mannitol versus hypertonic saline solution in neuroanesthesia.pdf

r e v c o l o m b a n e s t e s i o l . 2 0 1 5;4 3(S 1):2939

Revista Colombiana de AnestesiologaColombian Journal of Anesthesiology

www.revcolanest .com.co

Essay

Mannitol versus hypertonic saline solution inneuroanaesthesia

Gisela La NeuroanesSanto Dominb NeuroanesSection, Hos

a r t i c

Article histor

Received 26

Accepted 2

Available on

Keywords:

Osmotherap

Intracranial

Cerebral oed

Mannitol

Hypertonic

Severe TBI

Osmotic loa

Abbreviauid; Cr, serrandomizedmalformatio Please ci

Anestesiol. Correspon

E-mail a2256-2087/lorentea,, Maria Claudia Nino de Mejiab

thesiologist, Assistant professor in anesthesia ICU at UASD, Centro Cardio-Neuro-Oftalmolgico y Trasplante (CECANOT)go, Dominican RepublicthesiologistIntensivist, Associate Professor, Head of the Neuroanaesthesia Service, Head of the Preanaesthetic Assessmentpital Universitario Fundacin Santa Fe de Bogot, Universidad del Bosque, Universidad de los Andes, Bogot, Colombia

l e i n f o

y:

May 2014

July 2014

line 22 November 2014

y

hypertension

ema

saline solution

d

a b s t r a c t

Background: Hyperosmolar therapy with mannitol or hypertonic saline solution is the main

medical strategy for the clinical management of intracranial hypertension (IH) and cerebral

oedema. IH and cerebral oedema are usually the result of acute and chronic brain injuries

such as severe head trauma, ischaemic stroke, intracerebral haemorrhage, aneurismal sub-

arachnoid haemorrhage, tumours and cerebral infections.

Objective: We conducted this research in order to assess the benets and side effects of

osmotherapy and to identify the current trends in the management of IH and cerebral

oedema. These two conditions worsen neurological outcomes and are the major cause of

mortality in neurological patients.

In this article we show the current evidence supporting the use of HTS and mannitol,

and examine the question of which of the two agents is considered the best option for the

medical treatment of IH. We review the efcacy data for HTS compared with mannitol in

terms of clinical considerations.

Conclusion: Data availability is limited because of small sample sizes, inconsistent methods

and few prospective randomized comparative studies, although both agents are effective

and have a reasonable risk prole for the treatment of cerebral oedema and IH. Currently,

several trials show that HTS could be more effective in reducing ICP, with longer lasting

effects. HTS maintains systemic and cerebral haemodynamics.

2014 Sociedad Colombiana de Anestesiologa y Reanimacin. Published by Elsevier

Espaa, S.L.U. All rights reserved.

tions: SAH, subarachnoid haemorrhage; IH, intracranial hypertension; HTS, hypertonic saline solution; CSF, cerebrospinalum creatinine; M, mannitol; ARF, acute renal failure; PDBRT, prospective randomized double-blind trial; PRCT, prospective

controlled trial; ICP, intracranial pressure; TBI, traumatic brain injury; DVT, deep vein thrombosis; AVM, arterio-venousn; N-ICU, neurosurgical intensive care unit; CBV, cerebral blood volume.te this article as: Llorente G, de Mejia MCN. Manitol versus Solucin Salina Hipertnica en Neuroanestesia. Rev Colomb2015;43:2939.ding author at: P. O. Box 025650 Miami, Fl 33102.

ddress: [email protected] (G. Llorente). 2014 Sociedad Colombiana de Anestesiologa y Reanimacin. Published by Elsevier Espaa, S.L.U. All rights reserved.

30 r e v c o l o m b a n e s t e s i o l . 2 0 1 5;4 3(S 1):2939

Manitol versus solucin salina hipertnica en neuroanestesia

Palabras clav

Osmoterapi

Hipertensi

Edema cere

Manitol

Solucin sa

Trauma cran

Carga osm

smol

a pa

HIC y

nicas

, la h

infe

prod

igaci

cule

nte a

era l

de lo

los d

aleat

per

alida

PIC

a de

Introduct

Several stuthe efcacyplasma expinamatorithese agenof the etioldrug, dosag

Mannitothe 1960s. clinic for thblood brainthe vasculacellular spaeffectivenethat mannicompared w

Hypertotion for thethe treatme

Regardleates a seconbrain to iscwith the ris

Conventwith IH rainterventio

The primadequate C

t cerheraer.ebrain, ae:

a

n intracraneal

bral

lina hipertnica

eoencefalico severo

tica

r e s u m e n

Antecedentes: La terapia hipero

es la principal estrategia mdic

(HIC) y del edema cerebral. La

lesiones cerebrales agudas y cr

dente cerebrovascular isqumico

aneurismtica, y los tumores e

peores resultados neurolgicos y

Objetivo: Realizamos esta invest

secundarios de la osmoterapia y

y del edema cerebral. En el prese

SSH y al manitol y cul se consid

de la HIC. Revisamos la ecacia

consideraciones clnicas.

