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述评・
Thedebateofdopamine’sclinicalapplication
TIANSui-rong(American)
Dopamine(DA)is
a
hormoneinthecatecholaminefamily.Itisproducedinthebrain
asa
neurotransmitterand
isresponsibleformoodchangesincludingpersonality,loveandeuphoriaindrugaddicts.
DAwas
function
asa
firstsynthesizedin
was
1910bytheBritishscientistsGeorgeBargerandJamesEwens.In1958,DA’sfirstrecognizedbySwedenscientistsArvidCarlssonandNils一爻keHillarp.Forthis
or
neurotransmitter
discovery,Carlssonwasawardedthe2000NobelPrizeinPhysiology
However,DArarelyisused
applied
to
as
a
Medicine….
been
widely
neurotransmitterclinically;ratheritsvasopressoreffectshave
differentclinicalscenarios。Whenitisgiven
as
peripheralintravenousinfusion,DAactivatesDA
receptor,andⅨand
B
receptors
forthetreatmentof
shock.Thefollowinginformationcomesfrompharmacology
textbookinmymedicalschool30yearsago[2|.
DA
cardiac
pharmacology:①Cardiac:activatesB1receptorsinoutput.②Bloodvesselsandbloodpressure:activates
on
theheart,increasesmyocardialcontractility,and
a
receptor
to
inbloodvesselandDAreceptorwith
minimumeffectB2
receptor.③Kidney:dilates
DA
can
kidneybloodvessel
increasekidneybloodflow,andtherefore
increasesglomerularfiltrationrate。Also
increasesodiumexcretionandurineoutputwithoutsignificant
on
kidneyhemodynamicchange,whichmeansthatDAhasdirecteffect
ThetextbookalsomentionsthatDA。seffects
are
kidneytubulesystem.
on
dosedependantandalsodependthedistributionofreceptors
oftargetorgans。Atlowdose(intravenousinfusion
rateat
2P.g‘kg-1’min‘1),DAincreasesmyocardialcontractility,
blood
selectivelyconstrictsbloodvesselsofskinandskeletonvesselsbyactivating
DA
receptor
muscle,dilateskidney,splanchnic,andcoronary
with
minimumbloodpressurechange.Finallytextbookstates,”application:
call
shockandcombiningwithdiuretics,dopamine
beusedfor
us
acute
renalfailure”.Thereismyhandwriting
on
this
pagewhereIreligiouslyrecordedwhatmyprofessortold
intheclassroom:”useitinpatientswithcardiacandrenal
dysfunotion.”This
Kidneyis
was
myunderstandingofDA
at
thattime.
our
one
ofthemostimportantorgansinbodyandmanydiseasessuch
a
gs
hypertension,diahetesand
autoimmunediseases
candamage
kidney.Protectingkidneyisveryimportantgoalduringtreatmentplanning.
myresidencytraining,Ihaveto
at
a
Withtheadvancedsearch,wefurtherevaluateDA。sclinicaleffects.During
studyupdated
textbooks,joinjournalclub
were
discussionsandattenddifferentconferences.Onedaylecturegivenby
nephrologist,we
toldthatwestillcouldn’tfind
the”magickidneyprotection”medication.Afteryearsof
to
research,studiesshowthatdopaminedoesn’tprovidebenefitviewofdopamine。
In2000,Lancet
published
a
kidneydysfunction.Thisnewknowledgechangedmy
studyfromAustraliaandNewZealand.Thisisdouble—blind,randomized,
to
placebo—controlledtrialfor328patientsadmittedindicatorofearlyrenaldysfunction
23intensive
care
units(ICUs).Patientshave
or
at
least
one
Curine
output
averaging0.5ml・kg-1‘h~for4hours
an
longer,serumcreatinine
(SCr)concentration
morethan150I上mol/Lwithoutpremorbidrenaldysfunction,or
a
increaseinScrconcentration
or
ofmorethan80斗mol/Linlessthan24hourswithouttheurine)。Patientsreceivedadministeredthrough
outcomesincluded
a
creatininekinaselevelmorethan5000U/L
a
myoglobinin
either
venous
DAinfused
at
rate
of2P.g。kg-1‘rain’1
was
oran
identicalamountofplacebo
central
catheter.Theprimaryoutcome
peakSCrlevelduringthestudy.Secondary
reason
forcessationoftrialinfusion,developmentofcardiacarrhythmias,durationofmechanical
urea
ventilation,lengthofICUstayandhospitalstay,peakplasmaSCrand
urea
concentrationduringstudyinfusion,changein
at
concentrationfrombaseline
to
peakvalue,hourlyurineoutputpredetermined
times,numberof
DOt:10.3760h・mfl.j.issn.1003-0603.2012.08.002
作青单位:美l埘宝儿约婀余LIJ皇后陕院庥酗科通f占作者:哪穗荣.Email:tinaleungny@hatmail。(,onl
・452・
主垦鱼重痘垒墼医堂兰Q!!生!旦筮丝鲞笙!塑垦!垫鱼也堡塑丛型!垒!匙!!兰Q!!!y!!:丝!塑!:!
