Surgical Neurology 65 (2006) 539 546 www.surgicalneurology-online.

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Technique

Efficacy and safety of hypertonic saline solutions in the treatment of severe head injury
Sheng-Jean Huang, MDa,b, Lin Changa, Yin-Yi Han, MDb, Yuan-Chi Lee, MD, PhDb, Yong-Kwang Tu, MD, PhDa,4
a

Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan, ROC b Department of Traumatology, National Taiwan University Hospital, Taipei 100, Taiwan, ROC Received 15 May 2005; accepted 2 November 2005

Abstract

Background: The present study was undertaken to evaluate the efficacy and safety of hypertonic saline (HS) in the treatment of intracranial hypertension after severe head injury. Methods: This prospective, observational study was performed in an 11-bed neurosurgery intensive care unit of a teaching hospital. From February 2002 to September 2004, 18 severely head-injured patients with elevated intracranial pressure (ICP) and Glasgow Coma Scale scores of 5 to 8 (mean, 5.9 F 1.2) were admitted to the unit and treated according to a standard protocol. One dose per day of 3% saline was administered by rapid infusion (300 mL/20 min) when ICP values exceeded 20 mm Hg. After infusion, cerebral blood flow, ICP, blood pressure, end-tidal carbon dioxide, and heart rate were monitored continuously for 60 minutes and recorded. Serum osmolarity, sodium, potassium, chloride, arterial carbon dioxide pressure, arterial oxygen pressure, hemoglobin, lactic acid, and pH were measured immediately before infusion (zero time) and 20 and 60 minutes after infusion. Mean arterial pressure, cerebral perfusion pressure (CPP), mean flow velocity (MFV), and pulsatility index (PI) were also recorded and analyzed. Results: Intracranial pressure fell immediately after initiation of infusion with further significant decreases observed at 20 and 60 minutes (30.4 F 8.5, 24.3 F 7.4, and 23.8 F 8.3 mm Hg, respectively; P b .01). At these respective times CPP increased significantly (78.7 F 8.7, 83.2 F 7.8, and 87.2 F 12.8 mm Hg), PI dropped rapidly (1.51 F 0.42, 1.38 F 0.32, and 1.34 F 0.33) and MFV increased (66.26 F 25.91, 71.92 F 28.13, and 68.74 F 28.44). Serum sodium increased from 141.3 F 7.2 to 146.3 F 7.2 mmol/L after 20 minutes and returned to 144.3 F 7.36 mmol/L at 60 minutes. Potassium concentrations decreased significantly from 3.9 F 0.39 to 3.55 F 0.35 mmol/L after 20 minutes ( P b .01). Lactic acid values at 0, 20, and 60 minutes were 1.6 F 0.5, 1.47 F 0.48, and 1.38 F 0.53 mmol/L, respectively ( P b .01). Conclusion: Rapid infusion of single dose daily of HS is a safe alternative for the treatment of elevated ICP in severe head injury. Further evaluations of long-term consequences and complications and of maximal tolerance to this treatment are required. D 2006 Elsevier Inc. All rights reserved.
Severe head injury; Intracranial pressure; Hypertonic saline; Cerebral blood flow

Keywords:

Abbreviations: BE, base excess; Ca, Calcium; CBF, cerebral blood flow; CPP, cerebral perfusion pressure; CVP, central venous pressure; Etco2, end-tidal carbon dioxide pressure; GCS, Glasgow coma scale; HCO3, Hydrogen bicarbonate; HS, hypertonic saline; ICP, intracranial pressure; ICU, intensive care unit; IICP, increased intracranial pressure; IH, intracranial hypertension; MAP, mean arterial pressure; MCA, middle cerebral artery; MFV, mean flow velocity; Osm, osmolality; PaO2, arterial oxygen pressure; PaCO2, arterial carbon dioxide pressure; PI, pulsatility index; Sao2, oxygen saturation; TCD, transcranial Doppler. 4 Corresponding author. Tel.: +886 2 2312 3456x5078; fax: +886 2 23417454. E-mail address: yktu@ha.mc.ntu.edu.tw (Y.-K. Tu). 0090-3019/$ see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2005.11.019