Conclusin: La disponibilidad de

inconsistentes y pocos estudios

agentes son ecaces y tienen un

cerebral y en la HIC, en la actu

ms ecaz en la reduccin de la

sistmica y cerebral.

2014 Sociedad Colombian

ion

dies in animals and humans have demonstrated of hyperosmolar agents in lowering ICP, produce

prevenosmotdisord

Certhe braansion, change the blood rheology and have anti-os.1 However class I literature to support the use ofts is variable, and this is due to the heterogeneityogy of ICH, associated comorbidities, the choice ofe and methods of monitoreo.1

l is an osmotic agent management of ICH sinceBut it was not until 1962, where it is used in thee rst vez.2,3 Not cross the intact cell membrane or

barrier (BBB). Therefore, in the brain, remains inr uid compartment and thus removes the intra-ce and intersticial.2,3 Countless studies show itsss in reducing ICP, and at least one study showedtol reduced mortality in patients with IH due to TBI,ith the use of barbiturates.4,5

nic saline solution was used in a clinical applica- rst time in 1926 by Silver who used 5% HTS fornt of Burgers disease.ss of its aetiology, intracranial hypertension cre-dary lesion because it lowers CPP, predisposing thehaemia and triggering brain tissue displacementk of compressing vital structures.ional strategies for the management of patientsnge from pharmacological therapies to surgicalns.ary objective of these measures is to maintain

BF in order to meet neuronal metabolic needs and

form of focsied as cyit is usuallyincreased cfrom traumthe most aas swellingto an energmatter; it hcytosol as atial oedematransependexample.6

There isical literatuto conventidifferent ae

The rsabout in 1Medical Ceobserved thin anaesthelasting 15tion of hypthe craniotJavid Settlaar con manitol o solucin salina hipertnica (SSH)

ra el manejo clnico de la hipertensin intracraneal

el edema cerebral suelen ser las consecuencias de

tales como el trauma craneoenceflico severo, el acci-

emorragia intracerebral, la hemorragia subaracnoidea

cciones cerebrales. Ambas entidades, contribuyen a

ucen mayor mortalidad en los pacientes neurocrticos.

n con el objetivo de valorar lo efectos beneciosos y

s son las tendencias actuales para el manejo de la HIC

rtculo mostramos la evidencia actual que soporta a la

a mejor opcin como terapia mdica en el tratamiento

s datos para SSH frente a manitol hablando sobre sus

atos es imitada por las muestras pequenas, mtodos

orizados prospectivos comparativos, y aunque ambos

l de riesgo razonable para el tratamiento del edema

d varios ensayos demuestran que la SSH podra ser

y por ms tiempo. La SSH mantiene la hemodinamia

Anestesiologa y Reanimacin. Publicado por Elsevier

Espaa, S.L.U. Todos los derechos reservados.

ebral ischaemia. Regardless of the aetiology of IH,py is one of the pillars in the management of this

l oedema results from increased water content innd most cases of brain injury with IH begin in the

al cerebral oedema. Traditionally, oedema is clas-totoxic, vasogenic and interstitial. In most cases,

mixed. Vasogenic oedema is usually the result ofapillary permeability due to breakdown of the BBBa, tumours, abscesses, white matter usually beingffected. In contrast, cytotoxic oedema is dened

involving neurons, glia and endothelial cells duey failure that affects both the grey and the whiteappens when there is water accumulation in the

result of deranged osmolyte distribution. Intersti- results from altered CSF absorption and increasedymal CSF ow, as is the case in hydrocephalus, for

current evidence in the experimental and the clin-re in the sense that HTS is an effective alternativeonal osmotic agents in neurocritical patients withtiologies.t idea of osmotherapy for CNS diseases came919 when two research fellows from Reed Armyntre working at Johns Hopkins medical schoolat the intravenous injection of 30% saline solutiontized cats led to a 34 mm reduction in brain size,30 min after each injection.7 However, the injec-otonic solutions created brain herniation throughomy site. Fremont-Smith and Forbes in 1927, andge in 1950,8 began using intravenous injections of

r e v c o l o m b a n e s t e s i o l . 2 0 1 5;4 3(S 1):2939 31

concentrated urea, but its use was abandoned due to severaldisadvantages such as clinical toxicity, instability of the prepa-ration, timICP. By 19620% and 25control, smcost and ab

During boluses wehumans asshown by Ttion for 1 h and 480 mOventilationICP and of CBF.10,11

Mannitol

Mannitol i183 kDa. Itthe nephrolized, and 2.22.4 h asstudies,12,1

its maximuistration aaetiology. Ttory IOP, eIt acts on the rheoloity, lowerinsupply. Thistriction ofblood voluquently, thICP is by i(a structurlow permetemic vasctransient ineffect, impever, intravdiuretic efhaemodynaavoid hypoICP elevatioMannitol i5% g/100 mand 1.372 m

