J Neurosurg 91:185-191,1999

Little benefit from nlild hypotherⅡlia therapy for severely

head ittured paticnts with low intracranial pressure

TADAHIKO SⅢ OZAKI,PII.D。 ,PHoD。 ,AMAMI KATO,Ⅳ l.D。,PH.D。 ,

ⅣIAMORU TANEDA,Ⅳ IoD。,PH.D。 ,TosHIAKI HttYAKAT4,Ⅳ I.D。,

NAOYUШ IIASHIGUCⅢ ,Ⅳl.D。 ,HIROSⅡ I TANAICA,DIIoD。 ,PH.D。 ,

TAKESⅢ SHI「yIAZU,Ⅳl.D。,PH.D。 ,AND HISASIII SuGI1710TO,Ⅳ I.D。 ,PH.D。

Dく′α″771ιれrsげ 7′α“

771α′OJθ`り

α″ごN`“″οs“ 4g`7■l,OSαたαυ″ブッιパソ″iイ″′6α J Sc力θοみθsα′ン,J`ψα″メθ″″D"α″717`ん ′グ Ar`″ ″οS膨昭ιり,Kれた こカルθぉの Sc力οθ′げ ν

`グJεゴ

“,Osα /trr,Jのα″

OttιεムThiS study was performcd tO determinc whethcr mild hypothcrmia thcrapy is csscntial for thc trcatmcnt

of sevcrcly hcad illlurCd patients in whOm intracranial pressurc(ICP)Can bC maintaincd below 20 mm Hg by usingconvcntional thcrapics

Mer/1ο グs sixtcen consccutivc scvercly hcad ittured paticnts flllf1lled tllc lЭ llowing critcriai the paticnt'sICP wasmaintaincd bclow 20 mm Hg by using nuid restriction,hyperventilation,and high―dosc barbituratc thcrapy;and thc

籠 ::[緊 懺 瀧♀X=織 淵 篤 鍋 臓 l譜柵 1器 h棚 ぷ lttI増出 ]蹴 ::よm)悧 糧normotllcrnlia group(NT groupi cight paticnts)Thc HT grOup rcccivcd■ lild hypothcrnlia(intracranial tcmperaturc34° C)therapy for 48 hours fol10wcd by rcwarming at l° C pcr day for 3 days,whcrcas the NT group rcccived nor―

motllcrmia(intraCranial tempcratllrc 37° C)therapy for 5 days Spccimens of ccrebrospinal lluid(CSF)takcn f10man intravcntricular catheter evcry 24 hours were analyzcd for thc prcscnce of cxcitatory amino acids([Eノ Aヽs]glu―tamate,aspartatc,and glycinc)alld Cytokincs(tumOr necrosisね ctor―α,intcrleukin[IL]-lβ ,IL-6,IL-8,and IL 10)Thc t、vo groups did not diffcr signiicantly in paticnt age,ncurological status,orlevcl ofICP Thcre wcrc no sig―

niflcant diffcrcnccs in daily changes in CSF concentrations of EAAs and cytokincs betwccn the two groups Thcincidcncc of pncumonia was slightly higher in the HT group comparcd with thc NT group(p=0059)Thc inci_dcncc of diabetes insipidus associatcd with hypcrnatrcmia was signiicantly higher in thc HT grOup compared witll

thatin thc NT group(p<001)The tWO groups did not diffcr with rcspcct to thcir clinical outcomes

Cο″εルs′ο71s Thc authors rccommcnd normothermia therapy for thc trcatmcnt of sevcrcly head ittured paticnts

in wholan ICP can bc maintaincd atlowcr than 20■1ln Hg by using convcntional thcrapies,bccausc nlild hypothcr―

mia thcrapy docs not convcy any advantagc ovcr normothcrmia therapy in such paticnts

KEY｀VORDS e seVere head ittury O intracranial pressure ・ Inild hypothernlia ・normothernlia

I騨:蝉婁曜珊I器!11)祠showcd that mild hypotherllua tllcrapy、vas cffective for

thc ieatlllcnt of ptticnts with severe head inJury.On tl■ ebasis of thesc prelilllinacァ repolls,面 ld hypothcrnlia tller―

apy has been used for thc trcatmcnt of thesc patients atmany institutions 3,13,14,22 The C五teria for lllild hypother―

mia thcrapy.including Glasgow Coma Scalc(GCS)scOrc9on adIIllssiOn,intacranial prcssurc(ICP),and lesion typedcmonsiated on computcHzcd tomography(CT)SCan,havc not been standardizcd.

We havc uscd面 ld hypothergma thcrapy only a■ cr con―

vcntional therapics failcd to keep ICP lower than 20 mrnHg,whcrcas Mal■ on and collcagucs12 and Clifton,et al.,5

havc used lllild hypothcrmia thcrapy to teat sevcrcly head

ittured paticnts regardless of tlleir ICPヽ /itll respect to

patients with high ICR we concluded in our rcccnt repolt

that lllild hypothcJ「ua therapy was effcctivc for prcvent―

工Neν rοslrrg./Vo′“

771ι 9f/A″g71sち f999

ing ICI)clcvadon in patients whose ICP remaincd highcr

than 20 111111 11g but less than 40 1nm Hg aftcr undcrgoing

convcndonal thcrapics.22 Howcve■ fOr patients with low

ICR nO reports have shown that mild hypotllclma thcra―

py is effcctive.In tlle present study,we asscssed thc effi―

cacy oflllild hypothernlia therapy for the tcatment of sc―

vcrely head ittured paticnts in whom ICP was maintaincd

below 20 111111 Hg by using convcndonal thcrapies.

