Salino Hipertonico

8/12/2019 Salino Hipertonico

1/10

Hypertonic saline: First-line therapy for cerebral edema?

Wendy C. Ziai, Thomas J.K. Toung, Anish Bhardwaj

Neurosciences Critical Care Division, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Neurosciences Critical Care Division, Department of Neurological Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Neurosciences Critical Care Division, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Available online 21 June 2007

Abstract

This article highlights the experimental and clinical data, controversies and postulated mechanisms surrounding osmotherapy withhypertonic saline (HS) solutions in the neurocritical care arena and builds on previous reviews on the subject. Special attention is focused onHS therapy on commonly encountered clinical paradigms of acute brain injury including traumatic brain injury (TBI), post-operative retraction edema , intracranial hemorrhage (ICH), tumor-associated cerebral edema, and ischemia associated with ischemic stroke. 2007 Elsevier B.V. All rights reserved.

Keywords: Cerebral edema; Hypertonic saline; Intracranial hemorrhage

1. Introduction

Elevated intracranial pressure (ICP) from diverse etiolo-gies results in secondary brain injury by reducing cerebral perfusion pressure (CPP) to critical levels from ischemia and by causing distortion and displacement of brain tissueresulting in compression of vital structures ( herniation syndromes) [1 5,7]. Conventional strategies for resuscita-tion of patients with intracranial hypertension require both pharmacologic therapies and more definitive surgical inter-ventions. The overriding goal of these measures is tomaintain adequate cerebral blood flow (CBF) at a levelsufficient to meet neuronal metabolic requirements to prevent cerebral ischemia. Regardless of etiology of elevat-

ed ICP, osmotherapy remains the cornerstone of medicaltherapy for brain resuscitation. The premise for the use of osmotic agents is to reduce the volume of intracranialcontents coupled with other routine measures (head elevationto 30 60 to augment cerebral venous return, avoidance of

dehydration, hyperventilation, blood pressure augmenta-tion with vasopressors to maintain CPP) and allow time for

more definitive treatments (metabolic suppression with phar-macological coma, cerebrospinal fluid drainage, surgicaldecompression) [1 3].

Cerebral edema is a defined as an increase in brain water content. Most cases of brain injury resulting in elevated ICP begin as focal cerebral edema. Classically, though simplistic,cerebral edema has traditionally been classified into 3 major types: cytotoxic, vasogenic, and interstitial (hydrocephalic)[1 3,6,7] . Most brain insults involve a combination of thesefundamental mechanisms although one can predominatedepending on the type and duration of injury. Cytotoxicedema results from cellular swelling involving neurons, glia

and endothelial cells from energy failure (as in ischemia) andaffects both gray and white matter. This type of edema isresilient to any known medical treatment. Vasogenic edemaresults from increased capillary permeability causing break-down of the blood brain barrier (BBB) (trauma, tumor,cerebral abscess and other inflammatory conditions) andaffects mostly white matter. This type of edema responds to both steroids (notably tumor edema) and osmotherapy. Other causes include issue hypoxia and water intoxication that may be responsive to osmotherapy but resilient to steroids [13,6,7] . Interstitial edema is a consequence of impaired

Journal of the Neurological Sciences 261 (2007) 157 166www.elsevier.com/locate/jns

Corresponding author. Present address: Neurosciences Critical CareProgram, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L-226, Portland, OR 97239-3098, USA. Tel.: +1 503 418 1472; fax:+1 503 418 1495.

E-mail address: [email protected] (A. Bhardwaj).

0022-510X/$ - see front matter 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jns.2007.04.048
mailto:[email protected]://dx.doi.org/10.1016/j.jns.2007.04.048http://dx.doi.org/10.1016/j.jns.2007.04.048mailto:[email protected]


2/10

absorption of cerebrospinal fluid (CSF) and increases intransependymal flow of CSF resulting in acute hydroceph-alus. This edema subtype is also not responsive to steroidsand the response to osmotic agents is questionable [7].

Although HS solutions have existed for several decades,renewed interest in their use for the treatment of cerebraledema of diverse etiologies has resurfaced just over a decade[1 5]. A considerable body of evidence from bothexperimental and clinical literature has emerged suggestingthat this therapy may be an effective alternative to other conventional osmotic agents, especially in patients with headtrauma or post-operative cerebral edema. The controversiesfor the use of HS solutions as first-line agents exist in large part due to paucity of clinical studies delineating direct comparisons of HS therapy with conventional therapies, andinadequate knowledge regarding safety, optimum durationand dose, selectivity of benefit for specific cerebral lesionsand cost effectiveness [1 3].

2. Historical background

The concept of osmotherapy for central nervous systemdisorders dates back to 1919 when two research fellows fromWater Reed Army Medical Center were working at the JohnsHopkins Medical School. Weed and McKibben discoveredthat intravenous injection of concentrated 30% sodiumchloride solution into anesthetized cats caused the normalconvexity of the brain to shrink 3 to 4 mm below the inner table of the skull (as directly visualized via a craniotomy)with a maximal response at 15 to 30 min after each injection[8]. Conversely, injection of hypotonic solutions resulted in brain herniation via the craniotomy site. These sets of observations have constituted the first description of osmotherapy in the medical literature. In 1927, intravenousadministration of concentrated urea was brought into clinicaluse by Fremont-Smith and Forbes [9] and investigated further by Javid and Settlage [10,11] in the 1950s. About the sametime the use of concentrated solutions of human plasma proteins by Hughes et al. [12] was attempted, although thiswas abandoned quickly due to high cost and concern for allergic reactions. The disadvantages of urea as an osmoticagent were also quickly realized based its distributionthroughout total body water (thereby compromising its

ability to maintain an effective osmotic gradient), reports of a rebound overshoot effect on ICP, clinical evidence of toxicity, the instability of urea solutions and time required for preparation. It was not long before Wise and Charter in 1962[13], reported their experience and recommendations for mannitol (alcohol derivative of simple sugar mannose)solution (20% 25%), which had the benefits of a longer duration of ICP control, less rebound overshoot , stability insolution, lack of toxicity and relatively low cost. Interesting-ly, higher doses were used in this study (2.5 to 3 g/kg),although favorable results were also reported with 1 g/kg[14]. To date, mannitol has remained the osmotic agent of choice since its inception. It was not until the 1980s that the

trauma literature reported beneficial effects of small volumesof HS solutions for resuscitation for both human and animalhemorrhagic shock. In these studies, rapid improvement incardiac index, systemic blood pressure, tissue perfusion andsurvival were demonstrated with various combinations of HStherapy [15]. The cerebral effects of HS solutions were first demonstrated by Todd et al. [16], whereby neurologicallyintact rabbits hemodiluted with hypertonic lactated Ringer'ssolution (480 mosM/L) showed decreased ICP, decreasedtotal brain water content and enhance cerebral blood flow(CBF). These results prompted further laboratory and clinicalinvestigation with HS in the setting of brain injury.