MannitoII)19 and it imeasure toof active orThere is notol therapywhen ICP treatment.2

Several studies show that if ICP is >30 mmHg with a CPP25 mmHg is more benecial than symptomatic0,21

ICP 70 mmHg, with a p = 0.001.22,23

dose is concerned, ICP reduction and longer last-es have been observed when a dose between 0.5

is administered.24 Infusions must be given over aproximately 20 min. Faster infusion rates ( 2.0. Microscopic urinal-vealed vacuoles in tubular cells consistent withphrosis, which generally does not result in per-ury and reverts after the drug is removed. Severalort that the lowest total dose of mannitol that mays >200 g/day. It is important to note that in patientsred renal function the total dose of mannitol that


may cause ARF may be lower than that in patients with nor-mal renal function. Several factors need to be considered whenmannitol iuse of othelowering thpatient.18

Hyperton

In recent ymost popugrowing poplications aARF and ICit worsenstant conce3%, 7.5%, aneeds to bcentral lineperipheral rate of phlHTS, 6% Ndid not shafter bolusthere wereistration inpre-hospitareceiving Hdextran 70vascular coThere is noaccess forphase.

Indicatisub-arachnand also asor in comb

It is notsion. The bwith no evticular, butInfusions hof 0.12 mltarget of 1osmolality erature sug2% it must be delivered through a, thus avoiding the risk of thrombophlebitis andvein thrombosis; bolus doses result in a lowerebitis. Data in animals using infusions with 7.5%aCl and 6% dextran through the cephalic veinow any evidence of histological venous damage

administration.38 In 1991, Maningas showed that no complications associated with bolus admin-

48 patients with penetrating trauma in thel setting.39 A multi-centre study of 359 patientsTS before arriving at the hospital (7.5% NaCl, 6%) versus Ringers lactate did not show peripheralmplications secondary to HTS administration.40

current evidence for protocols requiring venous HTS administration, particularly in the acute

ons include lowering ICP in patients with TBI,4145

oid haemorrhage,4649 stroke,50,51 liver failure,52

adjunct therapy with mannitol, either sequentiallyination.43

yet clear if it must be a bolus dose or an infu-olus dose has been used at different concentrationsidence of superiority of any concentration in par-

consideration must be given to total osmolar load.ave shown to be effective with 3% HTS at a rate/kg/h, with step-wise titration of the dose to a45155 mEq/l NA+ (maximum 160 mEq/l) and anof 320330 mOsm/l (maximum 360 mEq/l). The lit-gests that HTS infusion lowers ICP over a periodthis effect cannot be maintained with prolongedThe bolus dose is used alone or as a comple-ntinuous infusion therapy. It is also used to lowerents who have not responded to prior mannitold this measure further reduces ICP, raises CPP

ses brain tissue oxygenation without adding side

re no pharmacokinetic data on HTS, but Lazaridisat the onset of the effects is similar to that ofIts action is similar to that of mannitol in that

ater outow from the nervous tissue towards thear space and reduces the rate of CSF production,ving intracranial compliance; it has a lower diuretic

loweriimprovred blan anadhesi

TheHTS, einfusioARF, armyelinaggresindividin thetremicwith Hrespec

In 2and ations (hypov5 advethat isHHS. the usdecade

Thesimilathe rebcient. Timpervcoefcmanniosmot1.16

Thewith TICU athey e0.9% ssome continneuro-renal dsigniCHS oincreahyperndysfun

Mann

There over afrom dVialet evaluaepisodP at the same time. Benecial effects includeystemic microcirculation through a reduction ofcell and endothelial cell oedema.54 It also hasammatory effect because it reduces leukocyte,56

st common problem associated with the use of in the form of repeated doses or in continuous

hyperchloremic acidosis. Other problems includehmias, haemolysis, acute lung oedema and pontineis. Pontine myelinolysis is usually observed withmanagement of hyponatremia in malnourished, alcoholics, and SIADH; it has not been describedtext of HTS-induced hypernatremia in normona-ents with ICH.57 ARF is an infrequent complicationrovided osmolality range and Na serum levels are8

Schimetta published a 9-year review on the safetye reactions of hyperosmolarhyperoncotic solu-) containing 7.27.5% HTS and 610% dextran inic states. They found that there are approximatelyreactions for every 100,000 units of HHS used,6 reactions for every 100,000 patients treated with

showed a low potential of complications with HHS in the clinical setting during almost one

und phenomenon, seen also with mannitol, has achanism of action, but both the escape as well asd phenomenon is less, due to the reection coef-eection coefcient is the ability of the BBB of being

to a compound and its value range is 01 (zero= permeable, 1 = impermeable). The coefcient ofs 0.9 and that of sodium chloride is =1. The bestents are those with a reection coefcient close to

plications of using HTS in neurocritical patientsbarachnoid haemorrhage and stroke in the neuro-own in the study by Froelich et al. In 2010,ted these potential complications with HTS and

solution in this patient population and, despitenesses in their study, they propose the safety of