Clinical ⅣIaterial and PIethods

Pα′′ιJl′ P9′“′α′ノο″

Bctween 1996 and 1998,a total of 42 padents with sc―

vcrc head ittury whO requircd continuous infllsion ofb笛 _

biturate medication to con■ ol intacranial hypeiension、vcrc adllllttcd to the lDepairnent of Traumatology of Osa―

ka Univcrsity Hospital.Patients youngcr than 10 yctts of

age were cxcluded frolll tllis study.In ninc ofthe 42 pa―

185

T.Shiozakiぅ et al.

Ъヽ BLE l

C′′″rc α′6みαttε′′ガ∫′7C‐Sゲ ′6′α′た4な ll′′力s′ッ`″

力`α

グ

“

/7rげ*

蝕Ｎ。

Agc GCS Ptlpil(yrS), SCOrc on Abnor―Scx Admission lmalitics

CTFindings

ICP Evacuatcd

(mm Hg)i MasSiAdditional

llllurics

GOSScorc§

mild hypothcrmia(34° C)grOup27,N1 434,M 456,M 421,N1 535,M 518,N1 720,M 840.M 8

mcan 31 4

con,SAHiCH,con,basc FxSDH,ICH,conEDH、 basc Fx

SAH,basc Fxcon,SAHSDH,basc FxEDH,SDH

con,SAHcon,SAH,basc Fxcon.basc Fx

SDH,conEDH,basc FxSDH,conEDH,basc FxSDH,con

3

4

5

6

7

8

1

2

3

4

5

6

7

8

十

+

十

+

SD5618

4

5

11

14

11

13

15

14

10942

14

10

17

6

8

17

7

7

10846

+

十

十

十

― SvD― GR― V― GR

chcst illJury,arm&lcg llacturcs MDpclvic fracture GR

chcst illlury,lcg fl acture GR

― GR

127

nol■ anothcrmia(37° C)grOup56,M 366,M 319,F 421,M 520,N1 648,F 619,M 873 F 8

nlcan 40 3 54

SI) 231 20

pclvic&lc.O fracturcs

chcst illlury,arm l‐ l actllrc

pclvic fracturc

MDVGRGRGRGRGRMD

*Thcrc wcrc no signillcant diltercnccs bct、vccn thc two groups Abbrcviations: basc Fx= sku‖ basc fracturci con = contusion;

EDH=cpidural hcmatoma:(〕R=good rccovcw;ICH=intraccrcbral hcmatomal MD=rnodcratc disability:SAH=subarachnoid hcm―orrhagc:SD=standard dcviationi SDH=subdural hcmatomai SvD=scvcrC diSabilityi V=vcgctativc statc:十 =prCScnti― =abscnt

l lntracranial prcssurc aftcr convcntional thcrapics

i MaSS Suttically cvacuatcd beforc randomizttion

§Thc GOS scorc 6 months a■ cr illJury

tients, ICP cqualed mcan artcrial blood prcssurc bcforethis study could bc initiatcd;these paticnts were excludcd

from this study.Four patients with scvtte life― thrcatcning

認 1群 R騰繁 1鮪 諾 1棚 省 :M・ t摺 蹴 鑑because wc could not kccp theif ICP below 20 mnl Hgby using conventional tllerapics such as lluid rcstriction,

hypcrvcntilation, and high― dosc bttbituratc mcdicadons;

these paticnts 、vere also excludcd. Thus, 16 paticnts in

wholll ICP was lllaintained bclow 20 111in Hg by usingconvcntional thcrapies wcrc includcd in this study Thcsc

16 consccutivc paticnts 、vere dividcd fandomly into tlle

two groups:the mdld hypotllcrrnia g■ oup(HT grOupl cight

椰 を朧 奪 蜆 不 仰 脚14、vere brought to our hospital dircctly fronl thc sccne

of tlleir accident within 40 minutcs after sustaining ittury.

Thc rcmaining two patients(one in cach group,respcc―tively)wcrC rcfered flom othcr hospitals within 2 hours

aftcrittu7 ThC Cause ofittury Was tranc accidcnts in 13paticnts,falls in two paticnts,and assault in one paticnt

Thc GCS scorcs8 of all paticnts on admission wcrc 8 orlcss ln each casc,informcd conscnt to paticipatc in this

study was obtained from tllc patient's fralllily.

Ma71αgι771`4r Bのら″ι Cθο′ブκg

、1l patients wcrc initially intubatcd,continuous hypcr―

vcntilation was induccd with PaC〕 (D2bCtWCen 25 and 30

mnl Hg,and ieatcd、 vith fluid restiction at l ll11/kg/hour.

186

If ccrcbral pcrfusion prcssurc(mcan artcrial blood pres―

sure― ICP)waS less tllal1 60 mm Hg,adequate amountsof albumin wcrc givcn.To maint五 nu五 ne output higherthan O.5 1111/1Ng/11our, adcquatc amounts of colloid lluids

and/or a continuous infusion of dopanlinc at 3 to 5 μg/1.g/

minutc were givcn during thc study period as needed Nocorticostcroid medication or mannitol was ad血 nistered

during tllc study After initial rcsuscitation, aH paticnts

illlmediately undcrwent CT scanning of the head Subse―qucntly, an inttaventtricular cathctcr was placcd in cach

patient for continuous ICP and intacranial tcmperaturc

monitoring.If ncccssary,intracranial lnass lcsions associ―

atcd、vith lllidline displaccmcnt grcatcr than 5 mlll wcrc

surgically cvacuatcd.

