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UNDERSTANDING AND CARING FOR

CRITICAL ILLNESS IN EMERGENCY MEDICINE

EM Critical Care

Volume 3, Number 1Author

Jeffrey A. Holmes, MDAttending Physician, Maine Medical Center, Portland, ME;Assistant Professor, Tufts University School of Medicine,Boston, MA

Peer Reviewers

David Callaway, MD, MPAAssociate Professor, Emergency Medicine, Carolinas MedicalCenter, Charlotte, NC

Catherine A. Gogela Carlson, MDCritical Care Medicine Fellow, Departments of Critical CareMedicine and Emergency Medicine, University of PittsburghMedical Center, Pittsburgh, PA

CME Objectives

Upon completion of this article, you should be able to:1. Describe the theoretical advantages of using hypertonic

saline over traditional crystalloid solutions for thetreatment of traumatic brain injury.

2. Describe the practical and theoretical advantages ofusing hypertonic saline over traditional resuscitativecrystalloid solutions for traumatic hemorrhagic shock.

3. Recognize the signs of cerebral edema secondary tosevere hyponatremia.

4. Describe the use of hypertonic saline in the treatmentof severe hyponatremia while avoiding overrapidcorrection of sodium levels.

Prior to beginning this activity, see the back page for faculty

disclosures and CME accreditation information.

Therapeutic Uses Of HypertonicSaline In The Critically IllEmergency Department Patient Abstract

Hypertonic saline is de ned as any crystalloid solution containingmore than 0.9% saline. The administration of hypertonic saline has been studied alone as well as in combination with colloid solutions

(most commonly dextran). Its many theoretical advantages (includ -ing small-volume resuscitation, reduction of intracranial pressure,improved hemodynamics, and improved microcirculation and im -munomodulation) have prompted research into its use as a resusci -tative uid for a variety of critically ill patients. The 2 patient cohortsmost frequently studied are patients with traumatic brain injury andtrauma patients with hemorrhagic shock. Hypertonic saline has beenshown to be safe and ef cacious in decreasing intracranial pressureand improving hemodynamics with few adverse effects, but thereare no prospective human trials demonstrating improved clinicaloutcomes for these patients. Hypertonic saline has been shown to be a valuable therapy for the treatment of severe hyponatremia inpatients with signs of cerebral edema, but treatment guidelines are

based mostly upon expert consensus and are not well de ned. Thisreview examines the evidence on the use of hypertonic saline for thetreatment of patients with traumatic brain injury and secondary in -tracranial hypertension, trauma patients in hemorrhagic shock, andpatients with severe hyponatremia.


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EMCC © 2013 2 www.ebmedicine.net • Volume 3, Number 1

tions (normal saline or lactated Ringer’s solution),a smaller volume of HTS is required to improvehemodynamic stability in hypotensive patients. 11 This has many practical advantages for the militaryand for other austere environments that precludecarrying a large volume of uid for the purpose ofresuscitation. 12 HTS also has an important role in the treatmentof severe hyponatremia. While hyponatremia in theED is typically chronic and requires no immediateintervention, acute severe hyponatremia can causesigni cant morbidity and mortality. Appropriate rec -ognition and treatment with HTS can help preventdevastating sequelae from both the hyponatremiaitself and its overaggressive treatment.

This issue of EMCC examines the evidence sup -porting the use of HTS for the treatment of patientswith TBI with elevated ICP, trauma patients in hemor -rhagic shock, and patients with severe hyponatremia.

Critical Appraisal Of The Literature

A literature search was performed using Ovid MED -LINE® , PubMed, and EMBASE from 1990 to thepresent. The area of focus was the use of HTS in thetreatment of TBI, hypovolemic shock, and severe hy -ponatremia. Search terms included hypertonic saline,traumatic brain injury, intracranial hypertension, shock,hypovolemic shock, hemorrhagic shock,and hyponatre-mia. Over 300 articles were retrieved and provided background for further literature review. The Co -chrane Database of System atic Reviews, Eastern As -sociation for the Surgery of Trauma (EAST) Guide -lines, Western Trauma As sociation (WEST) Guide-lines, American College of Emergency PhysiciansClinical Policies, National Neurotrauma Society,National Brain Trauma Foundation, NeurosurgicalSociety of America, Annals of Emergency Medicine’s Evidence-Based Emergency Medicine reviews, andNational Guideline Clearing house (www.guideline.gov) were also searched. All HTS solutions wereincorporated, with solutions ranging from 1.6% to30%, including those mixed with colloids.

The literature on the use of HTS for resuscita -tion of trauma patients is dif cult to interpret due toseveral confounding variables. For instance, studies

Case Presentations

Your shift is just beginning when you are noti ed thatEMS is bringing in a 20-year-old male patient who wasstruck by a motor vehicle. As your team assembles, younotify the CT scanner and ask him to keep it open andavailable. When the patient arrives, you nd that hehas decorticate posturing, a large scalp hematoma, and

multiple facial fractures. After you intubate him viaRSI and complete your initial assessment, he is quicklywheeled over to CT. His head CT shows a large epiduralhematoma with 10 mm of midline shift. His abdominalCT reveals a splenic laceration with active extravasation.You begin your interventions to manage the patient’s el-evated intracranial pressure and arrange transport to thenearest Level 1 trauma center. As you hear the helicopterlanding, you notice that the patient’s pupils have becomeasymmetric. You ask yourself, “Which would be better tocontrol the patient’s intracranial hypertension: mannitolor hypertonic saline?” A short time later, EMS wheels a rst-time marathon

runner into the critical care bay. She was witnessed tohave collapsed at mile 22 with seizure-like activity of 1minute duration. She is currently postictal with a normal

ngerstick blood glucose. Her vital signs are as follows:heart rate of 118 beats per minute, respiratory rate of 24breaths per minute, blood pressure of 138/90 mm Hg,rectal temperature of 38.3°C, and oxygen saturation of98% on a nonrebreather mask. You wonder if she mighthave suffered a heat stroke. Her temperature is elevated— but not enough to cause a seizure. Besides her contin-ued altered mental status, she has an otherwise normalexam. You send her off to the CT scanner to look for acuteintracranial pathology. As her scan is completed and theresults are con rmed by the radiologist as unremarkable,the lab calls back with a critical value: her serum sodiumis 109 mEq/L. The nurse calls out to you from the scan-ner, “Doc, she’s seizing again!”

Introduction

Hypertonic saline (HTS), which is de ned as anycrystalloid solution containing more than 0.9%saline, has a potentially important role in the treat -ment of several life-threatening conditions seenin the emergency department (ED). With respect

to the trauma patient, HTS has unique propertiesthat may make it an ideal resuscitative uid for themost common causes of traumatic death: centralnervous system injury, exsanguination, and organfailure.1 (See Table 1.) It has been shown to reduceintracranial pressure (ICP) in patients with trau -matic brain injury (TBI) and may have an immu -nomodulatory effect that further reduces neuronaldamage and multiple-organ failure. 2-7 HTS mayalso improve hemodynamics and microcirculation,resulting in improved resuscitation in hemorrhagicshock.8-10 Compared to traditional crystalloid solu -

Table 1. The Causes Of Death FollowingTrauma 1

Acute(< 2 d)

Early(3-7 d)

Late(> 7 d)

Central nervous system 40% 64% 39%

Blood loss 55% 9% 0%

Multiple organ dysfunction 1% 18% 61%

Other 4% 8% 0%


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3 EMCC © 2013www.ebmedicine.net • Volume 3, Number 1

Comparison Of Hypertonic Saline ToMannitolDespite the lack of evidence for any mortality bene t,22 mannitol is currently considered to be thegold standard for osmotic therapy in the treatmentof acute intracranial hypertension, and it is endorsed by the Brain Trauma Foundation’s most recentguidelines for the management of severe TBI. 23

However, HTS is being increasingly investigated asan alternative. Several retrospective studies havesuggested that HTS might be effective in reducingintracranial hypertension that is refractory to theuse of mannitol. 24,25 Only a few rigorous prospec -tive studies have compared the effectiveness of HTSor HTS combined with dextran to mannitol in ICPreduction. Kamel et al performed a meta-analysisof randomized clinical trials comparing HTS andmannitol for reduction of ICP. 26 Only studies thatadministered equiosmolar doses in human subjectsundergoing quantitative ICP measurements wereincluded in this meta-analysis. Five trials compris -

ing 112 patients with 184 episodes of intracranialhypertension were included. Despite small samplesizes and mild heterogeneity (mostly due to differ -ent formulations of HTS), they found that HTS wasmore effective than mannitol for the treatment of in-tracranial hypertension. In 2007, a Cochrane reviewassessed the effects of mannitol therapy for acuteTBI compared to other treatment regimens. Only 1trial was found that directly compared mannitol toHTS.27 In this study, which was performed by Vialetet al, it was suggested that mannitol therapy forintracranial hypertension may have a detrimentaleffect on mortality when compared to HTS therapy(relative risk for death = 1.25; 95% con denceinterval, 0.47-3.33).28 Unfortunately, this study wastoo small to make valid conclusions, as there wereonly 20 patients in each arm. In 2011, Cottenceauperformed a multicenter prospective study on 47severe TBI patients in intensive care units (ICUs). 29 Patients were randomized to equiosmolar doses of20% mannitol (4 mL/kg) or 7.5% HTS (2 mL/kg).Both treatment arms effectively reduced ICP. Therewas a trend toward HTS being signi cantly strongerand of longer duration than mannitol; however, thisdifference was not statistically signi cant. Therewere no reported signi cant adverse events or dif -ferences in neurologic outcome at 6 months betweenthe groups. While these studies suggest that HTS is asafe and effective alternative to mannitol for treatingintracranial hypertension, there is limited evidenceto support any superior ef cacy or improved patientoutcomes, and a large randomized controlled trialcomparing mannitol and HTS is needed.