HTS treatment in neurological patients in thecal care unit. They tested their hypothesis thatnction, deep vein thrombosis and infection are noty different between patients treated with 3% HTS,% SS. They concluded that HTS therapy does note incidence of infection or DVT rates. However,mia is closely linked to HTS infusions and renal

when sodium levels rise above 155 and 160 mEq/l.

versus HTS

Class I evidence showing superiority of one agenter in the management of cerebral oedema and IHent aetiologies in critically ill patients. In 2003,.44 conducted a randomized prospective study toe clinical benet of using HTS in refractory IHhey compared 20% mannitol and 7.5% HTS in 20


patients with TBI and refractory IH (ICP = 25 mmHg). Althoughthey foundshowed th2 ml/kg of Hin the contclinical tria7.45% HTS patients wof initiating35%, respecin terms ofagents. A dreducing IC

In 2011,HTS on cerused PET ttration of eor 23.4% HTeffective insignicant size is very

Kamel,6

all randomtreatment 112 patientout that thtension waICP of 2.0 msignicant.tive than mthe meta-aof the eligib

In 2009survey to itagement foused mostreceived 29were from

The majpreferred mmannitol inserum osmlar gap for reported byThose whoand had leslonger connitol mentof use becaclear that bthough theor follow-u

At presmannitol aapproximasaline solusaline solut

In 2012meta-analyincluded 36

controlled, 1 non-randomized prospective, 15 observationalctive and 10 retrospective studies. Of the 36, 12 com-manctivedies,rativandnitorativlled P thownudied thay thatcomroveshoorte

udy; 20 pogica

adm to badmdies,e effrospt infch Hize

showhile.

tum

al oepes atiorebrre arettincted ento

witissid Mag at ent ded ansroba

ous is any.007,ize

tol v no difference in clinical outcomes, their studyat, within its limitations, the administration ofTS is an effective and safe treatment in IH episodesext of TBI. Francony et al. conducted a prospectivel comparing equimolar doses of 20% mannitol with(255 mOsm; 230 and 100 ml, respectively) in stableith TBI or stroke and IH >20 mmHg. After 60 min

the infusion, ICP dropped signicantly (45% andtively), without statistically signicant differences

the extent of the reduction in ICP between the twoose of 20% mannitol is as effective as 7.45% HTS inP.59

Scalfani et al. studied the effects of mannitol andebral blood ow in 8 patients with severe TBI. Theyo measure CBF before and 1 h after the adminis-quiosmolar quantities of 20% mannitol at 1 g/kgS at 0.686 ml/kg. They found that both agents are

lowering ICP and increasing CPP. They did not nddifferences between the two agents, but the sample

small to allow a denitive conclusion.601 in that same year, carried out a meta-analysis ofized trials comparing mannitol and HTS for theof IH. Five well-designed trials were found, withs and 184 episodes of elevated ICP. They pointede odds ratio for the control of intracranial hyper-s 1.16 in favour of HTS, with a mean reduction ofmHg over mannitol; both results were statistically

The conclusion was that HTS may be more effec-annitol for the treatment of ICP elevation, althoughnalysis was limited by the small number and sizele trials.

, The Neurocritical Care Society sent an onlines members in order to determine the usual man-r the treatment of IH. They asked about the agent

frequently, dose, and follow-up method. They5 responses, 279 of which were complete and 80%physicians.ority (54.9%) favoured the use of HTS, while 45.1%annitol. However, 95.4% of the respondents used

clinical practice, 83% used bolus doses, 80% usedolality for follow-up, and only 22.5% used the osmo-follow-up. The use of HTS in clinical practice was

89%, mostly in the form of continuous infusion. preferred HTS reported that it was easier to assesss systemic side effects, less rebound and ARF, andtrol of ICP. In contrast, those who preferred man-ioned longer experience with the drug and easeuse no central venous access is required.62 It isoth agents are trusted by neuro-intensivists evenre is no agreement regarding dose, concentrationp.ent there is no pharmaco-economic analysis ofnd HTS solutions. The average purchase cost istely $12/100 g of mannitol versus $1.2/30 ml 23.4%tion. An equiosmolar dose is 0.686 ml/kg 23.4%ion versus 1 g/kg 20% mannitol.63

, Mortalazavi et al.64 carried out a review andsis on the treatment of IH with HTS. The review

articles, of which 10 were prospective randomized

prospepared prospe12 stucompaet al.59

to mancompacontroling ICwas shTwo stshoweper daical ouan impet al.68

and shtive stin the neurol

HTSshownbolus 11 stuit to bwere psuggesin whirandomstudy sion, wresults

Brain

Cerebrtwo tycal situintrace

Thepure scondusupratgroupson admreceivestartintreatmconcluin huma low pinfectiels. It surger

In 2randommanninitol with HTS: 1 prospective non-randomized, 7 randomized and 4 retrospective studies. Of these

only 6 compared mannitol and HTS. Of the 12e studies, those of De Vivo et al., 65 Francony

