Tiirkish Neiirosiirgei'Y 10: 1 - 13, 2000 A/kiiii: Hypothemiin iii bmiii pmtectioii

Hypothermia in Neuronal Protection

Nöronal Korunmada Hipotermi

TÜLIN ALKAN, ENDER KORFAL!

Department of Physiology, Uludag University School of Medicine (TA)Department of Neurosurgery, Uludag University School of Medicine (EK), Bursa

Abstract: During the last decade it has been repeatedlydemonstrated that mild to moderate hypothermia (30­34"C)reduces neurological injury in animal model s of focalor global ischemia, and of traumatic injury. This has ledto renewed interest in the application of hypothermia formanaging head injury, stroke, cardiac arrest and forundertaking aneurysm surgery. In this artiele, we reviewthe relevant literature and presented our experience withcases of intracerebral hemorrhage treated underhypothermia.

Keywords: Aneurysm surger, hypothermia, intracerebralhemorrhage, neuronal protection.

HISTORlCAL BACKGROUND

Profound hypothermia (1O-20°C) is a wellestablished and highly effectiye means of protectingcerebmm from global ischemia. Bigelow et aL. firstdescribed protection from global cerebral ischemia in1950, in experiments in which they induced totalcardiac arrest in dogs and maintained this state for 15minutes at 20°C (18). This work was done before the

oxygenator became available and was investigated asa strategy to permit surgical entry of the he art By 1959,Drew and Anderson had reported clinical trials whicheirculation was completely halted for up to 45 minutesat 13 to 15°C using a pump but no oxygenator (51).Hypothermic perfusion without an oxygenator was

Özet: Son 10yil içinde hafif ve orta derecede hipoterminin(30-34uC) fokal veya global iskemi ile ilgili deneyselçalismalarda ve ayni zamanda travmatik beyin hasarimodellerinde nörolojik harabiyeti azalttigina ait yayinlarmevcuttur. Bu sonuçlar hipoterminin kafa travmalari,serebrovasküler olaylar, kardiyak arrest ve anevrizmacerrahisi esnasinda kullanilmasini gündeme getirmistir.Bu yayinda hipotermi ile ilgili literatür taranmis vehipotermi altinda tedavi ettigimiz intraserebral kanamalihastalarin sonuçlari verilmistir.

Anahtar kelimeler: Anevrizma cerrahisi, hipotermi,intraserebral kanamalar, nöronal korunma.

then abandoned due to the high operatiye mortalities(91). Following it is proposal by Shumway and Lower,moderate hypothermia (30°C) came into wide clinicaluse in conjunction with the membrane oxygenator andselectiye cardiac caoling (112). From 1974 to 1980, largeseries reported successful total circulatory arrest at 10­20°C for up to 50 minutes during cardiac anomalyrepair in children (28). Since then, total circulatoryarrest at temperatures of 8 to 10°C has been usedduring repair of ascending aortic arch aneurysms inad ults (44). In 1969, White and colleaguesdemonstrated that profound hypothermia (15°C) witheirculatory arrest for periods of 30 minutes was welltolerated and was not associated with anyneurological sequelea in primates (129).

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HYPOTHERMIA

The ability to alter ischemic outcome bytemperature manipulations has been used as anexperimental tool for investigating mechanisms ofischemic brain injury. Elevating brain temperatureduring and folIowing a focal brain injury has beenshown to have detrimental effects on neurologicaloutcome. In addition to exacerbating ischemic celIinjury within selectively vulnerable brain regions,hyperthermia also leads to celI injury in brain regionsnormalIy resistant to brief periods of normothermicglobal ischemia (36, 49, 85)

