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Rev Bras Anestesiol ARTIGO DE REVISO

2003; 53: 1: 97 - 113 REVIEW ARTICLE

Uso de Dexmedetomidina em Anestesiologia *


Dexmedetomidine in Anesthesiology
Nivaldo Ribeiro Villela 1, Paulo do Nascimento Jnior, TSA 2
RESUMO SUMMARY
Villela NR, Nascimento Jr P - Uso de Dexmedetomidina em Villela NR, Nascimento Jr P - Dexmedetomidine in Anesthesio-
Anestesiologia logy

Justificativa e Objetivos - A dexmedetomidina um novo Background and Objectives - Dexmedetomidine is a new


agonista 2-adrenrgico que apresenta relao de seletividade 2-adrenergic agonist with a selectivity ratio of 1600:1 (a 2:a1). It
entre os receptores a 2:a1 de 1600:1, com importante ao h a s i m p o r ta n t s e d a t i v e a n d a n a l g e s i c e f f e c ts , g o o d
sedativa e analgsica, bom controle hemodinmico frente ao hemodynamic control at stress situations and may, by itself, in-
estresse e que pode produzir, por si s, anestesia. Este agente duce anesthesia. This drug has been used to promote postop-
tem sido empregado para promover analgesia e sedao no erative and intensive care sedation and analgesia. Due to such
perodo ps-operatrio e nas unidades de tratamento properties, dexmedetomidine has recently become a co
intensivo. Devido suas propriedades, recentemente, a adjuvant drug for anesthesia. So, this is a review of the litera-
dexmedetomidina passou a ser utilizada tambm na sala de ture about dexmedetomidine in anesthesia.
operaes, como frmaco coadjuvante em anestesia. Assim, Contents - Major studies on dexmedetomidine in Anesthesiol-
este artigo faz uma reviso da literatura com relao ao uso da ogy are presented, both as premedication and during anesthe-
dexmedetomidina na prtica anestsica. sia. Action mechanisms of a 2 -adrenergic agonists and
Contedo - So apresentados os principais trabalhos com o dexmedetomidine pharmacokinetic and pharmacodynamic
emprego da dexmedetomidina em Anestesiologia, seja como properties are also reviewed in this paper.
medicao pr-anestsica, ou durante o ato Conclusions - Dexmedetomidine premedication, infusion dur-
anestsico-cirrgico. O mecanismo de ao dos frmacos ing anesthesia or in the postoperative period improves
a2-agonistas e as propriedades farmacocinticas e hemodynamic stability. Anesthetic consumption is decreased
farmacodinmicas da dexmedetomidina tambm so revistos during anesthesia. Patients sedated with dexmedetomidine
neste artigo. may awake, when requested and become cooperative. Even
Concluses - O uso da dexmedetomidina como medicao high dexmedetomidine doses do not cause respiratory depres-
pr-anestsica, durante anestesia, ou no perodo sion. Bradycardia is a frequent side effect which may be mini-
ps-operatrio, promove boa estabilidade hemodinmica. H mized by slow drug infusion. So, dexmedetomidine is an
reduo do consumo de anestsicos durante a anestesia. Os important additional resource to anesthetic practice that may
pacientes sedados com a dexmedetomidina podem ser be used in different patients and surgical procedures.
despertados, quando solicitados, e tornarem-se cooperativos.
KEY WORDS: ANALGESICS: dexmedetomidine
Mesmo doses elevadas do frmaco no provocam depresso
respiratria. Bradicardia um efeito adverso observado com
freqncia, problema amenizado pela administrao lenta da INTRODUO
droga. Assim, a dexmedetomidina torna-se importante recurso

A
adicional para a prtica clnica da Anestesiologia, com dexmedetomidina, o enantimero dextrgiro da mede-
possibilidade de uso em diversos tipos de pacientes e tomidina, um agonista 2-adrenrgico superseletivo,
procedimentos cirrgicos.
apresentando relao de seletividade entre os receptores
UNITERMOS: ANALGSICOS: dexmedetomidina a2: a1 de 1600:1, com importante ao sedativa e analgsi-
ca, diminuindo em at 95% a concentrao alveolar mnima
(CAM) do halotano em estudos experimentais 1. O efeito se-
dativo, mesmo em doses elevadas, no acompanhado de
depresso respiratria e tambm permite que os pacientes
sejam facilmente despertados, permanecendo cooperati-
* Recebido do (Received from) Departamento de Anestesiologia da Fa- vos, tornando a dexmedetomidina muito til para promover
culdade de Medicina de Botucatu, UNESP
1. Ps-Graduando do Departamento de Anestesiologia da FMB - UNESP analgesia e sedao no perodo ps-operatrio e na unida-
2. Professor Assistente Doutor do Departamento de Anestesiologia da de de tratamento intensivo 2.
FMB - UNESP Os frmacos 2-agonistas foram sintetizados no incio da d-
Apresentado (Submitted) em18 de maro de 2002
cada de 60 e utilizados na prtica clnica inicialmente como
Aceito (Accepted) para publicao em 28 de maio de 2002 descongestionantes nasais e, posteriormente, como agen-
tes anti-hipertensivos 3. Com o surgimento dos inibidores da
Correspondncia para (Mail to): enzima conversora da angiotensina e dos antagonistas
Dr. Paulo do Nascimento Jnior
Departamento de Anestesiologia da FBM - UNESP -adrenrgicos mais seletivos, seu uso passou a ser menos
Distrito de Rubio Jnior difundido, sendo, ento, classificados como drogas de terce-
18618-970 Botucatu, SP ira linha para tratamento da hipertenso arterial 4. Estudos
E-mail: pnasc@fmb.unesp.br
subseqentes mostraram que esse grupo farmacolgico
Sociedade Brasileira de Anestesiologia, 2003 tambm apresentava atividade analgsica, sedativa, ansio-

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VILLELA E NASCIMENTO JR

ltica e simpatoltica, surgindo interesse no seu emprego em nilciclase, diminuindo a formao de AMPc, que regula vri-
Anestesiologia 5, pela possibilidade de reduzir o consumo de as funes celulares 17.
anestsicos e opiides, bem como pela profilaxia e trata- A dexmedetomidina liga-se tambm aos receptores imida-
mento da isquemia miocrdica no perodo per-operatrio 6,7. zolnicos. Estes receptores so classificados em I1, localiza-
Embora vrios estudos experimentais e clnicos mostrem dos no crebro e I2, localizados no crebro, rins e pncreas.
grandes benefcios no seu uso durante anestesia e tenha- Eles promovem hipotenso arterial de origem central e apre-
mos mais conhecimentos a respeito dos seus mecanismos sentam atividade antiarrtmica. provvel que algumas alte-
fundamentais de ao do que de outros vrios agentes anes- raes provocadas pelos frmacos a2-agonistas sejam me-
tsicos em uso 8, essas drogas permanecem ainda sendo diadas por esses receptores 17.
muito pouco utilizadas pelos anestesiologistas, talvez pela
pouca familiaridade com o frmaco, dificuldade de acesso FARMACOCINTICA E FARMACODINMICA
ao medicamento, ou mesmo, receio dos efeitos colaterais 4.
Com o desenvolvimento de agentes que apresentam maior A meia vida de distribuio da dexmedetomidina de 9 minu-
especificidade pelos receptores 2-adrenrgicos, como a tos e a de eliminao, 2,25 horas. A depurao 0,529
dexmedetomidina, com ao mais intensa sobre a viglia, l.h-1.kg-1 11,18. Cerca de 94% da dexmedetomidina liga-
bom controle hemodinmico frente ao estresse e que pro- vam-se a albumina e a 1-glicoprotena. metabolizada no
duz, por si s, anestesia 9, surge novo interesse na utilizao fgado e eliminada, aps metilao e glicoronidao, princi-
destes frmacos em Anestesiologia 9,10. palmente pelos rins 19.
Depois de vrios estudos experimentais e clnicos, o uso da Cunnigham e col. observaram aumento importante na meia
dexmedetomidina em humanos foi aprovado nos Estados vida de eliminao (7,5 horas) e diminuio na depurao
Unidos em 1999 11. Sua utilizao, neste pas, tem sido para da dexmedetomidina em pacientes com insuficincia hep-
promover analgesia e sedao em pacientes acamados em tica 20 .
unidades de cuidados intensivos. Contudo, a possibilidade Em estudo realizado por Dutta e col. 21, que avaliaram o dbi-
de obter-se maior estabilidade hemodinmica, em resposta to cardaco de voluntrios que receberam doses progressi-
a intubao traqueal e ao estresse cirrgico, reduo da ne- vas de dexmedetomidina, foi observada reduo na depura-
cessidade de anestsicos, sedao e analgesia 10, bem o da dexmedetomidina em at 20%, concomitante dimi-
como a disponibilidade de um antagonista especfico, o ati- nuio do dbito cardaco. Reduo s evidenciada quando
pamezol 12, tornam esta droga bastante promissora como co- se atingiram concentraes plasmticas da droga bem aci-
adjuvante da anestesia. ma das utilizadas clinicamente (cerca de 14 vezes).
Este artigo faz uma reviso da literatura com relao ao uso Wolf e col. 22 avaliaram a farmacocintica da dexmedetomi-
da dexmedetomidina na prtica anestsica. dina em 5 voluntrios com insuficincia renal grave (depura-
o de creatinina de 24 horas menor que 30 ml.min-1) que re-
MECANISMO DE AO ceberam infuso venosa de 0,6 g.kg -1, em 10 minutos. Hou-
ve diminuio da meia vida de eliminao da droga e os paci-
Os receptores a2-adrenrgicos so classificados em 2A, entes permaneceram sedados por um perodo maior que o
2B e 2C, conforme sua ao farmacolgica e em a2C10, grupo controle. Os autores justificaram o aumento no tempo
a2C2 e a2C4, conforme a localizao cromossmica dos ge- de sedao, embora tenha havido diminuio na meia vida
nes que os codificam e correspondem, respectivamente, aos de eliminao, pela menor ligao protica do medicamento
a2A, a2B e a2C 13. nestes pacientes.
Os receptores a2 pr-juncionais so principalmente os a2A, Ala-Kokko e col. 23 compararam a transferncia placentria
embora possam estar presentes tambm os a2C 14. Eles ini- da dexmedetomidina e da clonidina em modelo experimental
bem a liberao de noradrenalina nas terminaes nervosas de cotildones placentrios humanos perfundidos. Houve
simpticas e nos neurnios noradrenrgicos no sistema ner- maior reteno placentria da dexmedetomidina, diminuin-
voso central 15. Todos os trs subtipos de receptores podem do a exposio da droga do lado fetal. Esta alterao pode
ser identificados nas terminaes ps-sinpticas dos ms- ser explicada por ser a droga mais lipoflica que a clonidina
culos lisos dos vasos e promovem vasoconstrio, sendo ou, conforme a segunda possibilidade proposta pelo grupo,
que os a2C esto localizados principalmente nas veias 14. a dexmedetomidina ter maior afinidade pelos receptores imi-
So encontrados em grande nmero de tecidos, como fga- dazolnicos, j que a placenta os possui em abundncia.
do, pncreas, plaquetas, rins, tecido adiposo e olhos, promo- Kallio e col. 24 publicaram o primeiro trabalho sobre os efeitos
vendo diferentes funes fisiolgicas 15. da dexmedetomidina em seres humanos. Neste estudo, 5
O receptor a2-adrenrgico um receptor transmembrana e voluntrios receberam doses crescentes de dexmedetomi-
funcionalmente ligado protena G sensvel toxina pertus- dina em quatro momentos. As doses foram 12,5 g, 25 g, 50
sis 16. Sua ao pr-juncional ocorre principalmente por inibi- g e 75 g, por via venosa, injetadas em um intervalo de 30
o dos canais de clcio, ativao dos canais de potssio segundos. Observaram diminuio da presso arterial, sis-
pr-sinpticos e modulao direta de componentes do apa- tlica e diastlica, em at 18%. Houve discreto aumento da
rato de liberao vesicular de noradrenalina na terminao presso arterial, com posterior diminuio, aps a injeo da
nervosa. Uma vez estimulado, esse receptor bloqueia a ade- dose mais alta (75 g). Ocorreu diminuio da freqncia