In all patients, intracranial hypertension was initially

managcd using convcntional ICP reduction therapies suchas fluid resttiction,hyperventilation,and high― dose barbi―

turatc mcdications Barbituratc thcrapy was inidatcd byan intavcnous itteCtiOn of thiopcntal at 4 to 6 mgな gfollowed by a continuous infusion at 6 to 8 mg/kg/hour

to maintain a burst― suppression pattern on electroenceph―

alograpけ If ICP remaincd lower than 20 mm Hg aftcradnlinisttation of high― dosc bttbiturate medications,thcpatients were dividcd randomly betwccn the HT and NTgroups.

Sr"の P″′θεο′

Aftcr randomization,mild hypotlDcrmia(intracranialtel■pcratllrc 34° C)waS induccd in thc HT group as quicldyas possible by initiating surfacc cooling,which was ac―

工 Nerl″οsfrrg./VOJ“ 772ι 9]/Alrgrlsち ゴ999

Norlnothermia for scvere head ittury

complished by placing v/atcr― circulating blankets abovcand below thc paticnt.The intracranial telllperaturc,Inca―

sured in tllc latcral vcnuricle, was lllalntaincd at 33.5 to

34.5° C. Mild hypothcrlnia 、vas continucd for 48 hoursby using continuous infusion of barbituratcs at 6 to 8mg穐/110un whcn tlle tllerapy was discontinued,tllc pa―

tient was rcwallllcd slowly(apprOximaely l° C/day)byusing continuous infusion of bttbituratcs at 2 mg/1cg/11our

to prcvcnt shivc五ng.On Day 5,thc intracranial tennpcra―

ture reachcd 37° C in thc HT group.VVhen rewarⅡ ung wasCOlllplete,the barbiturates v/cre gradually withhcld.

Nomlotllcrmia(intracrallial tcmpcraturc 37° C)wasuscd in thc N「 F group after rando血 zauon. Intracranial

tclllperaturc was rnaintalncd at 36.5 to 37.5° C by sul・ face

cooling for 5 days To match conditions betwecn thc t、 vogroups,barbituratcs、、/crc continuously infuscd at 6 to 8mg/kg/11our du五 ng the initia1 48 hours,following by con―

tinuous infllsion of barbiturates at 2 1ng/1cg/13our to prevent

shive五 ng. Aftcr complcting tllc protocol,the bttbiturate

medicatlons wcrc gradually、vithhcld.

1イιαs“″ι771`″ rS αれ′ειrιわ″οψれα′Fル′″A4α″s′s

White blood cell(WBC)COunts,platclct counts,and C―rcacting protcin(CRP)values wcrc lllcasurcd cvcry day atour hospital laborttory.

Ccrcbrospinal■ llid(CSF)spccimcns wcrc dl・ awn fl・omthe inttavcntricul〔 r cathctcr inⅡnediately after insertion of

tllc cathctcr and 24,48,72,96,and 120 hours aftcr ittu7.

The CSF sallllples were centl■ fugcd to rcmovc ccllul冨dcb五s,and the supernatant was illllllcdiatcly frozcn un―

dl analysis Concentrations of cxcitatory amino acids

([EAAs]glutalllttc,aspartatc,alld glycine)were mCa_sured using high― pcJorlllance liquid chromatography.Tu―mor necrosis facto卜 α (TNFα )and intcrlcuhn(IL)-lβwcrc measured using a highly scnsidvc cnzymc-linkcdimmunosorbcnt assay(ELISA;Amcrsham lntcrnationalplc,Buchnghamshirc,UK).Interleuhn-6 was also deter面 ned by ELISA.Both IL-8 and IL-10 wcrc dctcrllunedusing commcrcially av五 lablc ELISAs(Toray,Tokyo,J″pan,and Phttmgen,San Diego,CA,К spcctivcly).

Cο焔りθJたα′′ο71s′れPα′′`ん

な

Pneumonia was dagnosed whcn a paticnt had at lcasttl■・ee of thc following ctttcriai ncw infiliatcs on chcst x―

ray illlls, pumlent iacheobronchial sccrcuons, positivcpathogenic bacterial culture in trachcobronchial sccrc―

tions,and impairmcnt of pullnonaw gas exchange.Men―ingitis was diagnosed when cell counts in tlle CSF wcrcgrcatcr than 100ヽ ハrBc/L.Tlle diagnosis of diabetcs insipi―

dus was defined as polyuria(>200m1/11our)with a 10Wurinc osmoldity(<200 mOsll1/kg).

Pα′′ιん′0“′θθ771ι

The outcome of cach paticnt was assessed 6 monthsaftcr ittury accOrding to tlle Glasgow Outcomc Scalc

(GOS)25 aS t‐ 01lows:1,dcatll;2,vcgetative state;3,severedisability;4,modcratc disability; and 5,mild or no dis―

abiliサ .For stadsucal cOmpttison,patients with a GOSscorc of 4 o1 5 wcrc classificd as having a favorablc out―

come and those with a GOS scorc of l,2,or 3 as having

工Ne″″οslrrg./Vo′“″2ι 91/A“g夕s41999

an unfavorablc outcome.Each survivor panicipated in apersonal follow― up intcⅣ icw eithcr by clinic visit Or tclc_

phonc.

S″′′s′たα′Aれαヶs′s

All values[rc cxprcssed as thc mcan± standard dcvia―

■on Physiological rneasurements bctween thc twO groupswere analyzcd using tlle Mann Whitncy U―tcst.Clinicalcharacte五sdcs,complicadons,and outcomcs bctwecn thctwo groups wcre coll■ pttcd using chi― squarc tcsts.A two―

II:鋼 獄 凛 I鰹 :露』獣 よ綿 Ъ :Ⅷ ∬ l鵬 鮒 羅two groups Signiicancc、 vas assigncd、vhen thc probabil―

ity valuc was less than O.05.