Although neuronal protective effects of deephypothermia «30°C) has been attributed to reducedmetabolic demand and decreased cerebral metabolic

rate, the mechanisms behind moderate hypothermia(32-34°C) are different (4). Moderate hypothermialimits postischemic damage (24) either by supressionof initial increase of excitatory aminoacids (EAAs)such as glutamate (8, B, 64, 89, 101, 122, 133) byreducing of calcium influx (16), by stabilizing theblood-brain barrier (BBB) (65), by reducing theproduction of lipid peroxidation products (7), of bysuppressing nitric oxide synthetase activity (66).Moderate hypothermia of 32°C providesneuroprotection with onlyaminimal decrease in thecerebral metabolic rate (94). Nakoshima et aL.demonstrated a significantly longer time period toischemic depolarization after cardiac arrest in aratmodel with moderate hypothermia compared tobarbiturate protection with comperable degree ofmetabolic supression (94) . Of all the mechanisms thathave been implicated in moderate hypothermia,likely the most significant is blockade of extracelIulerincrease of EAAs (24, 99).

BRAIN DAMAGE AND TEMPERATURE:CELLULAR AND MOLECULAR MECHANISMS

ExcitotoxicityBruno et aL. studied the effects of mild to

moderate hypothermia on cortical neurons exposedto oxygen-glucose deprivation or EAAs (21). Theauthors showed that cooling to 30°C virtuallyabolished anoxia-induced glutamate release into theextracelIular medium. This, and similar findings invivo (53, 89, 104) suggest that a major mechanism bywhich mild to moderate hypothermia protectsneurons against anoxia or ischemia attenuatingendogenous glutamate release and subsequentexcitotoxicity. Cooling to 30°C protected against briefischemic periods only if hypothermia was

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maintained beyond the initial insult, because muchof the damage occurred subsequent to the release ofendogenous glutamate (21).

Work with experimental model s has shown thatthe degree of inhibition of glutamate release afterischemia is directly dependent on the temperatureand that the effect rnight have been a combination ofa delayed initial release and reduction in the rate ofEAA release (93). Postischemic glutamate levelsdocumented by rnicrodialysis were found to bereduced by hypothermia (32°C) but hypothermia didnot influence the homeostatic release and uptake ofEAAs in the nonischemic areas (97).All this beneficialeffects of moderate hypothermia were also timedependent (9, 27). Nakashima and Todd suggestedthat the effects of hypothermia on EAAconcentrations during cerebral ischemia might be dueto both adelay in the time to depolarization and adirect reduction in the rate of postdepolarizationEAA increase (93).

Many celIular processes are slowed down bycooling. Some are maximally attenuated attemperatures lower than those that areconventionally considered as mild to moderatehypothermia (30 to 33 OC)

Transmembrane ionic fliixes and ionhomeostasis

Ionic channels are temperature sensitive. Single­channel recordings of N-metil-O-aspartat (NMDA)receptor activity shows that single NMDA channelconductance increases steeply at temperatures aboveof 20°C (52). Studies have shown that ionic currentsare decreased and the mean channel open timesincreased at lower temperatures. Hypothermia alsoslows ionic pumps and exchangers. Thus, coolingmay slow down the reverse operation of Na+/Ca2+exchanger during anoxia and excitotoxicity (130) that,in turn, would reduce cellular Ca2+ loading andresultant injury (71). The Ca2+-ATPase, anotherimportant mechanisrn for cellular Ca2+ extrusionand sequestration is also temperature sensitive.Higher temperatures increase the celI membrane'sCa2+-ATPase activity and cause it become morefluid (17).

Hiramatsu et aL. investigated the effects ofhypothermia on excitatory synaptic responses duringhypoxia (59). Their study showed that hypothermiaprotected against hypoxic damage by prolonging thedelay to hypoxic depolarization. Chen and colIeaquesfound a significant correlation between temperature

Tiirkish Neiirosiirgery 10: 1 - 13, 2000

and direct current potential deflections in a focalischemia model (32).

Cellular energy productioiiEarly theories of the mechanisms of protection

by hypothermia focused on reductions in cerebralmetabolic rate (S,19, 76,84). However, in vivo studiesof brain ischemia under conditions of mild to

moderate hypothermia have not yielded consistentevidence of report a significant salvage from ATPdepletion (53, 126). In vitro studies have alsoindicated that mild to moderate hypothermia hasvariable effects on cellular ATP. Work by Bruno andcolleagues showed that moderate hypothermiaslightly attenuated the cellular ATP loss observedduring 60 minutes of oxygen-glucose deprivation(21).Other in vitro investigations have suggested thatATP depletion is slowed by mild to moderatehypothermia only during the first few minutes afterthe insult (98, 138).