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USO DE DEXMEDETOMIDINA EM ANESTESIOLOGIA

cardaca nas trs maiores doses, sendo a diminuio mais tral, presso da artria pulmonar ocluda, presso mdia da
acentuada nas duas maiores doses. A noradrenalina plas- artria pulmonar e da resistncia vascular pulmonar e sist-
mtica diminuiu em at 92%. O nvel srico do hormnio do mica. O grau de sedao aumentou concomitantemente
crescimento aumentou significativamente, em relao concentrao sangnea do frmaco, sendo que, ao se atin-
dose-dependente, enquanto o cortisol plasmtico diminuiu, gir a concentrao mais alta, os pacientes permaneceram
sem haver, contudo, relao entre o nvel srico e a dose de no responsveis, mesmo com estmulos vigorosos. Ressal-
dexmedetomidina empregada. ta-se o fato de que no ocorreu depresso respiratria du-
Khan e col. 18 estudaram a farmacocintica e a farmacodin- rante o experimento. Quatro horas aps o trmino da infu-
mica de duas doses de dexmedetomidina, em comparao so, todos os pacientes apresentavam grau de sedao se-
com placebo, em 9 voluntrios anestesiados com isoflurano. melhante ao momento controle. A partir de concentraes
As concentraes plasmticas da droga foram 0,3 ng.ml-1 e plasmticas acima de 1,25 ng.ml-1, houve comprometimento
0,6 ng.ml-1. A CAM do isoflurano para prevenir resposta mo- da memria recente. A pontuao da escala anloga visual
tora foi de 0,72% no grupo que recebeu 0,3 ng.ml-1 de dexme- para mensurao subjetiva da dor diminuiu em 14%, j no
detomidina, 0,52% no de 0,6 ng.ml-1 e 1,05% no grupo place- primeiro momento. O aumento da concentrao plasmtica
bo. Aps 0,36 horas, 1,62 horas e 2,22 horas do trmino da da dexmedetomidina promoveu diminuio linear na respos-
infuso da droga e do agente inalatrio, 50% dos indivduos ta a dor, sendo que os indivduos que receberam a dose mais
ainda apresentavam algum grau de sedao nos grupos pla- alta no responderem ao estmulo doloroso.
cebo, baixa dose e alta dose de dexmedetomidina, respecti- Talke e col. 27 estudaram os efeitos da dexmedetomidina so-
vamente. O grupo placebo apresentou recuperao das fun- bre o limiar de sudorese, vasoconstrio e tremores em 9 vo-
es cognitivas mais rpido, mas ao trmino de 3 horas da in- luntrios que receberam, atravs de infuso alvo controlada,
fuso, os grupos de baixa dose e placebo apresentaram concentraes sangneas da droga de 0,3 e 0,6 ng.ml-1, em
comprometimento cognitivo semelhante. Aps 4 horas, os comparao com placebo. Os indivduos foram aquecidos
trs grupos se igualaram. As mdias da freqncia cardaca at evidenciar sudorese e, depois, resfriados para promover
e da presso arterial sistlica e diastlica foram menores nos vasoconstrio e tremores. A dexmedetomidina no alterou
grupos que receberam a droga, mesmo antes de iniciar a o limiar de sudorese, mas modificou o de vasoconstrio e
anestesia com o isoflurano. Houve 12 episdios de hipoten- tremores de forma significativa, mostrando ser a droga ca-
so arterial que necessitaram de interveno medicamento- paz de produzir hipotermia nos pacientes expostos a tempe-
sa, sendo que nenhum no grupo placebo. No ocorreu dife- raturas baixas dentro da sala de cirurgia, bem como eficaz
rena nos parmetros respiratrios e a incidncia de nuse- em evitar os tremores ps-anestsicos.
as e vmitos foi semelhante entre os grupos. Dutta e col. 28 avaliaram a interao farmacodinmica entre o
Dyck e col. 25 estudaram as alteraes hemodinmicas e a propofol e a dexmedetomidina em indivduos sadios que re-
farmacocintica da dexmedetomidina em dez voluntrios, ceberam placebo ou dexmedetomidina, atravs de infuso
que receberam a dose de 2 g.kg-1, em infuso venosa e, alvo controlada, para manter a concentrao srica em 0,7
aps duas semanas, a mesma dose por via muscular. A dro- ng.ml-1. Foi realizada, ento, administrao de propofol em
ga apresentou perfil farmacolgico muito semelhante ao fen- concentraes plasmticas progressivas at que os indiv-
tanil, com grande distribuio tecidual e depurao hepti- duos estivessem sedados a ponto de no mais conseguir se-
ca. Quando utilizada a via muscular, apresentou biodisponi- gurar uma seringa, que houvesse perda do reflexo ciliar e au-
bilidade de 70% a 80% e o pico de concentrao plasmtica sncia de resposta motora a um estmulo eltrico. No grupo
ocorreu em cerca de 15 minutos. A infuso venosa em 5 mi- controle, a dose de propofol para perda de resposta motora
nutos promoveu alterao bifsica da presso arterial, com ao estmulo eltrico, perda do reflexo ciliar e incapacidade de
aumento inicial, acompanhada de bradicardia, provavel- segurar a seringa foi de 6,63, 1,98 e 1,14 g.ml-1, respectiva-
mente reflexa, e posterior diminuio da presso arterial. mente. Nos indivduos que receberam a dexmedetomidina,
Estas alteraes no foram observadas quando foi empre- as doses de propofol foram de 3,89 g.ml-1 para perda da res-
gada a via muscular. posta motora ao estmulo eltrico, 0,64 g.ml-1 para perda do
Ebert e col. 26 pesquisaram o comportamento hemodinmi- reflexo ciliar e 0,28 g.ml-1 para incapacidade de segurar a
co, o grau de sedao, a memria e a analgesia em dez indi- seringa.
vduos que receberam dexmedetomidina atravs de infuso Talke e col. 29 pesquisaram o efeito da dexmedetomidina, em
alvo controlada para manter sete concentraes plasmti- concentrao plasmtica de 0,68 a 1,24 ng.ml-1, sobre o blo-
cas diferentes (0,5, 0,8, 1,25, 2,0, 3,2, 5,0 e 8 ng.ml-1), de for- queio neuromuscular com rocurnio em voluntrios aneste-
ma progressiva. O nvel plasmtico de noradrenalina dimi- siados com propofol e alfentanil. Houve diminuio no valor
nuiu 66%, mesmo na concentrao sangnea mais baixa da de T1 (contrao muscular do 1 estmulo) de 51% para 44%,
droga. A adrenalina plasmtica diminuiu 60%. Houve redu- aumento na concentrao plasmtica de rocurnio durante a
o da presso arterial em 13% nas duas primeiras etapas do infuso da dexmedetomidina, aumento da presso arterial
experimento. Com o aumento da concentrao plasmtica sistlica e diminuio do fluxo sangneo perifrico. Os auto-
da droga, ocorreu aumento da presso arterial, em mdia res concluram que a vasoconstrio induzida pela dexme-
12%. Ao se atingir o nvel plasmtico da droga de cerca de 1,9 detomidina pode interferir com a farmacocintica do rocur-
ng.ml-1, houve aumento significativo da presso venosa cen- nio. Embora estas alteraes tenham sido estatisticamente