2.1. Pathophysiologic basis for osmotherapy

It is suggested that like most osmotic agents, mannitol andHS generally exert similar mechanisms of action in the brain;an early effect (15 to 20 min) on ICP due to optimization of

rheological properties of the blood resulting in decreased blood viscosity and hematocrit (volume, rigidity andcohesiveness of red blood cell membranes), increasingCBF and oxygen delivery, resulting in reflex autoregulatoryvasoconstriction of cerebral arterioles that reduces CBV andICP [17 19]; this is followed by osmotic shrinkage of braincells which reaches peak effect at 15 to 30 min after administration and may last from 90 min to 6 h depending onthe specific etiology [20] resulting in reduced brain water content and ICP. The rheologic effects are most effectivewith rapid bolus administration rather than continuousinfusion [20,21] . Other properties of mannitol includereduction in systemic vascular resistance (and hence after-load), combined with transiently increased preload and amild positive ionotropic effect resulting in improved cardiacoutput and oxygen delivery [22,23] , and scavenging of toxicoxygen free radicals with potential cytoprotection [24].However, intravascular volume is often reduced following itsdiuretic effect and fluid replacement is an important component of mannitol therapy to avoid both hypovolemiaresulting in secondary ischemic injury or elevation of ICPdue to reflex vasodilation of cerebral arterioles [20].

HS solutions which are available and used in concentra-tions ranging from 2% to 23.4% produce increasing osmoticgradients with higher concentrations although there is little

clinical evidence for choosing one concentration over another in terms of attenuating brain water content [4]. HSsolutions have a different mechanism of action of diure-sis compared to mannitol which is freely filtered at theglomerulus and decreases the reabsorption of water (and to alesser extent sodium) [25] accounting for its diuretic effect and hyponatremia. It is postulated that HS produces itsdiuretic effect from stimulation of atrial natriuretic peptide(ANP) release rather than direct osmotic diuresis whichaccounts for its ability to augment intravascular volume andcardiac performance, avoiding hypotension and hypovole-mia [26]. Improved CBF and oxygen delivery are believed tooccur via dehydration of cerebrovascular endothelial cells,

158 W.C. Ziai et al. / Journal of the Neurological Sciences 261 (2007) 157 166


3/10

increasing vessel diameter and improving deformability of red blood cells [26]. HS may also produce more complextherapeutic actions including reducing the inflammatoryresponse and immunomodulatory effects via decreasingendothelial cell edema, reducing leukocyte adherence andmigration which may further attenuate secondary braininjury [4,26]. In TBI, HS may improve cellular function byre-establishing electrochemical gradients, restoring normalresting membrane potential and may interrupt cell hyper-stimulation and subsequent cell death [26].

Assuming the osmolality of plasma, interstitial fluid andcytosol are roughly equal in the normal state, and given that cell membranes are freely permeable to water, osmoticagents in concentrations used clinically draw water from theextracellular (interstitial) and possibly the intracellular spaces of the brain into the intravascular compartment, anddilute the plasma. This largely depends on an intact BBBwhich is relatively impermeable to small solutes and water

[27]. Osmotic solutions can be graded by their tonicity, the effective osmotic forces exerted by solutions in adjoiningcompartments [7]. The tonicity is expressed mathematically by the Osmotic reflection coefficient ( ) with valuesranging from 0 (a freely permeable particle with no osmoticforce) to 1, (a completely impermeable particle with idealosmotic activity). Mannitol has a reflection coefficient of 0.9. Glycerol ( =0.48) and urea ( =0.59) are even lessosmotically active and have potential for rebound cerebraledema from reversal of osmotic gradient. Sodium chloridehas a reflection coefficient of 1 and is theoretically an idealosmotic agent, and more effective than mannitol. Other properties which are desirable for osmotic agents include being pharmacologically inert, nontoxic, and rapidly excret-ed. Both mannitol and HS meet these goals under usualclinical use although potential the toxicity profile for HS isstill not fully ascertained.

The bulk flow of water from brain tissue in response to anosmotic challenge may therefore be significantly limited byanatomical constituents of the BBB, mainly small capillary pore size and reduced number of intercellular clefts. Thisfeature, referred to as the low hydraulic conductivity (Lp)of the cerebral microvasculature implies the need for hugeosmotic forces to achieve significant movement of water from the brain and may explain the importance of non-

osmotic actions of HS in reducing ICP [7]. Another experimental observation is that a substantially smaller change in brain volume is observed following administrationof HS than predicted by osmotic behavior alone [28].Furthermore, studies using ion-sensitive microelectrodeshave demonstrated that while extracellular volume de-creases, intracellular water content is maintained by uptakeof potassium and sodium chloride [29]. In fact, a rapidregulatory increase in intracellular volume occurs counter-intuitive to osmotic dehydration theory. This regulatorymechanism may be blocked by osmotic and loop diureticssuch as furosemide which inhibit membrane transport of ions, explaining their synergistic prolongation of ICP

reduction in addition to the mechanism of enhanced diuresis[28]. During prolonged elevation of plasma osmolality,which occurs with ongoing osmotherapy for brain edemaover days, excess brain electrolytes are replaced by organicsolutes (previously termed idiogenic osmoles ) which arenow known to be the same osmolytes used by all organismsfor volume regulation and include: myo-inositol, taurine,glycerylphosphorylcholine, and betaine, cotransported alongwith sodium from the extracellular to the intracellular compartment [30]. The slow loss of brain organic osmo-lytes, especially myo-inositol may explain prolonged edemastates and delayed rebound edema when osmotherapy iswithdrawn.

2.2. Conventional osmotic agents versus HS solutions intreatment of elevated ICP

Although a large scale randomized controlled trial

directly comparing equiosmolar doses of mannitol and HShas yet to be undertaken, several clinical studies suggest that HS solutions may be more effective in lowering elevated ICPthan mannitol. A prospective randomized study comparingthe effects of equal volumes of 7.5% HS to 20% mannitolduring elective neurosurgical procedures showed a higher increase in serum osmolality at 15 min after administrationof HS although mean arterial pressure, central venous pressure and CSF pressure were not different between the 2treatment groups [31]. Schwarz et al. compared 100 mL HS hydroxyethyl starch (HS HES) with 40 g mannitol in 9 patients with stroke and 30 episodes of ICP crisis [32].Treatment was effective in reducing ICP N 10% below baseline in all 16 HS HES-treated and in 10 of 14mannitol treated episodes. The rise in serum osmolarity inthe HS HES group (10.5 mmol/L) was more than in themannitol group (6.2 mmol/L). In both pediatric and adult TBI, HS has been used effectively to reduce elevated ICPwhich was refractory to mannitol administration [33 35]. Arandomized controlled crossover trial administered equios-molar bolus infusions of either 200 mL of 20% mannitol or 100 mL of 7.5% HS and 6% dextran-70 solution (HSD) in arandomized fashion to 9 patients with ICP N 20 mm Hg [36].The result was a significantly greater decrease in ICP andlonger duration of effect with HSD compared to mannitol.