Larive et al.66 did not nd HTS to be superiorl in terms of ICP or clinical outcomes. However, 9e studies, 7 of which were randomized prospectivestudies, showed that HTS was better at control-an mannitol. In 6 studies, greater ICP reduction

when adding HTS after mannitol administration.s showed prolonged control of ICP, and 1 studyt patients treated with HTS had less IH episodesn those who received mannitol.64 In terms of clin-es, the studies were not consistent: Ichai showedd GCS one year later in the HTS group; Yildizdaswed the best results with the lowest mortality rater time in coma, even though it was a retrospec-in contrast, Vialet et al.44 did not nd differencesatients in the study, in terms of mortality rate orl outcomes at 90 days.inistration, either as bolus or in infusion, has

e effective, although there are more studies withinistration than with infusion administration. In

HTS infusion was used and the majority showedective for ICP control, but only 3 of those studiesective and randomized. Of those 3 studies, only 2usion administration. In contrast, of the 26 studiesTS boluses were administered, 7 were prospectived studies, and 6 support bolus use. In 1999,67 oneed the worst mortality rate with the use of infu-

no study using bolus doses showed these poor

ours

dema rarely presents in a pure form, and theof oedema are found together in many clini-ns, making clinical distinction difcult. Generally,al peritumoral oedema is vasogenic.e few studies comparing mannitol and HTS in theg of cerebral relaxation in tumours. De Vivo et al.a prospective randomized comparative study inrial tumours. They randomized 30 patients into 3h ASAI-II, a mean age of 58 years, and GCS of 15on. One group received mannitol, the second groupnnitol + HTS and the third group received only HTSthe time of skin incision, and continued with thefor 72 h, using boluses three times per day. Theythat HTS is an effective alternative for lowering ICP

without reducing CVP or serum osmolality. It hasbility of anaphylactic reactions or of transmitting

agents, and it easily controlled by serum Na lev- effective alternative to mannitol in intracranial

Rozet et al. published a prospective double-blindd study on the effect of equiosmolar solutions ofersus HTS on intraoperative brain relaxation and

34 ;4 3(S 1):2939

electrolyte the majoritumours, pwith and wthem into tol (n = 20) haemodyntate and oassessed br2 = satisfacwas no difbral arteriobetween thbetween thdiuretic effThey conclosmolality ation, artercraniotomymannitol insubarachnodynamicall

In 2011,blind studysus 20% matumour suof hospitaluse of 3% Hmannitol iHTS led towhen compsis in the mlength of sstudy grouptics measuin humansnothing thapatients wior of the vaduring surgtics (tumoudeviation).7

Several mannitol aet al.71 repcerebral reThis studycedures anThe study 20 patientsdures, comHTS (7.2% cant differehence the clar load ofor generalproceduresdomized stproduce cetumours.72

atic brain injury

d ICbralent l impcondlity imanypotaramtionn, reses Cse.75

impct a ts coonclTS, ts apppre-hre aentsy as

as tol. Sect ie effals oebraitionts. On Pat thl outannifractnaget ac

th IHwereoxygdyn

IH ationuctire arTS

r andcted ss pe

afteing t

redu mefounpectietror e v c o l o m b a n e s t e s i o l . 2 0 1 5

balance. The study included 40 elective patients,ty ASA-III, taken to surgery for supratentorialosterior fossa procedures, AVM and aneurisms,ithout subarachnoid haemorrhage. They dividedtwo groups to receive 5 ml/kg of 20% manni-or 5 ml/kg of 3% HTS (n = 20). They measured

amic variables, uid balance, blood gases, lac-smolality (blood, CSF and urine). The surgeonain relaxation according to four scores (1 = relaxed,tory, 3 = rm, 4 = bulging). They found that thereference in brain relaxation, blood glucose, cere-venous O2 difference, or difference in lactate levels,e two hyperosmolar agents. Despite the similaritiese two, the mannitol group showed a more profoundect (p = 0.001) and a higher negative uid balance.uded that both mannitol and HTS increase CSFand are associated with equal levels of brain relax-iovenous O2 difference and lactate during elective. They recommend that HTS is a safe alternative to

brain size reduction in patients with and withoutid haemorrhage, in particular if they are haemo-y unstable.69

Wu published a prospective randomized double in 50 patients comparing the effect of 3% HTS ver-nnitol to assess brain relaxation in supratentorial

rgery, length of stay in the neuro-ICU and length stay. He concluded that brain relaxation with theTS was more satisfactory (p = 0.01) than with 20%

n craniotomy for supratentorial tumour surgery. a signicant increase in serum sodium (p < 0.001)ared with mannitol and there was greater diure-annitol group (p < 0.001). Hospital and neuro-ICU

tay were similar in the two groups. Although theed the patients for the majority of the characteris-

red, and although it is the largest study conducted until 2011 in supratentorial tumours, it is wortht it did not measure ICP routinely and it excludedth signs of IH. No mention is made of patient GCSrious parameters that may affect brain relaxationery, such as preoperative radiological characteris-r size, histology, peritumoral oedema, and midline0

studies have looked into the cerebral effects ofnd HTS in patients with normal ICP. Gemma

orted that HTS and mannitol provide satisfactorylaxation in patients taken to elective craniotomy.