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VILLELA E NASCIMENTO JR

significativas, improvvel que tenham algum significado anestesia foi realizada com tiopental sdico, isoflurano,
clnico. N2O/O2 (70%/30%) e vecurnio. O pneumoperitnio foi man-
tido com presso de 10 a 12 mmHg. O grau de sedao aps
USO EM ANESTESIA 45 a 60 minutos da medicao pr-anestsica foi semelhan-
te entre os grupos que receberam dexmedetomidina e oxico-
Adexmedetomidina apresentada sob a forma de cloridrato, dona. As pacientes que receberam a maior dose de dexme-
em soluo lmpida, incolor e isotnica, com pH de 4,5 a 7. A detomidina permaneceram mais calmas, porm quando
soluo no contm conservantes, aditivos ou estabilizan- avaliada a fadiga, atravs do preenchimento de um questio-
tes qumicos. Pode ser empregada como medicao nrio antes e aps a medicao pr-anestsica, as pacien-
pr-anestsica ou associada anestesia. H relatos de seu tes que receberam a dose de 2,4 g.kg-1 apresentaram pon-
uso por via venosa 25,26, muscular 25 ou peridural 30. tuao maior. Houve diminuio da presso arterial mdia
Quando a via venosa utilizada, a dose inicial deve ser ad- (PAM) no grupo da dexmedetomidina, de forma dose-depen-
ministrada, de preferncia, em intervalo mnimo de 10 mi- dente, bem como controle significativo e dose-dependente
nutos 21 . A injeo rpida est associada com aumento ini- da PAM aps a intubao traqueal. Durante a laparoscopia,
cial da presso arterial, acompanhada, freqentemente, ocorreu aumento da PAM em todos os grupos, sendo este au-
por diminuio reflexa da freqncia cardaca, decorrente mento menor nos pacientes que receberam a dose de 2,4
da ativao perifrica dos receptores a 2 -agonistas 25 . g.kg-1 de dexmedetomidina. Este grupo tambm apresen-
tou menor aumento da freqncia cardaca aps a intubao
Medicao Pr-Anestsica traqueal e na sala de recuperao ps-anestsica (SRPA).
Oito das vinte pacientes deste grupo necessitaram de atropi-
O primeiro relato do uso da dexmedetomidina em anestesia na por apresentarem freqncia cardaca menor que 40
foi como medicao pr-anestsica em 20 mulheres que fo- bpm. A concentrao do cortisol plasmtico foi menor antes
ram submetidas curetagem uterina 31. As pacientes foram da induo, nos grupos de 2,4 g.kg-1 de dexmedetomidina e
divididas em quatro grupos e receberam 0,167, 0,33, 0,67 e 1 da oxicodona. A dexmedetomidina promoveu diminuio de
g.kg-1 de dexmedetomidina, por via venosa, 15 minutos an- 70% do nvel plasmtico da noradrenalina e minimizou o au-
tes da induo da anestesia. A anestesia foi realizada com ti- mento da adrenalina plasmtica aps a intubao traqueal.
opental sdico e N2O. Houve diminuio dose-dependente No houve diferena entre os grupos na necessidade de
da necessidade de tiopental sdico, tanto na induo quanto analgsicos no perodo ps-operatrio.
na manuteno da anestesia. A presso arterial sistlica di- Levanen e col. 33 compararam a dexmedetomidina (2,5
minuiu em todos os grupos aps a infuso da droga, porm g.kg-1) e o midazolam (0,07 mg.kg-1), por via muscular,
no apresentou correlao com a dose. A presso arterial di- como medicao pr-anestsica em pacientes anestesia-
astlica tambm diminuiu sem relao com a dose e, no gru- dos com cetamina, xido nitroso e vecurnio, para cirurgias
po que recebeu 1 g.kg-1, permaneceu abaixo dos valores eletivas superficiais (hrnia inguinal, varicocele ou hidroce-
iniciais por perodo mais prolongado. Ocorreu diminuio da le). O grupo da dexmedetomidina apresentou diminuio da
freqncia cardaca 10 minutos aps a administrao das freqncia cardaca antes da induo da anestesia. Aps a
duas maiores doses de dexmedetomidina e discreto aumen- intubao traqueal, a presso arterial sistlica aumentou em
to na freqncia cardaca das pacientes que receberam a 38 mmHg, enquanto no grupo do midazolam aumentou 47
menor dose. Aconcentrao plasmtica de noradrenalina di- mmHg. No houve diferena na presso arterial diastlica,
minuiu em um tero nos grupos que receberam 0,67 e 1 mas a freqncia cardaca apresentou aumento menor no
g.kg-1 e no se alterou no grupo de menor dose. No houve grupo da dexmedetomidina aps a laringoscopia e a intuba-
alterao do nvel plasmtico da adrenalina em nenhum gru- o traqueal. Durante a cirurgia, no grupo da dexmedetomi-
po. O cortisol plasmtico no apresentou alterao aps a in- dina, a freqncia cardaca, a presso arterial sistlica e a di-
fuso ou logo aps o procedimento cirrgico, porm aumen- astlica mantiveram-se prximas aos valores basais, en-
tou 30 minutos aps a cirurgia, em todos os grupos. A dexme- quanto no grupo do midazolam houve aumento em torno de
detomidina diminuiu, em relao direta com a dose, o tempo 15 mmHg e 10 bpm. Apenas 10% dos pacientes que recebe-
necessrio para recuperao da conscincia ao trmino da ram dexmedetomidina necessitaram de dose complementar
administrao de xido nitroso. Os principais efeitos colate- de cetamina e 70% dos pacientes que receberam midazolam
rais foram boca seca e sonolncia. Os autores concluram necessitaram de outras doses. Cinqenta e cinco por cento
que, provavelmente, a dose entre 0,33 e 0,67 g.kg-1 seja a dos pacientes que receberam dexmedetomidina e 5% dos
dose ideal quando a dexmedetomidina utilizada como me- que receberam midazolam necessitaram de atropina para
dicao pr-anestsica em cirurgias de pequeno porte. tratar bradicardia (freqncia cardaca menor que 45 bpm).
Aho e col. 32 avaliaram trs doses de dexmedetomidina (0,6, Dois pacientes que receberam o agonista a2-adrenrgico
1,2 e 2,4 g.kg-1), por via muscular, comparando-as com dois apresentaram hipotenso arterial, que foi revertida apenas
grupos que receberam oxicodona (0,13 mg.kg-1) ou placebo. com reposio hdrica. Seis horas aps o procedimento, ain-
Cada grupo foi constitudo por 20 mulheres que seriam sub- da havia diferena significativa nos parmetros hemodin-
metidas cirurgia laparoscpica ginecolgica. A injeo foi micos entre os dois grupos. No houve diferena no tempo
realizada 45 a 60 minutos antes da induo da anestesia. A de despertar entre os dois grupos. O grupo da dexmedetomi-