exceeded
patientsrequiringrenalreplacementtherapy,numberofpatientswhoseserumereatinineconcentrations300ILLmol/L,andsurvivalbetween
DA
to
ICUand
to
hospitaldischarge.Studyshowsthat
or
no
significantdifferenceswerefound
and
placebo
not
in
anv
primary
secondaryoutcomemeasures.Theconclusionis:”Fenal—dose”DA
criticallyillpatients
at
(2斗g’kg-1’min一’)does
Another
failure
appeartoconferanybenefitto
use
riskforrenalfailure【3】.
or
meta—analysis
be
iustified
on
in200lshowsthe
oflow—doseDAforthetreatment
preventionof
acute
renal
cannotthebasisofavailableevidenceandshouldbeeliminatedfromroutineclinical
no
use‘….
use
DespitethefactthatDAhasbeenproventoprovide
renalprotection,myprofessortoldmethatwecould
DA
totreat
shock.Dowehave
new
studies
to
prove
or
disprovethisconcept?
occurrence
In2006,CriticalCareMedicinepublishedSOAPStudy(sepsisincludes3147patientswithshockfrom196ICUsinEurope.Thisis
inacutelyillpatientsstudy)which
a
cohoa,multiple—center,observationstudy.
PatientswerefollowedupuntiIdeath,untilhospitaldischarge,orfor60days.Of3147patients,1058(33.6%)hadshock
at
any
time;462(14.7%)hadsepticshock.Theintensive
shock.OfDatientsin
care
unitmortalityrateforshockwas
38.3%and
47.4%forseptic
shock,375(35.4%)receivedDA(DAgroup)and683(64.6%)never
receivedDA.ConclusionofthisstudysuggeststhatDAadministrationmaybeassociatedwithincreasedmortality
rates
inshock.
Again,in2010,
%e
New
England
JournalofMedicinepublished”ComparisonofDA
and
norepinephrine
(NE)inthetreatmentofshock”.Inthismuhicenter,randomizedtrial,researchersassigned1679patientswithshock
into2groups
(858patients
receiveDAand821patientsreceiveNE
as
firstlinevasopressor).Whentheblood
ora
pressurecouldnotbemaintainedwiththedoseof20斗g‘kg-1’min一1forDA
doseof0.19斗g。kg-1’min.1forNE,
rate
wasthe
open—labelnorepinephrine,epinephrine,orvasopressincouldbeadded.Theprimaryoutcome
at
ofdeath
28daysafterrandomization;secondaryendpointsincludedthenumberofdayswithoutneedfororgansupportand
occurrence
the
ofadverseevents.Conclusionsshowthatthedeath
rate
is
about
thesamein2groups;however,DA
grouphasgreaternumberofadverseeventsthatincludearrhythmia(P<0.001),open-labelvasopressors(P=
0.007),skinischemia(P=O.09)【6].
Let’s100k
at
a
meta—analysispublishedthisyear
to
compareDA
versus
NEinthetreatmentofsepticshock.This
to
studvshowsthatDAisassociatedwithmoredeathandhigherincidenceofarrhythmiacompared
Historicallynorepinephrinewasthefirstvasopressorused
totreat
NE【7|.
shock
yearsago.However,duetolackof
intravascularvolumeresuscitation
NEadministration
at
thattime,patientswith
shockshowthesignsofworsenedtissueperfusionafter
becauseithasstrongervasocontrictiveeffect.DAismuchmilderthanNEwithgreaterinotropic
as
aetivity;mallvphysiciansacceptittherapeuticstrategy
treat
totreat
vasopressorofchoice.Nowtimeisdifferent;fluidresuscitation
isthefirst—line
to
shockbeforevasopressor
application.Many
recent
studiesprovethatNEisbetterdrug
not
a
thesepticshockthanDA.Personallylrarely
use
DAnowadaysandIknowDAis
commondrugusedin
ICUsettinginUSA.However,DAhasmedication
been
arefamiliarwiththe
longusedbymedicalpersonnel;manydoctors
and
feelcomfortableforitsapplication,therefore,itbecomespartoftheirroutinetreatment.SOAPStudy
or
showsthatdopaminewasusedmoreincommunitythaninuniversity
cityhospitals
(43.6%,36.3%and29.9%,
respectively,P=0.016)【5J.Asbased.There
Dr.DavidBraccopointed
out
inhis
editorial
paper,oneFrenchsurveyshowedthatin
selectedclinicalsituations,thechoiceofcatecholamineisbased
issomeevidencethatsomecommunityhospital
personalandculturalpreferences,notevidence
physiciansareafraidofNEandhelieveinDAbecause
on
DA,”alittlebit
13and仅,as
to
inotrope
or
vasopressor,maydothe
to
job”【8】.With
to
the
new
strategyofpatientmanage-
ment,maybeweneed
Mavbeitistime
educatedoctors
change
as
theirpracticeaccording
to
evidence.
to
abandondopamine
prevent
or
thefirst—linevasopressor
treatthepatientswith
shockand”low-do跎
DA”asthetreatmentto
treat
renaldysfunction.
on
ThecontroversyofDA’sclinicalapplicationhasbeengoing
whileothersbelievethatDAis
to
consensus
foryezurs.Some
further
doctors
callDAas”silentkiller”
willallcome
all”obsolete”medicationto
treat
shock.With
research,ma.ybewe
to
thistopicanddecidethefateofDA.