Results

Pα′′`/1′

C力α″αθ′ι″′s′ブ`s

Clinical charact∝ istics in thc two groups ttc sulluna―

五zcd in Tablc l.The two groups did not differ signiiicantly in patient age,GCS scorc on admission,neurolog―

ical status, lcvcl of ICP after convcndonal thcrapies, or

additional ittu五 CS ThC incidencc of hypotension onadllllssion, dcined as a sustaincd fall in systolic blood

pressure to 100 1111n IIIg,、 vas sillllltt in tllc two groups:no

padentin thc HT group and onc paticnt(12.5%)in tlac NTgroup Thc incidcncc of hypoxia on adllllsSiOn,dcincd as

Pa021CSS than 60 mm Hg,was silniltt in the t、 vo groups:

one patient(12.5%)in tlle HT group and onc paticnt

(12.5%)in the NT group.

Dα力 C力α4gι s J″ CSF Cο″ει71r″′′θ″sげ Iん4S

Table 2 shows daily changes in CSF conccntrations ofEAAsin thc two groups.Thcrc wcrc no significant differmccs in thc daily changes in CSF EAA conccnttadonsbetwccn thc t、vo gfoups ln both groups,CSF glutalllateconccntations dcclincd by 24 hours a■ er ittury andrenlalned low du五 ng thc remainder of thc study pc五 od.

Witll thc exception of the irst sample obtalned fronl one

patient in the NT group, CSF glutttnatc concentations

wcrc witllin tlle normal rallgc(normal glutamatc level<2 μmo1/L)3 Thc csF conceniations of aspartatc alldglycine remaincd constant throughout thc study pe五 od

Dα′″ C力α″g`sブη CSF Cθ″ε`れ

′″′′θ4sげ cソθわれιS

Tablc 3 sho、 vs thc daily changcs in CSF conccntradonsof TNFα ,IL-lβ ,IL-6,IL-8,and IL-10 in thc two groups.There wcrc no significant differenccs in thc daily changcs

ofthcsc cytohnes betwccn thc t、 vo gfoups The CSF con―ceniadons of TNFα dcclined within 48 hours afterittury

and remaincd lo、v for thc rest of thc study pcriod ThcCSF concentations ofIL-lβ pctted 24 hours afterittuw,declined,and tllcn rcmaincd low for thc rcmainder of the

study pe五 od.The CSF conccntations of IL-6,IL-8,andIL-10 dccrcascd with ame during thc study pc五 od;how―ever,the inidal values of CSF IL-6 alld IL-8 werc ttallnat―

ically highcr tllan tlntt of IL-10.

Cο 771P′ たα′′θ77S'77 Pα′′ιれな

As shown in Table 4,fivc of cight ptticnts in thc HT

187

T.Shiozaki,ct al.

■へBLE 2

Dα Jlll`力 α″gι s,″ CSF cο ″σ′れ′″ r′ 0″sρ′五ИASJ″ ′力ιg″ lrPs″ノr/2■pο r72′′″2′αα″′″ο77770r/7`7 777Jα *

Days Aftcr illlury

EAA(μ mo1/L)

glutannatc

HT groupNT group

aspaicttc

HT groupNT group

glycinc

HT groupNT group

18± 2214± 05

04± 0105± 03

02± 0102± 01

10± 0511± 03

十一　＋一　　　＋一　＋

一

＋一

＋一

　

＋一

＋

一

　

十一

十一

04± 01 05± 0304± 02 05± 03

02± 01 02± 0102± 01 02± 00

＋一

＋一

　

＋一

十一

　

＋一

＋一

＋

一　＋一

＋一　十一

*Data arc cxprcsscd as thc mcan± SD Thcrc、 vcrc no significant diffcrcnccs bct、vcen groups

:roup suffcrcd frolll pncumonia during tlle lst wcck,vhcrcas only onc of cight paticnts in thc NT group hadhis complication(p=0.059).SiX patients in thc HT group

tlld four paticnts in tl■ c NT group suffcred from meningi―is du五 ng thc lst wcck(p=0.304).Only Onc Of cight pa―icnts in thc IIIT group showed no infectious complications

iu五ng the lst weck,whcrcas four of eight padcnts in thcTヽ group cxhibited no such complications(p=0.141).

Thc incidcncc of cardiac ttrhythmia did not differ sig―

niicantly bctwccn thc two groups(Table 4).SeriOus car―

diac aThytlllllla Witll cldiovascular instability was not ob―

served in eithcr group.

Sevcn(87.5%)of cight patients in thc HT group suifcrcd fl・om diabetes insipidus(me〔n dmcto onsct 30.4±12.8 hours ttter ittury).Of tllese scvcn patients,six re

quired condnuous adnlinistradon of arginine vasopressin

at a rate of O.01 to O.05 U/11our. In conttast, only two

(25%)of eight paticnts in the NT group had diabetes in―sipidus(timC t0 0nset 8 hours and 34 hours after ittuり ,

rcspectively)rcquiring continuous adlllinisiation of argi―

ninc vasoprcssin at thc samc dosagc.Hypeinattelllla(>145111q/L)duc tO diabetes insipidus during thc lst、 vcckwas obscrvcd in all padents in tlle HT group(153± 4.8

mEq/L)but in Only t、vo paticnts(149 1nEq/L ttd 147mEq/L)in tllC NT group(p<0.01)In the prescnt study,no othcr colllplications cnsued sccondary to diabetes in―

sipidus or hypematrc血 a in either group

All paticnts in both groups showed hypokalcmia.How―ever, tlle 面 nimum conccntrations of semm potassiumduring thc initial wcck were signiicantly lowcr in tllc HT

group(233± 0.26胡 q/L)tllan in the NT group(271±0.26 mEq/L).During the rewttming phasc,no rcboundhyperkalemia occured in cithcr group.