have used varied concentrations of HTS (from 2% to7.5%), have used varied methods of HTS administra -tion (bolus as well as maintenance drips), and haveincluded nontrauma patients in their study groups.In addition, the results from some clinical trialscomparing HTS to mannitol can be deceiving, asthey do not use equiosmolar doses of HTS. This dif -ference may make HTS appear more effective thanmannitol, where the primary effect could arguably be attributed to the higher osmotic load. Lastly, moststudies only demonstrate signi cance in surrogatephysiologic markers rather than meaningful clini -cal outcomes. For these reasons, current treatmentguidelines for the use of HTS in trauma resuscitationare based largely upon expert opinion.

The literature on the use of HTS to treat pa -tients with severe hyponatremia is weak and mostlycomprised of retrospective studies. Few prospectivestudies have been done, and treatment guidelinesare based mostly upon expert consensus.

Traumatic Brain InjuryAlthough the primary injury to the brain occursat the time of impact, subsequent compromise ofcerebral perfusion can extend the primary injuryand create a secondary injury. Current therapy inthe prehospital setting and the ED aims to mini -mize secondary injury by supporting systemicperfusion, reducing ICP, and optimizing cerebralperfusion pressure (CPP). The interventions todecrease intracranial hypertension that havehistorically been used in the ED include: headof bed elevation, supporting systolic blood pres -sure (SBP) > 90 mm Hg, preventing hypoxia, andensuring normocapnic ventilation. Additionally,for patients with signs of impending herniation(such as asymmetric pupillary response, dilatedand unreactive pupils, motor posturing, or rapidneurologic decline), osmotic agents (such as man -nitol or HTS) should be administered.

Intracranial Pressure ReductionMany trials have shown administration of HTS to be an effective method to reduce ICP for the brain-injured patient. Five case control studies have shown

that HTS alone or with a colloid reduces ICP in both adult and pediatric patients with TBI. 13-17 Fiverandomized controlled studies also compared HTSto mannitol, 18,19 isotonic crystalloid, or hypotoniccrystalloid 20,21 and found HTS to be effective in re -ducing intracranial hypertension secondary to bothtraumatic and nontraumatic causes. Most studiesused bolus dosing rather than continuous infusionand varied the solution concentration from 1.8% to10% with and without colloids.


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ment for patients with severe TBI emerges, futureguidelines are unlikely to be different from the cur -rent guidelines.

Traumatic Brain Injury With ConcurrentHypotensionTrauma patients with TBI often have accompanyinginjuries that lead to hypotension. Volume resuscita -

tion in this patient population can be challenging, asthe isotonic crystalloid solutions that are tradition -ally used to restore end-organ perfusion and preventsecondary anoxic brain injury could, theoretically,exacerbate cerebral edema. It would seem intui -tive that these patients would be an ideal cohort to bene t from HTS. Unfortunately, there is no strongevidence to support this. One multicenter trial us -ing 7.5% HTS with dextran suggested a mortality bene t in hypotensive patients who sustained a TBI.However, the strength of this conclusion is weak, asthe improvement was in comparison with predictedsurvival, not a direct comparison with the control

group.34

Wade et al performed a manufacturer-sup -ported cohort analysis of 223 patients with TBI andhypotension from 6 previous prospective random -ized double-blind trials. These trials compared 7.5%HTS with dextran versus a “standard-of-care iso -tonic crystalloid” (usually lactated Ringer’s). Theyshowed a trend toward survival until discharge(38% vs 27%;P = 0.08).35 Cooper et al from Australiaperformed a double-blind randomized controlledtrial focusing on the effect of prehospital resusci -tation with 7.5% HTS on neurologic outcomes inpatients with severe TBI and an SBP < 100 mm Hg. 31 A total of 229 patients were enrolled. Though therewas no signi cant neurologic difference betweenthe groups at 6 months, there was a trend towardsurvival in the HTS group (55% for the HTS groupand 47% for the control group; P = 0.25). While thesestudies show promise for the treatment of the hypo -tensive TBI patient with HTS, it is dif cult to drawde nitive conclusions from such small sample sizes.

Summary Of The Use Of Hypertonic SalineIn Severe Traumatic Brain InjuryAlthough the strength of the current literature isweak, it suggests that HTS is as effective as man -nitol for treating intracranial hypertension from TBI.Currently, there is no convincing evidence to suggestthat osmotic therapy (whether HTS or mannitol) re -sults in improved long-term neurologic outcome oroverall mortality bene t. HTS may be an acceptablealternative to mannitol, and indications for its use bythe emergency physician would include signi cantlydeteriorating neurologic status or signs of hernia -tion. While there is no agreement as to the dose orconcentration of HTS to use, most studies adminis -tered a 250 mL bolus of 7.5% HTS with dextran.

Clinical OutcomeFew studies have examined how the use of HTS mayaffect mortality or long-term neurological disabilityfor patients with TBI. In 2008, Bunn and colleaguesperformed a Cochrane review to determine whetherthe use of HTS decreases mortality in patients withhypovolemia with and without head injuries. 30 Theyfound only 1 trial that speci cally studied whether

prehospital resuscitation with intravenous (IV)HTS improves long-term neurological outcome inpatients with severe TBI compared to resuscitationwith crystalloid solutions. 31 There was no differ -ence in survival or neurologic outcome at 6 months between the 2 groups.

Shortly after the Cochrane review by Bunnet al, the National Institutes of Health sponsoredthe largest and most important study to date withrespect to these outcomes. This multicenter ran -domized double-blind placebo-controlled trialenrolled 1331 patients from the prehospital set -ting.32 Patients with concomitant hypotension were

excluded. Patients were randomized to receive a250-mL prehospital bolus of 7.5% HTS, 7.5% HTSwith 6% dextran 70, or normal saline and were fol -lowed for 6 months. The study was stopped afteran interim analysis determined that HTS providedno improvement in either mortality or neurologicoutcome and that enrolling new patients would notchange the outcome of the study.

In 2011, Tan et al conducted a systematic litera -ture review to investigate whether the infusion ofHTS or colloid solutions results in better outcomesthan standard isotonic crystalloid solutions forpatients with TBI. They identi ed 9 randomizedcontrolled trials and 1 cohort study that examinedthe effects of infusion of hypertonic solutions (withor without the addition of colloids) for prehospi -tal volume resuscitation. 33 Studies that includedpatients who had sustained a TBI, with and withoutother injuries, were included in the review. None ofthese trials reported better survival and functionaloutcomes with HTS compared to the use of standardisotonic crystalloid solutions. In 2007, the Brain Trauma Foundation, in con - junction with the American Association of Neuro -logical Surgeons and the Congress of NeurologicalSurgeons, published guidelines regarding the use ofhyperosmolar therapy for the management of severeTBI. The guideline authors only examined literatureon adult human hospitalized patients. The majoroutcomes they reviewed included reduction in ICP,changes in CPP, changes in cerebral blood ow, andlong-term morbidity and mortality. They concludedthat the current evidence is not strong enough tomake recommendations on the use, concentration,or method of administration of HTS in traumaticintracranial hypertension. 23 Until more conclusiveevidence regarding the use of HTS for ICP manage -