Arecent study (67) involving the use ofmagnetic resonance spectroscopy has shown thatmoderate hypothermia increases the fraction ofglucose metabolism shunted through the pentosephosphate pathway. The authours suggested thatupregulation of this pathway may play an importantrole in maintaining cellular integrity and functionduring ischemia by maintaining membrane potential,stabilizing mitochondrial permeability, andcountering potential oxidative damage.

Little is known currently about the effects ofdeeper levels of hypothermia on high-energymetabolite production during anoxia, ischemia orexcitotoxicity. In one study, mitochondrialrespiration and ATP synthesis were preserved in ratbrain, liver and kidney under ischemic conditions(ll).

The production of toxic reaction productsit has been suggested that the drop in the

production of free radical species that occurs afterneuronal injury is on of the possible protectiyemechanism of hypothermia. Experiments in vivohave shown that moderate hypothermia (30°C) issufficient to attenuate hydroxyl radical productionaf ter brain ischemia and trauma (54, 69). Mildhypothermia (33°C) mayaiso decrease postischemicproduction of nitric oxide (66). Other potentialmechanisms behind the protective effects ofhypothermia include cellular protein synthesis (l4,98, Bl), the activity of innumerable cellular enzymessuch as Ca+2/ calmodulin-dependent protein kinase

Alkaii: Hypofhennia iii braiii proleclioii

II (61) and protein kinase C (25), cell membranefluidity (l19), action potential propagation (70), andischemic induetion of heat-shock proteins (l08).

Mild to moderate hypothermia appears to bewell tolerated by the brain in vivo, and by individualneurons and glial cells in vitro, as there has been noreports in the literature of toxicity connected withmild temperature reductions.

, Excessive increases in intracellular Ca+2 are

believed to participate in neuronal vulnerability tovarious types of brain injuries (113). Mitani andcolleagues investigated the temperature dependenceof hypoxia induced Ca+2 accumulation in ahippocampal sIice (88). When hippocampal sliceswere superinfused with a hypothermic medium (at3SoC, 33°C or 31°C) Ca+2 accumulation as aconsequence of anoxic depolarization was delayedin a temperature dependent manner. An in vivostudy by Araki et aL. also showed a significantlysmaller increase in calcium signal in hypothermicconditions (3)

Protein kinase C (PKC) is part of theintracellular kinase cascade activated by growthfaetors and is intimately involved in regulation ofprotein synthesis initiation(81). PKC activity istranslocated and downregulated during ischemia.

Intraischemic brain temperature has beenshown to effect PKC activity after global ischemia(25,26). In both studies, hypothermia attenuated theischemia-induced reduction in PKC activity, andsuch findings suggest that PKC alterations may bean important faetor involved in how temperaturemodulates postischemic outcome.

Obrist et aL.studied severe head injury casesand measured regional cerebral blood flow (rCBF)by IV Xenon-133. They found that the initialposttraumatic reduction in blood flow was associatedwith depressed cerebral metabolism rate of oxygen(CMR02) and that the subsequent CBF increaseexceeded 02 requirements. The authors suggestedthat hypothermia retards the development of thisCBF increase, possibly via inflammatory yasoactiveprocesses (95).

The effects of temperature on the othersecond-messenger systems

Neuronal Ca~ dependent proteinphosphorylation, in brain ischemia is extremelysensitiye to temperature. Forebrain ischemia has been

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shown to induce an earlyand permanent inhibitionof Ca+2/ calmodulin-dependent protein kinase IIactivity (121). This protein mediates many of thesecond messenger effects of Ca+2 incIuding neuronalexcitability, synaptic modulation, cytoskeletalfunction and neurotransmitter release. Intraischemic

hypothermia (32°C) has been shown to protectagainst ischemia induced inhibition of Ca+2 /

calmodulin-dependent protein kinase II activity (36).Hypothermic protection following global ischemiamay involve the maintenance of this activity.