Dα′ケ Cttα

“g`sノ 4 NBC Cθ

“れな,P′θたJ`r Cο″刀な,αんグεRP

ソα′lJ`s

Table 5 shows daily changcs in WBC counts,plak〕 lct

counts,alld CRP valucs in the two groups.´ 、lthough thcovcrall incidcncc of infcctious complications was slightly

highcr in the HT group,there were no significant diffcr―

cnccs in daily changcs in WBC counts, platelet counts,and CRP vducs bctwccn tllc two groups.In botll groups,thc WBC counts dccrcascd continuously fronl 13,000 to7000 cclls/μl during tllc initia1 72 hours after illiury,but

CRP valucs incrcascd progrcssivcly to 13 mg/dl Platclctcounts decreased rapidly during the initia1 24 hours and

TABLE 3

Dαノ/1・ c力α″g`s772 CSF Cο ″``“

′κ″0″s9′り′οたれ`S171r/2ι

g″切,s lll'r/1カψ ο′力`r777'α

α″グ″ο″″20′力ι′77,′ α*

Days Aftcr lll ury

Cytoklnc(pg/ml)&Group 2

TNFαHTNT

IL lβ

HTNT

IL-6

HTNT

IL-8

HTNT

IL 10

HTNT

十一　十一

１

４

　

５

″

　

６

０

　

７４

“

＋一

＋

一

　

＋

一

＋

一

　

十一

十一

　

十一

＋

一

〇

０

　

‐

‐

　

６

６

　

３６

”

十一

＋一

　

十

一

十

一

＋一　＋一

01± 01 01± 0102± 01 02± 01

10± 13 06± 0310± 10 10± 10

114± 185

87± 113

306± 311

435± 412

31± 4717± 28

1074± 1249

929± 429

9564± 11,324

7804± 7980

226± 207212± 229

64± 11852± 72

573± 718391± 269

2227 ± 2023]854± 1644

139± 11087± 51

247± 337

229± 167

698± 417718± 466

77± 5347± 17

57± 4334± 18

２

３

　

２４

弱

　

９

β

＋一

＋一

　

＋一

＋

一

　

十一

十一

３

１

　

２９

３０

　

４

．

＋一　＋一

*I)ata arc cxprcssed as thc mcan± SD Thcrc wcrc no signiflcant ditfcrcnccs bctwccn groups

188 J 7Vι

“″οslJ″g /JO′

“/11ι 9f/ノ生lrg′ sち f999

Normothermia for scverc hcad ittury

rcmained at 100,000 to 120,000/μ l duttng the study pc五 ―

od, but no padent in cithcr group cxpc五 cnccd blecdingcol■plicadons.

Cノれ′εα′0′たο717`

Paticnt outcomcs arc sho、 vn in Tablc l. In thc HTgroup,outcomes at 6 months aftcr ittury wCrc gOod re―covery in fivc paticnts,llloderatc disability in onc,scverC

disabiliw in One,and vcgctative strltc in onc.In the NTgroup,thc outcomes at 6 montlls after ll■ Jury wCrc goodrecovery in fivc paticnts,modcratc disability in two,andvcgctativc statc in onc.Six(75%)of cight padcnts in thcHT group and scvcn(87.5%)of cight paticnts in the NTgroup acllicvcd a favorablc outcomc

Discusslon

The results of sevttal clinicJ stlldies on head ittury

havc dcmonstratcd that clcvatcd ICP is clcarly rclated to

incrcascd dcath ratcs.15,18,19,26 Bccausc tllc rcduction of ICP

is onc of thc maOf goals whcn trcating scvcrcly hcad in―jurcd patients,we have induccd llllld hypothcrlnia(34° C)in paticnts in whom ICP cannot be llldntained at lowcr

than 20 111m Hg by using convendonalICP rcduction thcr―apics.22(Dn the other hand,to prcvcnt dclctcrious hyper―

tllcmia,wc havc continucd to usc normothermia(37° C)therapy in patients whosc ICI)can bc maintaincd atlowerthal1 20 111111 Hg by using convcntional thcrapics.

Figure l shows thc relationships alllong ICP a■ cr con―

ventional therapies, GCS scorc on admission, and G(DSscorc 6 montlls afterittuv in 96 scvcrcly hcad itturcd pa―

ticnts、 vho、vcrc ad面 ttcd to our departlllent between 1990

and 1998.These patients requircd continuous infusion ofbttbituratc mcdication to control iniacranial hypelten―sion.Thc 16 patients in the prcscnt prospcctivc study arc

not included in thc padent population prcscntcd in Fig.1.