史旦鱼重疸鱼墼匿堂!!!!生!旦箜丝鲞箜!塑£丛!鱼也∈些丛型!△!鲤!!!Q!!:Y!!:!!!盟!:!
・453・
多巴胺临床应用的争议(译文)
田穗荣(美国)
多巴胺(Dopamine,DA)是儿茶酚胺家族内的一种激素,由脑内分泌,在大脑内作为神经递质,可影响一个人的情绪,这些情绪包括了爱情、上瘾的欣快感等。
1910年DA由英国科学家GeorgeBarger和JamesEwens合成,1958年,瑞典科学家ArvidCarlssont¨和
Nils一/l,keHillarp发现DA是神经递质,Carlsson并在2000年获得诺贝尔医学奖。
但是临床上医生们几乎不把DA作为神经递质来使用,历史悠久的DA长期被作为血管活性药物来使用,在外周静脉滴注,DA除激动DA受体外,也激动a和B受体发挥作用。下面资料来自我读医学院时的药
剂学教科书(30多年前)…:
多巴胺的药理作用:①对心脏的作用,能兴奋心脏pl受体,使心收缩力增强,心排血量增加。②对血管和血压的影响,能作用于血管的d受体和DA受体,而对B2受体的影响十分微弱。③对肾脏的作用,多巴胺能舒张肾血管,故肾血流量增加,肾小球的滤过率也增加。此外,本药尚有排钠利尿作用,在肾的总血流动力学无明显改变时,钠的排泄已增加,这可能是DA直接对肾小管的作用。
课本还谈到DA作用除与剂量或浓度有关外,还取决于靶器官中各受体亚型的分布和药物受体选择性的高低。低剂量时(滴注速度约为2斗g・kg一・min。1),DA使心肌收缩力增强,选择性地收缩皮肤、黏膜和骨骼肌血管,而激动血管的D.受体的作用产生血管舒张效应,特别表现在肾脏、肠系膜和冠状血管床,对血压的影响不明显。最后,教科书写道:“用途:用于抗休克。此外,本药尚可与利尿药合并应用于急性肾功能衰竭(肾衰竭)。”在课本里自己手写的笔记显示了我虔诚地记录了老师的教导:“用于休克而肾功能不好和心功能不好的患者。”这是当年我对DA的认识。
毫无疑问,肾脏是人身上非常重要的器官,而各种疾病,包括了高血压、糖尿病、药物和不同种类的自身免疫性疾病,以及疾病的发展过程都可能给肾脏带来损害。在为患者的治疗当中,如何保护肾脏是一个非常重要的医疗目标。
时代在不断进步,科研的进展使我们进一步评估了DA的临床作用。美国住院医生在培训期间要读教科书,学习文献,或是参加各种学术讲座。某天肾脏专科医生给我们上课,谈到了肾保护,令人悲哀的是,我们仍然无法找到保护。肾脏的神丹妙药,而DA,经过了多年的研究,并没有对肾功能不全的患者带来福音。这个说法颠覆了我对DA的理解。
2000年Lancet发表了来自澳洲和新西兰的研究,这是个双盲、随机、对照的研究,入住23个重症监护病房(ICU)的328例重症患者至少有一个肾功能不全的早期指征(发病前没有’净脏疾病,在4h或更长的时间
内患者尿量O.5m1.kg-I・h一,现在血清肌酐(SCr)超过150pLmol/L,或者24h内SCr的增加超过80Izmol/L,而
肌酸激酶不超过5000u/L,尿中也没有肌红蛋白]。患者随机分组,从中心静脉管道接受2斗g・kg一・min。1DA或者安慰荆滴注,主要结局是研究过程中scr的峰值,次要结局是停止滴注的原因,包括心律不齐、机械通气持续时间、住ICU时间和住院时间、滴注期间血浆尿素峰值、SCr和尿素峰值浓度与基础值的变化、每小时
的尿量、需要肾透析的患者数、SC,>300limol/I.的患者数,ICU的生存率和出院率。结果显示,主要和次要的
结局测量方面DA组和对照组没有明显差异。结论是:…肾剂量”的DA滴注(2pg-kg以・min。1)对有肾衰竭风险的重症患者没有提供任何益处…。
2001年发表的荟萃分析显示:没有证据证明我们应该用“肾剂量”的DA滴注(2斗g・kg一・min。1)来预防和治疗急性肾衰竭,应该淘汰这种临床使用….即使DA不能保护肾脏。但是我的老师认为DA可用于休克。那么最新的研究又如何考证这个问题呢?
2006年CriticalCare,Medicine发表了有关急性病患者感染性休克发生率研究(SOAPStudy)的文章,该研究纳入了在欧洲的196个ICU中的3147例休克患者,随访终点为死亡、出院或60d停止随访。1058例(33.6%)在任何时间段有休克,462例(14.7%)有感染性休克;休克和感染性休克的病死率分别为38.3%和47.4%;在休克患者中,375例(35.4%)接受DA(DA组),683例(64.6%)完全没有接受DA(非DA组)。DA组
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主垦丝重疸叁塾匿堂!Q!!笙!旦箜丝鲞笙!塑坠i!£旦!垡竺丛型!垒!鲤塾垫!!!!!!:丝!型!:!