Heat shock protein (HSP-72) and other proteinsare induced in rodent models of brain injury. Wheninduced prior to assault the induction of HSP-72 hasbeen associated with protection in neuronal injury(34).On the other hand, in examining the role of HSP­72 in hypothermic protection (30°C) after globalischemia, Chopp and colleagues found that HSPinduction was unlikely to be a potential mechanismby which hypothermia protects against ischemic ceiidamage (35).

Cytoskeletal proteins participate in manyneuronal functions, including neurotransmitterrelease, axoplasmic transportation and membranestabilisation. Miyazawa et aL. reported that mildintraischemic hypothermia lessens the decrease inpostsynaptic microtubule associated protein 2 (MAP­2) immunostaining that is usuaiiy seen after ischemia(90). Since MAP-2 is an important component of theneuronal cytoskeleton, these results indicate thathypothermia may protect postischemic neurons fromirreversible injury by the attenuating injury inducedMAP-2 loss. Ubiquitin synthesis also has been shownto increase after transient ischemia under conditionsof mild hypothermia (137). Thus, the improvedpostischemic synthesis of spesific proteins that occurswith hypothermia may promote ischemic protection.

NEURONAL PROTECTION(EXPERIMENT AL)

In 1962, Hirsch and Muller were the first topresent data that suggested that smaii differences inbrain temperature could affect the behavioralconsequences of complete global ischemia (60). Inthat study, postischemic survival time was linear asa function of brain temperature, and a difference of1-2 oC was suggested to alter ischemic outcome.Busto et aL.demonstrated that rectal temperature wasunreliable indicator of brain temperature duringglobal forebrain ischemia (23).They also highlightedthat the importance of smaIl differences in

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intraischemic brain temperature on histopathologicoutcome, noting that deereasing brain temperaturefrom 36 oC to 34°C significantly protected selectivelyvulnerable brain regions. Experiments on gerbilsdone by Clifton et aL.(38) showed that a 2°C fall inbody temperature provided 100% protection to theCAl hippocampus. Minamisawa et aL.studied theinfluence ofbrain and body temperature on ischemicdamage using the rat two-vessel model of forebrainischemia and confirmed that brain temperaturedropped during the ischemic period when bodytemperature was kept constant (86, 87). Reductionof brain temperature to 35°C decreased neuronalnecrosis. Another study reported that selective braincooling during and after prolonged global ischemiaalso significantly protects the cerebral cortex fromhistopathologic damage (73). Welsh and coiieaguesinvestigated the degree of hypothermia required todiminish CAl hypocampal injury by regulating bodyand head temperature (128). Reduction of headtemperature to 35.5°C and 32°C diminishedhis tologic injury in a dose-dependent manner.

The protective effect of hypothermia onreversibiIity of neuronal function has beeninvestigated using the hippocampal slice (96, 124).Okada and coworkers showed that the periods ofoxygen and glucose deprivation during whichneurons could recover functions was extended by 21­28°C hypothermia (96). Accelerated recovery ofglucose utilization at 24hr after ischemia withintraischemic hypothermia has also been reported(48).

Several studies have investigated the results ofposthypothermic intervention after various period sof brain ischemia. Chopp and colleaques observedsignificant protection of appIication of hypothermiaon the hippocampus 8 min after ischemia but noprotection after 12 min ischemic insult (33). Anotherstudy noted partial but significant protection of CA1neurons when 3 hr hypothermic period was initiatedat 5 minutes, but not 30 minutes, into the recirculationperiod (22). Chen and coworkers alsa failed todemonstrate histopathologic protection withpostischemic hypothermia after 12 minutes offorebrain ischemia (30). it is weii established thatshort periods of ischemia (less than 3 hours) resultin significantly greater variability in the infarct sizesobserved, which makes it difficult to accuratelydefine the "therapeutic window". (58).