This study had limitations, however, based on suboptimaladministration of mannitol (overly rapid bolus administra-tion and urinary output not specifically replaced) and for choosing a dextran-based HS solution [37]. Addition of dextran to HS significantly increases cost and use of a similar colloid, hetastarch has been associated with bleedingcomplications in patients with subarachnoid hemorrhage[38]. An earlier randomized study of 20% mannitol and 7.5%HS in 20 patients with TBI, refractory intracranialhypertension ( N 25 mm Hg) and persistent coma alsodemonstrated more effective ICP reduction in the HS-treatedgroup with fewer ICP refractory episodes and fewer interventions [39]. While there was no difference in clinical

159W.C. Ziai et al. / Journal of the Neurological Sciences 261 (2007) 157 166


4/10

outcome, this study did not compare equiosmolar doses of the 2 osmotic agents.

2.3. Clinical evidence in brain injury paradigms

2.3.1. Traumatic brain injury and post-neurosurgical procedures

Previous experimental studies in animal models havedemonstrated a beneficial effect of HS in reducing ICP and brain water content under conditions of hemorrhagic shock without brain injury [40 42] as well as in brain injurymodels of TBI [43]. Although lactate Ringers (LR) remainsthe resuscitation fluid of choice for trauma patients, a number of clinical studies report positive or improved results withvarious combinations of HS solutions in patients with TBIwith or without hypotension.

Brain injury resulting from external trauma or associatedwith neurosurgical procedures ( e.g. prolonged brain retrac-

tion) may result in intracranial hypertension as a consequenceof cerebral edema, reduced CBF, and consequent secondaryischemic injury. Accumulation of extracellular glutamateleading to cell death may be ameliorated by HS solutions andreestablish the normal direction of sodium glutamate co-transporters [44]. Worthley et al. [45] reported 2 patients withtraumatic cerebral edema and elevated ICP refractory tomannitol and furosemide who were each given a single bolusof 30% HS. In both cases, ICP decreased into the normalrange for 12 to 24 h with improvement in intravascular volume and renal function. In a prospective trial in 6 patientswith severe TBI refractory to standard therapy, intravenous bolus administration of 7.5% HS with 6% hydroxyethylstarch significantly lowered ICP and improved CPP at 30 minwithout affecting arterial blood pressure. Plasma sodiumnormalized within 30 min [46]. In a double-blind crossover study of 18 pediatric patients who sustained TBI [47],3%HSwas compared to 0.9% saline following initial resuscitation.Single boluses of 10 mL/kg of each solution wereadministered and ICP monitored for a 2 h period beforecross over. HS treatment was found to significantly reduceelevated ICP by 4 mm Hg for 2 h post-infusion versus nochange with 0.9% saline treatment. The maximal serumsodium concentration occurred at 30 min after bolusadministration of 3% HS and reached a modest increase to

152 mEq/L. ICP was reduced by 44% at 30 min after administration without any effect on blood pressure fol-lowing administration of repeated boluses of 7.5% HS in6% hydroxyethyl starch to 6 patients with severe TBI [48].Another pediatric cohort of 32 children with severe TBI(GCS b 8) with ICP monitoring was studied in a prospective,randomized controlled fashion comparing Ringer's lactate(LR) with 2% HS (268 mmol/L) as resuscitative fluids over 3days after injury [49]. A radiographic bias existed in thisstudy with more diffuse head injury in the LR group (6/17)compared with the HS group (3/15). Although ICP and CPPdid not differ significantly between groups, a significant correlation between serum sodium concentration and ICP

occurred after 8 h of treatment in the HS group with fewer interventions required to maintain ICP b 15 mm Hg. Other differences between the two groups included a higher fre-quency of acute respiratory distress syndrome, pneumonia,cardiac arrhythmia, and sepsis in the LR group. The HS grouphad significantly shorter ICU stays and shorter mechanicalventilation times although survival rates and total durationof hospital stay were similar in the two groups. Neurologicoutcomes were not assessed in this study. Serum sodiumconcentrations were in the range 145 to 155 mEq/L in the HSgroup compared to 130 145 mEq/L in the LR group. Noadverse effects of hypertonic resuscitation were observedin this study. Shackford et al. [50] performed a prospectiverandomized clinical trial using 1.6% HS or LR asresuscitative fluids during the first 5 days of ICU care in 34 patients with moderate to severe TBI. Any hemodynamicinstability (systolic blood pressure b 90 mm Hg or urineoutput b 0.5 mL/kg) was treated with the study solution to

restore hemodynamic stability in addition to continuousinfusions of 0.9% and 0.45% saline in the HS and LR groupsrespectively. Although the treatments effectively loweredICP in both groups without significant difference in ICP between groups at any time after entry, the HS group had alower admission GCS score and a higher initial mean ICP andrequired significantly more interventions. No conclusionsregarding the efficacy of HS or LR on lowering ICP could bedrawn from this study. However, there were no adverseeffects from the use of HS on renal, cerebral or pulmonaryfunction. Qureshi et al. [51] retrospectively reviewed 36 patients admitted with severe TBI (GCS 8) treated with HS(2% or 3%) within 48 h of admission for a mean of 7285 h(meanSD). Compared with 46 patients who did not receiveHS, the HS group was more likely to have a penetrating TBI,a mass lesion on CT scan and a higher requirement for pentobarbital coma. There was no difference in the frequencyof other interventions for cerebral resuscitation (hyperventi-lation, mannitol, CSF drainage and vasopressor use). After adjusting for differences between the two groups, in-hospitalmortality was higher in the HS group (OR 3.1, 95% CI 1.1 10.2), suggesting that prolonged infusions of HS may not favorably impact requirement for other interventions or survival. The maximum serum sodium concentration in theHS group was 156 mEq/L compared with 145 mEq/L in the

standard treatment group. Given the small number of patients and disparity in severity of TBI, it is difficult todraw definitive conclusions from this study. However, it wassuggested that the use of bolus administrations or short infusions of HS (up to 24 h) as opposed to prolongedinfusions may have impacted outcome differently due to potential for rebound edema from continuous infusions (over 72 87 h in this study). Qureshi et al. also investigated theeffect of 3% HS on ICP and lateral brain displacement on CTscans in a heterogeneous group of 27 patients with cerebraledema of various etiologies including 8 patients with TBI and5 patients with post-operative edema (4 with tumor resectionsand 1 aneurysmal clipping) [52]. The protocol which



5/10

involved continuous intravenous infusion of 3% saline/ acetate to increase the serum sodium concentration to 145 to155 mmol/L demonstrated reduction of the mean ICP withinthe first 12 h correlating with an increase in the serum sodiumconcentration in patients with TBI ( r 2 =0.91, p =0.03) and post-operative edema ( r 2 =0.82, p = 0.06), but not for patientswith non-traumatic ICH or cerebral infarction. In the same 2subgroups of patients, repeat CTscans within 72 h of infusionshowed reduction in lateral displacement of the brain.Beyond 3 days, however, the beneficial effect of HS therapyin the TBI group was diminished and 4 patients required pentobarbital coma due to refractory intracranial hyperten-sion. The selective benefit of HS in patients with TBI may besecondary to the underlying mechanism of edema being predominantly vasogenic and due to extensive edema on the pre-treatment CT scans without associated hematomas [52].Presently, the effect of HS solutions on cerebral water content in clinical TBI is not well studied. A case report of a patient

with TBI (multiple hemorrhagic contusions) and refractoryintracranial hypertension to mannitol treated with a smallvolume infusion (1.5 mL/kg) of 18% HS demonstrated that cerebral water content was dramatically reduced on MRI in both healthy and edematous brain regions followingtreatment, and associated with ICP reduction of 109% lastingapproximately 6 h [53].