的ICU病死率、30d病死率和住院病死率都比非DA组高[5J。
2010年弛eNewEnglandJournalofMedicine发表文章对比了DA和去甲肾上腺素(NE)治疗休克的效果,结果如何呢?在这个多中心、随机对照的研究中,患者总数为1679例,858例患者为DA组,821例患者为NE组。休克患者接受DA或者NE作为恢复和维持血压的一线血管活性药物治疗,如果20“g’kg-1‘min’1剂量的DA或0.19¨g・kg-1・min。1剂量的NE不足以维持血压,将加用NE、’肾上腺素和血管加压素。主要的结局是观察28d病死率,第二个终点包括不需要器官支持的天数和不良事件的发生率。结论:两组的病死率无明显差异,而DA组则有更多的不良事件,这些不良事件包括了心律不齐(P<O.001)、其他升压药使用率高(P=O.007)、皮肤缺血(P=O.09)[61。
2012年CriticalCareMedicine发表的荟萃分析对比了感染性休克患者使用DA和NE的结果。结果显
示,使用DA增加了病死率和心律不齐的发生率【7】。
历史上许多年前都认为NE是第一个用于治疗休克的血管活性药物。然而,当时尚未认识到血容量扩充的重要性,NE强烈的血管收缩作用使患者的组织灌注恶化。DA的血管收缩作用比NE远为温和,且有强心作用,许多医生选择DA为治疗休克的首选药物。时代不同了,容量抢救已经成为治疗休克的首选措施,然后才根据临床情况选用血管活性药物。许多近期的研究显示了NE在治疗感染性休克方面比DA效果好。现在我个人几乎不用DA作为血管活性药物,也知道在美国DA已经不是ICU的常用药物。但是许多医生习惯和熟悉这个药物的使用,将其作为常规药物。在SOAPStudy中,和大学医院及城市医院相比,社区医院使用DA最多(社区医院43.6%,大学医院36.3%,城市医院29.9%,P=0.016)ts]。正如DavidBracco医生在他的编者按中指出:法国的问卷调查显示,在某种临床情况下,儿茶酚胺类药物的选择是个人和传统的爱好,而非依据循证医学。有证据显示,社区医院医生害怕使用NE而相信DA的效果是因为DA有“一点13,一点Ot,强心或升压,也许有效"【8j。由于新的l临床管理方式,我们应该教育医生们要根据研究结果改变他们的医疗理念。
也许是时候摈弃使用DA作为治疗休克的首选药物的做法,也不应该使用“肾剂量”的DA作为预防和治疗肾衰竭的治疗措施。
DA使用的争论已持续多年,有医生说DA是“无形的杀手”,使用DA是“骨灰级”的思维。不过随着研究的延续,也许我们最终会对这个争论做出结论,这个结论将决定DA的命运。
参考文献
[1]BenesFM.Carlson
andthedi.seoveryofdopamine.Trends
Pharmaeol卧i.200I。22:46-47.
[2]巾山医学院.药理学.北京:人民卫生出版社.1979:152.[3]BellomoR,ChapmanM.Finfers,etal.Low—dose.dopaminein
2000.356:2139—2143.
patientswithearlyrenaldysfunction:aplacebo--controlledrandomisedtrial.Lancet.
[4]KellumJA,DeckerJM.Useofdopamineinacuterenalfailure:arecta-analysis.CritCareMed.2001,29:1526--1531.[5]sal【rY.ReinhartK,Vincent.IL.elal.Does
dopamineadministrationin
shockinfluen(x}outcome?Resultsofthe
sepsisoccurrPncein
acutelyill
patients(SOAP)study.CritCareMed.2006.34:589—597.
[6]DeBackerD,Biston[7]De
Backer
P.Devriendt
J,ela1.Compari.,mnofdopamineandnorepinephrineinthetreatmentofshock.NE.glJMed.2010.362:779-789.
vel3us
D.AldecoaC,NjimiH,ela1.DopaminenorepinephfineinthetrPatmentofsepticshock:arecta-analysis.CritcarPMed。2012,40:
725-730.
[8]BracoDD.Pharmacologicsupportofthefailingcirculation:practice.education.evidence.andfuturedirections.CritCareMed.2006.34:890-892.
(收稿日期:2012-07—18)(本文编辑:李银平)
・科研新闻速递・
烧伤患者入院24h内的低白蛋白血症与器官功能障碍有关
低白蛋ILI血症是烧伤患者常见的症状.但其与烧伤后病死率的相关性未知:最近,加拿大的研究人员研究了严蕈烧伤患者
入院24h内的低白蛋广1血症与器官功能障碍的关系:研究人员对2008年至2009年烧伤面积达到20%总体表面积、烧伤24h
内收入研究人员所在医院的56例患者进行了回顾分析:研究人员使用多元线性回归分析发现。入院24h内的低门蛋白血症是器官功能障碍的独立危险闪素;血清门蛋白浓度≤30g,L能使器官功能障碍的发生风险增加2倍.但不会导致死f:闪此研究人员认为.烧伤患者低白蛋白血症是患者发生器官功能障碍的危险因素;与那些不可改变的l嗣素(如年龄、烧伤面积、吸人性损伤)相比.纠正烧伤患者的低蛋白血症可能是将来防治器官功能障碍的重要手段之一。
杜明华,编译自《Bums》,2012-06.07(电子版);胡森,审校
生国蕉重瘟鱼整堕堂垫!;至!旦箜丝鲞笙!塑鱼!地垦也£!翌丛旦!垒!鲤坐!!121111:丝!型!:!