Forw― tWO(649b)of thC 66 padents with high ICP dicddu五ng this pc五od The moltality fttc in tllcsc paticnts was

vcry high,dcspitc thc usc of面 ld hypothc」glia thcrapy as

we described in our recent report.220f30 patients v/ithlow ICR howcVCr,24 paticnts(80%)achieved ftlnctionalrecovew,whiCh Clea■ y indicttcs tllat scvercly hcad in―

jurcd paticnts with low ICP have favorable outcomcs

、vithout undcrgoing llllld hypotheJΠ ua thcrapy. To our

Ъ BヽLE 4

C0771p17σ α′Jο″sブ″f6′α′′ι″徳″ブr/2′れf lll′

`たふ er

S`νι″ 力ιαグj77J″ 7nl

Complication

HT Group NT GroupNo(%) No(%) ｐ

珈no of cascs

infcctions

pncumonlamcningllls

arrhythmia

diabctcs insipidus

hypcrnatrcmia

8

5(625)6(750)2(250)7(875)8(100)

8

1(125) 00594(500) 03043(375) 08592(250) 00202(250) <001

ト

ロ

Ｆ

ｒ

Ｒ

」

Ｄ

Ｉ

Ｉ

Ｉ

Ｉ

Ｉ

Ｉ

howlcdgc, no repolts have mentioned the cfficacy ofmild hypotllermia tllcrapy in pttients with low ICRbecause most hospitals havc used lllild hypotherlllia ther―

apy to trcat severely hcad itturcd paticnts rcgardlcss of

lcP5,12,13

Thc prcscnt prospectivc study was dcsigned to answcr

i:愧髪建:h鑢選縞鐵講雖珊首low ICP?2)Does IIIllld hypothermia thcrapy incrcase thcincidence of systcmic complications whcn colllptted witll

nomothcllllia therapy?3)Does面 ld hypotherlllia thera―

py improvc thc clinica1 0utcomc in paticnts、 vitl1 low ICPcomparcd witll nomotherlllia thcrapy?

α″`b“

Pれα′F/1r′′Cο″εθん′“′′θ4sグらも4S

It is known tllat glutamate plays an impoltant rolc in

neuronal damagc aftcr traumatic brain ittuγ botll inhumansl.3,14 and in expedrncntal studics.7,9 Thesc rcports

havc demonsttatcd tllat glutalllatc is toxic to ncurons

寛鵠認総:惚ettilⅧ湖mT・l:1:胤tふ∴||glutamatc wcrc inhibited by■11ld intraischclnic hypotllcr―

面 a(33° C)but nOt by norlnothemnia(36° C)in tllC r江 .Thcprescnt study, however, clcarly demonstatcd that tllc

daily changes in CSF conccniadons of glutamatc did notdiffer significantly bctween tlle HT and NT groups(TablC

2).Thc mOSt likely explanation for this discFCpanCy bc―

twccn our result and thc cxpe五 rncntal rcsult of 13usto,et

TABLE 5

Dα′ケ ε力α″g`s:77 WBC ιο“

71′ S,′′αたル′εοン77な,α 77″ CRPツα′“s′

れr/7`g“ο″′swルたたッρο′77`r″ 2′α α72グ ″0乃

“ο′/7`″″2′α*

Days Aftcr llllu瑠

Factor

WBC counts(103/μ l)

HT groupNT group

platclet counts(104/μ l)

HT groupNT group

CRP(mg/dl)HT groupNT group

132± 36126± 28

210± 46198± 48

<02<02

83± 3394± 24

123± 41122± 54

66± 4981± 71

70± 2088± 37

114± 45120± 45

117± 83127± 59

106± 34125± 43

134± 81127± 67

十一　＋一

67± 19 71± 2373± 28 71± 22

103± 27 114± 26116± 52 125± 37

158± 68 178± 82145± 89 145± 79

*Data arc cxpresscd as lllc mcan ±SD

工 Ne′″οslrrg./Vo′ Il″`9f/24″

gttsち ′999

Thcrc wcrc no signiflcant diffcrcnccs bctwccn groups

189

８

７

６

５

４

３

●ｏ】∽沼目‘“口〇∽００

∞ 〇 ― ・

OQD O OO O ● ●

⑪ ∞ ● ∞ ● 〇●●●

⑩ ③ ∝D―・

‐

○○● O ‐ ‐ ― ●

● ● 0● ● ●‐ ●

‐

●

ICP aftcr convcntional therapics(mmHg)

FlG l Graph showing tllc rclatlonshlps all10ng ICP aftcr con―

ventional icre■ pics, CTCS score On attssion, and C.OS scorc 6months attcrillluw in 96 patlcllts witll severc hcad illluw WhO W∝ C

admittcd to a hospital bctwccn 1990 and 1998 Thc 16 patlcnts in

thc prcsellt pЮ spccivc stuゥ arC nOtincludcd O′`″

ε′κ′′s=fa―vorablc outcome(mOd∝atc dlsability or no disabiliり ):ノ′ルグο′r_ε′ιs=univOrablc outcome(dea■ ,VCgctaivc state,or scvcκ diS―

ab」 iサ )

al., is that CSF conccntrations of glutamatc in thc NTgroup did not incrcase du五 ng tllc study pe五 od becausethcse conccntrations wcrc inhcrcntly low.Bullock,et al.,3

showcd the reladonship between sustaincd high ICP andhigh levels of glutamate measurcd using a llllcrOdialy―

sis tech五 quc. Although tllcrc、 vcrc some diffcrences inpaticnt managcmcnt and sampling mcthods betwccn ourstudy and that ofBullock and colleagucs,it is possiblc tllat

CSF glutamtte conccniations in our padcnts wcre lowbccause their ICPs were malntaincd bclow 20 111111 Hg byusing convcntional therapies.Aspartate and glycine havebeen hypothesized to havc a ncurotoxic potcntial silllilar

to tllat of glutamatc.3.23 As shown in Tablc 2, tlle daily

Changes in cSF conccniations of aspaltate and glycincwere not diffcrent betwccn thc two groups Bascd on theseindings,thcreforc,wc think that CSF conccntradons ofEAAs ttc low in patients witl1low ICP cven though brttntempcrttures ttc m」 nt五ncd江 37° C.