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USO DE DEXMEDETOMIDINA EM ANESTESIOLOGIA

dina apresentou melhor desempenho psicomotor antes da durante a inciso da pele. Os pacientes foram divididos em 3
induo da anestesia, pois embora estivessem sedados, grupos, sendo um grupo controle (placebo) e os outros dois
respondiam adequadamente ao serem estimulados, voltan- receberam infuso de dexmedetomidina para manter a con-
do a dormir quando deixados tranqilos. Este grupo perma- centrao plasmtica em 0,3 ng.ml-1 e 0,6 ng.ml-1. A CAM do
neceu mais sedado na SRPA. Alteraes do sistema nervo- sevoflurano foi mantida no grupo controle em 2% e em 1,5% e
so central, decorrentes da ao da cetamina, foram mais fre- 1% nos grupos de maior e menor dose de dexmedetomidina,
qentes no grupo do midazolam (55%) que no da dexmede- respectivamente. Aps a manuteno por 15 minutos des-
tomidina (5%), sendo o sintoma mais comum sonhos desa- sas concentraes, foi feita a inciso na pele do paciente e,
gradveis. Amnsia antergrada foi mais freqente com o conforme houvesse reao ou no do paciente, haveria au-
midazolam. No houve diferena entre os dois grupos no mento ou diminuio na concentrao expirada do agente
consumo de analgsicos na SRPA. inalatrio em 0,25% no prximo sujeito. Houve diminuio
Aantaa e col. 34 avaliaram 49 mulheres que foram submeti- de 17% na CAM do sevoflurano no grupo com concentrao
das histerectomia abdominal sob anestesia geral, distribu- plasmtica da dexmedetomidina de 0,6 ng.ml-1. No houve
indo-as em trs grupos para receber placebo ou infuso de diferena significativa na CAM do sevoflurano no grupo con-
dexmedetomidina, suficiente para manter concentraes trole e no grupo com a dose menor de dexmedetomidina.
plasmticas em 0,3 ng.ml-1 ou 0,6 ng.ml-1. A infuso foi inicia- Em pacientes submetidos cirurgia plstica sob anestesia
da 15 minutos antes da induo e interrompida aps a inci- geral, as alteraes hemodinmicas e o consumo de oxig-
so da pele. A anestesia foi realizada com tiopental sdico e nio (VO2) per-operatrio foram estudados conforme o uso,
alfentanil. Aps a intubao traqueal, foi administrado isoflu- como medicao pr-anestsica, de clonidina (4 g.kg-1),
rano com concentrao de 1 CAM para o grupo controle, 0,6 dexmedetomidina (2,5 g.kg-1) ou placebo, por via muscular 37.
CAM no grupo com 0,3 ng.ml-1 e 0,3 CAM no grupo com 0,6 Observou-se diminuio no VO2 em 8% no momento da indu-
ng.ml-1 e, aps 15 minutos, foi avaliada a resposta motora do o anestsica, nos dois grupos que receberam os a2-ago-
paciente inciso da pele. Caso houvesse ou no reao nistas, e 17% aps a cirurgia. Durante o procedimento cirr-
das pacientes, a CAM do isoflurano era ajustada em 0,1%, gico, no houve diferena significativa entre os trs grupos,
para mais ou para menos, na prxima paciente. A CAM do provavelmente pelo fato da VO2 ter sido influenciada pela
isoflurano foi 47% e 35% menor nos grupos de 0,6 ng.ml-1 e tcnica anestesia. Tanto a clonidina quanto a dexmedetomi-
0,3 ng.ml-1 de dexmedetomidina, respectivamente. Ocorreu dina promoveram diminuio da presso arterial e da fre-
diminuio da necessidade de tiopental em 17% e 30% nos qncia cardaca de magnitude semelhante, porm, uma pa-
grupos de baixa e alta dose de dexmedetomidina, quando ciente que recebeu dexmedetomidina apresentou parada si-
comparados com o controle. nusal durante a laringoscopia.
Lawrence e De Lange 35, em comparao com placebo, ava- A eletroconvulsoterapia (ECT) um, tipo de tratamento utili-
liaram os efeitos da dexmedetomidina, na dose venosa nica zado para desordens depressivas graves e est freqente-
de 2 g.kg-1, como medicao pr-anestsica, em pacientes mente associada com respostas hemodinmicas agudas
submetidos a pequenas cirurgias ortopdicas e gerais. Os (hipertenso arterial e taquicardia) 38. Fu e White 39 avalia-
pacientes foram anestesiados com tiopental, N2O/O2, fenta- ram o benefcio da utilizao da dexmedetomidina como me-
nil e isoflurano, conforme a necessidade. Apenas 24% dos dicao pr-anestsica nestes procedimentos. Foram estu-
pacientes que receberam dexmedetomidina necessitaram dados 24 tratamentos com ECT em seis pacientes idosos, di-
de complementao com o agente inalatrio, enquanto que vididos em 3 grupos, sendo um grupo controle (placebo) e os
no grupo controle foram 72%. A concentrao mdia neces- outros dois com doses de 0,5 e 1 g.kg-1 de dexmedetomidi-
sria do isoflurano foi expressivamente diminuda com a na por infuso venosa, 10 a 30 minutos antes da realizao
dexmedetomidina. A laringoscopia e a intubao traqueal dos procedimentos. A anestesia consistiu em 0,1 a 0,2 mg de
no alteraram a presso arterial sistlica no grupo tratado, glicopirrolato, 10 mg de labetalol, 1 mg.kg-1 de metohexital e
que aumentou em 31 mmHg no grupo controle. A presso ar- 1,3 a 1,5 mg.kg-1 de succinilcolina. Os autores no encontra-
terial diastlica aumentou em 1 mmHg e 26 mmHg e a fre- ram diferena nas variveis hemodinmicas entre os grupos
qncia cardaca em 13 bpm e 29 bpm nos grupos da dexme- tratados e o controle, antes ou aps a ECT. Houve discreto
detomidina e controle, respectivamente. Com a dexmedeto- aumento no tempo de atividade convulsiva, motora e eletro-
midina, houve diminuio de 70% da noradrenalina e adre- encefalogrfica, nos pacientes tratados com dexmedetomi-
nalina plasmticas. Os pacientes estudados necessitaram dina. Estes pacientes tambm apresentaram maior nvel de
de menos analgsicos e antiemticos que os do grupo con- sedao e permaneceram por tempo mais prolongado na
trole. Na SRPA, ocorreu bradicardia (freqncia cardaca SRPA.
menor que 45 bpm) em 56% dos pacientes que receberam Peden e col. 40 avaliaram o efeito da dexmedetomidina sobre
dexmedetomidina contra nenhum do grupo controle. Um pa- a concentrao plasmtica necessria de propofol para su-
ciente que recebeu dexmedetomidina desenvolveu freqn- primir a conscincia e a resposta motora durante anestesia
cia cardaca menor que 33 bpm e hipotenso arterial sistlica com propofol e alfentanil, em pacientes submetidos a cirurgi-
(71 mmHg) 2 horas aps sua chegada na SRPA. as gerais superficiais. Nesse estudo houve necessidade de
Fragen e Fitzgerald 36 estudaram o efeito de duas doses de reduo das doses de dexmedetomidina por duas vezes, por
dexmedetomidina sobre a CAM do sevoflurano em adultos, razo do surgimento de efeitos adversos (bradicardia sinu-

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VILLELA E NASCIMENTO JR

sal e parada sinusal). Os pacientes receberam dose inicial dose inicial. Os pacientes que receberam as maiores doses
de 0,45 g.kg-1, em 15 minutos seguidos de infuso de 0,18 apresentaram aumento da PAM acima de 30% dos valores
g.kg-1.h-1, at que se realizasse a inciso da pele. Esses iniciais. Houve reduo dose-dependente da freqncia car-
pesquisadores encontraram diminuio de 40% na dose to- daca, sendo que a menor freqncia cardaca ocorreu cerca
tal de propofol necessria para produzir perda da conscin- de 8 minutos aps o incio da infuso. Houve reduo no con-
cia, em comparao com os resultados de outros autores sumo do agente inalatrio em todas as pacientes. A segunda
que, em modelo semelhante, avaliaram a perda da conscin- etapa do estudo envolveu comparao da dose de dexmede-
cia de indivduos com o uso de doses progressivas de propo- tomidina de 170 ng.kg - 1 .min - 1 (dose inicial) + 8,5
fol. ng.kg-1.min-1 (dose de manuteno) com placebo, seguin-
Na tabela I esto resumidos os dados dos artigos sobre o uso do-se o mesmo esquema de anestesia realizado na primeira
da dexmedetomidina como medicao pr-anestsica. etapa. No houve necessidade de complementao com
isoflurano no grupo da dexmedetomidina em 50% dos pacien-
Uso Durante Anestesia tes. Houve diminuio de mais de 90% na CAM do isoflurano
no grupo tratado e nenhum paciente relatou lembranas du-
Aho e col. 41 relataram o uso de dexmedetomidina para ma- rante a anestesia. No houve alterao significativa na PAM
nuteno da anestesia em pacientes submetidas histerec- aps a intubao traqueal, durante a cirurgia ou uma hora
tomia abdominal. Inicialmente, em anlise aberta, foram uti- aps o trmino do procedimento. A freqncia cardaca dimi-
lizados quatro regimes de infuso de dexmedetomidina, com nuiu significantemente aps a infuso inicial, aps a larin-
incio da administrao 10 minutos antes da induo da goscopia e uma hora aps a cirurgia no grupo tratado, sendo
anestesia e doses variando entre 120 ng.kg-1.min-1 (dose ini- que 40% das pacientes apresentaram freqncia cardaca
cial) + 6 ng.kg -1 .min -1 (dose de manuteno) e 270 menor que 40 bpm, necessitando de tratamento com atropi-
ng.kg-1.min-1 + 13,5 ng.kg-1.min-1. A anestesia foi realizada na. No houve diferena no tempo de despertar entre os gru-
com fentanil, tiopental, N2O/O2 (70%/30%) e isoflurano, con- pos.
forme a necessidade, para manter a PAM entre -30% a +15% Talke e col. 42, em comparao com placebo, estudaram trs
e a freqncia cardaca entre -40% a +20% dos valores ba- doses de dexmedetomidina, em concentrao plasmtica
sais. Houve aumento dose-dependente da PAM, aps a de 0,15 ng.ml-1, 0,30 ng.ml-1 e 0,45 ng.ml-1, iniciadas uma