HS has been evaluated clinically in acute resuscitation protocols for hemorrhagic shock with and without cerebralinjury. Pre-hospital resuscitation with HS in patients withTBI and hypotension has been shown to be efficacious, with beneficial effects on blood pressure and survival rates[54,55] . Compared with Ringer's lactate, hypertonic fluidsexert a positive ionotropic effect restoring cardiac output,expanding circulating blood volume by extracting volumefrom the intracellular compartment, especially from endo-thelial and red blood cells, and inducing pre-capillaryvasodilation through a direct action on vascular smoothmuscle facilitating oxygen delivery [56]. Intravascular volume is restored with significantly less volume and at lower capillary hydrostatic pressure than with LR [57 59].Multiple clinical trials have evaluated the use of smallvolume resuscitation with HS solutions. In most cases, 6%dextran-70 is added to the hypertonic solution to enhance theduration and intensity of volume expansion without loss of

the hemodynamic effects [56]. Holcroft et al. [60] admin-istered a 250 mL pre-hospital bolus injection of 7.5% HS/ dextran (HSD) to 10 patients with trauma with and without associated TBI. Despite the use of strictly LR for in-hospitalresuscitation, small number of patients and greater severityof injury in the LR group, the overall survival was better inthe HSD group. An expanded study of 166 patients with TBIshowed improved in-hospital survival with HSD treatment (32%) compared to those treated with LR (16%, p b 0.05).The overall survival in the expanded study was, however, not significantly different between HSD and LR groups [61]. Asubsequent ambulance transport study [54] observedimproved survival over predicted for hypotensive trauma

patients treated with 250 mL of 7.5% HS compared withnormal saline. A cohort analysis was performed onindividual patient data from 6 previous prospective random-ized double-blind trials to evaluate the efficacy of HSD in patients with TBI and hypotension [55]. After adjusting for potential confounding factors, a survival benefit emergedwith an in-hospital survival of 38% in the HSD groupcompared with 27% in the standard of care group (OR, 2.1; p = 0.048). A meta-analysis of controlled clinical studiesevaluating efficacy of 7.5% HS and 6% dextran-70 intreating patients with trauma indicated that HS may doublethe survival rate of the subgroup of patients with bothhemorrhagic shock and TBI [62]. Although favorable effectsin terms of survival have been demonstrated from the use of HS solutions in the trauma resuscitation setting, resultsshould be interpreted with caution as all clinical trials haveused relatively small volumes of hypertonic fluid together with conventional crystalloid therapy and have been unable

to define a specific patient population that benefits most fromthis therapy. A separate issue in the trauma literature iswhether hypertonic solutions should be given aloneespecially in the setting of uncontrolled hemorrhagic shock in which HS may increase blood loss from injured bloodvessels and accelerate death [63].

The use of HS should not necessarily be restricted tosupratentorial pathologic processes as supported by one casereport of a 14 year old with TBI afflicted with flaccidtetraparesis secondary to pontine contusion and brain stemcompression, who 2 weeks after admission showed evidenceof angiographic vasospasm of the intracranial vertebralarteries and MRI evidence of ischemic brain stem damage.Although the patient's neurologic status had been stable,treatment with 2 subsequent HS infusions (2.7% and 5.4%)for a total of 60 h accompanied by relative hypervolemiaresulted in improvement of somatosensory evoked potentialsand transient improvement in motor performance. Brainstem auditory evoked potentials were unchanged. It isarguable that the transient clinical improvement was theresult of improved perfusion alone in this case because the peak serum sodium level was only 143 mEq/L (serumosmolarity of 292 mosM/L) although treatment with 5.4%HS concentration produced the best improvement in motor function [64].

2.3.2. Brain tumor and neurosurgical proceduresIn a well-characterized model of experimental brain

tumor, Toung et al. [65] demonstrated that continuousintravenous infusion of 7.5% HS and maintenance of serumsodium between 145 155 mEq/L for 48 h attenuates water content more effectively than high dose bolus mannitol (2 g/ kg) or furosemide. Thus far, one prospective randomizedtrial has investigated the role of HS in the setting of electivesupratentorial neurosurgical procedures [31]. Treatment during the 4 h of surgery with 2.5 mL/kg of 20% mannitol(1400 mosM/kg) was compared to 7.5% HS (2560 mosM/ kg) producing similar effects on CSF pressure and clinical



6/10

assessment of brain bulk although the different osmolalitiesof the two solutions precluded direct comparison.

2.3.3. Intracerebral hemorrhage (ICH)To date, there have been no clinical trials of HS therapy in

the ICH paradigm. However, several experimental studies inanimal models suggest a benefit with this therapy. Qureshiet al. [66] demonstrated the reversal of transtentorialherniation and restoration of regional CBF and CMRO 2with a bolus administration of 23.4% HS in a canine modelof ICH. In the same model, the investigators in a subsequent study compared the effects of equiosmolar doses of 20%mannitol, 3% and 23.4% HS [67]. While there was animmediate decrease in ICP in all treatment groups, after 2 honly animals receiving continuous 3% HS continued todemonstrate decreased ICP compared to pre-treatment values. Animals in this treatment group also demonstratedhigher CPP and significantly lower hemispheric water

content compared to those that receive 23.4% HS or mannitol. There were no significant differences in regionalCBF, oxygen extraction or consumption between different treatment groups. It should be noted, however, that malignant and delayed rebound edema has been reportedfollowing the use of HS in patients with ICH [68]. In anearlier retrospective study by Qureshi et al. [52], there wasno correlation between ICP reduction with HS therapy in patients with ICH.

2.3.4. Subarachnoid hemorrhage (SAH)An experimental study in the rat model of SAH

demonstrated attenuation of elevated ICP with 7.5% HStreatment with sustained improvement in neurologic recov-ery particularly in treatment arm comprising of 7.5% HS plus6% dextran 70 [69]. Based on the premise that HS may havesignificant rheologic effects, it has been used in patients withcerebral vasospasm following SAH to enhance regionalCBF. Suarez et al. [70] in a retrospective series reported theeffects of a continuous infusion of HS in 29 patients withmild hyponatremia and symptomatic vasospasm followingSAH. No adverse effects were reported and there were nochanges in cerebral blood flow velocities that were detected by transcranial Doppler ultrasonography. Tseng et al. [71]reported the effects of repeated bolus infusions of 23.4% HS

(17 episodes) in patients with high grade SAH. Xenon-CTdetermined regional CBF was improved with HS treatment as compared to pre-treatment with accentuation of CPP over a period of observation for 3 h.

