Possible new mechanism underlying hypertonic saline

therapy for cerebral edema

Adam Chodobski

Journal of Applied Physiology 100:1437-1438, 2006. doi:10.1152/japplphysiol.01560.2005

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on the following topics:
Chemistry .. Osmosis
Physiology .. Rats
Neuroscience .. Brain Edema
Medicine .. Brain Injuries
Medicine .. Edema
Medicine .. Epidemiology

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J Appl Physiol 100: 14371438, 2006;

doi:10.1152/japplphysiol.01560.2005.

Invited Editorial

Possible new mechanism underlying hypertonic saline therapy

for cerebral edema

http://www. jap.org

activity of the Na-K-2Cl cotransporter, an important cell

volume regulator, and its ability to affect the function of the
ATP- and calcium-sensitive K channels, may play a role in
the formation of cellular edema. Consistent with this concept,
a 50% reduction in brain water content has been shown in
Na-K-2Cl cotransporter knockout mice subjected to middle cerebral artery occlusion (4). The AVP-mediated disruption
of the BBB may, in turn, be related to the ability of AVP to
promote the formation of stress fibers, an action likely amplified by the increased AVPR1A expression seen in cerebral
microvessels after injury.
This new mechanism suggested by Chang et al., by which
HS infusion would alleviate cerebral edema, is possible; however, further studies are needed to test this hypothesis. At a first
glance, the decrease in serum AVP levels in response to HS, a
potent stimulus for AVP synthesis and release, appears paradoxical. These observations are, however, consistent with previous studies in patients who underwent coronary bypass
surgery, or had burn injuries, and were treated with HS solutions (5, 6). In these patients, no correlation was found between
plasma osmolality and AVP levels. It is thus possible that the
normal hyperosmotic regulation of AVP synthesis and release
is impaired under conditions of injury or stress. Unfortunately,
Chang et al. do not provide an explanation of why, in ischemic
rats, the serum AVP levels drop after HS infusion.
The authors opted for a continuous 3-day infusion rather
than multiple bolus injections of HS. Such an approach leads to
a gradual intracellular accumulation of organic osmolytes, a
part of brain adaptation to chronic hyperosmolality, and, consequently, carries a risk of rebound edema after the end of HS
infusion. In fact, brain areas where the BBB is intact and that
are, therefore, the most responsive to HS are also the most
susceptible to rebound edema. Therefore, an effective strategy
for weaning from chronic HS infusion has to be developed
before this mode of osmotherapy could safely be used in
humans. Another important variable that requires further study
is the timing of the initiation of HS therapy. Indeed, the same
group has previously demonstrated that, when HS infusion is
started immediately after reperfusion, it can have deleterious
effects (1). Finally, a potential risk of myelinolysis associated
with HS therapy should be taken into consideration. Although
demyelination has traditionally been associated with the rapid
correction of hyponatremia, several cases of pontine and extrapontine myelinolysis have also been reported in hypernatremic patients (2, 8).
In summary, the study by Chang and colleagues provides
further evidence to support the use of HS solutions to combat
cerebral edema. The authors also give us a hint about a potential
novel mechanism by which osmotherapy may control edema
formation. However, as with any clinically important problem,
this report leaves us with many questions that require answers
before HS can become commonly accepted for clinical use.
REFERENCES
1. Bhardwaj A, Harukuni I, Murphy SJ, Alkayed NJ, Crain BJ, Koehler
RC, Hurn PD, and Traystman RJ. Hypertonic saline worsens infarct
volume after transient focal ischemia in rats. Stroke 31: 1694 1701, 2000.

8750-7587/06 $8.00 Copyright 2006 the American Physiological Society

1437

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CEREBRAL EDEMA IS A SIGNIFICANT cause of mortality in patients