・451・
述评・
Thedebateofdopamine’sclinicalapplication
TIANSui-rong(American)
Dopamine(DA)is
a
hormoneinthecatecholaminefamily.Itisproducedinthebrain
asa
neurotransmitterand
isresponsibleformoodchangesincludingpersonality,loveandeuphoriaindrugaddicts.
DAwas
function
asa
firstsynthesizedin
was
1910bytheBritishscientistsGeorgeBargerandJamesEwens.In1958,DA’sfirstrecognizedbySwedenscientistsArvidCarlssonandNils一爻keHillarp.Forthis
or
neurotransmitter
discovery,Carlssonwasawardedthe2000NobelPrizeinPhysiology
However,DArarelyisused
applied
to
as
a
Medicine….
been
widely
neurotransmitterclinically;ratheritsvasopressoreffectshave
differentclinicalscenarios。Whenitisgiven
as
peripheralintravenousinfusion,DAactivatesDA
receptor,andⅨand
B
receptors
forthetreatmentof
shock.Thefollowinginformationcomesfrompharmacology
textbookinmymedicalschool30yearsago[2|.
DA
cardiac
pharmacology:①Cardiac:activatesB1receptorsinoutput.②Bloodvesselsandbloodpressure:activates
on
theheart,increasesmyocardialcontractility,and
a
receptor
to
inbloodvesselandDAreceptorwith
minimumeffectB2
receptor.③Kidney:dilates
DA
can
kidneybloodvessel
increasekidneybloodflow,andtherefore
increasesglomerularfiltrationrate。Also
increasesodiumexcretionandurineoutputwithoutsignificant
on
kidneyhemodynamicchange,whichmeansthatDAhasdirecteffect
ThetextbookalsomentionsthatDA。seffects
are
kidneytubulesystem.
on
dosedependantandalsodependthedistributionofreceptors
oftargetorgans。Atlowdose(intravenousinfusion
rateat
2P.g‘kg-1’min‘1),DAincreasesmyocardialcontractility,
blood
selectivelyconstrictsbloodvesselsofskinandskeletonvesselsbyactivating
DA
receptor
muscle,dilateskidney,splanchnic,andcoronary
with
minimumbloodpressurechange.Finallytextbookstates,”application:
call
shockandcombiningwithdiuretics,dopamine
beusedfor
us
acute
renalfailure”.Thereismyhandwriting
on
this
pagewhereIreligiouslyrecordedwhatmyprofessortold
intheclassroom:”useitinpatientswithcardiacandrenal
dysfunotion.”This
Kidneyis
was
myunderstandingofDA
at
thattime.
our
one
ofthemostimportantorgansinbodyandmanydiseasessuch
a
gs
hypertension,diahetesand
autoimmunediseases
candamage
kidney.Protectingkidneyisveryimportantgoalduringtreatmentplanning.
myresidencytraining,Ihaveto
at
a
Withtheadvancedsearch,wefurtherevaluateDA。sclinicaleffects.During
studyupdated
textbooks,joinjournalclub
were
discussionsandattenddifferentconferences.Onedaylecturegivenby
nephrologist,we
toldthatwestillcouldn’tfind
the”magickidneyprotection”medication.Afteryearsof
to
research,studiesshowthatdopaminedoesn’tprovidebenefitviewofdopamine。
In2000,Lancet
published
a
kidneydysfunction.Thisnewknowledgechangedmy
studyfromAustraliaandNewZealand.Thisisdouble—blind,randomized,
to
placebo—controlledtrialfor328patientsadmittedindicatorofearlyrenaldysfunction
23intensive
care
units(ICUs).Patientshave
or
at
least
one
Curine
output
averaging0.5ml・kg-1‘h~for4hours
an
longer,serumcreatinine
(SCr)concentration
morethan150I上mol/Lwithoutpremorbidrenaldysfunction,or
a
increaseinScrconcentration
or
ofmorethan80斗mol/Linlessthan24hourswithouttheurine)。Patientsreceivedadministeredthrough
outcomesincluded
a
creatininekinaselevelmorethan5000U/L
a
myoglobinin
either
venous
DAinfused
at
rate
of2P.g。kg-1‘rain’1
was
oran
identicalamountofplacebo
central
catheter.Theprimaryoutcome
peakSCrlevelduringthestudy.Secondary
reason
forcessationoftrialinfusion,developmentofcardiacarrhythmias,durationofmechanical
urea
ventilation,lengthofICUstayandhospitalstay,peakplasmaSCrand
urea
concentrationduringstudyinfusion,changein
at
concentrationfrombaseline
to
peakvalue,hourlyurineoutputpredetermined
times,numberof
DOt:10.3760h・mfl.j.issn.1003-0603.2012.08.002
作青单位:美l埘宝儿约婀余LIJ皇后陕院庥酗科通f占作者:哪穗荣.Email:tinaleungny@hatmail。(,onl
・452・
主垦鱼重痘垒墼医堂兰Q!!生!旦筮丝鲞笙!塑垦!垫鱼也堡塑丛型!垒!匙!!兰Q!!!y!!:丝!塑!:!