Tabela I - Uso da Dexmedetomidina como Medicao Pr-Anestsica. Dose, Via de Administrao, Procedimento Cirrgico
e Principais Efeitos
Via de administr ao e
Autor e ano de publicao Dose de dexmedetomidina Principais efeitos
procedimento cirrgico
Aantaa e col., 1990 31 0,167; 0,33; 0,67 e 1 g.kg-1 IV, curetagem uterina dose-dependente da necessidade
de tiopental; da PA e FC
Aho e col., 1992 32 0,6; 1,2 e 2,4 g.kg-1 IM, cirurgias laparoscpica do aumento da PA e FC aps IOT;
ginecolgica de 70% da noradrenalina plasmtica
Levanen e col., 1995 33 2,5 g.kg-1 IM, cirurgias eletivas superficiais Estabilidade hemodinmica aps IOT;
bradicardia (55% dos pacientes);
incidncia de alteraes do SNC
Aantaa e col., 1997 34 CPA de 0,3 e 0,6 ng.ml-1 IV, histerectomia abdominal da CAM do isoflurano em at 47%;
da necessidade de tiopental em at
30%
Lawrence e col., 1997 35 2 g.kg-1 IV, cirurgias ortopdicas e gerais Estabilidade hemodinmica aps IOT;
necessidade de isoflurano; em
70% da noradrenalina e adrenalina
plasmticas; necessidade de
analgsicos e antie m ti co s;
bradicardia freqente
Fragen e col., 1999 36 CPA de 0,3 e 0,6 ng.ml-1 IV, cirurgia geral em 17% da CAM do sevoflurano

Taittonen e col., 1997 37 2,5 g.kg-1 IM, cirurgias plsticas 8% VO2 antes da cirurgia; 17%
VO2 no ps-operatrio; um caso de
parada sinusal
Sem pr oteo da r e sp o sta
Fu e col., 1999 39 0,5 e 1 g.kg-1 IV, eletroconvulsoterapia
hemodinmica; tempo da atividade
convulsiva
Peden e col., 2001 40 0,45 g.kg-1 + 0,18 g.kg-1.h-1 IV, cirurgias gerais superficiais 40% na dose total de propofol;
bradicardia e parada sinusal
CPA = concentrao plasmtica alvo, = aumento, = reduo, PA = presso arterial, FC = freqncia cardaca, CAM = concentrao alveolar mnima,
IM = intramuscular, IV = intravenoso, VO2 = consumo de oxignio, IOT= intubao orotraqueal

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USO DE DEXMEDETOMIDINA EM ANESTESIOLOGIA

hora antes da induo da anestesia e mantidas at 48 horas ceberam dexmedetomidina relataram estar mais satisfeitos
no perodo ps-operatrio, de pacientes submetidos a gran- com o alvio da dor na primeira hora e meia em que permane-
des cirurgias vasculares. A anestesia foi realizada com al- ceram na SRPA. A incidncia de tremores, nuseas e vmi-
fentanil, tiopental, vecurnio, N2O/O2 (70%/30%) e isoflura- tos foi menor no grupo tratado. No houve diferena no tem-
no, conforme a necessidade para manter os parmetros he- po de extubao ou de despertar entre os grupos, porm os
modinmicos dentro de limites previamente determinados. pacientes que receberam dexmedetomidina permaneceram
Houve diminuio na freqncia cardaca (menor dose, mais confortveis na SRPA, segundo a avaliao da equipe
11%; dose intermediria, 5%; e maior dose, 20%) e da pres- de enfermagem.
so arterial sistlica (menor dose, 3%; dose intermediria, Talke e col. 45 avaliaram a possibilidade da dexmedetomidina
12%; e maior dose, 20%) nos pacientes que receberam dex- atenuar a resposta hemodinmica, durante a emergncia da
medetomidina, sendo que estes pacientes necessitaram anestesia, em pacientes submetidos cirurgia vascular. Os
uso de drogas vasoativas com mais freqncia no per-ope- autores compararam 19 pacientes que receberam placebo
ratrio para manter estabilidade hemodinmica. Quarenta e com 22 pacientes que receberam dexmedetomidina, no se-
quatro por cento dos pacientes tratados necessitaram de an- guinte esquema de infuso, com incio 20 minutos antes da
ticolinrgico para tratar a bradicardia durante a cirurgia, con- induo da anestesia: 1,2 g.min-1 nos primeiros 20 minutos;
tra nenhum do grupo controle. No perodo ps-operatrio, os 0,8 g.min-1, do 20 ao 60 minuto; 0,35 g.min-1, do 60 ao
grupos tratados apresentaram menor incidncia de taquicar- 300 minuto e 0,15 g.min-1 do 300 minuto at 48 horas aps
dia, tendo sido necessrio o uso de esmolol no grupo contro- a cirurgia. A anestesia foi realizada com fentanil, tiopental,
le e no de menor dose de dexmedetomidina. vecurnio, N2O/O2 (50%) e isoflurano. Durante a emergn-
Jalonen e col. 43 estudaram o uso de dexmedetomidina, em cia da anestesia, a freqncia cardaca e a presso arterial
comparao com placebo, em pacientes selecionados para sistlica elevaram-se a valores acima dos basais no grupo
cirurgia de revascularizao do miocrdio. A dose inicial de controle, porm no apresentaram alteraes no grupo tra-
dexmedetomidina foi de 50 ng.kg-1.min-1 por 30 minutos, an- tado. Aps a extubao traqueal e 60 minutos depois de es-
tes da induo da anestesia, e 7 ng.kg-1.min-1, at o final da tar na SRPA, a concentrao plasmtica de noradrenalina
cirurgia. Os pacientes receberam escopolamina e morfina era 2 a 3 vezes menor no grupo que recebeu dexmedetomidi-
como medicao pr-anestsica e a anestesia foi realizada na. O nvel plasmtico de adrenalina permaneceu menor
com fentanil e enflurano. Trinta e oito por cento dos pacientes apenas aps a extubao. Dois pacientes apresentaram efe-
tratados e 82% dos pacientes do grupo controle apresenta- itos adversos, que foram relacionados com a dexmedetomi-
ram rigidez muscular aps a infuso de fentanil. Durante a in- dina: hipotenso arterial no perodo ps-operatrio e parada
duo da anestesia, a presso arterial sistlica e a freqn- sinusal (10 segundos), durante a laringoscopia.
cia cardaca permaneceram maior no grupo controle e aps Bekker e col. 46 relataram o uso de dexmedetomidina, na
a intubao traqueal aumentaram expressivamente apenas dose de 1 g.kg-1.h-1, durante 30 minutos, seguida da dose
no grupo controle. Aps a inciso da pele, a presso arterial de 0,4 g.kg-1.h-1, associada com N2O e sevoflurano, para re-
sistlica, diastlica e a freqncia cardaca permaneceram alizao de craniotomia e mapeamento da rea cortical da
mais elevadas no grupo controle. Durante os primeiros 60 fala, em um paciente de 38 anos. O mapeamento da rea cor-
minutos da circulao extracorprea (CEC) a PAM foi menor tical foi realizado aps interrupo da administrao do se-
no grupo tratado. Aps a CEC, a presso arterial sistlica voflurano, mantendo-se o paciente sedado apenas com a in-
permaneceu menor no grupo da dexmedetomidina, no ha- fuso de dexmedetomidina, na dose de 0,1 g.kg-1.h-1. O
vendo diferena entre os grupos na freqncia cardaca. A procedimento foi realizado com sucesso, tendo o paciente
dose total de fentanil e a concentrao expirada de enflurano permanecido calmo e sonolento, sendo facilmente acordado
foram maiores no grupo controle. Os pacientes tratados ne- e cooperativo quando solicitado. Aps o mapeamento, a res-
cessitaram de maior volume de lquidos para tratamento de seco do tumor cerebral foi realizada, novamente sob anes-
hipotenso arterial durante a cirurgia e, tambm, mais vaso- tesia com sevoflurano, sem complicaes. O paciente lem-
pressores durante a CEC. Os pacientes do grupo placebo brou-se do perodo em que estava apenas sedado com dex-
necessitaram de esmolol para tratamento de taquicardia du- medetomidina, porm no foi capaz de se lembrar de ne-
rante a cirurgia e metoprolol no perodo ps-operatrio. No nhum detalhe.
houve diferena significativa na incidncia de isquemia do O uso da dexmedetomidina por via peridural foi descrito por
miocrdio entre os grupos. Tremores ps-operatrios ocor- Fukushima e col. 27, que estudaram 15 pacientes submetidas
reram em 32,5% dos pacientes que receberam a dexmedeto- a histerectomia abdominal sob anestesia geral, com o objeti-
midina e em 57,5% dos pacientes do grupo controle. Houve vo de avaliar a analgesia ps-operatria. Foram analisados
maior diurese no grupo tratado. 4 grupos, com administrao peridural de: soluo fisiolgi-
Badner e col. 44 avaliaram 249 pacientes submetidos artro- ca; lidocana a 1,5%; 2 g.kg-1 de dexmedetomidina e lidoca-
plastia total de joelho, dividindo-os em dois grupos: placebo na a 1,5% com 2 g.kg-1 de dexmedetomidina. A dexmedeto-
e dexmedetomidina, na concentrao plasmtica de 0,6 midina diminuiu a freqncia cardaca em 25% e a presso
ng.ml-1, iniciada 15 minutos antes da induo da anestesia e arterial em 20%, que coincidiu com a diminuio em 35% da
mantida at 2 horas aps a cirurgia. Foi realizada anestesia noradrenalina e da adrenalina plasmticas. A durao da
geral com infuso contnua de fentanil. Os pacientes que re- analgesia nas pacientes que receberam dexmedetomidina