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1. Introduction Cerebral edema, particularly vasomotor edema, occurs within the first few days after head injury and can lead to severe IH, brain tissue shift, transtentorial herniation, and, possibly, brain death. Increased ICP has traditionally been treated with head elevation, maintenance of venous outflow, controlled hyperventilation, drainage of cerebrospinal fluid, osmotic diuresis, decompressive craniectomy, and barbiturate administration [3,15,25,26]. However, all these modalities have limitations [23,29,46]. The efficacy of HS solution in treatment of IH has been recently investigated in studies utilizing rats, rabbits, or humans as subjects [9,17,41,49,55]. Certain adverse effects of this method were observed in some of these studies [49,55]. The purpose of the present study, therefore, was to evaluate more extensively the efficacy and safety of HS in the treatment of patients with IH. 2. Methods 2.1. Subjects This prospective, single-center study was performed between February 2002 and September 2004. This research project was approved by the Institutional Ethics Committee, and signed, written informed consent was provided by a close relative. This research is in compliance with the Declaration of Helsinki. Patients with severe head injury were evaluated after admission to the level I neurosurgical ICU of the National Taiwan University Hospital. Patients aged 18 to 75 years and who presented with Glasgow Coma Scale [48] scores of 5 to 8 (mean, 5.9 F 1.2) and ICP values greater than 20 mm Hg were included in this study. There were 46 patients who met the inclusion criteria. Among them, 18 patients signed the informed consents and were enrolled into this study. They were treated in the neurocritical care unit according to a standard protocol. 2.2. Procedure In the neurocritical care unit, mannitol 0.25 to 1.0 g/kg was administered whenever the patients ICP is equal to or greater than 20 mm Hg. For the patients entering this study, 300 mL of 3% saline was administered to replace mannitol by rapid infusion (900 mL/h) when needed. To avoid possible hypernatremia after repeated infusion, this replacement was only applied once in 24 hours. Serum osmolarity, sodium, potassium, chloride, calcium, arterial carbon dioxide pressure, arterial oxygen pressure, hemoglobin, lactic acid, base excess, and pH values were determined for arterial blood samples withdrawn at zero time (immediately before infusion), at 20 minutes (termination of infusion), and at 60 minutes. MAP, CPP, defined as MAP minus ICP, ICP, MFV, PI, end-tidal carbon dioxide (ETco2), and heart rate were recorded continuously for 60 minutes and analyzed. CBF was monitored by continuous TCD. During the course of recordings, all patients

were mechanically ventilated, sedated, and paralyzed to minimize ICP-interfering factors. Events associated with factors confounding ICP, CPP, or CBF measurements, such as coughing, suction, agitation, or unexpected nursing activities observed during treatments, were excluded. 2.3. Standard clinical management During the stay in the ICU, the head of the bed was elevated by 308. The neck was kept in a neutral position. End-tidal carbon dioxide was maintained at approximately 30 to 35 mm Hg, and Sao2 as measured by an oximeter was maintained at 99% to 100%. Crystalloid and colloid solutions were used to provide euvolemia or mild hypervolemia. Central venous pressure (monitored via the femoral vein) was kept at 8 to 12 mm Hg. Levophed and dopamine were administered as required to maintain CPP values at greater than 70 mm Hg. Some patients received sedatives and neuromuscular blockers during postoperative intensive care for ICP control. Osmotherapy with intravenous mannitol (20% solution, 3 -6 times per day, 0.25-1 g/kg) was administered whenever an acute increase in ICP was observed. All signals were transmitted to an HP monitor (model 66s-M116A) through a pressure transducer and module.

Fig. 1. A: ICP and CPP, B: MFV, and C: PI change after 300 mL 3% saline infusion.

S.-J. Huang et al. / Surgical Neurology 65 (2006) 539 546 Table 1 Effect to ICP and CBF 0 min ICP CPP MFV PI 30.4 78.7 66.26 1.51 F F F F 8.5 8.7 25.91 0.42 20 min 24.3 83.2 71.92 1.38 F F F F 7.4 7.8 28.13 0.32 60 min 23.8 87.2 68.74 1.34 F F F F 8.3 12.8 28.44 0.33 a, b a, b, c a a, b

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a: P b .05 between b0 minQ and b20 minQ; b: P b .05 between b0 minQ and b60 minQ; c: P b .05 between b20 minQ and b60 min.Q