exceeded
patientsrequiringrenalreplacementtherapy,numberofpatientswhoseserumereatinineconcentrations300ILLmol/L,andsurvivalbetween
DA
to
ICUand
to
hospitaldischarge.Studyshowsthat
or
no
significantdifferenceswerefound
and
placebo
not
in
anv
primary
secondaryoutcomemeasures.Theconclusionis:”Fenal—dose”DA
criticallyillpatients
at
(2斗g’kg-1’min一’)does
Another
failure
appeartoconferanybenefitto
use
riskforrenalfailure【3】.
or
meta—analysis
be
iustified
on
in200lshowsthe
oflow—doseDAforthetreatment
preventionof
acute
renal
cannotthebasisofavailableevidenceandshouldbeeliminatedfromroutineclinical
no
use‘….
use
DespitethefactthatDAhasbeenproventoprovide
renalprotection,myprofessortoldmethatwecould
DA
totreat
shock.Dowehave
new
studies
to
prove
or
disprovethisconcept?
occurrence
In2006,CriticalCareMedicinepublishedSOAPStudy(sepsisincludes3147patientswithshockfrom196ICUsinEurope.Thisis
inacutelyillpatientsstudy)which
a
cohoa,multiple—center,observationstudy.
PatientswerefollowedupuntiIdeath,untilhospitaldischarge,orfor60days.Of3147patients,1058(33.6%)hadshock
at
any
time;462(14.7%)hadsepticshock.Theintensive
shock.OfDatientsin
care
unitmortalityrateforshockwas
38.3%and
47.4%forseptic
shock,375(35.4%)receivedDA(DAgroup)and683(64.6%)never
receivedDA.ConclusionofthisstudysuggeststhatDAadministrationmaybeassociatedwithincreasedmortality
rates
inshock.
Again,in2010,
%e
New
England
JournalofMedicinepublished”ComparisonofDA
and
norepinephrine
(NE)inthetreatmentofshock”.Inthismuhicenter,randomizedtrial,researchersassigned1679patientswithshock
into2groups
(858patients
receiveDAand821patientsreceiveNE
as
firstlinevasopressor).Whentheblood
ora
pressurecouldnotbemaintainedwiththedoseof20斗g‘kg-1’min一1forDA
doseof0.19斗g。kg-1’min.1forNE,
rate
wasthe
open—labelnorepinephrine,epinephrine,orvasopressincouldbeadded.Theprimaryoutcome
at
ofdeath
28daysafterrandomization;secondaryendpointsincludedthenumberofdayswithoutneedfororgansupportand
occurrence
the
ofadverseevents.Conclusionsshowthatthedeath
rate
is
about
thesamein2groups;however,DA
grouphasgreaternumberofadverseeventsthatincludearrhythmia(P<0.001),open-labelvasopressors(P=
0.007),skinischemia(P=O.09)【6].
Let’s100k
at
a
meta—analysispublishedthisyear
to
compareDA
versus
NEinthetreatmentofsepticshock.This
to
studvshowsthatDAisassociatedwithmoredeathandhigherincidenceofarrhythmiacompared
Historicallynorepinephrinewasthefirstvasopressorused
totreat
NE【7|.
shock
yearsago.However,duetolackof
intravascularvolumeresuscitation
NEadministration
at
thattime,patientswith
shockshowthesignsofworsenedtissueperfusionafter
becauseithasstrongervasocontrictiveeffect.DAismuchmilderthanNEwithgreaterinotropic
as
aetivity;mallvphysiciansacceptittherapeuticstrategy
treat
totreat
vasopressorofchoice.Nowtimeisdifferent;fluidresuscitation
isthefirst—line
to
shockbeforevasopressor
application.Many
recent
studiesprovethatNEisbetterdrug
not
a
thesepticshockthanDA.Personallylrarely
use
DAnowadaysandIknowDAis
commondrugusedin
ICUsettinginUSA.However,DAhasmedication
been
arefamiliarwiththe
longusedbymedicalpersonnel;manydoctors
and
feelcomfortableforitsapplication,therefore,itbecomespartoftheirroutinetreatment.SOAPStudy
or
showsthatdopaminewasusedmoreincommunitythaninuniversity
cityhospitals
(43.6%,36.3%and29.9%,
respectively,P=0.016)【5J.Asbased.There
Dr.DavidBraccopointed
out
inhis
editorial
paper,oneFrenchsurveyshowedthatin
selectedclinicalsituations,thechoiceofcatecholamineisbased
issomeevidencethatsomecommunityhospital
personalandculturalpreferences,notevidence
physiciansareafraidofNEandhelieveinDAbecause
on
DA,”alittlebit
13and仅,as
to
inotrope
or
vasopressor,maydothe
to
job”【8】.With
to
the
new
strategyofpatientmanage-
ment,maybeweneed
Mavbeitistime
educatedoctors
change
as
theirpracticeaccording
to
evidence.
to
abandondopamine
prevent
or
thefirst—linevasopressor
treatthepatientswith
shockand”low-do跎
DA”asthetreatmentto
treat
renaldysfunction.
on
ThecontroversyofDA’sclinicalapplicationhasbeengoing
whileothersbelievethatDAis
to
consensus
foryezurs.Some
further
doctors
callDAas”silentkiller”
willallcome
all”obsolete”medicationto
treat
shock.With
research,ma.ybewe
to
thistopicanddecidethefateofDA.
