doi: 10.1161/01.STR.0000012517.43732.D8
(Stroke. 2002;33:1166.)
© 2002 American Heart Association, Inc.
Letters to the Editor |
Use of Hypertonic Saline in Ischemic Stroke
Neurosciences Critical Care Division, Johns Hopkins University School of Medicine, Baltimore, Maryland
To the Editor:
We read with interest the article recently published by Schwarz et al.1 In a small prospective study (n=8 patients), the authors report that an intravenous bolus injection of 10% hypertonic saline lowered intracranial pressure (ICP) (with or without clinical herniation) in patients with stroke for a duration of 4 hours after failure to observe such a response to intravenous administration of 20% mannitol. The conclusions reached by the authors are difficult to reconcile for 2 reasons: (1) the criterion for ICP reduction to <10% of pretreatment values is arbitrary; and (2) patients received different combinations of ICP-lowering therapies (2 patients with decompressive hemicraniectomy, 4 patients with hypothermia, and 2 patients with cerebrospinal fluid drainage via intraventricular catheter), and timing of these interventions remains unclear.
Various concentrations of hypertonic saline solutions have been used for the treatment of cerebral edema and elevated ICP from diverse etiologies.2 We3,4 and others have previously reported a similar beneficial effect of hypertonic saline in patients with elevated ICP, although the patient populations in our reports were more heterogeneous, including patients with traumatic brain injury, brain tumors, intracerebral hemorrhage, and ischemic stroke. Thus, the reported efficacy of hypertonic saline in ameliorating elevated ICP over a short period of observation is not unique, and some fundamental questions regarding its utility, especially in ischemic and hemorrhagic strokes, remain unanswered.
First, is hypertonic saline more efficacious than the widely used and accepted osmotic agent mannitol as a first-line therapy for treatment of elevated ICP and brain resuscitation? The answer to this question would require a well-executed prospective, randomized, blinded trial comparing equiosmolar concentrations as well as equal volumes of hypertonic saline and mannitol in patients with elevated ICP. Such a study is long overdue. Carefully defined end points, including timing, duration, and the osmolar load required to ameliorate elevated ICP (degree, duration of decrement, "rebound’ increases in ICP), are key elements that are presently being examined by such an ongoing study at our institution. Second, what is the long-term outcome in patients with ischemic stroke when treated with hypertonic saline? Differential effects of hypertonic saline on accompanying edema during cerebral ischemia (cytotoxic and vasogenic) are not well studied. We point out that midline shift on CT scans performed within 72 hours of admission in our case series was worsened with induction and maintenance of systemic hypernatremia with hypertonic saline in patients with cerebral infarction.2
Third, and more importantly, is hypertonic saline deleterious to the brain during cerebral ischemia? Experimental evidence suggests this to be the case. Under controlled experimental conditions, in a well-characterized intraluminal suture model of focal cerebral ischemia (middle cerebral artery occlusion) in the rat, we have demonstrated that a hypernatremic state (serum Na+ 145 to 155 mEq/L; osmolality 310 to 320 mOsm/L) induced and maintained with continuous hypertonic saline infusion intravenously started at 2 hours of ischemia onset markedly worsened infarction volume compared with saline-treated controls.5 While the mechanism(s) of this deleterious effect is unclear, it was demonstrated that this was not due to unfavorable redistribution of regional cerebral blood flow during early reperfusion. Furthermore, in this study hypertonic saline did not cause neuronal or glial injury in naive nonischemic rats. Conversely, the effects of mannitol on ischemic stroke have yielded mixed results.6 Its neuroprotective effects in cerebral ischemia are attributed largely to its nonosmotic and rheological properties.6 However, our experimental study demonstrated a trend toward worsening of infarction volume with continuous intravenous mannitol infusion to achieve and maintain a target serum osmolality.5 It has been previously suggested6 that all these studies may have partial validity, and results are dependent on different experimental techniques and models used. In our opinion, the outcomes are largely dependent on the timing of onset, duration of treatment with osmotic agents, and integrity of the blood-brain barrier in relation to evolution and "maturation" of the ischemic lesion. Thus, while hypertonic saline may ameliorate elevated ICP over a short period of observation, its long-term effects (eg, "rebound" in ICP, stroke volume) remain largely unknown, especially in the cerebral ischemia paradigm. Until some of these important questions are answered with carefully performed experiments in appropriate animal models and with clinical trials, caution is advised in using hypertonic saline solutions in patients with ischemic stroke.