Revista Brasileira de Anestesiologia 103


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VILLELA E NASCIMENTO JR

se estendeu por mais de 7 horas, comparada com apenas 3 raes hemodinmicas decorrentes da administrao da
horas no grupo que recebeu apenas lidocana. dexmedetomidina.
Na tabela II esto resumidos os dados dos artigos sobre o Scheinin e col. 50 estudaram a dose de atipamezol necess-
uso da dexmedetomidina durante a anestesia. ria para reverter a sedao obtida com a administrao de
2,5 g.kg-1 de dexmedetomidina, por via muscular, em volun-
ANTAGONISMO DA DEXMEDETOMIDINA trios sadios. A infuso do antagonista 2-adrenrgico foi ini-
ciada uma hora aps a dexmedetomidina. A menor e a maior
Assim como os frmacos agonistas a2-adrenrgicos, os an- dose de atipamezol necessrias para reverter os efeitos de-
tagonistas a2-adrenrgicos tm sido utilizados na prtica ve- terminados pela dexmedetomidina foram 50 e 163 g.kg-1.
terinria h bastante tempo. Em animais, os mais utilizados Em uma segunda fase, os autores avaliaram trs doses de
so a ioimbina, tolazolina, idazoxan e atipamezol 47. Eles atipamezol (15 g.kg-1, 50 g.kg-1 e 150 g.kg-1), compara-
apresentam, entre si, diferena na especificidade e seletivi- das com placebo, administradas 1 hora aps terem sido inje-
dade com os receptores a2-adrenrgicos e variam quanto tados 2,5 g.kg-1 de dexmedetomidina por via muscular, em
capacidade de ligar-se aos receptores imidazolnicos. 8 voluntrios sadios. A sedao foi revertida completamente
O atipamezol um potente e seletivo antagonista dos recep- com as duas maiores doses, contudo com a dose de 15
tores a2-adrenrgicos, desprovido de atividade importante g.kg-1 no houve diferena com relao ao placebo. A redu-
sobre os receptores imidazolnicos. Apresenta relao de o da presso arterial, observada aps o uso da dexmede-
seletividade entre os receptores a2:a1 de 8.500:1 48. tomidina, foi revertida pelo atipamezol de forma dose-de-
Karhuvaara e col. 49 avaliaram os efeitos de trs diferentes pendente. Adose de 150 g.kg-1 aumentou os nveis de nora-
doses de atipamezol (6,7 g.kg-1, 27 g.kg-1 e 67 g.kg-1) em drenalina plasmtica acima dos valores basais. Os autores
voluntrios que receberam dexmedetomidina na dose de concluram que, provavelmente, a dose mais adequada de
0,67 g.kg-1. A dexmedetomidina promoveu, em todos os pa- atipamezol para reverter os efeitos da dexmedetomidina
cientes, sedao, diminuio na presso arterial sistlica e deve manter uma relao com a dose desta entre 20:1 e 60:1.
diastlica e reduo de 80% da noradrenalina plasmtica. Aho e col. 51 estudaram os efeitos do atipamezol (50 g.kg-1)
Apenas as doses de 27 g.kg-1 e 67 g.kg-1 de atipamezol fo- aps a administrao de dexmedetomidina (2 g.kg-1) ou mi-
ram efetivas em reverter completamente a sedao e as alte- dazolam (0,15 mg.kg-1), em pacientes submetidas cureta-

Tabela II - Uso da Dexmedetomidina Durante a Anestesia. Dose, Via de Administrao, Procedimento Cirrgico e Principais
Efeitos
Autor e ano de publicao Dose de dexmedetomidina Via de administrao e procedimento Principais efeitos
cirrgico
Aho e col., 1992 41 170 ng.kg-1.min-1 (dose inicial) + IV, histerectomia abdominal CAM do isoflurano em 90%
8,5 ng.kg-1.min-1 (manuteno)

IV, grandes cirurgias vasculares da PA e da FC em 20%;


Talke e col., 1995 42 CPA de 0,15; 0,3 e 0,45 ng.ml-1
necessidade de drogas
vasoativas; br a d i ca r d i a
freqente; da incidncia de
taquicardia
IV, revascularizao do miocrdio Menor incidncia de rigidez ps
Jalonen e col., 1995 43 50 ng.kg-1.min-1 (dose inicial) +
fentanil; necessidade de drogas
7 ng.kg-1.min-1 (manuteno) 1
vasoativas, incidncia de
tremores ps-operatrios;
Badner e col., 1999 44 CPA de 0,6 ng.ml-1 IV, artroplastia de joelho da incidncia de tremores e
vmitos ps-operatrios;
conforto ps-operatrio
1,2 g.min-1 e reduo progressiva at IV, cirurgias vasculares Estabilidade hemodinmica du-
Talke e col., 2000 45
0,15 g.min-1 at 48 horas aps cirurgia rante o despertar da anestesia;
em 2 a 3 vezes da noradrenalina
plasmtica aps extubao; 1
caso de hipotens o n o
ps-operatrio e 1 caso de
par ada sinusal dur a n te a
laringoscopia
1 g.kg-1.min-1 (dose inicial) + IV, craniotomia e mapeamento Mapeamento da rea cortical
Bekker e col., 2001 46
0,4 g.kg-1.h-1 da rea cortical realizado com o paciente sedado
apenas com dexmedetomidina
Fukushima e col., 1997 30 2 g.kg-1 Peridural, histerectomia abdominal A nalgesia ps- op e r a t r i a
prolongada
CPA = concentrao plasmtica alvo, = aumento, = reduo, PA = presso arterial, FC = freqncia cardaca, CAM = concentrao alveolar mnima,
IV = venoso

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gem uterina. O atipamezol reverteu completamente a seda- and clinical studies have shown major benefits of their use
o obtida com a dexmedetomidina, mas no apresentou during anesthesia and more knowledge has been acquired
efeito sobre o midazolam. about their fundamental action mechanisms than about sev-
eral popular anesthetic agents 8, but these drugs are still sel-
CONCLUSO dom used by anesthesiologists, maybe due to lack of famil-
iarity with the drug, difficult access to the medication or even
A dexmedetomidina um potente frmaco agonista a2-adre- fear of side-effects 4.
nrgico, que pode ser empregado como coadjuvante em With the development of agents with more a2-adrenergic re-
Anestesiologia. Possui importante ao analgsica, sedati- ceptors specificity, such as dexmedetomidine, with a deeper
va, ansioltica e simpatoltica. Seu uso como medicao action over sleep, good hemodynamic control in stress situa-
pr-anestsica, durante a anestesia, ou no perodo ps-ope- tions and which, alone, produce anesthesia 9, there is a re-
ratrio, promove boa estabilidade hemodinmica. H redu- newed interest in the use of such drugs in Anesthesiology 9,10.
o do consumo de anestsicos durante a anestesia. Os pa- After several experimental and clinical trials, the use of
cientes sedados com a dexmedetomidina podem ser des- dexmedetomidine in humans was approved in the USA in
pertados, quando solicitados, e tornarem-se cooperativos. 1999 11 and has been used since then to promote analgesia
Mesmo doses elevadas do frmaco no provocam depres- and sedation in intensive care unit patients. However, the
so respiratria. Bradicardia um efeito adverso observado possibility of obtaining more hemodynamic stability in re-
com freqncia, sendo este problema amenizado pela admi- sponse to tracheal intubation and surgical stress, of decreas-
nistrao lenta da droga. Assim, esse novo frmaco a2-ago- ing anesthetics, sedatives and analgesics consumption 10,
nista, a dexmedetomidina, torna-se importante recurso adi- as well as the availability of a specific antagonist,
cional para a prtica clnica da Anestesiologia, com possibili- atipamezole 12, make this drug very promising as an anes-
dade de uso em diversos tipos de pacientes e procedimentos thetic coadjuvant.
cirrgicos. This paper is a review of the literature on the use of
dexmedetomidine in Anesthesiology.