was conducted with different neurosurgical pro-d non-equiosmolar doses of HTS and mannitol.by Vilas Boas et al. also assessed relaxation in

taken to different elective neurosurgical proce-paring the use of 20% mannitol with iso-oncoticHTS + 6% HES [200/0.5]). No statistically signi-nces were found in terms of cerebral relaxation,onclusion that single doses with equivalent osmo-f either of these agents are effective and safe

cerebral relaxation during elective neurosurgical under general anaesthesia. Of 4 prospective ran-udies, 3 recommend HTS as a safe alternative torebral relaxation in patients with supratentorial

Traum

Elevateor cereof paticriticaand semortain its that hlated ppopuladextraincrearesponshouldcondupatienThey ct of Hthere iof the

Thetwo agquentlby HTSmanniilar effis morThe gobut ceran addpatienbetweegest thclinicaand mand reIH mawas noTBI wiHTS lobrain haemoHTS onto sedaICP red

The23.4% Hgreateconduto asse60 minby statwhich

In atazavi 1 prosand 4 rP may occur in TBI in the presence of haematomas oedema, and continues to be an important focuscare. Fluid resuscitation in patients with TBI is ofortance because of the need to avoid hypotensionary neurological injury, which result in increasedn these patients. The Brain Trauma Foundationagement guidelines for TBI is clear in statingension must be avoided because it is an iso-eter of poor prognosis. Fluid resuscitation in this

, particularly with HTS alone or combined withstores intravascular volume with less volumes,73

PP, lowers ICP,74 and modulates the inammatory82 Given all these benets, neurological outcomesrove at least in theory. This led Bulger et al.77 to

multi-centre randomized controlled study in 1282mparing saline solution, HTS or HTS + dextran.ude that although they do not rule out the bene-here was no benet in terms of survival, and thatarently no strong reason to use HTS in TBI as partospital management.78

re no rm recommendations as to which of the should be used, but mannitol is used more fre-

rst-line therapy for TBI-associated IH, followedsecond-line therapy when there is no response toeveral authors report that both agents have a sim-n equiosmolar doses,59 and others show that HTSective than mannitol in lowering ICP in TBI.44,79

f osmotherapy are to maintain CPP and lower ICP,l oxygen tissue tension (PbtO2) is now emerging asal therapeutic target in the management of thesebservational studies have shown a relationshipbtO2 reduction and poor outcomes80,81 and sug-erapy targeted on maintaining PbtO2 may improvecomes.82 Little is known about the impact of HTStol on PbtO2 in patients with severe IH from TBIory IH. In 2009, Odd published a study on TBI withd with mannitol, followed by HTS when controlhieved. They studied PbtO2 and concluded that in

refractory to mannitol the administration of 7.5%d ICP further, increased CPP, cardiac output andenation, thus maintaining systemic and cerebralamics.43 Rockswold examined the effects of 23.4%nd PbtO2 in patients with TBI that did not respond, hyperventilation and CSF drainage. They obtainedon and PbtO2 increase.83

e multiple studies that show that HTS particularly used in TBI with IH after the use of mannitol, led to

longer ICP reduction. Lazaridis, in a meta-analysisin 2013, identied 11 papers on the use of 23.4% HTSrcentage reduction of ICP with a 95% CI of 55.6% at

r the administration, with p =


a signicant ICP reduction was found, with a mean reductionof 2060%, and no evidence of rebound phenomenon. Of the 16studies revand multipof HTS as aThe 5 that nicant lowout of the 3in patients

The onlythe use of have a bentobarbital, compared were foundtol.

Stroke

Infarction a1020% of large heminial pressufollowing awithin 35

There istherapies iuniform apeffect of 10200 ml of 2with 30 epwas used ito be preseity. ManageICP, and thmannitol aclude that are effectivbral oedemalthough Hlowering ebeing able tol has failprospectiveIH, which husing 200 m10% HTS f22 episodestained up towith theseeffect of HTrst study rneurons inhyperoncotin 2001. Thbility of hereduced bywere not einjured ne

not appropriate to extrapolate data obtained in a cell culturemodels to clinical situations, these data show that HTS may