2.4. Cerebral monitoring The TCD insonation was performed using a 2-MHz real-time and pulse-Doppler transducer. For continuous monitoring, the 2-MHz probe was applied at a temporal window with a fixed head holder (Spenser Marco 600) connected to the TCD monitor (Nicolet/EME Companion II, Germany) to detect the middle cerebral artery at the depth of 55 to 65 cm and to record the MFV. An intraparenchymal ICP monitor (Codman electrode MicroSensor, Johnson & Johnson Medical, Ltd, New Jersey) was used for monitoring the ICP. The ICP monitor was connected to an HP monitor (model 66s-M116A) via a pressure transducer (Codman neuromonitor interface control unit, 82-6605) and module. All necessary pretreatments and care were completed before initiation of the HS infusion. The patient was subjected to continuous TCD monitoring, the ventilator was set such that the ETco2 was stabilized between 30 and 35 mm Hg, and arterial blood was harvested for baseline measurements of blood gases (0 minutes). The HS solution was then administered within 20 minutes, and arterial blood was aspirated at 20 and 60 minutes for data analyses. Stimulation to patients during this period was prevented, and MFV and PI were continuously recorded with the TCD monitor. In addition, blood pressure, ICP, CPP, ETco2, Sao2, and body temperature were recorded for 24 hours continuously in the ICU. 2.5. Data collection Patient data were collected prospectively by standard procedures. Data included age, initial Glasgow Coma Scale, ICP, MAP, CPP, MFV, PI, and hemoglobin and blood chemistry values. 2.6. Data analysis All data are presented as mean F SD. Repeatedmeasures analysis of variance was used between groups. Statistical significance was defined as a P value of less than .05. Commercially available software (version 10.0, SPSS, Inc, Chicago, Ill) was used. 3. Results For the 18 patients included in the study, 38 events occurred for which HS infusion was performed. However, three of these events were found to be attributable to

coughing, agitation, and unexpected nursing activity. Therefore, 35 events were recruited for this study. Intracranial pressure fell immediately after initiation (Fig. 1 and Table 1) of infusion with further significant decreases observed at 20 and 60 minutes (30.4 F 8.5, 24.3 F 7.4, and 23.8 F 8.3 mm Hg, respectively). At these respective times CPP increased significantly (78.7 F 8.7, 83.2 F 7.8, and 87.2 F 12.8 mm Hg), PI dropped rapidly (1.51 F 0.42, 1.38 F 0.32, and 1.34 F 0.33) and MFV increased (66.26 F 25.91, 71.92 F 28.13, and 68.74 F 28.44). Serum sodium (142.0 F 6.7 mmol/L) and chloride concentrations both increased modestly after 20 minutes (146.6 F 7.0 mmol/L) but then declined to approach (Fig. 2) pretreatment concentrations 60 minutes later (144.8 F 7.0 mmol/L). Potassium concentrations decreased significantly after 20 minutes (from 3.8 F 0.4 to 3.5 F 0.4 mmol/L). Lactic acid values at 0, 20, and 60 minutes (Fig. 3) were

Fig. 2. A: Sodium, B: potassium, C: chloride, and D: calcium concentration at 0 (before), 20, and 60 minutes during HS infusion study.

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S.-J. Huang et al. / Surgical Neurology 65 (2006) 539 546 Table 2 Complete electrolyte profile after 300 mL 3% saline ABG Na K Cl pH Hb Lactic acid Osm Ca HCO3 BE 0 min 142.0 F 6.7 3.8 F 0.4 111.0 F 7.4 7.504 F 0.034 10.6 F 1.5 1.8 F 0.8 282.6 F 13.5 0.97 F 0.15 23.0 F 2.5 0.9 F 2.6 20 min 146.6 F 7.0 3.5 F 0.4 116.9 F 7.3 7.488 F 0.034 9.9 F 1.5 1.6 F 0.7 291.2 F 14.3 0.90 F 0.16 22.3 F 2.4 0.2 F 2.5 60 min 144.8 F 3.7 F 115.1 F 7.497 F 10.3 F 1.5 F 288.5 F 0.96 F 22.9 F 0.3 F 7.0 0.4 7.3 0.035 1.5 0.8 14.1 0.14 3.1 2.7 a, a, a, a, a, a, a, a, a, a b, c b, b, b b, b, b, c c c c c c c

