardized ventilation
management, head of bed elevation, ICP monitoring, N-acetylcystine aministration, hemodynamic monitoring with intervention for hypotension, enteral feeding, prophylactic antibiotics,
and hemoglobin goals.58
Transtentorial Herniation
Mannitol, in combination with hyperventilation, has been
shown to reverse transtentorial herniation in a cohort of
28 patients with a variety of underlying illnesses causing cerebral edema (including neoplasm, ICH, TBI, and ischemic
stroke).59 Hypertonic saline has also shown promise in reversing transtentorial brain herniation. A retrospective analysis
of boluses (30-60 mL) of 23.4% HS reversed 75% of clinical
herniation events in a cohort of patients with a variety of
neurologic illnesses.60
Monitoring
Intracranial Pressure
Hyperosmolar agents are frequently used to reduce ICP and/or
reverse brain herniation events. Thus, it is recommended to
have an ICP monitor in place to aid titration.
Osmolar Gap
Unfortunately, a test for serum mannitol concentration is not
commercially available. Despite its frequent clinical use, serum
osmolality is a poor surrogate for serum mannitol concentrations.65 To surmount this issue, some authors have advocated
the use of osmolar gap (OG) as a method of monitoring mannitol concentrations to avoid complications such as renal failure.
Osmolar gap is the difference between osmolality and osmolarity, which is used to detect the presence of unmeasured osmoles
such as mannitol.62 If the OG falls within the normal range
(varying by formula and patient population), Garcia-Morales
et al assert a patient has sufficiently cleared the mannitol,
and may be redosed.66 It has been suggested that maintaining
an OG below 55 mmol/kg of H2O will help to prevent renal
failure.67 OG may be calculated by several different formulas;
Diringer et al report utilizing 1.86 (Na K) (blood urea
nitrogen/2.8) (glucose/18) 10 provided the best correlation
to measured mannitol levels.62
Complications
Renal Failure
Of particular interest is avoiding renal failure. Mannitol may
become nephrotoxic by several mechanisms, including dosedependent vasoconstriction of the renal artery and intravascular
volume depletion from osmotic diuresis.68,69 In one study, the
mean total dose of mannitol that precipitated acute renal failure
in healthy kidneys was 626 + 270 g over 2 to 5 days.70 There is
an association between prolonged hypernatremia (serum
sodium concentration >160 mEq/L) and oliguric acute renal
failure observed in burn patients receiving HS as resuscitation
fluid.71 Observations of renal failure associated with HS in neurological patients is limited;72,73 however, close monitoring of
renal function is advised. Patients that already require intermittent or continuous renal replacement pose a special challenge to
Conclusion
Nearly a century after mannitol was noted to reduce cerebral
edema, osmotic agents including mannitol still play an important role in the medical management of both cerebral edema
and elevated ICP. Despite the lack of randomized, controlled
trials, our knowledge base on the appropriate clinical use of
osmotic agents continues to expand. While not definitively
superior to mannitol, HS shows promise in not only reducing
ICP but also in reversing neurologic deterioration and improving hemodynamics. Future work will further define agent
selection and dosing regimen. The disease state as well as the
type of edema encountered (vasogenic versus cytotoxic) will
likely guide agent selection as clinical practice evolves.
Authors Note
KNS is supported by an American Academy of Neurology Clinical
Research Award
Rebound Phenomenon
After exposure to osmotic agents, ICP may precipitously rise
back to an elevated level after an initial response. This is
termed the rebound phenomenon and occurs particularly
after mannitol administration. Previously rebound was feared
as a consequence of the osmotic agent leaking into injured tissue across a damaged blood-brain barrier, and pulling water
with it, promoting swelling in the injured area. However, observations of mannitol exiting the brain down its concentration
gradient make this explanation less compelling.62 Rebound is
more likely related to osmotic compensation within the central
nervous system, allowing for increased intracellular concentrations of electrolytes. Repeated administration of osmotic
agents, especially in the setting of poor CNS compliance where
small volemic changes result in dramatic changes in ICP,
promote the rebound phenomenon.75 Additionally, repeat
dosing or continuous infusions of these agents without time
allotted for the osmotic agent to clear might also contribute
to this phenomenon.
Metabolic Acidosis
Hypertonic saline inhibits the resorption of bicarbonate from
the proximal renal tubules. It may also produce hyperchloremic
metabolic acidosis from the large amount of chloride delivered
in the fluid. One possible solution to this problem is to change
the fluid admixture to 50:50 sodium chloride-sodium acetate.76
Hypokalemia
Hypokalemia might also be encountered as the kidney
exchanges potassium for sodium in the distal tubule. Addition
of potassium to maintenance fluids may correct this.
Funding
The authors received no financial support for the research and/or
authorship of this article.
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