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who received HTS with dextran had better survivalthan predicted by trauma scores. 41 Bunn and colleagues performed a Cochrane re -view to determine whether HTS decreases mortal -ity in patients with hypovolemia from causes otherthan hemorrhage. Their search included random -ized trials comparing isotonic and near-isotoniccrystalloid solutions to HTS in patients with trau -ma, with burns, or who were undergoing surgery.Fourteen trials with a total of 956 participants wereincluded in the meta-analysis. They concluded thatthe con dence intervals for relative risk were wide,and no conclusions could be drawn about a mortal -ity bene t. 30 In 2011, a multicenter double-blind randomizedcontrolled trial sponsored by the National Institutesof Health examined whether the effect of 7.5% HTS(with and without 6% dextran 70) compared tonormal saline improved mortality in hypotensive blunt and penetrating trauma patients. 48 This study,which included 853 patients, is the largest study to

date. Patients were randomized to receive a 250-mLprehospital bolus of 7.5% HTS with dextran 70, 7.5%HTS, or normal saline. Like the previously men -tioned National Institutes of Health TBI study, it wasterminated early by the Data and Safety MonitoringBoard after they found that patients who receivedHTS and did not receive blood transfusions in the

rst 24 hours had a higher mortality (HTS withdextran: 10%; HTS: 12.2%; normal saline: 4.8%). Theauthors of this study offered 2 possible explanationsfor this early mortality. The rst is that the patientstreated with HTS had a higher rate of early hemor -rhage (possibly precipitated by the HTS). However,if increased bleeding was the primary mechanismfor earlier mortality, one would anticipate highermortality among penetrating rather than blunttrauma patients; the opposite effect was seen in thisstudy. Moreover, those patients requiring emergenthemorrhage control who received hypertonic uidsdid not have an increase in mortality. The other,more likely, explanation is that the administrationof HTS caused a change in physician behavior thatdelayed the recognition of shock and subsequenttransfusion. It is unclear whether any of these earlydeaths were preventable, as there was no overall dif -ference in the 28-day survival between the groups. 48

Summary Of The Use Of Hypertonic SalineIn Hypotensive Trauma PatientsHTS improves hemodynamics for trauma patientsin hemorrhagic shock. Small-volume resuscitationmay make HTS an ideal crystalloid solution forcombat casualty situations. Most studies on theuse of HTS in hypotensive trauma patients admin -istered a 250-mL bolus of 7.5% HTS with dextran.While small trials suggest that there may be somesubsets of patients who may bene t from the use of

Hypotensive Trauma Patients

For the trauma patient in hemorrhagic shock, thechoice and amount of resuscitative uids are issuesof continued debate. Current Advanced Trauma LifeSupport ® guidelines recommend treating patientsin hemorrhagic shock by infusing 2 L of isotonicor near-isotonic crystalloid solutions, followed by

blood products. However, in the last decade, 2 majorconcepts have challenged this approach. The rstis the concept of “hypotensive resuscitation” (ie,the premise that resuscitation to “normal” bloodpressures may increase bleeding at a site of uncon -trolled hemorrhage). The second is the use of HTSas an alternative resuscitative uid. It is cheap, isportable, improves microcirculation, and has immu -nomodulatory properties. It allows “small volume”resuscitation (4 mL/kg) in austere environments andempowers a single medic to treat multiple combatcasualties. The 1999 Institute of Medicine report onresuscitation of combat casualties recommended

HTS with dextran as the optimal resuscitation uidin that environment. 36 HTS may also have practicaladvantages for civilian emergency medical services.Due to short transport times, restoration of meanarterial pressure (MAP) for patients with TBI is dif -cult with traditional crystalloid solutions. HTS withdextran administered by prehospital providers mayrestore MAP more quickly and reduce the potentialfor secondary neurologic injury in TBI patients. In 1980, de Felippe et al reported astonish -ing results of survival in 11 of 12 patients withrefractory hemorrhagic shock who were treatedwith HTS.37 That same year, researchers from theUniversity of Sao Paulo published the rst animalstudy on the use of HTS. 38 They subjected dogs tohemorrhagic shock and reported that 7.5% sodiumchloride (NaCl) infused in a volume equal to only10% of shed blood volume rapidly restored bloodpressure. 38 These initial studies prompted severalsubsequent trials to evaluate the use of HTS for thetreatment of hemorrhagic shock. From 1987 to 2011, there were 10 random -ized controlled trials comparing the use of HTS toisotonic crystalloid solutions in hypotensive traumapatients. 34,39-47 Many of these trials had very low pa -tient numbers and compared bolus therapy of 7.5%HTS with dextran to 7.5% HTS or normal saline,followed by standard resuscitation with crystalloidsand blood products, if necessary. Most of the trialsfound that 7.5% HTS with dextran increased MAPmore than a similar volume of isotonic crystalloidsolution. No signi cant side effects were noticed.Unfortunately, no studies showed an overall mor -tality bene t. In post-hoc analysis, some studiesshowed mortality difference in certain subgroups,such as those requiring surgery 40 or when MAP was< 70 mm Hg. 39 Vassar et al remarked that, whilethere was no difference in overall mortality, patients


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than 10 to 12 mEq/L in 24 hours. 51 Certain patientsmay be at a particularly high risk of ODS second -ary to underlying abnormalities in cerebral osmoticregulation. These include patients with alcoholism,malnutrition, hypokalemia, and burns as well aselderly women on diuretics. 52

Considerations For The Treatment Of Severe

HyponatremiaWhen considering whether or not to treat hypona -tremia with HTS, 3 questions must rst be answered:1. Does the patient’s corrected serum sodium cor -

respond to his clinical picture?2. Does the patient have severe neurologic symp -

toms (eg, coma, seizure, focal neurologic exami -nation) that warrant treatment with HTS?

3. Is the duration of hyponatremia acute or chronic?

The corrected serum sodium should correlatewith the patient’s neurologic symptoms. Mostpatients with severe neurologic symptoms from hy -

ponatremia have serum sodium levels < 115 mEq/L.If a patient’s serum sodium level does not correlatewith his neurologic symptoms, consider an alterna -tive etiology for their presentation (such as toxico -logical, infectious, or metabolic). Patients who present with acute severe hypo -natremia (ie, hyponatremia for < 48 h) have hadlittle time for their brain to adapt and are moreprone to cerebral edema, but they are less likely todevelop ODS with rapid correction. These patientsusually present with seizures, encephalopathy, orfocal neurologic signs. The most common clinicalscenario an emergency physician might encounteris water intoxication that is secondary to psy -chosis, ecstasy use, or endurance sports (such asmarathon running).

Patients with chronic hyponatremia (ie, hypona -tremia lasting > 48 h) have had time for their brainto adapt, are less prone to cerebral edema, and aremore likely to develop ODS with rapid correction.These patients generally present with only mild neu -rologic symptoms (such as gait disturbances, confu -sion, lethargy, and nausea). Sometimes, the durationof hyponatremia is not known. In this setting, it issafest to assume that the patient has chronic hypona -tremia and to treat accordingly. Patients who have only mild symptoms ofhyponatremia (eg, confusion) are unlikely to havesevere neurologic sequelae from their hyponatremia,if treated conservatively. Only patients with severeneurologic symptoms such as coma, seizure, or focalneurologic signs warrant treatment with HTS.

Treatment Of Severe HyponatremiaOptimal treatment strategies with HTS for severehyponatremia are based on expert consensus andare not well de ned. (See Table 2 on page 8.) There

HTS (eg, those requiring surgery or patients withSBP < 70 mm Hg), there is currently no strong evi -dence to support its use in hypotensive trauma pa -tients. Further, it may worsen mortality in patientswho do not receive blood transfusions in the rst24 hours, as it may delay the recognition of shockand subsequent transfusion.

Severe HyponatremiaHyponatremia (de ned as a serum sodium concen -tration < 135 mEq/L) is one of the most commondisorders of electrolytes in clinical practice, occur -ring in up to 30% of both acutely and chronicallyhospitalized patients. 49 The majority of patientswho present to the ED with hyponatremia do notrequire emergent management; however, patientswho present with severe hyponatremia need imme -diate attention and an appropriate rate of correctionto prevent devastating neurologic de cits or evendeath. Recognizing and appropriately instituting

treatment is critical for this life-threatening electro -lyte emergency.

Brain Adaptation And OsmoticDemyelination SyndromeTo understand the reasoning behind the recom -mended guidelines for treating severe hyponatremia(including the pitfalls of overly rapid correction), itis necessary to review how the brain adapts to hypo -natremia and the time course over which this occurs.Brain adaptation to hyponatremia begins fairlyquickly after an acute fall in serum sodium and iscomplete within 2 days. 50 Initially, water movesfrom the hyposomolar extracellular compartmentto the relatively hyperosmolar cells. There is a lossof interstitial sodium and water in the cerebrospinal

uid due to increased hydraulic pressure. Withinhours, intracellular potassium, sodium, and organicsolutes are pumped out of the cell. This adaptationhelps reduce the severity of neurologic symptomsand the risk of cerebral edema. Once adaptation iscomplete, however, the neurons are hyposmolarand, if exposed to excess sodium (as may occur dur -ing overcorrection of the hyponatremia), are proneto suffering cellular injury; this is termed osmotic

demyelination syndrome (ODS). (See Figure 1.) ODS is an irreversible or only partially revers -ible neurologic injury that may include dysarthria,dysphagia, paraparesis or quadriparesis, behavioraldisturbances, lethargy, confusion, obtundation,or coma. The most important risk factors for thedevelopment of ODS include the serum sodiumconcentration at presentation, the duration of hypo -natremia, and the rate of correction. While no rate ofcorrection is totally protective, ODS can usually beavoided by limiting correction of chronic hypona -tremia (ie, hyponatremia lasting > 48 h) to no more


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The initial goal of treating hyponatremic pa -tients with severe neurological symptoms is toreverse the cerebral edema with 3% HTS. Perhapsthe easiest method of administration was developed by the Second International Exercise-Associated

is no study that compares the ef cacy and safety ofdifferent treatment regimens. Therefore, patientstreated with HTS should have frequent neurologicchecks and measurement of serum sodium levelsevery 1 to 2 hours.