2.3.5. Ischemic strokeExperimental studies with the use of HS in the ischemic

stroke paradigm have yielded mixed results. Bhardwaj et al.demonstrated that injury volume is worsened with HStreatment as a continuous infusion when begun at the timeof reperfusion in a well-characterized transient focal ischemiarodent model [72]. The mechanism of this detrimental effect was not due to impaired CBF. Little is known about the

differential response of neurons and glia to HS solutionsduring evolution of cerebral infarction. For example, in vitrostudies have demonstrated that hypertonic hyperoncoticsaline differentially affects healthy and glutamate-injured primary hippocampal neurons and astrocytes [73]. However, brain water content was decreased significantly whentreatment was begun 24 h following onset of focal ischemiaand serum Na + was maintained 145 155 mEq/L [74].Likewise, attenuation in brain edema produced with HS inthis model was comparable to that achieved with large doses(2 g/kg every 6 h) of bolus mannitol [74]. In a subsequent study, brain water was markedly attenuated in the ipsilateralas well as the contralateral hemispheres when onset of treatment was delayed for 6 h following permanent focalischemia [75]. There may be competing (anti-neuronal andanti-edema) effects of HS solutions in ischemic stroke, andthe beneficial osmotic effects on stroke-associated cerebraledema may be dependent on timing of the onset and duration

of therapy in relation to

maturation

of the lesion followingischemic stroke.Very few clinical studies have investigated the beneficial

role of HS in ischemic stroke. Schwarz et al. [32]demonstrated 7.5% HS 6.5% hydroxyethylstarch attenuatedelevated ICP more reliably than 20% mannitol in 9 patientswith large hemispheric strokes. The same group subsequent-ly reported effectiveness of treatment with 10% HS incontrolling ICP elevations that were refractory to treatment with mannitol in 9 patients with acute ischemic stroke [76].

2.4. Toxicity profile and safety considerations

Therapeutic concerns with mannitol include significant and well known systemic side effects including hypotension,hemolysis, hyperkalemia, renal insufficiency and pulmonaryedema [1 5,7,15] . The literature suggests that side effect profile of HS therapy is much better in comparison tomannitol, but some theoretical complications are possible. Todate, there have been no Phase 1 safety trials with HSsolutions. Myelin injury is a well-known complication of rapid over-correction of preexisting hyponatremia. Studieson patients treated with HS have not shown evidence of myelin injury on MRI or post-mortem examination [34,35]despite their serum sodium levels in excess of 180 mEq/L

[34]. However, the threshold for myelin injury due to achange in serum sodium from a normonatremic to a sustainedhypernatremic state is ill defined. In nave-uninjured rats,induced hypernatremia (145 155 mEq/L) with HS does not cause myelin injury ( 17 mEq/L) [33] and a change of 35 40 mEq/L is required to induce myelinolysis [77]. Other potential neurologic complications of rapid changes insodium and plasma osmolality include symptoms and signsof encephalopathy (confusion, lethargy, seizures, and occa-sionally coma) [1 3,15] . Subdural hematomas or effusionsmay occur due to shearing of bridging veins as a result of hyperosmolar contracture of the brain. Risk of rapid volumeexpansion is a concern in patients with poor cardiovascular



7/10

reserveand history of heart failure, neurogenic cardiac stun or pulmonary edema. Anecdotal observations suggest that, likemannitol, bolus administration of HS can paradoxicallyinduce transient acute hypotension. Rapid expansion of the plasma volume could lead to hypokalemia and cardiacarrhythmias [1 3,15] . Use of HS solutions as a mixture of chloride:acetate (50:50) is recommended and frequentlyutilized in clinical practice as an increased plasma chlorideconcentration could result in metabolic (hyperchloremic)acidemia [1 3,15] . HS-induced coagulopathy may enhance bleeding from dilution of plasma coagulation factors, prolonged activated prothrombin and partial thromboplastintimes and decreased platelet aggregation [15]. Whenever possible, slow infusion of HS solutions is recommended because rapid changes in osmotic gradients in the serum maylead to hemolysis. Phlebitis may also occur if concentratedsolutions are given through the peripheral route. Thus, acentral venous route of administration is recommended. Thus

far, there are no reports of toxicity or organ system failurefrom HS other than ventilatory failure secondary to pul-monary edema in patients with poor cardiovascular reserve[52]. Thus caution is advised in the use of HS in patients inthis subset of patients. Although not rigorously studied, rapidwithdrawal of therapywith HS may result in rebound cerebraledema, leading to elevated ICP or herniation syndromes(Table 1 ).

3. Future perspectives

While the complex mechanisms of both osmotic and non-osmotic action of mannitol have been extensively studied inthe cerebral resuscitation paradigm, little is known of actionof HS beyond its osmotic effects. Although some literaturesuggests that serum osmolality of 300 320 mosM/L isoptimal in patients with brain injury [78,79] , this recom-mendation is not supported by systematic laboratory-basedor clinical studies. Much of the evidence for this goal isindirectly supported by studies that utilized mannitol whereits beneficial effects were offset by significant systemic sideeffects [7], when serum osmolality exceeded 320 mosM/L.However, these observations have not been substantiated[80]. We recently demonstrated improved mortality and potent anti-edema action with HS treatment to target levels

of N 350 mosM/L when treatment onset was delayed for 24 hfollowing onset of ischemia in a well-characterized animalmodel of ischemic stroke [75]. The efficacy of HS solutionsfollowing global cerebral ischemia has not been investigated,although HS solutions have recently been shown to enhanceCBF following cardiopulmonary resuscitation in a swinemodel of cardiac arrest [81].

Few studies have demonstrated non-osmotic effects of HSon CBF and CSF dynamics, but other potential mechanismsof its action require further study. For example, HS has beenshown to modulate inflammatory molecules [82 84] ,regulate neutrophil endothelial cell interactions [85] andattenuate polymorphonuclear neutrophil cytotoxicity [86].

While many inflammatory mediators have been implicatedin modulating BBB permeability following acute braininjury, the anti-inflammatory in vivo effects of HS in braininjury remain unexplored.

Newer molecular mechanisms of cerebral edema are now being considered by several laboratories. In this regard, theglial membrane water channel, aquaporin4 (AQP4), hasreceived recent attention in the pathogenesis of cerebraledema [87]. Induced hyponatremia causes a pronounced andrapid increase in AQP4 [88] and mice deficient in AQP4have significantly less cerebral edema following water intoxication as well as following experimental stroke [89].Conversely, it is not known whether alteration in AQP4water channels plays an important role in determining thetherapeutic efficacy of HS in these brain injury paradigms.Furthermore, timing, duration, most efficacious method of instituting therapy (intravenous bolus versus continuousinfusion) and specific lesions responsive to HS remains

unclear at the present and require carefully controlledexperiments in appropriate animal models of brain injury.