On the basis of these studies it appears that the"therapeutic window" for postischemic hypothermia

Tiirkish Neiirosiirgery 10: 1 - 13, 2000

may be relatively narrowand that ischemic durationand severity are important factors in determiningwhether neuroprotection is seen with postischemichypothermia. The durations of applied hypothermiadescribed in recent publications range from Oto 30hours (55, 68) and the timing for the application ofhypothermia after an ischemic event ranged from 30min before ischemia (128) to 6 hours after an ischemicevent (39).Markarian and colleagues used arat focalischemia model to delineate the optimum parametersfor postischemic hypothermia, and found thetherapeutic window for this model to be no more than30 minutes after onset of ischemia to at least 3 hoursthereafter (80).

Research has also emphasized the importanceof the duration of the hypothermia. While 6 hours ofimmediate postischemic hypothermia resulted insignificant histopathologic protection there was noprotection when a 1 hour hypothermic period wasinvestigated(62). Working with a model of brief (10minutes) transient cerebral ischemia Coimbra andWieloch reported that, with postischemichypothermia (28°C) hippocampal protection begunat 2 hour after the initiation of hypothermia andlasted for several hours (39). In addition to the lengthischemic period, the duration of postischemichypothermia is also critica i in terms of determiningbeneficial effects. Zhang et aL.also demonstrated thatinduetion of hypothermia at 30°C 1 hour after focalischemia led to significantly smailer infaret sizes(140).

Intraischemic hypmhermia OO°C) has beenshown to provide chronic histopathologicalproteetion for up to 2 months following transientglobal ischemia (56). As well Dietrich et aL.documented significant protection of CA 1hippocampus at postischemic day 3, with lessprotection at day '7 and no protection at 2 months(47). These data indicate that intraischemic but notpostischemic, brain hypothermia (30°C) provideschronic proteetion. it has been suggested that themain advantage of postischemic hypothermia mayextension of the "therapeutic window" for delayedpharmologic treatment (46).

Using a rat model of permanent middle cerebralartery (MCA) occlusion, Morikawa et aL.reported nosignificant differences in infarct size in hypothermic(30°C) and normothermic (36°C) rats (92); thus itappears that, in conditions of permanent focalischemia profound degrees of hypothermia or anextended period of moderate hypothermia may be

Alkaii: Hypolhermia iii bmiii prokctioii

necessary to protect the brain. Moderatehypothermia is protectiye in several models oftransient MCA occlusion (31, 92, 103, 140), and alsoin permanent occlusion models (31, 103, 135). Chenand colleaques reported that hypothermia (30°C)induced prior to ischemia and maintained for 2hoursfollowing MCA occlusion decreased brain injury (31).In 1992 Morikawa et aL. observed that brain

hypothermia OO°C) during the 2 hour period ofreversible MCA occ!usion significantly reducedinfarct volume (92). Many reports have describedinitiating of the cooling at the onset ofMCA occlusion(10,20,55), whereas others have described startingto cooling at later time points. Xue et aL.investigatedrats that were subjected to 3 hours of focal ischemiaand cooled to 32uC. Hypothermia lasting 3 hours andinitiated at the time of MCA occ!usion led to 92%

reduction in cortical infarct size. Cooling for 1.5 hourswas equally effeetiye if it was started at the onset ofocclusion or was deferred by 1.5 hours (45-49%cortical protection), whereas a 3-hour hypothermiadelayed by 1.5 hours yielded greater protection (73%cortical protection) (135). Huh et aL.investigated theeffects of prolonged hypothermia. They observedcaoling of the brain to 32uC for 3 hours followed by a2 hour graded rewarming period that was initiatedat the time of recirculation after 2 hour period ofocclusion. This resulted in high grade histological andbehavioral protection equivalent to that observedwith intraischemic caoling (63).