Figure 1. The Danger Of Overly Aggressively Correction Of HyponatremiaNormal state. The extracellular uid is in osmotic equilibrium with the intracellular

uid, including that of the brain cells, with no net movement of water across theplasma membrane.

Acute hyponatremia. If the extracellular uid suddenly becomes hypotonic relativeto the intracellular uid, water is drawn into the cells by osmosis, potentially caus -ing cerebral edema.

Adaptation. Over the ensuing few days, brain cells pump out osmoles, rst potas -sium and sodium salts and then organic osmoles, establishing a new osmoticequilibrium across the plasma membrane and reducing the edema as watermoves out of the cells.

Overly aggressive therapy with hypertonic saline after adaptation has occurredraises the serum sodium level to the point that the extracellular uid is more con -centrated than the intracellular uid, drawing more water out of the brain cells andcausing the syndrome of osmotic demyelination.

Reprinted from: Vaidya C, Ho W, Freda BJ. Management of hyponatremia: Provid-ing treatment and avoiding harm. Cleve Clin J Med 2011; 77:715-726. Reprintedwith permission. Copyright © 2011 Cleveland Clinic Foundation. All rightsreserved.

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brain barrier may be compromised in TBI, leading toaccumulation of mannitol in already edematous tis -sue, which ultimately causes an increase in cerebraledema and ICP. Additionally, mannitol is an osmoticdiuretic and may cause hypotension, which worsenssecondary brain injury. HTS has the theoretical potential to improve bothCPP and intracranial hypertension without the delete -

rious effects of mannitol. The primary effect by whichHTS reduces ICP is by setting up an osmotic gradientacross an intact blood-brain barrier and dehydrat-ing brain tissue in the mostly uninjured portions. 55 Itis more attractive than mannitol as a hyperosmotictherapy, as it is less permeable across an intact blood- brain barrier and has a higher osmotic gradient in thevascular compartment. 8,9 Because the osmotic effectof HTS alone is transient, it is usually combined witha colloid (hydroxyethyl starch or dextran). This mayprolong the clinical effect by 2 to 4 hours. 56

Hemodynamic And Microcirculatory Effects

Isotonic crystalloid solutions currently predominateover all other resuscitative uids for the hypotensivetrauma patient. When NaCl or lactated Ringer’sis given, it is rapidly redistributed throughout theentire extracellular space with no preference for thevascular space. Ultimately, only 10% to 20% of theinfused isotonic crystalloid remains in the circula -tion.57-59 This can necessitate large volumes of uidfor resuscitation, potentially worsening hemorrhageand neuronal injury. (See Figure 2.) In contrast, HTS allows for resuscitation withsmaller volumes (4 mL/kg of 7.5% NaCl). Theosmotic effect is immediate, and it can increase theintravascular volume by as much as 4 times theinfused volume within minutes of infusion. 60 Thatsaid, it is most likely an oversimpli cation to con -sider HTS as a potential treatment for TBI and shocksolely from its actions as an osmotic agent. Fortu -nately, there are many rheological effects by which itmay improve microcirculation, including decreasing blood viscosity, endothelial cell edema, and capil -lary resistance via dehydration of erythrocytes. 8-10 Hypertonicity also has a direct relaxant effect on thevascular smooth muscle with resultant arteriolarvasodilation. 2 Last but not least, the optimizationof blood ow and CPP is supported by the effect ofHTS on increasing the MAP.

Immunologic EffectsOne of the more intriguing aspects of HTS is itspotential to modulate the immune system in thetrauma patient. It is well known that dysfunctionalactivation of the immune system after traumaticinjuries and other shock states can cause subse -quent tissue and organ injury. 61 Basic science stud-ies have con rmed that HTS has marked effects onthe immune system. 2 It has been shown to blunt

Consensus Development conference. 53 They recom-mend that any athlete with severe hyponatremiaand encephalopathy be treated immediately witha bolus infusion of 100 mL of 3% NaCl to acutelyreduce brain edema. Two additional 100-mL bolusesof 3% NaCl should be repeated at 10-minute inter -vals if there is no clinical improvement. This wouldtranslate to 6 mL/kg of 3% NaCl for a 50-kg woman,which is enough to raise the serum sodium concen -tration by 5 to 6 mEq/L. While this guideline wasdeveloped to treat those with exercise-associatedhyponatremia, it is probably a reasonable regimen toextrapolate to all patients with severe hyponatremia,regardless of etiology or duration. After the initial treatment with HTS to addressthe serious signs and symptoms of hyponatremia,the subsequent rate of correction should be closelymonitored. The goal is not to correct the patient’sserum sodium to “normal” values. For patients witheither chronic hyponatremia or hyponatremia ofan unknown duration, an expert panel suggested a

correction of no more than 10 to 12 mEq/L duringthe rst 24 hours of treatment. 51 They also suggestedthat, due to a sometimes unexpected “autocorrec -tion” during the course of treatment, it may be bestto aim for undercorrection (more near the rate of 8mEq/L/d). It is important to emphasize that theserecommendations were derived from relativelysmall numbers of patients and that they only give anestimate of reasonable correction rates.

Going Deeper: How Hypertonic Saline Works

Intracranial Pressure EffectsAs mentioned previously, the primary goals ofmanaging a patient with TBI are to reduce cere - bral edema, decrease ICP, and improve CPP. Whilemannitol has historically been considered the drugof choice for acute intracranial hypertension, it hassome drawbacks. 54 First, it is believed that the blood-

Table 2. Recommended Steps For TheTreatment Of Severe Hyponatremia 53

1. Determine whether the patient’s corrected serum sodium valueexplains his clinical condition.

2. Assess for severe neurologic signs suggesting cerebral edema(seizures, coma, focal neurologic signs).

3. Assess the patient’s duration of hyponatremia. Patients withchronic hyponatremia (duration > 48 h) are at a higher risk ofdeveloping ODS from overrapid correction.

4. Administer an IV bolus of 100 mL of 3% HTS. Repeat twice over10-minute intervals, if needed.

5. Monitor serum sodium every 1-2 hours.6. The serum sodium should not be raised more than 10-12

mEq/L/d.

Abbreviations: HTS, hypertonic saline; IV, intravenous; ODS, osmoticdemyelination syndrome.


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One obvious potential complication of HTS issequelae from unintended iatrogenic-induced hyper -natremia (other than ODS). A retrospective analysisof more than 600 neurointensive care unit patientsexamined upper threshold values of hypernatremia.Unless serum sodium values exceeded 160 mEq/L,no worse outcomes were detected. This is well beyond the value that would commonly be reachedafter initial treatment in the ED. 62

ODS is arguably the most-feared complicationfrom the administration of HTS. Fortunately, it israre and generally only associated with chronichyponatremic patients who undergo overrapidcorrection. There is little evidence from the currentliterature to support the fear of ODS from treatingpatients with TBI or hemorrhagic shock with HTS.However, since ODS is a devastating condition, cau -tion should still be exercised when using HTS in apatient who may have chronic hyponatremia (suchas an alcoholic patient or a patient with congestiveheart failure).

In head-injured patients whose blood-brain barrier is disrupted, the potential exists for HTSto permeate into the injured tissue, raising watercontent, increasing ICP, and exacerbating braindamage. 11 The majority of studies do not report this

neutrophil activation, modify cytokine production, 3 and augment T-cell function. 4,5 In animal models, itdecreases hemorrhage-induced neutrophil activationand is protective against acute lung injury. 6,7 To date,no clinical studies have been conducted that demon -strate a patient-oriented bene t from these immuno -modulation properties.

Adverse EffectsAs a resuscitative uid, HTS is cheap, does nottransmit infection, and is unlikely to provoke ananaphylactic reaction. It has a strong safety record based on previous clinical trials and reported use.However, it is worthy to note that the patients at thehighest risk of being harmed by HTS (such as thosewith heart failure, pulmonary edema, and kidneyfailure) were often excluded from these trials.