ACTION MECHANISM
Dexmedetomidine in Anesthesiology
Alpha2-adrenergic receptors are classified in a2A, a2B and
Nivaldo Ribeiro Villela, M.D., Paulo do Nascimento Jnior, a 2 C, according to their pharmacological action, and in
TSA, M.D. a2C10, a2C2 and a2C4, according to the chromosomal loca-
tion of codifying genes and correspond, respectively, to a2A,
a2B and a2C 13.
INTRODUCTION Pre-junctional a 2 receptors are mainly a 2 A although being
also present in a 2 C 14 . They inhibit norepinephrine release
Dexmedetomidine, the dextrogyrous medetomidine enan- in sympathetic terminations and central nervous system
tiomer, is a super-selective a2-adrenergic with a 1600:1 se- noradrenergic neurons 15 . All three receptor subtypes may
lectivity (a2:a1). It has important sedative and analgesic ef- be identified in smooth muscle post-synaptic terminations
fects, decreasing halothane minimum alveolar concentra- of vessels and promote vasoconstriction, being a 2 C lo-
tion (MAC) in up to 95%, according to experimental studies 1. cated primarily in the veins 14 . They are found in a great
Even in high doses, sedative effects are not followed by respi- number of tissues, such as liver, pancreas, platelets, kid-
ratory depression and allow patients to be easily awakened neys, fatty tissue and eyes and promote different physio-
and cooperative, what makes dexmedetomidine very useful logic functions 15 .
for postoperative and intensive care sedation and analgesia Alpha2-adrenergic receptors are transmembrane receptors
2
. Alpha2- agonists were synthesized in the early 60s and functionally bound to G protein sensitive to the pertussis
were initially used as nasal decongestives and then as toxin 16. Their pre-junctional activity is primarily triggered by
anti-hypertensive agents 3. With the introduction of angioten- the inhibition of calcium channels, activation of pre-synaptic
sin converting enzyme inhibitors and of more selective potassium channels and direct modulation of components of
b-adrenergic antagonists they became less popular and norepinephrine vesical release apparatus in nervous termi-
were classified as third class drugs for treating arterial hyper- nations. Once stimulated, these receptors block
tension 4. Subsequent studies have shown that this pharma- adenyl-ciclase, decreasing the formation of cAMP, which
cological group also presented analgesic, sedative, anxiolyt- regulates several cell functions 17.
ic and sympatholytic activity, thus raising the interest in their Dexmedetomidine is also bound to imidazoline receptors.
use in Anesthesiology 5 to decrease anesthetic and opioid These are classified in I1, located in the brain, and I2, located
consumption, as well as for perioperative myocardial in brain, kidneys and pancreas. They promote central
ischemia prevention and treatment 6,7. Several experimental hypotension and present anti-arrhythmic activity. It is possi-

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VILLELA AND NASCIMENTO JR

ble that some a2-agonist-induced changes are mediated by 0.6 ng.ml-1. Isoflurane MAC to prevent motor response was
such receptors 17. 0.72% in the group receiving 0.3 ng.ml-1, 0.52% in the group
receiving 0.6 ng.ml-1 and 1.05% in the placebo group. At 0.36
PHARMACOKINETIVS AND PHARMACODYNAMICS hours, 1.62 hours and 2.22 hours after drug and inhalational
agent infusion completion, 50% of individuals still presented
Dexmedetomidine distribution half-life is 9 minutes and elim- some degree of sedation in the placebo, low and high
ination half-life is 2.25 hours. Clearance is 0.529 dexmedetomidine dose groups, respectively. The placebo
l.h-1.kg-1 11,18. Approximately 94% of dexmedetomidine are group had a faster cognitive function recovery, but 3 hours af-
bound to albumin and a1-glycoprotein. It is metabolized in the ter infusion, placebo and low dose groups had similar cogni-
liver and excreted primarily by the kidneys, after methylation tive involvement. After 4 hours all groups were similar. Heart
and glycoronidation 19. rate, systolic and diastolic blood pressure means were lower
Cunningham et al. have observed a major elimination in the groups receiving the drug even before anesthesia in-
half-life increase (7.5 hours) and decrease in duction with isoflurane. There were 12 arterial hypotension
dexmedetomidine clearance in renal failure patients 20. episodes needing drug intervention, but none of them in the
Dutta et al 21, in a study evaluating cardiac output of volun- placebo group. There were no differences in respiratory pa-
teers receiving progressive dexmedetomidine doses, have rameters and the incidence of nausea and vomiting was simi-
observed a decrease in dexmedetomidine clearance of up to lar for all groups.
20%, together with cardiac output decrease, which was only Dyck et al. 25 have studied dexmedetomidine hemodynamic
observed when drug plasma concentrations were well above and pharmacokinetic changes in 10 volunteers receiving in-
clinical doses (approximately 14-fold). travenous 2 g.kg-1 and, after two weeks, the same dose by
Wo l f e t a l . 2 2 h a v e e v a l u a t e d d e x m e d e t o m i d i n e s the muscular route. Drug was pharmacologically very similar
pharmacokinetics in 5 severe renal failure volunteers to fentanyl, with major tissue distribution and liver clearance.
(24-hour creatinine clearance less than 30 ml.min-1) who re- The intramuscular route presented 70% to 80%
ceived 0.6 g.kg-1 intravenous infusion in 10 minutes. There bioavailability and plasma peak concentration was reached
has been a decrease in elimination half-life and patients re- in approximately 15 minutes. Intravenous infusion in 5 min-
mained sedated for a longer period as compared to the con- utes has promoted a two-phase blood pressure change with
trol group. Authors have justified this increased sedation in initial increase followed by possibly reflex bradycardia and
spite of decreased elimination half-life by the lower protein posterior blood pressure decrease. This changes were not
binding of the drug in such patients. observed when the muscular route was used.
Ala-Kokko et al. 23 have compared placental Ebert et al. 26 have evaluated hemodynamic behavior, de-
dexmedetomidine and clonidine transfer in an experimental gree of sedation, memory and analgesia in 10 individuals re-
model of perfused human placental cotyledons. There has ceiving target controlled dexmedetomidine infusion to
been a higher placental dexmedetomidine retention de- maintain seven different and progressive plasma concen-
creasing drug exposure at the fetal side. This change may be trations (0.5, 0.8, 1.25, 2.0, 3.2, 5.0 and 8 ng.ml -1 ).
explained because the drug is more lipophylic than clonidine Norepinephrine plasma concentration has decreased 66%
or, according to the second possibility proposed by the group, even in the lowest blood drug concentration. Plasma epi-
dexmedetomidine has greater affinity to imidazoline recep- nephrine has decreased 60%. There has been a 13% de-
tors since placenta has large numbers of them. crease in blood pressure during the first two stages of the ex-
Kallio et al. 2 4 have published the first study about periment. Blood pressure had a mean increase of 12% with
dexmedetomidine effects on human beings. In this study, 5 the increase in drug plasma concentration. At approxi-
volunteers have received increasing intravenous mately 1.9 ng.ml -1 drug plasma concentration there has
dexmedetomidine doses in four moments. Doses were 12.5 been a significant increase in central venous pressure, oc-
g, 25 g, 50 g and 75 g, injected at 30-second intervals. cluded pulmonary artery pressure, mean pulmonary artery
They have observed systolic and diastolic blood pressure de- pressure and pulmonary and systemic vascular resistance.
crease in up to 18%. There was a mild blood pressure in- Sedation degree has increased together with drug blood
crease followed by a decrease after the highest dose injec- concentration and at the highest concentration patients
tion (75 g). There has been heart rate decrease with the were not responsive even after vigorous stimulations.
three highest doses being it more marked with the two high- There has been no respiratory depression during the experi-
est doses. Plasma norepinephrine decreased in up to 92%. ment. Four hours after infusion completion all patients had a
Growth hormone plasma levels have significantly increased sedation degree similar to the control moment. As from
in a dose-dependent manner, while plasma cortisol has de- plasma concentrations above 1.25 ng.ml -1 there has been
creased however without correlation between serum levels recent memory impairment. Visual analog scale for subjec-
and dexmedetomidine dose. tive pain measurement decreased 14% already in the first
Khan et al. 1 8 have studied pharmacokinetics and moment. Dexmedetomidine plasma concentration in-
pharmacodynamics of two dexmedetomidine doses as com- crease has promoted a linear decrease in pain response
pared to placebo in 9 volunteers anesthetized with and individuals receiving the highest dose have not re-
isoflurane. Drug plasma concentrations were 0.3 ng.ml-1 and sponded to painful stimulations.