ABG: arterial blood gas analysis. a: P b .05 between b0 minQ and b20 minQ; b: P b .05 between b0 minQ and b60 minQ; c: P b .05 between b20 minQ and b60 min.Q

1.6 F 0.5, 1.47 F 0.48, and 1.38 F 0.53 mmol/L, respectively. Decreases in Ca, HCO3, and BE and the increase in Osm, all of which were observed at 20 min, were statistically significant (Table 2). During the course of treatment, ETco2 and MAP remained unchanged. No major neurological complications, including those reported in the literature, were noted during the treatment. 4. Discussion 4.1. Hypertonic saline When administered intravenously, HS exhibits osmotic, vasoregulatory, hemodynamic, neurochemical, and immunologic properties. Sodium has a high reflection coefficient and a low blood-brain barrier permeability as compared with mannitol, glycerol, urea, and other substances with osmotic potential [10,19]. The osmolality of 3% HS is 1026 (mOsm/L), which is similar to that of 20% mannitol (1100 mOsm/L), whereas the osmolalities of 7.5% and 23.4% HS are 2565 and 8008 mOsm/L, respectively [12,47]. Because of safety concerns, 3% HS, which has properties similar to 20% mannitol, was selected for this study. In regions where the blood-brain barrier is intact, water is mobilized from interstitial and intracellular spaces of the brain to the intravascular compartment after administration of HS [2,39,45,56]. Hypertonic saline also affects the renal, cardiovascular, pulmonary, and hematological systems. Hypertonic saline administration is known to promote diuresis by increasing renal circulation and glomerular filtration and by decreasing resorption of sodium. This diuretic action tends to overturn much of the hypernatremia and hypokalemia attributable to HS infusions. Hypertonic saline administration increases MAP by increasing effective intravascular volume and cardiac output. Hypertonic saline also increases the air exchange capacity of the lung by decreasing extrapulmonary water content. Hypertonic saline appears to counteract hypoperfusion and vasospasm via an increase in blood vessel diameter and through expansion of plasma volume. In addition, therapy with HS

Fig. 3. A: pH, B: hemoglobin, C: osmolarity, D: bicarbonate, E: base excess, and F: lactic acid level at 0, 20, and 60 minutes.

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can attenuate the rise in ICP experienced during hyperemia [18,28,31,34,38,50-53]. 4.2. Hypertonic saline and intracranial pressure In 1988, Worthley et al [54] reported that two patients with traumatic brain injury and intractable increased ICP were successfully treated with 20 mL of 29.2% HS; each had ICP elevations refractory to mannitol and each experienced a decrease in urine output despite additional mannitol therapy. Additional older findings are consistent with beneficial effects of HS in control of ICP [54]. More recently, a bolus infusion of HS was reported to be effective in controlling ICP [11,14,16,43,44]. In the present study, 300 mL of 3% HS was administered at an infusion rate of 900 mL/h over 20 minutes. Intracranial pressure was observed to fall immediately after initiation of infusion and to drop further to significant degrees after 20 and 60 minutes. Mean arterial pressure, however, remained unchanged throughout the treatment. Consequently, CPP increased significantly. Suarez et al [47] described 8 patients for whom HS was administered for ICP control after failure with mannitol. Twenty episodes of acute increased ICP unresponsive to conventional therapies were treated with a 30-mL bolus of 23.4% HS. A decrease in ICP from a mean of 41.5 to 17 mm Hg was subsequently observed, which persisted for several hours in every case. Qureshi et al [34] compared the effects of 3% HS administered as a bolus with those of 3% HS administered by continuous infusion. In patients given continuous infusion, serum sodium increased to 145 to 155 mEq/L and less edema and mass effect were present. Qureshi et al [36] also tested the effects of 2% or 3% HS/ acetate administered at an infusion rate of 75 to 150 mL/h followed by a 250-mL bolus of 3% HS. However, these treatments had no significant effect on mortality. Two factors were proposed to contribute to the lack of benefit of the infusion in this study. The first was the prolonged nature of the infusion with extensive disruption of the blood-brain barrier, and the second was the limited osmotic effects of HS in the presence of diffuse injury. Interestingly, Khanna et al [22,30] reported that serum sodium can be tolerated at a concentration of 170 mEq/L and that an inverse relationship exists between serum sodium and ICP. The clinical efficacy of hypertonic solutes for the reduction of ICP has been recognized for many years, but the mechanism(s) responsible for this efficacy remains controversial. Four hypotheses are proposed. The first is that administration of a hypertonic solute will provoke a reduction in the volume of cerebral cells and a reduction in ICP. The second invokes a vascular expansion induced by the infusion, leading to an increase in MAP. If selfregulation of CBF persists, the increase in MAP will then trigger vasoconstriction of the cerebral arteries, promoting a reduction in arterial blood volume and, consequently, a reduction in ICP. The third hypothesis invokes a reduction in vascular volume, explained by the improvement in blood rheology and the self-regulation of CBF. A fourth