The largest randomized controlled trial of HTSand TBI (which included 1331 patients) did not

nd a statistically signi cant difference in the rateof adverse events between the treatment groups,

although they did describe a not statistically signi -cant trend toward a higher nosocomial infection ratein the HTS groups. Importantly, they observed noincrease in progression of intracranial hemorrhage inthe hypertonic uid groups. 32

Figure 2. Distribution Of Crystalloid Solution Administration

Abbreviations: H 2O, water; IV, intravenous; NaCl, sodium chloride.Adapted from: Johnson AL, Criddle LM. Pass the salt: indications for and implications of using hypertonic saline. Crit Care Nurse . 2004.24(5):36-44.

IV isotonic crystalloids (isotonic NaCl solution, lactated Ringer’ssolution) diffuse throughout the extracellular space and do not(normally) enter the cells. Therefore, the majority of the 3000 mLof an IV isotonic NaCl solution will be distributed in the extracel-lular compartment, with three-quarters (2250 mL) entering theinterstitial space and one-quarter (750 mL) remaining in theintravascular space. Although this intravascular volume gain isnot insigni cant, the majority of infused uid enters the interstitialspace, promoting edema.

A. Distribution of isotonic crystalloids (3000 mL isotonic solution)

Interstitial

3000 mL

2250 mL

Extracellular Intracellular

Hypertonic crystalloids infused into the circulation actually drawbody water from the large reservoirs of the intracellular andinterstitial compartments into the vessels. This shift dramaticallyincreases blood volume by many times the actual volume infused.

B. Distribution of hypertonic crystalloids (250 mL of 7.5% NaCl)

Interstitial

H20 H 20

Extracellular Intracellular

Intravasculature

750 mL

2000 mL

Intravasculature


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Clinical Course In The ED

StabilizationAfter an osmotic agent has been administered to aTBI patient with an asymmetric pupillary response,dilated and unreactive pupils, motor posturing, orrapid neurologic decline, the focus should be onreducing ICP and optimizing CPP. This includes

head of bed elevation, supporting MAP > 90 mmHg, preventing hypoxia, and obtaining immediateneurosurgical consultation. For the trauma patient in shock who has sta - bilized after uid resuscitation, further evaluation(including ultrasound, plain lms, and computedtomography) should be used to pursue the cause forthe patient’s hypotension.

For the hyponatremic patient whose neurologicsymptoms have stabilized, you can reduce the riskof overrapid correction by not administering ad -ditional infusions of HTS. Careful monitoring of theserum sodium level should be performed every 2 to3 hours.

DeteriorationThe administration of an osmotic agent for severeTBI is only a temporizing measure while further di -agnostic procedures or interventions are performed.If a patient continues to show signs of deterioration,efforts to reduce ICP and optimize CPP should bemaximized. Immediate neurosurgical consultationis essential, as refractory intracranial hypertensionmay require urgent neurosurgical intervention. For the trauma patient in refractory shock, re -suscitation should continue with packed red bloodcells. For patients with penetrating trauma andongoing hemorrhage, an SBP of 80 to 90 mm Hgmay be a more optimal resuscitation endpoint untilde nitive hemorrhage control can be achieved. 69 Continue an aggressive search for both hemor -rhagic causes (external bleeding, hemothorax, he -moperitoneum, pelvic fracture, long bone fracture)and nonhemorrhagic causes (tension pneumotho -rax, pericardial tamponade, myocardial contusion,spinal cord injury, coincident medical event such asgastrointestinal bleeding). Focus on etiologies thatare immediately correctable in the ED (eg, tension

pneumothorax), and obtain immediate consultation by a trauma surgeon.For the hyponatremic patient whose neurologic

symptoms persist or worsen, an additional 100-mL bolus of 3% HTS can be repeated 1 or 2 more timesat 10-minute intervals. This will usually be effec -tive at terminating the seizures. If seizures continue,standard anticonvulsant therapy may also be ad -ministered but should not distract the provider fromtreating the primary cause.

nding. These effects are more likely to be secondaryto changes in serum osmolality. 63 Table 3 summarizes the adverse effects of HTSas well as its bene ts.

Tools And Techniques: PracticalConsiderations For Hypertonic Saline

HTS for the trauma patient with TBI and/or hemor -rhagic shock is most often infused as a single 250-mLIV bolus of 7.5% NaCl solution with 60% dextran 70.An alternative weight-based bolus of 4 mL/kg hasalso been used.

The military has examined the intraosseousroute as an alternative method for infusing resuscita -tion uids for the treatment of hemorrhagic shockin animals. It appears to be as effective in restoringMAP as the IV route, 64-66 and no short- or long-termmajor tissue damage was observed. Caution shouldstill be exercised, however, as extravasated hyper -tonic uid has the potential to cause tissue necrosis.This may have accounted for 1 study reporting tibialnecrosis 2 days after the infusion of HTS with dex -tran into dehydrated pigs. 67

For the treatment of severe hyponatremia, 100mL of 3% HTS saline should be given as an IV bolus.This should raise the serum sodium concentration by 2 to 3 mEq/L. Be careful, as the serum sodiummay autocorrect and rise faster than expected. Someexperts suggest a target increase of no more than 8 to10 mEq/L/d.

Due to the high osmolarity of HTS, infusionthrough a central line is preferred to minimize phlebi -

tis.68

Most studies used a 7.5% HTS solution, which hasan osmolarity of 2567 mOsm/L. The usual maximumrecommended osmolarity infused via a peripheral IVline is 900 mOsm/L. For this reason, when central ac -cess is not available, it is advisable to administer HTSthrough a large-bore peripheral IV line.

Table 3. Proposed Benefts And AdverseEffects Of Hypertonic Saline

Benefts Adverse Effects

• Inexpensive• Reduces ICP• Improves CPP• Improves hemodynamics

and microcirculation• Immunomodulation• Vasoregulation• Small-volume resuscitation

• Theoretical risk of ODS• ‘Rebound’ increase in ICP• Elevating MAP and worsen-

ing bleeding in patients withuncontrolled hemorrhage

Abbreviations: CPP, cerebral perfusion pressure; ICP, intracranialpressure; MAP, mean arterial pressure; ODS, osmotic demyelinationsyndrome.


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This begs the question: Does the use of HTSwork against this new resuscitative strategy? Asdiscussed previously, HTS has been shown to in -crease MAP more than a similar volume of isotoniccrystalloid solution, and some animal studies ofuncontrolled hemorrhage have raised concern for in -creased bleeding after administration of HTS. 71-75 Inthe largest study to date evaluating HTS for traumapatients in hemorrhagic shock, the HTS group had ahigher earlier mortality and lower admission hemo -globin,48 which might have been caused by the arti -

cially high MAP hiding the fact that the patient hasorgan hypoperfusion and delaying the recognitionof shock by the emergency physician (and therebydelaying subsequent transfusion).

Hypertonic Saline For SepsisDue to its various effects at the systemic, organ, andmicrocirculatory levels, HTS appears to be a promis -ing therapy in sepsis for improving tissue oxygen -ation and patient outcomes. To date, there are few

prospective human trials that have studied HTS asa resuscitative uid in sepsis. Those that have beenperformed showed an improvement in physiologicendpoints with HTS (increased cardiac output, de -creased systemic vascular resistance, and increasedpulmonary capillary wedge pressure), but they didnot measure clinical outcomes. 76-78

It is also theorized that, because of its immu -nomodulatory effects, HTS may help prevent thedevelopment of multiple organ failure in the septicpatient. Thousands of patients with sepsis have been entered into various studies where differentin ammatory mediators were blocked or modu -lated in the hope that HTS might alter outcome.Unfortunately, none of these have proven success -ful, and this author believes that it is doubtful thatHTS will prove to have a bene cial patient effectsecondary to these properties.

Disposition

Patients with a TBI requiring hyperosmolar therapywill most likely require neurosurgical specialistsand transfer to either the ICU or the operatingroom for urgent neurosurgical intervention. Trans -

fer from community hospitals should be performedin the most expeditious method available. (Fora review of critical care transport, see Volume 2,Number 4 of EMCC: “Air Transport Of The Criti -cally Ill Trauma Patient.”) Trauma patients with hemorrhagic shock willlikely require a surgical intervention in the operatingroom for de nitive hemorrhage control. If a patientinitially presents at a community hospital, transfershould begin as soon as the initial life threats areaddressed. Transfer should not be delayed for anyadditional imaging.