Table 1Comparison of mannitol and hypertonic saline (HS)

Characteristic Mannitol HS

Dosing(Neurotraumaguidelines)

2 mL/kg 20%mannitol infusedover 20 min [79]

30 60 cm3 of 23.4%salineinfused over 20 min [4]

Relativeeffectiveness

Reflectioncoefficient=0.9

Reflection coefficient =1.0

Effectiveness maydecrease with repeated

administration

Potentially greater andmore prolonged effect

Rheologic effect Yes YesDiuretic effect Osmotic diuretic Diuretic action via ANPHemodynamic effect Diuresis may

compromiseintravascular volumecausing hypotension,hypovolemia, reboundintracranialhypertension if not replaced

Augments intravascular volume, maintains MAP,CVP, CO

Proposed cellular effects

Antioxidant via freeradical scavenging

Restores resting membrane potential and cell volumeModulates inflammation

Maximum serum

osmolarity at osmotic effects on brain are observed

320 mosM/L Up to 360 mosM/L

Potential for reboundedema

Yes Yes

Half-life 2 4 h Not knownAdverse effects Hypotension, rebound

elevation in ICP,hyperkalemia,hemolysis, renal failure

Rebound elevation in ICP,hypokalemia, congestiveheart failure, hemolysis,coagulopathy, central pontine myelinolysis

MAP: Mean arterial pressure; CVP: central venous pressure; CO: cardiacoutput; ICP: intracranial pressure. Guidelines refer to trauma patients withelevated ICP, clinical herniation or progressive neurologic deterioration(before ICP monitoring). Adapted from [90].



8/10

In the clinical paradigm, there are no large randomizedclinical trials to date comparing the conventional osmoticagent mannitol versus HS (equiosmolar concentrations) for cerebral resuscitation (reversal of cerebral herniation, ICPlowering effects, CPP augmentation, rebound cerebraledema) and long-term functional outcomes in critically ill brain injured patients with ICH, SAH, TBI, brain tumor,global cerebral ischemia following cardiac arrest andischemic stroke.

4. Summary and conclusions

Osmotherapy remains the cornerstone of medical therapyfor cerebral edema in patients with acute brain injury with or without elevated ICP. While mannitol has remained theosmotic agent of choice for several decades, experimentalstudies, small case series and a few randomized trialscoupled with a more desirable toxicity profile suggest that

HS solutions may be more desirable therapeutic agents.Osmotherapy with HS is particularly promising in patientswith TBI, brain tumor and post-operative cerebral edema.Further studies, in carefully controlled experimental animalmodels and randomized clinical trials, are required todetermine the safety, timing of onset of therapy, optimumduration of benefit and the particular brain injury paradigmsthat are most likely to benefit from this therapy. Until thesedefinitive trials are performed, caution is advised in clinicaluse of these solutions as first line therapy in acute braininjury.

Acknowledgments

This work is supported in part by the Clinical ResearchTraining Fellowship Award from the American Academy of Neurology (WCZ) and US Public Health Service NationalInstitutes of Health grant NS046379 (AB, TJKT).

References

[1] Bhardwaj A, Ulatowski JA. Cerebral edema: hypertonic salinesolutions. Curr Treat Options Neurol 1999;1:179 87.

[2] Harukuni I, Kirsch JR, Bhardwaj A. Cerebral resuscitation: role of osmotherapy. J Anesth 2002;16:229 37.

[3] Bhardwaj A, Ultaowski JA. Hypertonic saline solutions in brain injury.Curr Opin Crit Care 2004;10:126 31.

[4] Qureshi AI, Suarez JI. Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med2000;28:3301 13.

[5] Ogden AT, Mayer SA, Connolly SE. Hyperosmolar agents inneurosurgical practice: the evolving role of hypertonic saline. Neurosurgery 2005;57:207 15.

[6] Klatzo I. Neuropathological aspects of cerebral edema. J NeuropatholExp Neurol 1967;26:1 14.

[7] Paczynski RP. Osmotherapy. Basic concepts and controversies. Crit Care Med 1997;13:105 29.

[8] Weed LH, McKibben PS. Experimental alteration of brain bulk. Am JPhysiol 1919;48:531 55.

[9] Fremont-Smith F, Forbes HS. Intraocular and intracranial pressure: anexperimental study. Arch Neurol Psychiatr 1927;18:550 64.

[10] Javid M, Settlage P. Effect of urea on cerebrospinal fluid pressure inhuman subjects; preliminary report. J Am MedAssoc Mar17 1956;160:943 9.

[11] Javid M. Urea in intracranial surgery. A new method. J Neurosurg1961;18:51 7.

[12] Hughes J, Mudd S, Strecker EA. Reduction of elevated intracranial pressure by concentrated solutions of human lyophile serum. Arch

Neurol Psychiatr 1938;12:1277 87.[13] Wise BL, Chater N. The value of hypertonic mannitol solution in

decreasing brain mass and lowering cerebro-spinal-fluid pressure.J Neurosurg 1962;19:1038 43.

[14] Shenkin HA, Goluboff B, Haft H. The use ofmannitol for the reductionof intracranial pressure in intracranial surgery. J Neurosurg 1962;19:897 901.

[15] Zornow MH. Hypertonic saline as a safe and efficacious treatment of intracranial hypertension. J Neurosurg Anesthesiol 1996;8:175 7.

[16] Todd MM, Tommasino C, Moore S. Cerebral effects of isovolemichemodilution with hypertonic saline solution. J Neurosurg 1985;63:944 8.

[17] Muizelaar JP, Wei EP, Kontos HA, Becker DB. Mannitol causescompensatorycerebral vasoconstriction and vasodilation in response to blood viscosity changes. J Neurosurg 1983;59:822 8.

[18] Hudak ML, Jones Jr MD, Popel AS, Koehler RC, Traystman RJ, Zeger SL. Hemodilution causes size-dependent constriction of pial arteriolesin the cat. Am J Physiol 1989;257:H912 7.

[19] Burke AM, Quest DO, Chien S, Cerri C. The effects of mannitol on blood viscosity. J Neurosurg 1981;55:550 3.

[20] Brain Trauma Foundation, American Association of NeurologicalSurgeons, Joint Section on Neurotrauma and Critical Care. Guidelinesfor the management of severe head injury. J Neurotrauma 2000;6-7:449 627.

[21] Cruz J, Minoja G, Okuchi K. Improving clinical outcomes from acutesubdural hematomas with the emergency preoperative administrationof high doses of mannitol: a randomized trial. Neurosurgery 2001;4:864 71.

[22] Cote CJ, Greenhow DE, Marshall BE. The hypotensive response torapid intravenous administration of hypertonic solutions in man and in

the rabbit. Anesthesiology 1979;50:30 5.[23] Willerson JT, Curry GC, Atkins JM. Influence of hypertonic mannitol

on ventricular performance and coronary blood flow in patients.Circulation 1975;51:1095 100.

[24] Suzuki J, Imaizumi I, Kayama T, Yoshimoto T. Chemiluminescence inhypoxic brain: Second report: cerebral protective effect of mannitol,vitamin E, and glucocorticoid. Stroke 1985;16:695 700.

[25] Nau R. Osmotherapy for elevated intracranial pressure: a criticalreappraisal. Clin Pharmacokinet 2000;1:23 40.

[26] Doyle J, Davis D, Hoyt D. The use of hypertonic saline in thetreatment of traumatic brain injury. J Trauma Inj Infect Crit Care2001;2:367 83.

[27] Raichle MD. Neurogenic control of blood brain permeability. Acta Neuropathol (Berl) 1983;SVIII:75 9.

[28] McManus ML, Churchwell KB, Strange K. Regulation of cell volumein health and disease. NEJM 1995;333:1260 6.