proposal is that the osmotic effect produced by HS promotes a reduction in the volume of the cerebrospinal fluid [7,8,27,32,33,42]. A major drawback to the use of mannitol is a rebound effect associated with diffusion of this agent into injured tissue. Experimental and clinical findings reveal that an injection of mannitol for therapy of IH decreases ICP by approximately 5 mm Hg, and the gain in CPP can only be due to the fall in ICP, with MAP remaining constant. The effect of mannitol on ICP is delayed until the gradient in osmolality between plasma and cells is established, although it appears that mannitol acts before intracellular water is diminished. Findings involving use of mannitol for cerebral lesions are more controversial, and mannitol therapy has not been observed to reduce the size of lesions in trauma models. Some authors claim that mannitol must not be used if osmolality exceeds 320 mOsm/L. By contrast, some investigators have observed longer increases in osmolality (up to 2 hours) with HS. Furthermore, experimentally induced rapid increases in serum sodium were found to reduce intracerebral water in a manner persisting for 24 to 48 hours and disappearing after 1 week. Finally, it is recognized that treatment with 6.5% HS will reduce total intracerebral water on the noninjured side of the head in patients with hypovolemic shock. 4.3. Hypertonic saline and cerebral blood perfusion Dehydration of the cerebrovascular endothelium, shrinkage of erythrocytes, decreased ICP, and augmentation of intravascular volume after rapid infusion of HS may each contribute to improvement of CBF [33,42]. Based on the findings of the present study and those of other investigators, it is clear that HS can be used successfully for resuscitation after severe injury whether or not head injury is present; for patients with traumatic brain injury, the decrement in ICP is significant. Cerebral perfusion pressure is equal to MAP minus ICP. Since MBP remained unchanged during the treatment in the present study, CPP increased significantly. Pulsatility index dropped rapidly and concurrently with elevation of MFV. The latter events are especially prominent in cases of high PI [1,20,21]. 4.4. Hypertonic saline, electrolytes, and arterial blood gases Other than an elevation in serum sodium concentration, little is currently known regarding acute changes in other electrolytes after HS therapy. In the present study, a complete series of electrolyte profiles was obtained at 0, 20, and 60 minutes after HS infusion. Sodium was elevated immediately after HS administration and at the end of the infusion (20 minutes) but returned gradually to baseline values at 60 minutes. Chloride concentrations increased modestly after 20 minutes and then declined to values approaching pretreatment concentrations at 60 minutes. By contrast, potassium concentrations decreased to very low concentrations at the end of infusion such that supplementation was