Special Circumstances

Pediatric Patients With Traumatic BrainInjuryLike many areas of pediatric critical care, the major -ity of evidence for using HTS to treat severe TBI inchildren is extrapolated from the adult literature.There have been few rigorous prospective stud -

ies examining the effect of HTS for severe TBI inchildren. Fisher et al performed a randomizedcontrolled crossover study of 18 children with severeTBI and compared bolus dosing of 3% HTS with nor -mal saline. 20 They reported that HTS was associatedwith a lower ICP and a reduced need for additionalinterventions (thiopental and hyperventilation) tocontrol ICP. Simma et al prospectively randomized35 consecutive pediatric patients with severe TBI toreceive either lactated Ringer’s solution or 1.7% HTSfor 72 hours.21 All patients subsequently receivedICP monitors, and their ICU courses were compared.While there was no signi cant difference in sur -vival rate, patients treated with HTS had a shorterlength of ICU stay and required fewer interventionsto maintain ICP control. These studies suggest thatHTS is promising for the treatment of severe TBIin children, but the strength of their conclusions islimited due to small sample sizes. The pediatric section of the Society of CriticalCare Medicine and the World Federation of Pediat -ric Intensive and Critical Care Societies publishedguidelines in 2012 for the treatment of the pediatricpatient with severe TBI. 70 They cited 2 pediatricstudies 20,21 as evidence for the use of HTS and adapt -ed adult severe TBI guidelines. They recommendedthat HTS be considered for the treatment of pediatricTBI associated with elevated ICP (Level II evidence).While they recognized that there was insuf cientevidence to recommend speci c concentrations ordoses, they recommended bolus dosing between 6.5and 10 mL/kg of 3% HTS.

Controversies And Cutting Edge

Hypertonic Saline And HypotensiveResuscitationIn trauma patients, restoring intravascular volume

and blood pressure in an attempt to achieve normalsystemic pressure may cause further blood loss,dilutional coagulopathy, and increased mortal -ity. This has led to an increasing emphasis on theconcept of hypotensive resuscitation (ie, loweringresuscitation endpoints to an SBP of 80 to 90 mm Hguntil de nitive hemorrhage control can be achieved).This strategy has been shown to improve mortal -ity for patients with penetrating trauma. 69 Whileit is tempting to hope for a similar bene t in blunttrauma patients, the current literature has not dem -onstrated this.


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• Recognize neurologic signs of cerebral edemasecondary to hyponatremia (seizures, encepha -lopathy, or focal neurologic signs).

• Do not try to correct the patient’s serum sodiumlevel to “normal” values.

• Avoid overcorrection of chronic hyponatremiaor undercorrection of acute symptomatic hy -ponatremia, as these can lead to serious neuro -logic injury.

• Do not increase a patient’s serum sodium bymore than 10 to 12 mEq/L/d, as this may pre -cipitate ODS.

References

Evidence-based medicine requires a critical ap -praisal of the literature based upon study methodol -ogy and number of subjects. Not all references areequally robust. The ndings of a large, prospective,random ized, and blinded trial should carry moreweight than a case report.

To help the reader judge the strength of eachreference, pertinent information about the study,such as the type of study and the number of patientsin the study, will be included in bold type followingthe reference, where available. In addition, the mostinformative references cited in this paper, as deter -mined by the authors, will be noted by an asterisk (*)next to the number of the reference.

1. Sauaia A, Moore FA, Moore EE, et al. Epidemiology oftrauma deaths: a reassessment. J Trauma. 1995;38(2):185-193.

2. Rocha-e-Silva M, Poli de Figueiredo LF. Small volumehypertonic resuscitation of circulatory shock. Clinics. 2005;60(2):159-172.(Review)

3. Rizoli SB, Rhind SG, Shek PN, et al. The immunomodulatoryeffects of hypertonic saline resuscitation in patients sustain -ing traumatic hemorrhagic shock: a randomized, controlled,double-blinded trial. Ann Surg. 2006;243(1):47-57.(Prospec-tive randomized controlled trial; 27 patients)

4. Hirsh M, Dyugovskaya L, Bashenko Y, et al. Reduced rateof bacterial translocation and improved variables of naturalkiller cell and T-cell activity in rats surviving controlled hem -orrhagic shock and treated with hypertonic saline. Crit Care Med.2002;30(4):861-867.(Laboratory)

5. Loomis WH, Namiki S, Hoyt DB, et al. Hypertonicity rescuesT cells from suppression by trauma-induced anti-in amma -tory mediators. Am J Physiol Cell Physiol. 2001;281(3):C840-C848. (Laboratory)

6. Angle N, Hoyt DB, Coimbra R, et al. Hypertonic saline re -suscitation diminishes lung injury by suppressing neutrophilactivation after hemorrhagic shock. Shock. 1998;9(3):164-170.(Laboratory)

7. Homma H, Deitch EA, Feketeova E, et al. Small volumeresuscitation with hypertonic saline is more effective in ame -liorating trauma-hemorrhagic shock-induced lung injury,neutrophil activation and red blood cell dysfunction thanpancreatitic protease inhibition. J Trauma. 2005;59(2):266-272.(Laboratory)

8. Qureshi AI, Suarez JI. Use of hypertonic saline solutions intreatment of cerebral edema and intracranial hypertension.Crit Care Med.2000;28(9):3301-3313. (Review)

9. Suarez JI. Hypertonic saline for cerebral edema and elevatedintracranial pressure. Cleve Clin J Med. 2004;71 Suppl 1:S9-S13.(Review)

10. Mortimer DS, Jancik J. Administering hypertonic saline to

Patients with severe hyponatremia requiringHTS administration should be admitted to an ICU.

Summary

HTS has been shown to be safe and effective forreducing ICP and improving hemodynamics for thetrauma patient in hemorrhagic shock. Currently, no

convincing data show any improvement in clinicaloutcomes. HTS is an important therapy for patientswith severe hyponatremia with signs of cerebraledema. A bolus of 100 mL of 3% saline is a reason -able start and may be repeated twice over 10-minuteintervals to abate neurologic symptoms. Correctionof a patient’s serum sodium < 10 to 12 mEq/L inthe rst 24 hours is unlikely to precipitate ODS. Thetheoretical bene ts of HTS raise the possibility of itsuse as a therapy for other critically ill patients; how -ever, little data exist to make any recommendations.

Case Conclusions

You were worried about the motor vehicle accident pa-tient’s worsening mental status and signs of herniation.Based on the available evidence indicating that HTSwith dextran is as effective as mannitol to reduce ICP(and the fact that it may help support this patient’s sys-temic pressure and CPP during helicopter transport ifhis splenic laceration continues to bleed), you decided toinfuse 250 mL of 7.5% HTS with dextran. Fortunately,his neurologic status did not deteriorate any further, andhe was quickly transferred to the nearest Level 1 traumacenter, where he underwent acute decompression for hisepidural hematoma and angiography embolization forhis splenic laceration. Based on your second patient’s history and sodiumlevel, you quickly determined that she had sufferedexercise-associated hyponatremia. It was acute in onset,and, because of her seizures, you determined that she mostlikely had cerebral edema. After intubation, you adminis-tered 100 mL of 3% HTS. She had no continued seizuresand was transferred to the ICU. Her repeat serum sodium1 hour later had increased by 4 mEq/L. After a short stayin the ICU, she was discharged home with a normal neu-rologic status.

Must-Do Markers Of Quality Care• Avoid secondary brain injury caused by hypo -

tension and hypoxia.• Reduce ICP and maximize CPP by using head

of bed elevation, supporting SBP > 90 mm Hg,preventing hypoxia, and using normocapnicventilation.

• Administer osmotic agents to patients with signsof impending herniation (asymmetric pupillaryresponse, dilated and unreactive pupils, motorposturing, or rapid neurologic decline).


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tonic solutes (sodium chloride or mannitol) in the treatmentof refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol.Crit Care Med.2003;31(6):1683-1687.

29. Cottenceau V, Masson F, Mahamid E, et al. Comparison of ef -fects of equiosmolar doses of mannitol and hypertonic salineon cerebral blood ow and metabolism in traumatic braininjury. J Neurotrauma. 2011;28(10):2003-2012.(Prospective; 47patients)

30.* Bunn F, Tasker R, Daksha T. Hypertonic versus near isotoniccrystalloid for uid resuscitation in critically ill patients.Cochrane Database Syst Rev.2008;(4):CD002045.(Cochranesystematic review and meta-analysis; 956 patients)

31.* Cooper DJ, Myles PS, McDermott FT, et al. Prehospitalhypertonic saline resuscitation of patients with hypotensionand severe traumatic brain injury: a randomized controlledtrial. JAMA.2004;291(11):1350-1357.(Prospective random-ized controlled trial; 229 patients)

32.* Bulger EM, May S, Brasel KJ, et al. Out-of-hospital hyper-tonic resuscitation following severe traumatic brain injury: arandomized controlled trial. JAMA. 2010;304(13):1455-1464.(Prospective randomized controlled trial; 1331 patients)

33. Tan PG, Cincotta M, Clavisi O, et al. Review article: prehos -pital uid management in traumatic brain injury. Emerg MedAustralas. 2011;23(6):665-676.(Review article)

34. Vassar MJ, Fischer RP, O’Brien PE, et al. A multicenter trialfor resuscitation of injured patients with 7.5% sodium chlo -ride. The effect of added dextran 70. The Multicenter Groupfor the Study of Hypertonic Saline in Trauma Patients. ArchSurg. 1993;128(9):1003-1011. (Prospective randomized con-trolled trial; 194 patients)