References
1.
Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of hypertonic (10%) saline in patients with raised intracranial pressure after stroke. Stroke. 2002; 33: 136–140.
2. Bhardwaj A, Ulatowski JA. Cerebral edema: hypertonic saline solutions. Curr Treat Options Neurol. 1999, 1: 179–188.[Medline] [Order article via Infotrieve]
3. Qureshi AI, Suarez JI, Bhardwaj A, Mirski MA, Schnitzer MS, Hanley DF, Ulatowski JA. Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema: effect on intracranial pressure and lateral displacement of the brain. Crit Care Med. 1998; 26: 440–446.[CrossRef][Medline] [Order article via Infotrieve]
4. Suarez JI, Qureshi AI, Bhardwaj A, Williams MA, Schnitzer MS, Mirski M, Hanley DF, Ulatowski JA. Treatment of refractory intracranial hypertension with 23.4% saline. Crit Care Med. 1999; 26: 1118–1122.
5.
Bhardwaj A, Harukuni I, Murphy SJ, Alkayed NJ, Crain BJ, Koehler RC, Hurn PD, Traystman RJ. Hypertonic saline worsens infarct volume after transient focal ischemia in rats. Stroke. 2000; 31: 1694–7001.
6. Paczynski RP. Osmotherapy: basic concepts and controversies. Crit Care Clin. 1997; 13: 105–129.[CrossRef][Medline] [Order article via Infotrieve]
Department of Neurology
Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
Response
We appreciate the valid comments of the correspondents, which reinforce many of the points we made in our article.1 We fully agree that large randomized trials are necessary to evaluate both the possible benefits and negative effects of hypertonic solutions such as hypertonic saline or mannitol in the treatment of intracranial hypertension. However, the points of criticism raised by Ziai et al miss the aim of our study. We did not attempt to evaluate the long-term effects of hypertonic saline or to compare different osmotic agents (which we did previously in a randomized study2). In this study we investigated the efficacy of hypertonic saline in patients with ischemic stroke with an acute intracranial pressure (ICP) crisis after conventional therapies, including mannitol, had failed, and our data clearly show that hypertonic saline can successfully be used in this life-threatening emergency situation. Of course, our criterion for ICP reduction to <10% of pretreatment values is arbitrary. Since no other criteria have been established yet, use of arbitrary criteria is the only way to perform this type of study. Of course, our patient population is not entirely homogeneous; in an intensive care unit setting, it is nearly impossible to establish a homogeneous patient population. This is also a critical point in a previous study on the use of hypertonic saline for brain edema by 2 of the correspondents, in which patients with traumatic brain injury, brain tumor, intracranial hemorrhage, and ischemic stroke were mixed.3 Although we certainly agree that a randomized trial would be desirable, we are doubtful that results from a "well-executed prospective, randomized, blinded trial" addressing the very specific question of our study will be available in the near future.
References
1. Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of hypertonic (10%) saline in patients with raised intracranial pressure after stroke. Stroke. 2002; 33: 136–140.
2.
Schwarz S, Schwab S, Bertram M, Aschoff A, Hacke W. Effects of hypertonic saline hydroxyethyl starch solution and mannitol in patients with increased intracranial pressure after stroke. Stroke. 1998; 29: 1550–1555.
3. Qureshi AI, Suarez JI, Bhardwaj A, Mirski M, Schnitzer MS, Hanley DF, Ulatowski JA. Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema: effect on intracranial pressure and lateral displacement of the brain. Crit Care Med. 1998; 26: 440–446.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||