Even mild hypothermia (31°C) extended over6 hours reduced the volum e of cortical infaretion after

permanent MCA occ!usion(136). Ridenour et aL.demonstrated that mild hypothermia (33°C) duringa 1-hour ischemic period and the first hour ofreperfusion reduced infarct size by 48% comparedto the normothermic group(103). Zang et aL. alsoreported that immediate or Iate hypothermia (32°C)also reduces infaret area (140).

Other researchers have investigated the effectsof moderate hypothermia on the pharmocologic,neurobehavioral and functional consequences ofglobal ischemia and cardiac arrest (96, 124). Using aneonatal, newbom, hypoxic-ischemic brain injurymodel Alkan et aL. measured corpus striataldopamine (DA) and dihydroxyphenylaceticacit(DOPAC) levels and showed that early postischemichypothermia provides complete neural protectionand reduces tissue damage (2). it has beendemonstrated that intraischemic hypothermia (30°C)during 12.5-minute ischemic period attenuated theneurobehavioral consequences of global ischemia

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recorded at 2 months after ischemia (56). Studies in

experimental global ischemia have shown that,although shorter durations of postischemic moderatehypothermia are not permanently neuroprotective(47), prolonged reductions in body temperatureconfer sustained behavioral and histologicalneuroprotection (40, 41). In experiments using a dogcardiac arrest model, Leonov et aL.reported that mildhypothermia (34OC)resulted in significant neurologicfunction at 96 hour post arrest than in normothermicanimals (75).

NEURONAL PROTECTION (CLINICAL)

The results of experimental studies iiKreasedneurosurgical interest in hypothermia. However, bythe Iate 1960s, neurosurgical experience involvingprofound hypothermia was limited to the treatmentof surgically difficult intracranial aneurysms. At thattime the neurosurgical literature reported over 100patients who were operated on under profoundhypothermia with circulatory arrest, usingcardiopulmonary bypass to accomplish to coolingand rewarming O, 12, 42, 50, 82, 83, 100, 107, 114,115, 118-120, 125, 132)

In the last decade, numerous papers haveappeared in the literature in support of usinghypothermia for aneurysmal surgery especially in thebasilar ar tery territory(57, 74, 106, 116, 117)

Head injiin}According to Marion, the first report of the use

of hypothermia appeared in 1943 in literaturepertaining to the treatment of brain injury (77). Inthis study, Fay applied hypothermic conditions aslow as 28°C to severe head injury cases for 4-7 daysand claimed to record better outcomes than in cases

where hypothermia was not applied. The 1960s and1970s saw little enthusiasm for this treatment because

of severe hypothermia-associated complicationsincluding cardiac arrhytmia, coagulation disordersand pneumonia. However in the 1980s, severalinvestigators demonstrated in the experimentalstudies that mild or moderate hypothermia (32-34 oC)effectively achieved significant improvement inneurochemical, histological and behavioral outcomesin both ischemia and brain injury modeL. Since 1990,many clinical studies have been conducted involvingmild or moderate hypothermia for severe closed headinjuries (37, 78, 79, 111).

Controlled randomized clinical studies have

been published on the therapeutic use of moderate

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Alkaii: Hypotliemi/tl iii bmiii protectivii

hypothermia (32-34°C) for severe closed head injuries(Glasgow Coma Scale 8 or below). Clifton et aL. (37)and Marion et aL. (78) continued hypothermia for 24hours maintained temperatures of 32-33"C andShiozaki et aL. applied moderate hypothermia for 2days (11). Tateishi et al applied titration methodmild hypothermia in severely head-injured patientsfor whom reduction in intracranial pressure was themain goal (123). They reduce the patient's bodytemperature to the minimum sufficient level, titratingit according to the desired drop in intracranialpressure. The duration of hypothermia was extendedif intracranial pressure remained elevated. Thus, inthis studyoveralL, the hypothermia was less intensebut prolonged. Work by Xiang et aL.also documentedthat the benefits of keeping patients hypothermic for12 hours or more af ter brain injury.(34).