史旦鱼重疸鱼墼匿堂!!!!生!旦箜丝鲞箜!塑£丛!鱼也∈些丛型!△!鲤!!!Q!!:Y!!:!!!盟!:!
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多巴胺临床应用的争议(译文)
田穗荣(美国)
多巴胺(Dopamine,DA)是儿茶酚胺家族内的一种激素,由脑内分泌,在大脑内作为神经递质,可影响一个人的情绪,这些情绪包括了爱情、上瘾的欣快感等。
1910年DA由英国科学家GeorgeBarger和JamesEwens合成,1958年,瑞典科学家ArvidCarlssont¨和
Nils一/l,keHillarp发现DA是神经递质,Carlsson并在2000年获得诺贝尔医学奖。
但是临床上医生们几乎不把DA作为神经递质来使用,历史悠久的DA长期被作为血管活性药物来使用,在外周静脉滴注,DA除激动DA受体外,也激动a和B受体发挥作用。下面资料来自我读医学院时的药
剂学教科书(30多年前)…:
多巴胺的药理作用:①对心脏的作用,能兴奋心脏pl受体,使心收缩力增强,心排血量增加。②对血管和血压的影响,能作用于血管的d受体和DA受体,而对B2受体的影响十分微弱。③对肾脏的作用,多巴胺能舒张肾血管,故肾血流量增加,肾小球的滤过率也增加。此外,本药尚有排钠利尿作用,在肾的总血流动力学无明显改变时,钠的排泄已增加,这可能是DA直接对肾小管的作用。
课本还谈到DA作用除与剂量或浓度有关外,还取决于靶器官中各受体亚型的分布和药物受体选择性的高低。低剂量时(滴注速度约为2斗g・kg一・min。1),DA使心肌收缩力增强,选择性地收缩皮肤、黏膜和骨骼肌血管,而激动血管的D.受体的作用产生血管舒张效应,特别表现在肾脏、肠系膜和冠状血管床,对血压的影响不明显。最后,教科书写道:“用途:用于抗休克。此外,本药尚可与利尿药合并应用于急性肾功能衰竭(肾衰竭)。”在课本里自己手写的笔记显示了我虔诚地记录了老师的教导:“用于休克而肾功能不好和心功能不好的患者。”这是当年我对DA的认识。
毫无疑问,肾脏是人身上非常重要的器官,而各种疾病,包括了高血压、糖尿病、药物和不同种类的自身免疫性疾病,以及疾病的发展过程都可能给肾脏带来损害。在为患者的治疗当中,如何保护肾脏是一个非常重要的医疗目标。
时代在不断进步,科研的进展使我们进一步评估了DA的临床作用。美国住院医生在培训期间要读教科书,学习文献,或是参加各种学术讲座。某天肾脏专科医生给我们上课,谈到了肾保护,令人悲哀的是,我们仍然无法找到保护。肾脏的神丹妙药,而DA,经过了多年的研究,并没有对肾功能不全的患者带来福音。这个说法颠覆了我对DA的理解。
2000年Lancet发表了来自澳洲和新西兰的研究,这是个双盲、随机、对照的研究,入住23个重症监护病房(ICU)的328例重症患者至少有一个肾功能不全的早期指征(发病前没有’净脏疾病,在4h或更长的时间
内患者尿量O.5m1.kg-I・h一,现在血清肌酐(SCr)超过150pLmol/L,或者24h内SCr的增加超过80Izmol/L,而
肌酸激酶不超过5000u/L,尿中也没有肌红蛋白]。患者随机分组,从中心静脉管道接受2斗g・kg一・min。1DA或者安慰荆滴注,主要结局是研究过程中scr的峰值,次要结局是停止滴注的原因,包括心律不齐、机械通气持续时间、住ICU时间和住院时间、滴注期间血浆尿素峰值、SCr和尿素峰值浓度与基础值的变化、每小时
的尿量、需要肾透析的患者数、SC,>300limol/I.的患者数,ICU的生存率和出院率。结果显示,主要和次要的
结局测量方面DA组和对照组没有明显差异。结论是:…肾剂量”的DA滴注(2pg-kg以・min。1)对有肾衰竭风险的重症患者没有提供任何益处…。
2001年发表的荟萃分析显示:没有证据证明我们应该用“肾剂量”的DA滴注(2斗g・kg一・min。1)来预防和治疗急性肾衰竭,应该淘汰这种临床使用….即使DA不能保护肾脏。但是我的老师认为DA可用于休克。那么最新的研究又如何考证这个问题呢?
