Possible new mechanism underlying hypertonic therapy for Adam Chodobski Journal of Applied Physiology 100:1437-1438, 2006. doi:10.1152/japplphysiol.01560.2005

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This article cites 10 articles, 1 of which you can access free at: http://jap.physiology.org/cgi/content/full/100/5/1437#BIBL Medline items on this article's topics can be found at http://highwire.stanford.edu/lists/artbytopic.dtl on the following topics: Chemistry .. Osmosis Physiology .. Rats Neuroscience .. Brain Edema Medicine .. Brain Injuries Medicine .. Edema Medicine .. Epidemiology Updated information and services including high-resolution figures, can be found at: http://jap.physiology.org/cgi/content/full/100/5/1437 Downloaded from Additional material and information about Journal of Applied Physiology can be found at: http://www.the-aps.org/publications/jappl

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Journal of Applied Physiology publishes original papers that deal with diverse areas of research in applied physiology, especially those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the American Physiological Society. ISSN: 8750-7587, ESSN: 1522-1601. Visit our website at http://www.the-aps.org/. J Appl Physiol 100: 1437–1438, 2006; doi:10.1152/japplphysiol.01560.2005. Invited Editorial

Possible new mechanism underlying hypertonic saline therapy for cerebral edema

ϩ ϩ Ϫ CEREBRAL EDEMA IS A SIGNIFICANT cause of mortality in patients activity of the Na -K -2Cl cotransporter, an important cell with and ischemic or hemorrhagic volume regulator, and its ability to affect the function of the . Yet our understanding of the cellular and molecular ATP- and calcium-sensitive Kϩ channels, may play a role in mechanisms underlying this condition is rather limited, and the formation of cellular edema. Consistent with this concept, new treatments showing promise in laboratory studies have a 50% reduction in brain water content has been shown in frequently been found ineffective in clinical practice. Two Naϩ-Kϩ-2ClϪ cotransporter knockout mice subjected to mid- types of edema, namely vasogenic and cellular/cytotoxic, occur dle cerebral artery occlusion (4). The AVP-mediated disruption in brain injury. Vasogenic edema is predominantly associated of the BBB may, in turn, be related to the ability of AVP to with the expansion of the extracellular space caused by the promote the formation of stress fibers, an action likely ampli- disruption of the blood-brain barrier (BBB), whereas cellular fied by the increased AVPR1A expression seen in cerebral edema refers to the intracellular accumulation of water. With microvessels after injury. the paucity of currently available treatments, hyperosmotic This new mechanism suggested by Chang et al., by which therapy is a strategy of choice to cope with increased brain HS infusion would alleviate cerebral edema, is possible; how- water content. is the osmotically active agent most ever, further studies are needed to test this hypothesis. At a first commonly employed in clinical practice; however, there has glance, the decrease in serum AVP levels in response to HS, a Downloaded from been an increasing interest in using hypertonic saline (HS) potent stimulus for AVP synthesis and release, appears para- instead of mannitol for osmotherapy (9). Indeed, HS has been doxical. These observations are, however, consistent with pre- shown to be effective in patients who did not respond to vious studies in patients who underwent coronary bypass mannitol. Unlike mannitol infusions, HS therapy does not surgery, or had burn injuries, and were treated with HS solu- appear to be associated with the risk of renal insufficiency, and tions (5, 6). In these patients, no correlation was found between thus HS may be used to produce higher plasma osmolalities plasma osmolality and AVP levels. It is thus possible that the without serious adverse effects. normal hyperosmotic regulation of AVP synthesis and release jap.physiology.org Creation of an osmotic force that draws water from brain is impaired under conditions of injury or stress. Unfortunately, tissue into the intravascular space is by no means the only Chang et al. do not provide an explanation of why, in ischemic mechanism underlying the beneficial effects of HS infusions. rats, the serum AVP levels drop after HS infusion. Although these mechanisms are still incompletely understood, The authors opted for a continuous 3-day infusion rather there is good evidence that the decrease in hematocrit and than multiple bolus injections of HS. Such an approach leads to blood viscosity, and possibly the dehydration of erythrocytes a gradual intracellular accumulation of organic osmolytes, a and cerebrovascular endothelium, play an important role in part of brain adaptation to chronic hyperosmolality, and, con- on April 14, 2006 improving blood flow and, consequently, reducing ischemic sequently, carries a risk of rebound edema after the end of HS injury and edema. The study by Chang et al. (3) in this issue of infusion. In fact, brain areas where the BBB is intact and that the Journal of Applied Physiology suggests yet another mech- are, therefore, the most responsive to HS are also the most anism by which HS may reduce brain edema. The authors used susceptible to rebound edema. Therefore, an effective strategy a rat model of transient focal produced by the occlu- for weaning from chronic HS infusion has to be developed sion of the middle cerebral artery. With a several-hour delay before this mode of osmotherapy could safely be used in following reperfusion, the animals were continuously infused humans. Another important variable that requires further study with 7.5% HS that significantly decreased brain water content is the timing of the initiation of HS therapy. Indeed, the same group has previously demonstrated that, when HS infusion is 3 days after the insult. This therapy was more effective than started immediately after reperfusion, it can have deleterious mannitol infusions. The most important and novel finding effects (1). Finally, a potential risk of myelinolysis associated reported by Chang et al. was the reduction in serum arginine- with HS therapy should be taken into consideration. Although (AVP) levels in response to HS, which, as pro- demyelination has traditionally been associated with the rapid posed by the authors, may represent an “additional mechanism correction of , several cases of pontine and ex- by which osmotherapy attenuates the edema associated with trapontine myelinolysis have also been reported in hypernatre- ischemic stroke.” mic patients (2, 8). AVP has long been postulated to play a role in promoting the In summary, the study by Chang and colleagues provides formation of edema in various forms of brain injury. Animal further evidence to support the use of HS solutions to combat experiments have demonstrated the efficacy of AVP subtype 1a cerebral edema. The authors also give us a hint about a potential receptor (AVPR1A) antagonists in decreasing the permeability novel mechanism by which osmotherapy may control edema of the BBB and reducing edema after injury, consistent with formation. However, as with any clinically important problem, augmented AVPR1A expression in the injured brain (10). this report leaves us with many questions that require answers These laboratory findings are consistent with the increased before HS can become commonly accepted for clinical use. serum AVP concentrations previously observed in patients with ischemic stroke (7) and now also found by Chang and REFERENCES colleagues in a rat model of cerebral ischemia. The mecha- 1. Bhardwaj A, Harukuni I, Murphy SJ, Alkayed NJ, Crain BJ, Koehler nisms by which AVP exacerbates cerebral edema remain RC, Hurn PD, and Traystman RJ. Hypertonic saline worsens infarct unclear, but the ability of this neuropeptide to stimulate the volume after transient focal ischemia in rats. Stroke 31: 1694–1701, 2000. http://www.jap.org 8750-7587/06 $8.00 Copyright © 2006 the American Physiological Society 1437 Invited Editorial