with traumatic brain injury and ischemic or hemorrhagic
stroke. Yet our understanding of the cellular and molecular
mechanisms underlying this condition is rather limited, and
new treatments showing promise in laboratory studies have
frequently been found ineffective in clinical practice. Two
types of edema, namely vasogenic and cellular/cytotoxic, occur
in brain injury. Vasogenic edema is predominantly associated
with the expansion of the extracellular space caused by the
disruption of the blood-brain barrier (BBB), whereas cellular
edema refers to the intracellular accumulation of water. With
the paucity of currently available treatments, hyperosmotic
therapy is a strategy of choice to cope with increased brain
water content. Mannitol is the osmotically active agent most
commonly employed in clinical practice; however, there has
been an increasing interest in using hypertonic saline (HS)
instead of mannitol for osmotherapy (9). Indeed, HS has been
shown to be effective in patients who did not respond to
mannitol. Unlike mannitol infusions, HS therapy does not
appear to be associated with the risk of renal insufficiency, and
thus HS may be used to produce higher plasma osmolalities
without serious adverse effects.
Creation of an osmotic force that draws water from brain
tissue into the intravascular space is by no means the only
mechanism underlying the beneficial effects of HS infusions.
Although these mechanisms are still incompletely understood,
there is good evidence that the decrease in hematocrit and
blood viscosity, and possibly the dehydration of erythrocytes
and cerebrovascular endothelium, play an important role in
improving blood flow and, consequently, reducing ischemic
injury and edema. The study by Chang et al. (3) in this issue of
the Journal of Applied Physiology suggests yet another mechanism by which HS may reduce brain edema. The authors used
a rat model of transient focal ischemia produced by the occlusion of the middle cerebral artery. With a several-hour delay
following reperfusion, the animals were continuously infused
with 7.5% HS that significantly decreased brain water content
3 days after the insult. This therapy was more effective than
mannitol infusions. The most important and novel finding
reported by Chang et al. was the reduction in serum argininevasopressin (AVP) levels in response to HS, which, as proposed by the authors, may represent an additional mechanism
by which osmotherapy attenuates the edema associated with
ischemic stroke.
AVP has long been postulated to play a role in promoting the
formation of edema in various forms of brain injury. Animal
experiments have demonstrated the efficacy of AVP subtype 1a
receptor (AVPR1A) antagonists in decreasing the permeability
of the BBB and reducing edema after injury, consistent with
augmented AVPR1A expression in the injured brain (10).
These laboratory findings are consistent with the increased
serum AVP concentrations previously observed in patients
with ischemic stroke (7) and now also found by Chang and
colleagues in a rat model of cerebral ischemia. The mechanisms by which AVP exacerbates cerebral edema remain
unclear, but the ability of this neuropeptide to stimulate the

Invited Editorial
1438

HYPERTONIC SALINE THERAPY FOR CEREBRAL EDEMA

2. Brown WD and Caruso JM. Extrapontine myelinolysis with involvement of the hippocampus in three children with severe hypernatremia.
J Child Neurol 14: 428 433, 1999.
3. Chang Y, Chen TY, Chen CH, Crain BJ, Toung TJK, and Bhardwaj
A. Plasma arginine-vasopressin following experimental stroke: effect of
osmotherapy. J Appl Physiol 100: 14451451, 2006.
4. Chen H, Luo J, Kintner DB, Shull GE, and Sun D. Na-dependent chloride
transporter (NKCC1)-null mice exhibit less gray and white matter damage after
focal cerebral ischemia. J Cereb Blood Flow Metab 25: 5466, 2005.
5. Cross JS, Gruber DP, Gann DS, Singh AK, Moran JM, and Burchard
KW. Hypertonic saline attenuates the hormonal response to injury. Ann
Surg 209: 684 691, 1989.
6. Crum R, Bobrow B, Shackford S, Hansbrough J, and Brown MR. The
neurohumoral response to burn injury in patients resuscitated with hypertonic saline. J Trauma 28: 11811187, 1988.
7. Franceschini R, Tenconi GL, Zoppoli F, and Barreca T. Endocrine
abnormalities and outcome of ischaemic stroke. Biomed Pharmacother 55:
458 465, 2001.

8. McComb RD, Pfeiffer RF, Casey JH, Wolcott G, and Till DJ.
Lateral pontine and extrapontine myelinolysis associated with
hypernatremia and hyperglycemia. Clin Neuropathol 8: 284 288,
1989.
9. Suarez JI. Hypertonic saline for cerebral edema and elevated intracranial
pressure. Cleve Clin J Med 71, Suppl 1: S9 S13, 2004.
10. Szmydynger-Chodobska J, Chung I, Kozniewska E, Tran B, Harrington FJ, Duncan JA, and Chodobski A. Increased expression of
vasopressin V1a receptors after traumatic brain injury. J Neurotrauma 21:
1090 1102, 2004.

Adam Chodobski
Department of Clinical Neurosciences
Brown University School of Medicine
Providence, Rhode Island
e-mail: Adam_Chodobski@brown.edu

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J Appl Physiol VOL

100 MAY 2006

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