Cι′`ら

′ο人,′ I17α′F/1r′″Cθ4ε`4″

α″θれsげ htοわη`S

Several kinds Of cytokines havc bccn reported to be in―

crcased in CSF aftcr traumatic brain lll」 ury ln humans.2.1フ

It is thought that these cytokincs causc secondtty brainittury Or cercbral cdcma.17 Thc beneicial cffcct of mildhypother面 a thcrapy for padents with sevcrc head ittuヮis considercd to be due,at least in palt,to tlle supprcssion

of postiaumatic inflallllnatory responscs by reducing thc

rclcase of cytonncs into thc CSE13 1n tllc prcscnt study.

the daily changes in CSF conccntrations of inflammatorycytokincs(TNFα ,IL-lβ,IL-6,and IL-8)and an antiin―flamlllatory cytohnc(IL-10)did nOt differ bctwccn tllctwo groups(Tablc 3).Unlike EAAs in CSE tlle initialconccntations of thesc CSF cytokincs were sufficicntlyhigh colllpared with thosc mcasurcd on Days 3 to 5.Forexamplc,initial conccntratlons of CSF IL-6 and IL-8 wcrc15 to 30 times highcr on Day l than t13ose on Day 3 inbotll groups. Nevel・ tlleless, CSF conccntrations of thcsc

cytoHncs decreased rapidly ovcr tilllc in both groups.Thesc rcsults s■ ongly indicate that norlllothcrgua thcrapy

would rcduce tlle CSF concentrations of cytoHnes as wcllas llllld hypothc」

「lia therapy in padents with lo、 vI(〕 ]R

190

T,Shiozaki,et al.

C0771P′ Jcα′ノοんsプ/1 Pα′′`れ

な

In our prcvious study.wc shOwcd that the incidence of

i鮮Wi∬盪淑i緋霧ぎ構Al

∬聞Ъ胤譜i曽

糠誤:∫::lTttiЪ鳳:隠『監:響鷺

榊 蝉 継機 椰 撫 iF聯礎需跳轟謂Ъtthi:]聴斐;l籍穏瑞∬環many culturc― positivc surgical― wound infccuons as nor―

infections.TO rcsolve thc problelll of infections,Inulticcn―

揚 鷺鴫∬d°面ZCd饉」s tte curcndy bdng un―

h」搬 臨きW:暇辮 露柵 l硼 :

絲概鷲 撤 幡職1撒

椰 讐

蠍締I糞典螺嚇膳聯勒謡濫出器鷲甑野き出網龍器艦辮魃 騨 柵 捌譜琴濾

蹴 鮒 朧喘[儡町t欄known that prolongcd hypotllcrΠ ua causcs cold diurcsisduc to tlle supprcssion of antidiuretic hol‐ll10ne and re―

綺 揮 [紺 1:孵 i讐 幾 i聾 難 榊urctic horlllonc or a dccrcased sensidvity of tllc antidi_

urctic homone rcceptor.

Cο771pα r′ sο″グ ルイブJご ″ル οr/2ι r“′αIう4′r/2 Ⅳο′″tθ力″“′αれ

Pα′セ″な Tlζ′r/1Lοw lcP

絆脚齢:柵r詢椰榊讐榊兄漑 ∬ 器 猟 曽8:l∬舅鵠 き札鼠 計 T:::&鑑 漁 _

lisnl;14,21 and 5)presCrvation of the blood― brain bttie■ 6,24

Bascd on thc rcsults ofthc prcsent study,howcvcr,the first

糖 椰 押 鮒 椰 盛 鐵 鞣 :111

| l l l 1 1 1 120 40 60 80

工 Nelr′οsrrrg./Vo′ 77771`9f/Attglrsち f999

Normothermia for severe head ittury

study. Bccause clinical outcomes did not differ betv/ccn

thc two groups in this stlldy,wc do notthink that factors 4

o■ 5 playcd an illlpo■ ant role in paticnts with low ICPFronl thc prcscnt study,we could not ind any cvidencethat rnild hypotllel面 a therapy is advantageous ovcr nor―

mothemia thcrapy.To cl肛 itt whether llllld hypotllcr面atherapy is csscntial for the trcatmcnt of patients with sc―

vere hcad ittu7 with 10W ICR multiCenter prospectiverandomizcd tl・ ials arc now undcrway in Japan

Conclusions

Wc prospccivcly comparcd tllc cl[icacy of normothcr―lnia thcrapy witll that of lllild hypotherlllla therapy for thc

teatmcnt of scvcrcly hcad itturcd paticnts with low ICPmaintaincd by convcntional tllerapics. Daily changes inCSF conccntrations of Eメロヘs and cytoHncs did not differ

bctween tlle NT group and tlle HT group.「 Fhe incidcnccof complications in the NT group was lo、vcr than tllat in

tlle HT group. Morcovcr,paticnts in both groups had a

similar ncurological outcomc.Thcrcforc,for thc icatmentof scvcrcly hcad itturcd paticnts witl1low ICR WC rccom―

mend thc usc of nomothcrlllia tllcrapy to prcvcnt dclctc―

五ous hype■hcrlllia.