1438 HYPERTONIC SALINE THERAPY FOR CEREBRAL EDEMA

2. Brown WD and Caruso JM. Extrapontine myelinolysis with involve- 8. McComb RD, Pfeiffer RF, Casey JH, Wolcott G, and Till DJ. ment of the hippocampus in three children with severe hypernatremia. Lateral pontine and extrapontine myelinolysis associated with J Child Neurol 14: 428–433, 1999. hypernatremia and hyperglycemia. Clin Neuropathol 8: 284–288, 3. Chang Y, Chen TY, Chen CH, Crain BJ, Toung TJK, and Bhardwaj 1989. A. Plasma arginine-vasopressin following experimental stroke: effect of 9. Suarez JI. Hypertonic saline for cerebral edema and elevated intracranial osmotherapy. J Appl Physiol 100: 1445–1451, 2006. pressure. Cleve Clin J Med 71, Suppl 1: S9–S13, 2004. ϩ 4. Chen H, Luo J, Kintner DB, Shull GE, and Sun D. Na -dependent chloride 10. Szmydynger-Chodobska J, Chung I, Kozniewska E, Tran B, Har- transporter (NKCC1)-null mice exhibit less gray and damage after rington FJ, Duncan JA, and Chodobski A. Increased expression of focal cerebral ischemia. J Cereb Blood Flow Metab 25: 54–66, 2005. vasopressin V1a receptors after traumatic brain injury. J Neurotrauma 21: 5. Cross JS, Gruber DP, Gann DS, Singh AK, Moran JM, and Burchard 1090–1102, 2004. 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 Adam Chodobski neurohumoral response to burn injury in patients resuscitated with hyper- Department of Clinical Neurosciences tonic saline. J Trauma 28: 1181–1187, 1988. 7. Franceschini R, Tenconi GL, Zoppoli F, and Barreca T. Endocrine Brown University School of Medicine abnormalities and outcome of ischaemic stroke. Biomed Pharmacother 55: Providence, Rhode Island 458–465, 2001. e-mail: [email protected] Downloaded from jap.physiology.org on April 14, 2006

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