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required to prevent serious hypokalemia. The diuretic effects of HS in combination with volume expansion may explain the decreased potassium concentrations. Hemoglobin, calcium, HCO3, BE, and pH values decreased at 20 minutes, most probably as a consequence of dilution effects, and returned to baseline values at 60 minutes. Similarly to observations of others [22,30,34], hypernatremia appeared to be inversely related to the ICP, possibly through a decrease in intracellular water content. Throughout the treatment, ETco2 and MAP remained unchanged. 4.5. Hypertonic saline and lactic acid Severe acidosis during cardiopulmonary resuscitation can be detected reliably by lactate measurements. For example, lactate concentrations exceeding 7.0 mmol/L predict a base excess of less than 10.0 with a high sensitivity and a considerable specificity. Correlations are not straightforward, however. Lactate is a product of tissue ischemia and increases in response to low perfusion and/or hypoxemia. Therefore, lactate concentrations depend on circulation capacity and oxygenation. Carden et al [5] reported that the degree of lactate acidosis is a predictor of the downtime during cardiopulmonary arrest in dogs. Other investigators have reported a correlation between changes in blood lactate concentrations and outcome during CPR. In experimental settings, for example, successfully resuscitated animals displayed a constant or decreasing lactate concentration, whereas during failure of resuscitation, lactate was found to rise throughout the observation period [6]. Lactate measurements, therefore, are often used to predict effectiveness of CPR and prognosis. Epinephrine, administered in most cases where vital signs are unstable or to increase brain perfusion, is recognized to increase lactate production by stimulation of muscle glycogen breakdown. In the present study, lactic acid concentrations declined throughout the HS infusion and declined to even lower values at 60 minutes. This observation cannot be explained by a dilution effect. It is important to note that lactate metabolism takes place in the liver and therefore depends on liver function and perfusion. The observed decline in lactate after HS infusion may therefore reflect improved liver perfusion and better circulation and may thus contribute to a better prognosis in patients with severe head injury. 4.6. Hypertonic saline and safety Safety represents the most important issue associated with use of HS to reduce ICP. Complications can be generally divided into two groups: neurological and systemic. Neurological complications are mainly due to abrupt changes in serum osmolarity and sodium concentration, which may result in coma, seizures, and central pontine myelinolysis. Despite promising studies, the relationship between the concentrations of sodium chloride present in HS solutions and the efficacy of such solutions is not established [17]. In the present study, 3% NaCl was chosen, not only because of its osmolar similarity to 20% mannitol, but

also because of its availability in this hospital. In addition, 300 mL of 3% saline is equivalent to total concentrations used by other investigators for bolus infusions. The incidence of central pontine myelinolysis in response to HS therapy appears to be rare. In a multicenter perspective study investigating neurological sequelae after treatment of severe hyponatremia with HS, rapid correction of chronic hyponatremia was found to cause demyelinating brain lesions [4,13,24,37]. However, these lesions were observed mainly in patients with extreme hyponatremia who were given rapid continuous infusions during the first 48 hours. Two patients with cerebral edema caused by hypertensive intracranial hemorrhage and who were treated with an HS infusion deteriorated 48 to 96 hours after initiation of therapy [35]. However, follow-up head computed tomography revealed the presence of malignant cerebral edema, raising the possibility of a rebound phenomenon. It should be noted that no significant complications were reported for patients given HS treatments either as a continuous infusion or by bolus injection. Other systemic complications such as cardiopulmonary failure or electrolyte imbalance due to abrupt volume expansion, renal failure, bleeding tendency [40], or vasculitis due to local injection have been reported rarely. No major neurological complications or other adverse events related to hypernatremia were observed in the present study. 5. Conclusions Hypertonic saline (3% NaCl) administered as a bolus infusion represents an effective and safe option for treatment of elevated ICP during severe head injury. This therapy is especially helpful for ICP refractory to mannitol. Severe neurological sequelae, which were not observed in this study, are anticipated to occur rarely. However, significant hypokalemia may occur during treatment, requiring potassium supplementation. An observed gradual decline in lactic acid concentrations may be attributable to improved hepatic perfusion. Because it is cheaper than mannitol, HS provides a cost-effective rescue alternative treatment. Acknowledgment This study is supported by the grant from the National Taiwan University Hospital (NTUH93081). References
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[53]

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[55] [56]

trauma. The number of patients is small, and there is no control group. However, the authors collected interesting data on the acute changes of sodium, potassium, and lactate levels, as well as ICP and CPP at specific time intervals after the infusion of 3% saline. The treatment appeared safe and effective in immediately reducing ICP. Hypertonic saline is emerging as an effective and inexpensive treatment for increased intracranial pressure. This article directs our attention to the immediate effect of the infusion of 3% NaCl on serum sodium, potassium, and lactate concentrations. The decrease in potassium concentration is probably important. It makes sense to consider prophylactic potassium supplementation for patients treated with hypertonic saline. Ben Roitberg, MD Department of Neurosurgery University of Illinois at Chicago Chicago, IL 60612, USA

Commentary This article joins a burgeoning literature on the use of hypertonic saline for the treatment of elevated ICP in head