In these clinical studies (37, 78, 79, 111)

hypothermia significantly reduced intracranialpressure (lCP) and CBF and other physiologicalparameters showed no significant rebound af terpatients were gradual1y rewarmed. The authorsconcluded that patient tolerance of therapeutichypothermia was good and that there was associatedimprovement in ICP, cerebral oxygen supply, andoutcome. Although the North American Multicentreprospective study sponsored by the National Instituteof Health was terminated after 398 patients in 1998because of a unfavourable outcome in the four of the

seven centres involved, the study showed thatmoderate hypothermia to 32-33°C for 48 hours didnot produce to significant neurological improvementfor the group as a whole. There was evidence ofbenefit, however, in the group of patients who wereunder 45 years of age, were kept normovolaemic andhad an initial GCS of 5-8 or more (77). Shiozaki et aL.

observed that mild hypothermia effectively preventsICP elevations in patients who have no diffuse brainswelling and have ICP of 20-40mmHg af terconventional therapy (10). Another study looked attreating severely head injured patients in whom!CPcan be maintained below 20mmHg by usingconventional therapies. Hypothermia did not conferany advantage over normothermia in theseindividuals (09).

Careful analysis of research done to date clearlyindicates that certain subgroups of patients willbenefit from this treatment, but the multicentre trial

also raised concern that other subgroups, such ashead-injured patients who are hypovolaemic, mayactually be harmed by it. Thus, it would be prematureto advocate this therapy as a standard treatment of

Tiirkis/i Neiirosiirgery 10: 1 - 13, 2000

head injuried patients but should be kept in mindthat some patients are likely to benefit.

Aneiin}sm Siirgen}A 1994 survey revealed that a large majority of

neuroanesthesiologists use mild to moderatehypothermia introperativelyfor intracerebralaneurysm cases (43). Preliminary results on the useof mild hypothermia in aneurysm surgery areencouraging (57). In this study patients in theexperimental group were cooled only to 33.5°Cduring procedures for elipping aneurysms. Theresults showed that, compared to the normothermicpatients, there were more good outcomes in patientsin the hypothermia group who had acutesubarachnoid hemorrhage, and fewer of thesepatients had neurological deficits at discharge.However, these differences were not statisticaiiysignificant.

Intracerebral hemorrhageOur elinic ran a prospective randomized study

to determine the effects of moderate hypothermia(32-34°C) on cerebral hemorrhage (72). Thispreliminary study was based on 14patients, men andwomen age 16-65 years, who had suffered acuteintracerebral hemorrhage and were admitted tointensive care. The criteria for inclusion in our studyGCS score of 8 or below, computed tomographyevidence of acute intracerebral hemorrhage(hematoma size>30cm3), signs of brain sweiiingsuch as lateral ventricle compression, midline shiftmore than 1cm, and neurological deteriorationcompared to baseline clinical status on admission tothe ICU.

Angiography was performed in cases ofhemispheric hematoma in which aneurysm orarteriovenous malformation were suspected. Inhypothermic group, cooling of patients startedduring evacuation of the hematoma, andi or clipingof the aneurysm or removal of the AVM. While themost favorable hypothermia depth of 32-34°C hasbeen weii established by our experience and that ofothers, there is less known about optimal durationof hypothermia and optimal time to treat af terischemia. We took the approach that therapy shouldbe started as soon as po ssibIe; therefore, a designatedcriterion for inclusion our study was that caolingbegin within 6 hours after brain insult. Twenty-fourhours was the longest duration of hypothermia,and patients were not actively rewarmed, butwere left to warm to normal temperaturespontaneously.

Alkaii: Hypol/ieriiiia iii bmiii pl"oleclioii

Randomly selected cases were assigned to oneof two groups. Hypothermic group (n:8) wasmanaged at 32-34°C, and the normothermic group(n:6) 36-37°C for the first 24 hours after intracerebralheomorrhagia. In the hypothermic group, ICP valuesfel1 a mean of 5.59±1.98mmHg when hypothermiawas initiated. During the hypothermic period, ICPwas significantly lower than it was on admission inthis group (p<0.05). After hypothermia and duringrewarming, ICP rose continuously, with the mean ofthe highest measured values being 16.33±2.01mmHg.Paral1el testing of the two groups at given time pointsshowed that rewarming did not cause thehypothermic group's ICP values to exceed those ofthe normothermic patients.