35. Wade CE, Grady JJ, Kramer GC, et al. Individual patientcohort analysis of the ef cacy of hypertonic saline/dextranin patients with traumatic brain injury and hypotension. J Trauma.1997;42(5 Suppl):S61-S65.(Cohort analysis; 223patients)

36.* Committee on Fluid Resuscitation for Combat Casualties,Institute of Medicine. State of the Science for Treating CombatCasualties and Civilian Injuries. Washington DC: NationalAcademies Press: 1999. (Textbook)

37. de Felippe J Jr, Timoner J, Velasco IT, et al. Treatment ofrefractory hypovolaemic shock by 7.5% sodium chlorideinjections. Lancet. 1980;2(8202):1002-1004.(Case report; 12patients)38. Velasco IT, Pontieri V, Rocha e Silva M Jr, et al. Hyperos -motic NaCl and severe hemorrhagic shock. Am J Physiol. 1980;239(5):H664-H673.(Laboratory)

39. Younes RN, Aun F, Ching CT, et al. Prognostic factors topredict outcome following the administration of hyper -tonic/hyperoncotic solution in hypovolemic patients. Shock. 1997;7(2):79-83.(Prospective randomized controlled trial;212 patients)

40. Mattox KL, Maningas PA, Moore EE, et al. Prehospital hy -pertonic saline/dextran infusion for post-traumatic hypoten -sion. The U.S.A. Multicenter Trial. Ann Surg. 1991;213(5):482-491. (Multicenter prospective randomized controlled trial;422 patients).

41. Vassar MJ, Perry CA, Holcroft JW. Prehospital resuscita -tion of hypotensive trauma patients with 7.5% NaCl versus

7.5% NaCl with added dextran: a controlled trial. J Trauma. 1993;34(5):622-632.(Prospective randomized controlledtrial; 258 patients)

42. Alpar EK, Killampalli VV. Effects of hypertonic dextranin hypovolaemic shock: a prospective clinical trial. Injury. 2004;35(5):500-506.(Prospective randomized controlledtrial; 180 patients)

43. Maningas PA, Mattox KL, Pepe PE, et al. Hypertonicsaline-dextran solutions for the prehospital management oftraumatic hypotension. Am J Surg. 1989;157(5):528-533; dis-cussion 533-524. (Prospective randomized controlled trial;prehospital; 48 patients)

44. Vassar MJ, Perry CA, Holcroft JW. Analysis of potential risksassociated with 7.5% sodium chloride resuscitation of trau -matic shock. Arch Surg. 1990;125(10):1309-1315.(Prospective

patients with severe traumatic brain injury. J Neurosci Nurs. 2006;38(3):142-146.(Review)

11. Krausz MM. Controversies in shock research: hypertonicresuscitation--pros and cons. Shock. 1995;3(1):69-72.(Review)

12. Alam HB, Rhee P. New developments in uid resuscitation.Surg Clin North Am.2007;87(1):55-72.(Review)

13. Hartl R, Ghajar J, Hochleuthner H, et al. Hypertonic/hyper -oncotic saline reliably reduces ICP in severely head-injuredpatients with intracranial hypertension. Acta Neurochir Suppl.1997;70:126-129.(Prospective; 6 patients)

14. Horn P, Munch E, Vajkoczy P, et al. Hypertonic saline solu -tion for control of elevated intracranial pressure in patientswith exhausted response to mannitol and barbiturates. Neurol Res.1999;21(8):758-764.(Prospective; 10 patients)

15. Khanna S, Davis D, Peterson B, et al. Use of hypertonic sa -line in the treatment of severe refractory posttraumatic intra -cranial hypertension in pediatric traumatic brain injury. CritCare Med. 2000;28(4):1144-1151.(Prospective; 10 children)

16. Munar F, Ferrer AM, de Nadal M, et al. Cerebral hemo -dynamic effects of 7.2% hypertonic saline in patients withhead injury and raised intracranial pressure. J Neurotrauma.2000;17(1):41-51.(Prospective; 14 patients)

17. Schatzmann C, Heissler HE, Konig K, et al. Treatment ofelevated intracranial pressure by infusions of 10% salinein severely head injured patients. Acta Neurochir Suppl. 1998;71:31-33.(Prospective randomized controlled trial)

18. Battison C, Andrews PJ, Graham C, et al. Randomized,controlled trial on the effect of a 20% mannitol solution anda 7.5% saline/6% dextran solution on increased intracranialpressure after brain injury. Crit Care Med.2005;33(1):196-202.(Prospective randomized controlled trial; 9 patients)

19. Harutjunyan L, Holz C, Rieger A, et al. Ef ciency of 7.2%hypertonic saline hydroxyethyl starch 200/0.5 versus man -nitol 15% in the treatment of increased intracranial pressurein neurosurgical patients - a randomized clinical trial [IS -RCTN62699180].Crit Care. 2005;9(5):R530-R540.(Prospectiverandomized; 40 patients)

20. Fisher B, Thomas D, Peterson B. Hypertonic saline lowersraised intracranial pressure in children after head trauma. JNeurosurg Anesthesiol. 1992;4(1):4-10.(Prospective double-blind crossover trial; 18 patients)

21. Simma B, Burger R, Falk M, et al. A prospective, random -ized, and controlled study of uid management in children

with severe head injury: lactated Ringer’s solution versushypertonic saline. Crit Care Med. 1998;26(7):1265-1270.(Pro-spective randomized controlled trial; 35 pediatric patients)

22.* Roberts I, Schierhout G, Wakai A. Mannitol for acutetraumatic brain injury. Cochrane Database Syst Rev.2003;(2):CD001049.(Cochrane systematic review and meta-analysis; 4 trials)

23. Brain Trauma Foundation, American Association of Neuro -logical Surgeons, Congress of Neurological Surgeons, et al.Guidelines for the management of severe traumatic brain in - jury. J Neurotrauma. 2007;24 Suppl 1:S1-S2.(Evidence-basedguideline)

24. Ware ML, Nemani VM, Meeker M, et al. Effects of 23.4%sodium chloride solution in reducing intracranial pressurein patients with traumatic brain injury: a preliminary study.Neurosurgery. 2005;57(4):727-736.(Retrospective; 13 patients)

25. Oddo M, Levine JM, Frangos S, et al. Effect of mannitol andhypertonic saline on cerebral oxygenation in patients withsevere traumatic brain injury and refractory intracranial hy -pertension. J Neurol Neurosurg Psychiatry. 2009;80(8):916-920.(Prospective; 12 patients)

26.* Kamel H, Navi BB, Nakagawa K, et al. Hypertonic salineversus mannitol for the treatment of elevated intracranialpressure: a meta-analysis of randomized clinical t rials. CritCare Med.2011;39(3):554-559.(Meta-analysis; 5 trials, 112patients)

27.* Wakai A, Roberts I, Schierhout G. Mannitol for acutetraumatic brain injury. Cochrane Database Syst Rev. 2007;(1):CD001049.(Cochrane systematic review and meta-analysis; 4 trials)

28. Vialet R, Albanese J, Thomachot L, et al. Isovolume hyper -


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66. Dubick MA, Kramer GC. Hypertonic saline dextran (HSD)and intraosseous vascular access for the treatment of haem -orrhagic hypotension in the far-forward combat arena. AnnAcad Med Singapore. 1997;26(1):64-69.(Laboratory; 12 pigs)

67. Alam HB, Punzalan CM, Koustova E, et al. Hypertonicsaline: intraosseous infusion causes myonecrosis in a dehy -drated swine model of uncontrolled hemorrhagic shock. JTrauma. 2002;52(1):18-25.

68. Patanwala AE, Amini A, Erstad BL. Use of hypertonic salineinjection in trauma. Am J Health Syst Pharm.2010;67(22):1920-1928.