References

l Bakcr A」 ,Ⅳloulton RJ,NIach/1illall VH,et al:Excitatory arnino

acids in ccrcbrospinal iuid following tlallmmc brraln illJuw in

humans.J Neurosurg 79:369-372,19932 Bcll MJ,Kochanek PM,Doughty LA,ct ali lntcrlcuhn-6 and

intcrlcubn-10 in ccrcbrospinal iuid afler severe traumatic

brain lllJuW ln children J Neurotrauma 14:451-457,1997

3 Bullock R,Zauncr A,ヽ ″ヽoodv/ard JJ,et al:Factors affecting cx―citatory alluno acid rclcasc fo1lo、 /ing scvere human hcad in―juw J Neurosurg 89:507-518,1998

4 Busto R,Globus MYT,Dicttich WD,ct al:Effcct of mildhypolllcrHua on ischcllua― induccd release of ncurotransmittcrs

and frcc fatty acids in rat brain Stroke 20:904-910,1989

5 Clifton GL,Allcn S,Baげ odale P,et alノ pヽhasc II study ofmod―

erate hypothermia in severe brain ittury J Neurotrauma 10:263-273,1993

6

7

Dietlich WD,Busto R,Halley M,ct ali Thc inlpo■ ance ofbrain

tclnlpcraturc in altcra■ ons of the blood― brain baricr following

ccrebral ischenlia J Neuropathol Exp Neuro1 49:486-497,1990Fadcn´」,Dcmcdiuk P,Panter SS,ct al:■ hc rolc of cxcitatory

amino acids and NMDA rcccptors in ttaumatic brain ittuッ

Science 244:798-800,1989Jennett B,Bond WI:AsscssmCnt Of outcomc aftr scvcrc brdn

damagc A practlcal scalc Lalllcet l:480-484, 1975

Katayama Y,Becker DP,Tamura T,et al Massive increases in

cxtraccllular potassium and tllc indisc五 rninate release of glu―

tamate following concussivc brain illluw J Neurosurg 73:

889-900,1990

10 Kllrz A,Scsslcr DI,Lcnhardt R,ct al:Pcnoperativc norinothcr―

l■ua to rcducc tlle incidcncc of suttgical― wound infection andshortcn hOspitalization N Engl J ⅣIed 334:1209-1215,1996

1l Lipton SA,Rosenberg PA:Excitatoぃ /allrllno acids as a inalcommon patllway for ncurologic dlsordcrs N Engl J ⅣIed 330:613-622,1994

12.Marion DW,Ob五 stヽVD,Carlicr PM,ct al Tllc use of moder―ate tllcrapcutlc hypOthcrllua for patlents witll scvcre hcad

ilaJuncsl a prelilluntty repO■ J Neurosurg 79:35■ 362,199313 1/1allon Dヽr,Pcmod LE,Kclsey SF,et ali Trcatment of tlau―

matic braln illJuw with modcratc hypotllcrma N Engl Jレ Ied336:540-546,1997

14 Metz C,Holzscllllh M,Bcin T,et al Modcratc,potllCrma inpaticnts witll scvcκ hcad illJuゥ i cCICbral alld cxtraccrcbral

cffccts J Neurosurg 85:533-541,199615 ⅣIillcr J[): Disordcrs of ccrebral blood flow and intlacranial

prcssurc aftcr hcad ittu,Clin Neurosurg 29:162-173,1982

16 0gura H,Tttalca H,Koh T,ct al:Pl■ ning,second― hit p五ming,and apoptosis in leukocytcs iom ttauma paticnts J Trauma46:774-783,1999

17 0ttL,McClain CJ,Glllespic M,et ali Cytohnes and metabolic dysftlncion aftcr scvcre head ittuヮ J Neurotrauma ll:447-472,1994

18. Saul TG:Is ICP Inonitonng wolthwhilc?Clin NeurOsurg 34:560-571,1987

19 Scclig JM,Bcckcr I)P,Miller JD,ct al:Traumatlc acute sub―

dllral hematoma Mttor mO■ ality rcduction in comatosc pa―

ticnts ttcated、vithin four hours N Engl Jル led 304:1511-1518,1981

20 Sogarヽ VE,RIley PA Jr,Ba●la TG,etal U五 ntt compositiondlulng hypotllermia Am J Physiol 185:528-532,1956

21 ShiozaL T,sugilnoto H,Tancda 1/1,ct al:Effcct of nild hypo―

thcnrua on uncontlollablc inttacranial hypcttnsion aftcr scvere

hcad illlu,J Neurosurg 79:363-368,199322 Sluoztt T,Sugimoto H,Tancda M,ct ali Sclcction of scvcrely

head illlllrCd paticnts for mlld hypotllcrllua tllerapy J Neuro…

surg 89:206-211,199823 Sl血 th DH,OHyama K,ThOmas M,et al:An NMDA Кccptor―

associatcd glycinc sitc antagonist attcnuates memoEy loss aftcr

cxpcrimcntal braln illJuw SoC NeurOsci 16:779,1990(Ab―stract)

24 Slluth SL,Hall ED:Mild prc― and posttraumatic hypotller■lla

attenuates blood―brain balrier damagc following con廿 ollcd cor―

ticd impact ill」 uw in tlle rat J Neurotrauma 13:1-9,199625 Teasdale G,Jcnnctt B:Assessment of coma and impaircd con―

sciousncss i practlcal scale Lancet 2:81-84,197426 Wilbcrgcr JE,Haris M,Diamond DL:Acutc subdural hema―

toma:mol・ bidiり,mO■aliり,alld Opcratlvc timing J Neurosurg74:212-218,1991

Manuscript rcccived I)eccmbcr 14,1998

Acccptcd in inalfom March 17,1999This study was suppo■ cd by a grant liom tllc Ministw Of Health

and Wclfarc in Japan

Aググ″ss '中万4′ ″クン`Sな

わr Tadahiko ShiozJd,MD,Dcpart―mcnt of Traumatology,Osaka Univcrsity Mcdical School,2-2,Ya―mada― oka,Suita― shi,Osalca,565 Japan

工 Ne′′οslr■8./Vo′2771ι 9f/スタgfrsち f999 191