The hypothermia group required significantlyless dose mannitol, narcotics, moderatehyperventilation or vecoronium than thenormothermia group (p<O.Ol). Rewarming did notcal1for more aggressive measures to control ICP. Thehypothermia patients had significant lower mortality,with patient survival in this group being 87.5%,compared to 17% in the normothermia group(p<O,05). There was also a significant differencebetween the groups with regard to Glasgow outcomescore during 12months of fol1ow-up. The two groupshad similar incidences of pneumonia, sepsis, andcardiac or other complications.

The hypothermic patients exhibitedsignificantly greater decreases in platelet count(p<0.05), and their counts dropped to below theirinitial values. Three patients developed cardiacarrhythmias with prolonged PR and QT intervals andsinus bradycardia.

Stroke

During recent years, it has become increasinglyevident that moderate hyperthermia, when presentaf ter brain ischemia or trauma exacerbated theresulting neuronal injury (02). Several recent clinicalstudies emphasized the importance of bodytemperature for stroke prognosis and severity.Azzimondi et aL.showed that fever in the first 7 daysaf ter stroke was independent predictor of pooroutcome (6). Higher fever was associated with apoorer prognosis and patients with high fever weremore likely to die within the first 10 days after strokethat those with lower temperatures. Wang et aL.retrospectively studied 509 patients with acute strokepatients and examined the relationship betweenadmission body temperature and mortality both in­hospital and at I-year after discharge. The found an

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association between admission body temperature onadmission and stroke mortaIity and this wasindependent of clinical variables of stroke severity.Hyperthermia was associated with higher mortalityin l-year mortality. H ypothermia, on the other hand,was associated with lm-ver in-hospital mortality (27).Another investigation divided 390 patients, based ontheir temperature on admission, into hypothermic(36.5°C<), normothermic (>36.5°C-37.5°C), and

hyperthermic (>37.5°C). The results showed strongcorrelations between body temperature, clinicaloutcome and infaret size(02). Davalos et aL.observed

that patients with above normal temperatures onadmission were more likely to showearlyneurological deterioration and have significantlypoorer outcome (45). The same group foundincreased levels of glutamate in their hyperthermicpatients thus pointing to a possible mechanism forthe observed changes (29). Schwab et aL. studiedpatients with MCA infarction who were treated with

moderate hypothermia. The mortality rate was only44%, considerably lower than that noted whenhypothermia was not applied and showed afavorable outcome (105). These authors also

emphasized the important effects of rewarming,which consistently led to arise in icr and increasedpatients mannitol requirements.

Cardiac Arrest

One recent clinical investigation examined theeffect of inducing moderate hypothermia at theemergency department in patients with anoxic braininjury who had suffered out-of-hospital cardiacarrest. The result was a significantly lower mortalityrate in patients who were subjected to hypothermiacompared to normothermic controls (5). As well,another study showed that mild resuscitativehypothermia af ter cardiac arrest is a feasible and safeapproach (39).

Candusian

In summary, the investigations done to dateindicate that the application of mild to moderatehypothermia in patients with head injury, cerebralhemorrhage, or stroke is a feasible method of treatmentthat benefits many patients. A clinical multicenter trialcurently underway is expeeted to further support anddefine hypothermia as effective therapy, and may leadto its wider acceptance based on improved patientoutcome. We know that rnild to moderate hypothermiaproteets against primary or secondary ischemic injury,but the clinical strategies needed to maximize theeffectiveness of hypothemiia and minimize its adverseeffeets have yet to be determined.

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Alkaii: HypofJiermia iii braiii prolecfioii

Correspondenee: Tülin Alkan

Uludag UniversitySchool of Medicine

Dept. of Physiology16384 BURSA

Phone: (90.224) 442 88 55

Email: talkan@uludag.edu.tr

REFERENCE

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