[29] Cserr HF, DePasquale M, Nicholson C, Patlak CS, Pettigrew KD, RiceME. Extracellular volume decreases while cell volume is maintained by ion uptake in rat brain during acute hypernatremia. J Physiol1991;442:277 95.

[30] Strange K. Regulation of solute and water balance and cell volume inthe central nervous system. J Am Soc Nephrol 1992;3:12 27.

[31] Gemma M, Cozzi S, Tommasino C, Mungo M, Calvi MR, Cipriani A,et al. 7.5% hypertonic saline versus 20% mannitol during electiveneurosurgical supratentorial procedures. J Neurosurg Anesthesiol1997;9:329 34.

[32] Schwarz S, Schwab S, Bertram M, Aschoff A, Hacke W. Effects of hypertonic saline hydroxyethyl starch solution and mannitol in patientswith increased intracranial pressure after stroke. Stroke 1998;29:1055 63.



9/10

[33] Horn P, Mnch E, Vajkoczy P, Herrmann P, Quintel M, SchillingL, et al.Hypertonic saline solution for control of elevated intracranial pressure in patients with exhausted response to mannitol and barbiturates. NeurolRes 1999;21:758 64.

[34] Peterson B, Khanna S, Fisher B, Marshall L. Prolonged hypernatremiacontrols elevated intracranial pressure in head-injured pediatric patients. Crit Care Med 2000;4:1136 43.

[35] Khanna S, Davis D, Peterson B, Fisher B, Tung H, O'Quigley J, et al.Use of hypertonic saline in the treatment of severe refractory posttraumatic intracranial hypertension in pediatric traumatic braininjury. Crit Care Med 2000;4:1144 51.

[36] Battison C, Andrews PJD, Graham C, Petty T. Randomized controlledtrial on the effect of a 20% mannitol solution and a 7.5% saline/6%dextran solution on increased intracranial pressure after brain injury.Crit Care Med 2005;33:196 202.

[37] Schrot RJ, Muizelaar JP. Sugar or salt? Crit Care Med 2005;33:257 8.[38] Trumble ER, Muizelaar JP, Myseros JS, Choi SC, Warren BB.

Coagulopathy with the use of hetastarch in the treatment of vasospasm.J Neurosurg 1995;82:44 7.

[39] Vialet R, Albanese J, Thomachot L, Antonini F, Bourgouin A, AlliezB, et al. Isovolume hypertonic solutes (sodium chloride or mannitol) inthe treatment of refractory posttraumatic intracranial hypertension: 2

ml/kg 7.5% is more effective than 2 mL/kg 20% mannitol. Crit CareMed 2003;31:1683 7.

[40] Ducey JP, Mozingo DW, Lamiell JM, Okerburg C, Gueller GE. Acomparison of the cerebral and cardiovascular effects of completeresuscitation with isotonic and hypertonic saline, hetastarch, and whole blood following hemorrhage. J Trauma 1989;29:1510 8.

[41] Schmoker J. Hypertonic fluid resuscitation improves cerebraloxygendelivery and reduces intracranial pressure after hemorrhagic shock.J Trauma 1991;31:1607 13.

[42] Prough DS, Whitley JM, Taylor CL, Deal DD, DeWitt DS. Regionalcerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural mass. Anesthesiology1991;75:319 27.

[43] Mirski MA, Denchev DI, Schnitzer MS, Hanley DF. Comparison between hypertonic saline and mannitol in the reduction of elevated

intracranial pressure in a rodent model of acute cerebral injury.J Neurosurg Anesthesiol 2000;12:334 44.

[44] Phillis JW, Song D, O'Reagan MH. Effect of hyperosmolarity and ionsubstitutions on amino acid efflux from the ischemic rat cerebralcortex. Brain Res 1999;828:1 11.

[45] Worthley LI, Cooper DJ, Jones N. Treatment of resistant intracranialhypertension with hypertonic saline: report of two cases. J Neurosurg1988;68:478 81.

[46] Hartl R, Ghajar J, Hochleuthner H, Mauritz W. Treatment of refractoryintracranial hypertension in severe traumaticbrain injury with repetitivehypertonic/hyperoncotic infusions. Zentralbl Chir 1997;122:181 5.

[47] Fisher B, Thomas D, Peterson B. Hypertonic saline lowers raised intra-cranial pressure in children after head trauma. J Neurosurg Anesthesiol1992;4:4 10.

[48] Hartl R, Ghajar J, Hochleuthner H, Mauritz W. Hypertonic/ hyperoncotic saline reliably reduces ICP in severely head-injured patients with intracranial hypertension. Acta Neurochir Suppl (Wien)1997;70:126 9.

[49] Simma B, Burger Falk M, Sacher P, Fanconi S. A prospective,randomized, and controlled study of fluid management in children withsevere head injury: lactated Ringer's solution versus hypertonic saline.Crit Care Med 1998;26:1265 70.

[50] Shackford SR, Bourguignon PR, Wald SL, Rogers FB, Osler TM,Clark DE. Hypertonic saline resuscitation of patients with head injury:a prospective, randomized clinical trial. J Trauma 1998;44:50 8.

[51] Qureshi AI, Suarez JI, Castro A, Bhardwaj A. Use of hypertonic saline/ acetate infusion in treatment of cerebral edema in patients with headtrauma. Experience at a single center. J Trauma 1999;47:659 65.

[52] Qureshi AI, Suarez JI, Bhardwaj A, Mirski M, Schnitzer MS, HanleyDF, et al. Use of hypertonic (3%) saline/acetate infusion in the

treatment of cerebral edema: effect on intracranial pressure and lateraldisplacement of the brain. Crit Care Med 1998;26:440 6.

[53] Saltarini M, Massarutti D, Baldassarre M, Nardi G, De Colle C, FabrisG. Determination of cerebral water content by magnetic resonanceimaging after small volume infusion of 18% hypertonic saline solutionin a patient with refractory intracranial hypertension. Eur J Emerg Med2002;9:262 5.

[54] Vassar MJ, Fischer RP, O'Brien PE, Bachulis BL, Chambers JA, Hoyt DB, et al. A multicenter trial for resuscitation of injured patients with7.5% sodium chloride. The effect of added dextran 70. The Multicenter Group for the Study of Hypertonic Saline in Trauma Patients. ArchSurg 1993;128:1003 11.

[55] Wade CE, Grady JJ, Kramer GC, Younes RN, Gehlsen K, Holcroft JW.Individual patient cohort analysis of the efficacy of hypertonic saline/ dextran in patients with traumatic brain injury and hypotension.J Trauma 1997;42:S61 5.

[56] Rocha e Silva M. Hypertonic saline resuscitation. Medicina (B Aires)1998;58:393 402.

[57] Shackford SR, Norton CH, Todd MM. Renal, cerebral, and pulmonaryeffects of hypertonic resuscitation in a porcine model of hemorrhagicshock. Surgery 1988;104:553 60.

[58] Velasco IT, Pontieri M, Rocha e Silva JR. Hyperosmotic NaCl and

severe hemorrhagic shock. Am J Physiol 1980;239:H664 73.[59] Nakayama S, Sibley L, Gunther RA. Small volume resuscitation with

hypertonic saline (2300 mOsm/liter) during hemorrhagic shock. CircShock 1984;12:149 59.