2006年CriticalCare,Medicine发表了有关急性病患者感染性休克发生率研究(SOAPStudy)的文章,该研究纳入了在欧洲的196个ICU中的3147例休克患者,随访终点为死亡、出院或60d停止随访。1058例(33.6%)在任何时间段有休克,462例(14.7%)有感染性休克;休克和感染性休克的病死率分别为38.3%和47.4%;在休克患者中,375例(35.4%)接受DA(DA组),683例(64.6%)完全没有接受DA(非DA组)。DA组
・454・
主垦丝重疸叁塾匿堂!Q!!笙!旦箜丝鲞笙!塑坠i!£旦!垡竺丛型!垒!鲤塾垫!!!!!!:丝!型!:!
的ICU病死率、30d病死率和住院病死率都比非DA组高[5J。
2010年弛eNewEnglandJournalofMedicine发表文章对比了DA和去甲肾上腺素(NE)治疗休克的效果,结果如何呢?在这个多中心、随机对照的研究中,患者总数为1679例,858例患者为DA组,821例患者为NE组。休克患者接受DA或者NE作为恢复和维持血压的一线血管活性药物治疗,如果20“g’kg-1‘min’1剂量的DA或0.19¨g・kg-1・min。1剂量的NE不足以维持血压,将加用NE、’肾上腺素和血管加压素。主要的结局是观察28d病死率,第二个终点包括不需要器官支持的天数和不良事件的发生率。结论:两组的病死率无明显差异,而DA组则有更多的不良事件,这些不良事件包括了心律不齐(P<O.001)、其他升压药使用率高(P=O.007)、皮肤缺血(P=O.09)[61。
2012年CriticalCareMedicine发表的荟萃分析对比了感染性休克患者使用DA和NE的结果。结果显
示,使用DA增加了病死率和心律不齐的发生率【7】。
历史上许多年前都认为NE是第一个用于治疗休克的血管活性药物。然而,当时尚未认识到血容量扩充的重要性,NE强烈的血管收缩作用使患者的组织灌注恶化。DA的血管收缩作用比NE远为温和,且有强心作用,许多医生选择DA为治疗休克的首选药物。时代不同了,容量抢救已经成为治疗休克的首选措施,然后才根据临床情况选用血管活性药物。许多近期的研究显示了NE在治疗感染性休克方面比DA效果好。现在我个人几乎不用DA作为血管活性药物,也知道在美国DA已经不是ICU的常用药物。但是许多医生习惯和熟悉这个药物的使用,将其作为常规药物。在SOAPStudy中,和大学医院及城市医院相比,社区医院使用DA最多(社区医院43.6%,大学医院36.3%,城市医院29.9%,P=0.016)ts]。正如DavidBracco医生在他的编者按中指出:法国的问卷调查显示,在某种临床情况下,儿茶酚胺类药物的选择是个人和传统的爱好,而非依据循证医学。有证据显示,社区医院医生害怕使用NE而相信DA的效果是因为DA有“一点13,一点Ot,强心或升压,也许有效"【8j。由于新的l临床管理方式,我们应该教育医生们要根据研究结果改变他们的医疗理念。
也许是时候摈弃使用DA作为治疗休克的首选药物的做法,也不应该使用“肾剂量”的DA作为预防和治疗肾衰竭的治疗措施。
DA使用的争论已持续多年,有医生说DA是“无形的杀手”,使用DA是“骨灰级”的思维。不过随着研究的延续,也许我们最终会对这个争论做出结论,这个结论将决定DA的命运。
参考文献
[1]BenesFM.Carlson
andthedi.seoveryofdopamine.Trends
Pharmaeol卧i.200I。22:46-47.
[2]巾山医学院.药理学.北京:人民卫生出版社.1979:152.[3]BellomoR,ChapmanM.Finfers,etal.Low—dose.dopaminein
2000.356:2139—2143.
patientswithearlyrenaldysfunction:aplacebo--controlledrandomisedtrial.Lancet.
[4]KellumJA,DeckerJM.Useofdopamineinacuterenalfailure:arecta-analysis.CritCareMed.2001,29:1526--1531.[5]sal【rY.ReinhartK,Vincent.IL.elal.Does
dopamineadministrationin
shockinfluen(x}outcome?Resultsofthe
sepsisoccurrPncein
acutelyill
patients(SOAP)study.CritCareMed.2006.34:589—597.
[6]DeBackerD,Biston[7]De
Backer
P.Devriendt
J,ela1.Compari.,mnofdopamineandnorepinephrineinthetreatmentofshock.NE.glJMed.2010.362:779-789.
vel3us
D.AldecoaC,NjimiH,ela1.DopaminenorepinephfineinthetrPatmentofsepticshock:arecta-analysis.CritcarPMed。2012,40:
725-730.
[8]BracoDD.Pharmacologicsupportofthefailingcirculation:practice.education.evidence.andfuturedirections.CritCareMed.2006.34:890-892.
(收稿日期:2012-07—18)(本文编辑:李银平)
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杜明华,编译自《Bums》,2012-06.07(电子版);胡森,审校