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a sige detigh ged biewed, including 4 prospective randomized studiesle observational studies, the data support the usen effective means to lower ICP in patients with TBI.compared HTS with mannitol showed a more sig-ering of ICP after HTS administration. Only 1 study6 articles reviewed found a better long-term result

treated with HTS, compared with mannitol.64

Cochrane meta-analysis on mannitol reports thatthis agent for the treatment of elevated ICP mayecial effect on mortality when compared to pen-but may have a negative effect on mortality whento hypertonic saline solution. No sufcient data

on the effectiveness of pre-hospital use of manni-

ffecting the entire territory of the MCA occurs inpatients with ischaemic stroke.83,84 Patients withspheric infarctions are at a high risk of intracra-re elevation because of cerebral oedema. Oedeman ischaemic stroke begins within 13 days, peaksdays, and lasts up to two weeks.85,63

little research about the use of hyperosmolarn patients with ischaemic stroke, and there is noproach to its use. Schwarz et al.50 compared the0 ml and 75 ml of HTS, and of 60 g/l of HES and0% mannitol in equiosmolar doses in 9 patientsisodes of IH. Therapy with hyperosmolar agentsn an alternating fashion and IH was considerednt with an ICP >25 mmHg or pupillary abnormal-ment success was dened as a 10% reduction inis happened in 10 out of 14 patients treated withnd in 16 patients treated with HS/HES. They con-single doses of 100 ml HS-HES or 40 g of mannitole at lowering elevated ICP in patients with cere-a and show no negative effects on MAP or CPP,S-HES appear to be faster and more effective atlevated ICP. Moreover, there is the advantage ofto use HS-HES successfully again after manni-ed. In 2002, Schwarz conrmed these data in a

study with 8 stroke patients and 22 episodes ofad not responded to conventional managementl of 20% mannitol. They administered 75 cc of

or 15 min and observed a reduction of IH in the, with improvement of PPC which was still main-

4 h later.51 Although it is known that osmotherapy two agents is effective, little is known about theS on healthy and injured neurons in the brain. Theeporting on the response of healthy neurons, andjured in vitro with glutamate in a hypertonic andic environment, was conducted by Himmelseheris study in rats showed that, after 24 h, the via-althy hippocampal neurons exposed to HTS was

30% (p < 0.05), and injuries induced by glutamatexacerbated, which indicates that the mortality ofurons was not increased by HTS. Although it is

potentconsidoedemand brity in study bral oeas welprogrewater equall(ischaeis whethat din rodeof the at the Toungapy wNA+ wanotheICP in One tha secocular rand retol veroedemation attempagentscontraafter osure. Tosmotthey reAHA gother acally ilcerebrtestedIIa, lev

Subar

Cerebrfested patienTseng in areaSAH. Tgrade Simportand inCPP. Hwith himprov damage hippocampal neurons in vitro.86 Anotheron in stroke patients is post-ischaemia cerebralich increases ICP, contributing to secondary injuryerniation, and increasing morbidity and mortal-

e patients. Toung et al. conducted a prospectivets and showed the presence of signicant cere-a after stroke in both hemispheres (the injuredhe contralateral hemisphere), but with a different. Mannitol therapy was more effective at reducinge ischaemic hemisphere of the brain, but HTS wasctive at dehydrating both hemispheres of the brainand non-ischaemic).87 The question to be solvedstart hyperosmolar therapy in stroke, consideringnt studies have shown mixed results. In a studyin 2000, Bhardwaj et al.88 showed that the volumen worsened with HTS when it was administered

of focal ischaemia reperfusion. Two years later,. showed that the volume diminished when ther-itiated 24 h after the focal ischaemia and serumaintained between 145 and 155 mEq/l.87 Finally,

estion is how do osmotic agents work in reducinge patients. Several theories have been proposed.

is that they reduce water content in the brain, andeory is that they reduce viscosity and cerebrovas-ance, giving rise to compensatory vasoconstrictiond CBV. In 2011, Diginger et al. compared 20% manni-3.4% HTS in 9 patients severely affected by cerebralcondary to brain ischaemia with a midline devi-m. They measured CBF, CBV and CMRO2 in anunderstanding the mechanism of action of osmoticy found varying degrees of increased CBF in theal hemisphere of patients with ischaemic stroketic therapy, apparently mediated by blood pres-did not nd evidence to support the theory thatents reduce CBV, arguing against the theory thate ICP by creating cerebral vasoconstriction89 Theines still in force show that osmotherapy is amongssive medical measures for the treatment of criti-ients with malignant cerebral oedema after a largefarction. However these measures have not been, consequently, they are not recommended (Classevidence).90

noid haemorrhage (SAH)

od ow drops globally after SAH and this is mani-orsening of the neurological status. The worse theurological status, the lower CBF will be.91 In 2003,itted an interesting report on HTS effects on CBF

poor cerebral perfusion in patients with high gradeadministered 23.5% HTS to 10 patients with highand measured CBF, ICP and CPP. HTS resulted in anrop in ICP, which persisted for more than 200 min,nicant increase in MAP, leading to an increase inermined that 23.5% HTS increases CBF in patientsrade SAH, and that this effect is associated withlood rheological indices.92 Al-Rawi et al.93 showed


that the increase in CBF is accompanied by improved tissueoxygenation and metabolism when patients are treated with23.5% HTSmetabolic rsame groupHTS increaicantly duris associatemore thanet al.64 founinjury and IH peaks apatients wcompared bthe controlreduction dwas a signiimum reduof time of 3was observperiods.