69.* Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versusdelayed uid resuscitation for hypotensive patients withpenetrating torso injuries. N Engl J Med. 1994;331(17):1105-1109. (Prospective randomized; 717 patients)

70. Kochanek PM, Carney N, Adelson PD, et al. Guidelines forthe acute medical management of severe traumatic braininjury in infants, children, and adolescents--second edition.Pediatr Crit Care Med.2012;13 Suppl 1:S1-S82.(Guideline)

71. Bickell WH, Bruttig SP, Millnamow GA, et al. Use of hyper -tonic saline/dextran versus lactated Ringer’s solution as aresuscitation uid after uncontrolled aortic hemorrhage inanesthetized swine. Ann Emerg Med. 1992;21(9):1077-1085.(Laboratory; 24 pigs)

72. Gross D, Landau EH, Klin B, et al. Treatment of uncontrolledhemorrhagic shock with hypertonic saline solution. SurgGynecol Obstet. 1990;170(2):106-112.(Laboratory)

73. Krausz MM, Landau EH, Klin B, et al. Hypertonic salinetreatment of uncontrolled hemorrhagic shock at differentperiods from bleeding. Arch Surg. 1992;127(1):93-96.(Labora-tory)

74. Leppaniemi A, Soltero R, Burris D, et al. Fluid resuscitationin a model of uncontrolled hemorrhage: too much too early,or too little too late? J Surg Res. 1996;63(2):413-418.(Labora-tory)

75. Matsuoka T, Hildreth J, Wisner DH. Liver injury as a modelof uncontrolled hemorrhagic shock: resuscitation with dif -ferent hypertonic regimens. J Trauma. 1995;39(4):674-680.(Laboratory)

76. Hannemann L, Reinhart K, Korell R, et al. Hypertonic salinein stabilized hyperdynamic sepsis. Shock. 1996;5(2):130-134.(Prospective; 14 patients)

77. Muller L, Lefrant JY, Jaber S, et al. Short term effects of

hypertonic saline during severe sepsis and septic shock. AnnFr Anesth Reanim.2004;23(6):575-580.(Prospective observa-tional; 12 patients)

78. Oliveira RP, Weingartner R, Ribas EO, et al. Acute haemo -dynamic effects of a hypertonic saline/dextran solutionin stable patients with severe sepsis. Intensive Care Med. 2002;28(11):1574-1581.(Prospective randomized controlledtrial; 29 patients)

randomized trial; 194 patients)45. Bulger EM, Jurkovich GJ, Nathens AB, et al. Hypertonic

resuscitation of hypovolemic shock after blunt trauma: arandomized controlled trial. Arch Surg. 2008;143(2):139-148.(Prospective randomized controlled trial; 209 patients)

46. Younes RN, Aun F, Accioly CQ, et al. Hypertonic solutions inthe treatment of hypovolemic shock: a prospective, random -ized study in patients admitted to the emergency room.Surgery. 1992;111(4):380-385.(Prospective randomized trial;105 patients)

47. Holcroft JW, Vassar MJ, Turner JE, et al. 3% NaCl and 7.5%NaCl/dextran 70 in the resuscitation of severely injured pa -tients. Ann Surg. 1987;206(3):279-288.(Prospective, random-ized controlled trial; 32 patients)

48.* Bulger EM, May S, Kerby JD, et al. Out-of-hospital hyper -tonic resuscitation after traumatic hypovolemic shock: a ran -domized, placebo controlled trial. Ann Surg. 2011;253(3):431-441. (Prospective randomized controlled trial; 853 patients)

49. Upadhyay A, Jaber BL, Madias NE. Incidence and preva -lence of hyponatremia. Am J Med.2006;119(7 Suppl 1):S30-S35.(Review)

50. Widdess-Walsh P, Sabharwal V, Demirjian S, et al. Neuro -logic effects of hyponatremia and its treatment. Cleve Clin J Med. 2007;74(5):377-383.(Case report)

51.* Sterns RH, Cappuccio JD, Silver SM, et al. Neurologic se-quelae after treatment of severe hyponatremia: a multicenterperspective. J Am Soc Nephrol.1994;4(8):1522-1530. (Retro-spective; 56 patients)

52. Lauriat SM, Berl T. The hyponatremic patient: practical focuson therapy. J Am Soc Nephrol. 1997;8(10):1599-1607.(Review)

53.* Hew-Butler T, Ayus JC, Kipps C, et al. Statement of the Sec-ond International Exercise-Associated Hyponatremia Con -sensus Development Conference, New Zealand, 2007. Clin JSport Med.2008;18(2):111-121.(Evidence-based guideline)

54. Bullock MR, Povlishock JT. Guidelines for the managementof severe traumatic brain injury. Editor ’s Commentary. JNeurotrauma.2007;24 Suppl 1:2 p preceding S1. (Editor com-mentary)

55. Levine JM. Hypertonic saline for the treatment of in -tracranial hypertension: worth its salt. Crit Care Med.2006;34(12):3037-3039.(Editor commentary)

56. Thompson R, Greaves I. Hypertonic saline--hydroxyethylstarch in trauma resuscitation. J R Army Med Corps.

2006;152(1):6-12.(Review)57. Tollofsrud S, Bjerkelund CE, Kongsgaard U, et al. Cold andwarm infusion of Ringer’s acetate in healthy volunteers: theeffects on haemodynamic parameters, transcapillary uid balance, diuresis and atrial peptides. Acta Anaesthesiol Scand.1993;37(8):768-773.(Laboratory; 20 healthy volunteers)

58. Lamke LO, Liljedahl SO. Plasma volume changes after infu -sion of various plasma expanders. Resuscitation.1976;5(2):93-102. (Prospective comparative study)

59. Johnson AL, Criddle LM. Pass the salt: indications for andimplications of using hypertonic saline. Crit Care Nurse.2004.24(5):36-44.(Review)

60. Sapsford W. Hypertonic saline dextran--the uid of choicein the resuscitation of haemorrhagic shock? J R Army MedCorps. 2003;149(2):110-120.(Review)

61. Mannick JA, Rodrick ML, Lederer JA. The immunologic

response to injury. J Am Coll Surg. 2001;193(3):237-244.(Re-view)62. Aiyagari V, Deibert E, Diringer MN. Hypernatremia in the

neurologic intensive care unit: how high is too high? J CritCare. 2006;21(2):163-172.(Retrospective; over 600 patients)

63.* Adrogue HJ, Madias NE. Hyponatremia. New Engl J Med. 2000;342(21):1581-1589.(Review)

64. Dubick MA, Pfeiffer JW, Clifford CB, et al. Comparison ofintraosseous and intravenous delivery of hypertonic saline/dextran in anesthetized, euvolemic pigs. Ann Emerg Med.1992;21(5):498-503.(Laboratory; 12 pigs)

65. Runyon DE, Bruttig SP, Dubick MA, et al. Resuscitationfrom hypovolemia in swine with intraosseous infusion of asaturated salt-dextran solution. J Trauma. 1994;36(1):11-19.(Laboratory; 14 pigs)


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CME Questions

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Current subscribers can receive CME creditabsolutely free by completing the following test.This issue includes 3 AMA PRA Category 1 CreditsTM. Online testing is now available for current andarchived issues. To receive your free CME credits forthis issue, scan the QR code below or visitwww.ebmedicine.net/C0213

1. In regards to the evidence for the use of HTS inpatients with TBI:

a. The evidence is strongly in support of adextran and HTS admixture over mannitol.

b. The evidence is strongly in support ofmannitol over HTS solutions.

c. The evidence, as of yet, has not shownimproved mortality outcomes with HTS.

d. The evidence has shown that HTS clearlyworsens mortality.

2. With regard to the evidence for the use of HTSin patients with TBI and concurrent hypoten-

sion: a. HTS is recommended for all patientswith TBI and concurrent hypotension.

b. HTS may be of use in some populations,such as combat casualty resuscitations.

c. HTS improves mortality in patients whodo not receive blood transfusions in the rst24 hours.

d. HTS improves mortality in patientswho require surgery.

3. ODS is characterized by: a. Cellular injury after adaptation to acute

hyponatremia when the neurons arehyposmolar and are subsequentlyexposed to excess sodium

b. Cellular injury after adaptation toacute hyponatremia when the neuronsare hyperosmolar and are subsequentlyexposed to excess sodium

c. Initial cerebral edema that results fromacute hyponatremia

d. Initial cerebral edema that results from acutehypernatremia

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4. In order to reduce the risk of ODS in patientswith chronic hyponatremia, the recommenda-tion is to limit correction to:a. < 20 to 24 mEq/L in 24 hours

b. < 20 to 24 mEq/L in 48 hours c. < 6 to 8 mEq/L in 24 hours d. < 10 to 12 mEq/L in 24 hours

5. Patients with severe hyponatremia for < 48hours can present with seizures, encephalopa-thy, or focal neurologic signs and are:

a. Less prone to cerebral edema but morelikely to develop ODS with rapid correction

b. Less prone to cerebral edema and lesslikely to develop ODS with rapid correction

c. More prone to cerebral edema but less likelyto develop ODS with rapid correction

d. More prone to cerebral edema and morelikely to develop ODS with rapid correction

6. Current recommendations are that any athlete

with severe hyponatremia and encephalopathybe treated immediately with a bolus infusionof:

a. 500 mL of 3% NaCl followed by 2 additional100-mL boluses of 3% NaCl repeated at10-minute intervals if there is noimprovement.

b. 100 mL of 3% NaCl followed by 2 additional100-mL boluses of 3% NaCl repeated at10-minute intervals if there is noimprovement.

c. 100 mL of 3% NaCl followed by 1 additional100-mL bolus of 3% NaCl repeated after 10minutes if there is no improvement

d. 100 mL of 1.5% NaCl followed by 2additional 100-mL boluses of 1.5% NaClrepeated at 10-minute intervals if there is noimprovement.


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Documents

0213 Hypertonic Saline.pdf