[60] Holcroft JW, Vassar MJ, Turner JE, Derlet RW, Kramer GC. 3% NaCland 7.5% NaCl/dextran 70 in the resuscitation of severely injured patients. Ann Surg 1987;206:279 88.

[61] Vassar MJ, Perry CA, Gannaway WL, Holcroft JW. 7.5% sodiumchloride/dextran for resuscitation of trauma patients undergoinghelicopter transport. Arch Surg 1991;128:1003 11.

[62] Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN. Efficacy of hypertonic 7.5% saline and 6% dextran-70 in treating trauma: a meta-analysis of controlled clinical studies. Surgery 1997;122:609 16.

[63] Krausz MM, Amstislavsky T. Hypertonic sodium acetate treatment of hemorrhagic shock in awake rats. Shock 1995;4:56 60.

[64] Gemma M, Cozzi S, Piccoli S, Magrin S, De Vitis A, Cenzato M.Hypertonic saline fluid therapy followingbrain stemtrauma. J NeurosurgAnesthesiol 1996;8:137 41.

[65] Toung TJK, Tyler B, BremH, Traystman RJ, KirschJR, Hurn PD,et al.Hypertonic saline ameliorates cerebral edema associated withexperimental brain tumor. J Neurosurg Anesthesiol 2002;14: 187 93.

[66] Qureshi AI, Wilson DA, Traystman RJ. Treatment of transtentorialherniation unresponsive to hyperventilation using hypertonic saline indogs: effect on cerebral blood flow and metabolism. J NeurosurgAnesthesiol 2002;14:22 30.

[67] Qureshi AI,WilsonDA, TraystmanRJ. Treatment ofelevated intracranial pressure in experimental intracerebral hemorrhage: comparison betweenmannitol and hypertonic saline. Neurosurgery 1999;44:1055 64.

[68] Qureshi AI, Suarez AI, Bhardwaj A. Malignant cerebral edema in patients with hypertensive intracerebral hemorrhage associated withhypertonic saline infusion: a rebound phenomenon? J NeurosurgAnesthesiol 1998;10:188 92.

[69] Zausinger S, Thal SC, Kreimeier U, Messmer K, Schmid-Elsaesser R.Hypertonic fluid resuscitation from subarachnoid hemorrhage in rats. Neurosurgery 2004;55:679 86.

[70] Suarez JI, Qureshi AI, Parekh PD, Razumovsky A, Tamargo RJ,Bhardwaj A, et al. Administration of hypertonic (3%) sodium chloride/ acetate in hyponatremic patients with symptomatic vasospasm followingsubarachnoid hemorrhage. J Neurosurg Anesthesiol 1999;11:178 84.

[71] Tseng MY, Al-Rawi PG, Pickard JD, Rasulo FA, Kirkpatrick PJ. Effect of hypertonic saline on cerebral blood flow in poor-grade patients withsubarachnoid hemorrhage. Stroke 2003;34:1389 96.

[72] Bhardwaj A, Harukuni I, Murphy SJ, Alkayed NJ, Crain BJ, Koehler RC, et al. Hypertonic saline worsens infarct volume after transient focal ischemia in rats. Stroke 2000;31:1694 701.



10/10

[73] Himmelseher S, Pfenninger E, Morin P, Kochs E. Hypertonic hyperoncotic saline differentially affects healthy and glutamate-injured primary rat hippocampal neurons and cerebral astrocytes. J NeurosurgAnesthesiol 2001;13:120 30.

[74] Toung TJK, Hurn PD, Traystman RJ, Bhardwaj A. Global brain water increases after experimental focal cerebral ischemia: effect of hypertonic saline. Crit Care Med 2002;30:644 9.

[75] Toung TJ, Chang Y, Lin J, Bhardwaj A. Increases in lung and brainwater following experimental stroke: effect of mannitol and hypertonicsaline. Crit Care Med 2005;33:203 8.

[76] 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 40.

[77] Soupart A, Penninckx R, Namias B, Stenuit A, Perier O, Decaux G.Brain myelinolysis following hypernatremia in rats. J Neuropathol Exp Neurol 1996;55:106 13.

[78] Ropper AH, Gress DR, Diringer MN, GreenDM, Mayer SA, Bleck TP.Treatment of intracranial hypertension. Neurological and neurosurgicalintensive care. New York: Raven Press Ltd; 2003. p. 26 51.

[79] Brain Trauma Foundation, American Association of NeurologicalSurgeons, Joint Section on Neurotrauma and Critical Care: use of mannitol: Brain Trauma Foundation, The American Association of

Neurological Surgeons, The Joint Section on Neurotrauma and CriticalCare. J Neurotrauma 2000;17:21 5.

[80] Diringer MN, Zazulia AR. Osmotic therapy: fact and fiction. Neurocrit Care 2004;1:219 34.

[81] Krep H, Briel M, Sinn D, Hagendorff A, Hoeft A, Fischer M. Effects of hypertonic versus isotonic infusion therapy on regional cerebral bloodflow after experimental cardiac arrest cardiopulmonary resuscitation in pigs. Resuscitation 2004;63:73 83.

[82] Arbabi S, Garcia I, Bauer G, Maier RV. Hypertonic saline induces prostacyclin production via extracellular signal-regulated kinase(ERK) activation. J Surg Res 1999;83:141 6.

[83] Oreopoulos GD, Hamilton J, Rizoli SB, Fan J, Lu Z, Li YH, et al. Invivo and in vitro modulation of intracellular adhesion molecule(ICAM)-1 expression by hypertonicity. Shock 2000;14:409 14.

[84] Oreopoulos GD,BradwellS, Lu Z, FanJ, KhadarooR, Marshall JC,et al.

Synergistic induction of IL-10 by hypertonic saline solution andlipopolysaccharides in murine peritoneal macrophages. Surgery 2001:57 65.

[85] Angle N, Cabello-Passini R, Hoyt DB, Loomis WH, Shreve A, NamikiS, et al. Hypertonic saline infusion: can it regulate human neutrophilfunction? Shock 2000;14:503 8.

[86] Ciesla DJ, Moore EE, Zallen G, Biffl WL, Silliman CC. Hypertonicsaline attenuation of polymorphonuclear neutrophil cytotoxicity:timing is everything. J Trauma 2000;48:388 95.

[87] Wen H, Nagelhus EA, Amiry-Moghaddam M, Arge P, Ottersen OP, Nielsen S. Ontogenyof water transport in rat brain: postnatal expressionof the aquaporin-4 water channel. Eur J Neurosci 1999;11:935 45.

[88] Vajda Z, Promeneur D, Doczi T, Sulyok E, Frokiaer J, Ottersen OP, et al.Increasedaquaporin-4 immunoreactivity in ratbrain in response to systemichyponatremia. Biochem Biophys Res Commun 2000;270:495 503.

[89] Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, et al.Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 2000;6:159 63.

[90] Knapp JM. Hyperosmolar therapy in the treatment of severe headinjury in children. Mannitol and hypertonic saline. AACN Clin Issues2005;16:199 211.


Salino Hipertonico

Documents

Transcript of Salino Hipertonico