Intracere

IntracraniaICH and it There is nmodalities rst reportsin 1998, inwhom he 24 h after tsion, 4896patients reing a reboumannitol.97

tal studiesdoses of 20haematomcerebral oxas CBF in reof the meastudy, beforment. Theyrestorationgroups afteuous infusia lower voluthat receivesaline soluof intracrana longer dution. None oblood ow

In 2007,cerebral iscgrade SAH23.5% HTS in MAP, CP

dropped by 93.1% (p < 0.01) after 1 h. These changes persistedfor a period of 80180 min.99

usio

beensolutol de nuh mtrollratioity; inircu

useal paonse. Themorof IHat 3%oursis fo

rate whe

infune oes ltemit, conP, bu

ben comctiveestionce nitiar agtratania

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thor

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re-Heacraingerrocrs ANroinwartdrewspecnnito and saline solution and monitored for cerebralate of oxygen and microdialysis probes. In 2010, the

showed, in 44 patients with high grade SAH, thatses CBF and improves cerebral oxygenation signif-ing 4 h after the infusion. This favourable resultd with improved cerebral tissue oxygenation for

210 min.94 In a review study in 2012, Mortalazavid 11 studies in patients with non-traumatic brainSAH. Of the 11 studies, two46,95 used HTS duringnd increased CBF was found in 5 studies92,93,96 inith high grade SAH. The study by Bentsen et al.95

olus therapy with HTS/HES with saline solution for of ICP in patients with SAH and found enhanceduring the 210 min of the study. In 6 studies therecant reduction of ICP from the start, and the max-ction went from 38% to 93% over an average period060 min after the infusion. No ICP rebound effected in any of the trials during their respective study

bral haemorrhage (ICH)

l hypertension occurs during the acute phase ofis a predictor of poor prognosis in these patients.o clear knowledge to date of which are the bestfor the management of this condition. One of the

on the use of HTS in ICH was published by Qureshivolving two patients with non-traumatic ICH ininfused HTS and observed clinical improvementhe infusion. Still under the continuous HTS infu-

h after the episode, the brain CT scan of bothvealed extension of the cerebral oedema, suggest-nd effect similar to that already described withOne year later, Qureshi conducted experimen-

in dogs, comparing the effects of equiosmolar% mannitol, 3% HTS and 23.4% HTS. After inducingas, they measured ICP, cerebral perfusion pressure,ygen extraction and oxygen consumption, as wellgions close to the haematoma and distant to it. Allsurements were recorded at the beginning of thee treatment, and 15, 30, 60, and 120 min after treat-

observed reversal of transtentorial herniation and of CBF and CMRO2. ICP dropped in all treatmentr 2 h, but only in the animals that received contin-on of 3% HTS. They also showed increased CPP andme of hemispheric water compared to the animalsd 23.4% or mannitol. Both 3% and 23.4% hypertoniction was as effective as mannitol in the treatmential hypertension observed in ICH.98 HTS may haveration of action, especially when used in a 3% solu-f the three treatment regimens inuenced cerebral

or brain metabolism.7

Tseng showed that HTS administration may reverthaemia to normal perfusion in patients with poor. After 30 min of the administration of 2 ml/kg ofin a patient with SAH, there was a 10.3% increaseP also increased by 21.2% (p < 0.01), and the ICP

Concl

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very difcult to assess the efcacy of hypertoniction or compare it with other protocols used forue to the wide variety of concentrations availablember of protocols employed.annitol and HTS have proven to be effectiveing ICP, through different mechanisms; osmoticn of the cerebral interstitium; reduction of bloodcreased red blood cell deformation; and improved

lation. of mannitol and hypertonic saline solution in neur-tients varies considerably among centres and therensus regarding which of the two is the agent of

majority of the data reviewed suggest that HTSe favourable results in the control of ICP and all, regardless of concentration. Some authors sug-

HTS and 23.4% HTS show more benecial effects and TBI, respectively, than mannitol. A meta-

und 8 prospective randomized studies with a high of mannitol-based therapy. It is still to be deter-ther HTS should be administered in the form of asion; both are effective but there are more results,f them worse, with the use of bolus doses. HTS

ess osmotic diuresis, thus maintaining more sta-c and cerebral haemodynamics in the neurocriticalsidering that it does not only lower ICP and main-t it also increases PtbO2.et of HTS relative to long-term neurological out-pared to that of mannitol is yet unclear. A large

randomized study is needed in order to answern. Many of the problems have not been elucidatedthe need for additional research in order to arriveve conclusion about the superiority of these hyper-ents and for protocols with adequate doses andions of these agents as rst-line therapy to controll hypertension.

f interest

s have no conicts of interest to declare.

c e s

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Mannitol versus hypertonic saline solution in neuroanaesthesiaIntroductionMannitolHypertonic saline solutionMannitol versus HTSBrain tumoursTraumatic brain injuryStrokeSubarachnoid haemorrhage (SAH)Intracerebral haemorrhage (ICH)ConclusionsConflict of interestReferences

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