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DEXMEDETOMIDINE IN ANESTHESIOLOGY

Talke et al. 27 have studied dexmedetomidine effects on ted to uterine curettage 31. Patients were divided in four
sweating, vasoconstriction and shivering thresholds in 9 vol- groups receiving 0.167, 0.33, 0.67 and 1 g.kg-1 intravenous
unteers receiving target-controlled infusions of 0.3 and 0.6 dexmedetomidine, 15 minutes before anesthetic induction.
ng.ml-1 as compared to placebo. Individuals were warmed to Anesthesia was induced with sodium thiopental and N2O.
evidence sweating and then cooled to promote There was a dose-dependent decrease in sodium thiopental
vasoconstriction and shivering. Dexmedetomidine has not need, both at induction and during anesthetic maintenance.
changed sweating thresholds but significantly changed Systolic blood pressure decreased in all groups after drug in-
vasoconstriction and shivering thresholds, showing that the fusion, but was not correlated to dose. Diastolic blood pres-
drug is able to induce hypothermia in patients exposed to low sure also decreased without relation to dose and, in the group
temperatures in the operating room, in addition to be effec- receiving 1 g.kg-1 it remained below baseline values for a
tive in preventing postanesthetic shivering. longer period. There was a decrease in heart rate 10 minutes
Dutta et al. 28 have evaluated pharmacodynamic interactions after administration of the two highest dexmedetomidine
between propofol and dexmedetomidine in healthy individu- doses and a mild heart rate increase in patients receiving the
als receiving target-controlled placebo or dexmedetomidine lowest dose. Norepinephrine plasma concentration had a 1/3
to maintain serum concentrations of 0.7 ng.ml -1. Then, decrease in groups receiving 0.67 and 1 g.kg-1 and was not
propofol was administered in progressive plasma concentra- changed in the lowest dose group. There was no epinephrine
tions until individuals were sedated to the point of no longer plasma concentration change in all groups. Plasma cortisol
being able to hold a syringe and presenting lack of ciliary re- was not changed after infusion or soon after surgery, but was
flex and of motor response to an electric stimulation. In the increased 30 minutes after surgery in all groups.
control group, propofol doses for loss of motor response to Dexmedetomidine has decreased in a dose-dependent way,
electric stimulation, loss of ciliary reflex and impossibility to time needed for consciousness recovery at nitrous oxide
hold a syringe were 6.63, 1.98 and 1.14 ng.ml-1, respectively. withdrawal. Major side-effects were dry mouth and somno-
In individuals receiving dexmedetomidine, propofol doses lence. Authors concluded that probably a dose between 0.33
were 3.89 g.ml-1 for loss of motor response to electric stimu- and 0.67 g.kg-1 would be ideal when dexmedetomidine is
lation, 0.64 g.ml-1 for loss of ciliary reflex and 0.28 g.ml1 for used as preanesthetic medication for minor surgeries.
not being able to hold a syringe. Aho et al. 32 have evaluated three muscular
Talke et al. 29, have studied dexmedetomidine effects on dexmedetomidine doses (0.6, 1.2 and 2.4 g.kg-1), compar-
plasma concentrations of 0.68 to 1.24 ng.ml - 1 on ing them to two groups receiving oxycodone (0.13 mg.kg-1) or
neuromuscular block with rocuronium in volunteers anesthe- placebo. Each group was composed of 20 women to be sub-
tized with propofol and alfentanil. There has been a T1 de- mitted to gynecologic laparoscopic surgeries. Injection was
crease (muscle contraction at first stimulation) from 51% to performed 45 to 60 minutes before anesthetic induction. An-
44%, an increase in rocuronium plasma concentration during esthesia was induced with sodium thiopental, isoflurane,
dexmedetomidine infusion, an increase in systolic blood N2O/O2 (70%/30%) and vecuronium. Pneumoperitoneum
pressure and a decrease in peripheral blood flow. The au- was maintained with pressures of 10 to 12 mmHg. Sedation
thors concluded that dexmedetomidine-induced degree 45 and 60 minutes after preanesthetic medication
vasoconstriction might interfere with rocuroniums was similar among groups receiving dexmedetomidine and
pharmacokinetics. Although statistically significant, it is un- oxycodone. Patients receiving the highest
likely that such changes will have any clinical meaning. dexmedetomidine dose remained more relaxed, but when fa-
tigue was evaluated through a questionnaire applied before
ANESTHETIC USE and after preanesthetic medication, patients receiving 2.4
g.kg-1 had higher scores. There was a dose-dependent de-
Dexmedetomidine is presented as a chloridrate in clear, crease in mean blood pressure (MBP) in the
uncolored and isotonic solution, with a pH of 4.5 to 7. Solution dexmedetomidine group, as well as a significant dose-de-
does not have preservatives, additives or chemical stabiliz- pendent MBP control after tracheal intubation. There was an
ers. It may be used for preanesthetic medication or associ- MBP increase during laparoscopy in all groups, but it was
ated to anesthesia. There are reports on intravenous 25,26, less pronounced in the group receiving 2.4 g.kg - 1
muscular 25 and epidural 30 administration. dexmedetomidine. This was also the group with the lowest
When intravenously administered, initial dose should be heart rate increase after tracheal intubation and in the
preferably injected in a minimum 10-minute interval 21. Rapid post-anesthetic recovery unit (PACU). Eight out of twenty
injection is associated to an initial blood pressure increase, women in this group needed atropine because of a heart rate
frequently followed by reflex heart rate decrease as a conse- below 40 bpm. Cortisol plasma concentration was lower be-
quence of peripheral activation of a2-agonists 25. fore induction in the 2.4 g.kg -1 dexmedetomidine and
oxycodone groups. Dexmedetomidine has promoted 70%
Preanesthetic Medication decrease in norepinephrine plasma levels and has mini-
mized plasma epinephrine increase after tracheal
The first report on dexmedetomidine in anesthesia was as intubation. There were no differences among groups in post-
preanesthetic medication administered to 20 women submit- operative analgesics consumption.

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VILLELA AND NASCIMENTO JR

Levanen et al. 33 have compared muscular dexmedetomidine cebo. Patients were anesthetized with thiopental, N2O/O2,
(2.5 g.kg-1) and midazolam (0.07 mg.kg-1) as preanesthetic fentanyl and isoflurane, according to their needs. Only 24%
medication in patients anesthetized with ketamine, nitrous of patients receiving dexmedetomidine needed inhalational
oxide and vecuronium for superficial elective surgeries (in- agent complementation, while in the control group they were
guinal hernia, varicocele or hydrocele). There was a heart 72%. Mean necessary isoflurane concentration was signifi-
rate decrease in the dexmedetomidine group before anes- cantly decreased with dexmedetomidine. Laryngoscopy and
thetic induction. Systolic blood pressure increased 38 mmHg tracheal intubation have not changed systolic blood pressure
after tracheal intubation while in the midazolam group it in- in the treated group, which has increased to 31 mmHg in the
creased 47 mmHg. There were no diastolic blood pressure control group. Diastolic blood pressure increased 1 mmHg
differences, but heart rate was lower in the dexmedetomidine and 26 mmHg and heart rate 13 bpm and 29 bpm in the
group after laryngoscopy and tracheal intubation. During dexmedetomidine and control groups, respectively. There
surgery, the dexmedetomidine group had heart rate, systolic was a 70% plasma norepinephrine and epinephrine de-
and diastolic blood pressure close to baseline values, while crease in the dexmedetomidine group. Patients studied
the midazolam group had an increase of approximately 15 needed less analgesics and antiemetics than the control
mmHg and 10 bpm. Only 10% of patients receiving group. In PACU there has been bradycardia (heart rate below
dexmedetomidine needed additional ketamine dose and 45 bpm) in 56% of patients receiving dexmedetomidine
70% of patients receiving midazolam needed additional against none in the control group. One dexmedetomidine
doses. Fifty five percent of patients receiving group patient developed heart rate below 33 bpm and sys-
dexmedetomidine and 5% of patients receiving midazolam tolic arterial hypotension (71 mmHg) 2 hours after PACU ad-
needed atropine to treat bradycardia (heart rate below 45 mission.
bpm). Two patients receiving a2-adrenergic agonists had ar- Fragen and Fitzgerald 36 have studied the effects of two
terial hypotension, which was treated with fluid replacement dexmedetomidine doses on sevofluranes MAC in adults dur-
alone. Six hours after procedure there were still significant ing skin incision. Patients were divided in 3 groups, being one
differences in hemodynamic parameters between groups. control group (placebo) and the other two receiving
There were no differences in emergence time between dexmedetomidine infusion to maintain plasma concentra-
groups. The dexmedetomidine group presented a better tions in 0.3 ng.ml-1 and 0.6 ng.ml-1. Sevoflurane MAC was
psychomotor performance before anesthetic induction be- maintained in 2% for the control group and in 1.5% and 1% for
cause, although sedated, patients would adequately re- highest and lowest dexmedetomidine dose groups, respec-
spond to stimulation and return to sleep when left alone. This tively. After a 15-minutes maintenance of such concentra-
group remained more sedated in the PACU. Central nervous tions, skin was incised and, in the presence or absence of re-
system changes as a consequence of ketamine were more action, there would be a 0.25% increase or decrease in ex-
frequent in the midazolam group (55%) as compared to pired concentration of the inhalational agent in the next pa-
dexmedetomidine (5%), being unpleasant dreams the most tient. There has been a 17% decrease in sevoflurane MAC in
frequent symptom. Anterograde amnesia was more frequent the 0.6 ng.ml-1 dexmedetomidine group. There were no sta-
with midazolam. There were no differences between groups tistically significant sevoflurane MAC changes in the control
in PACU analgesics consumption. group and in the lowest dexmedetomidine dose group.
Aantaa et al. 34 have evaluated 49 women submitted to ab- In patients submitted to plastic surgery under general anes-
dominal hysterectomy under general anesthesia who were thesia, perioperative hemodynamic changes and oxygen con-
distributed in three groups to receive placebo or enough sumption (VO 2 ) were studied according to the use as
dexmedetomidine infusion to maintain plasma concentra- preanesthetic medication of muscular clonidine (4 g.kg-1),
tions of 0.3 ng.ml-1 or 0.6 ng.ml-1. Infusion was started 15 min- dexmedetomidine (2.5 g.kg-1) or placebo 37. There was 8%
utes before induction and withdrawn after skin incision. An- VO2 decrease at anesthetic induction and 17% after surgery in
esthesia was induced with sodium thiopental and alfentanil. both groups receiving a2-agonists. There were no significant
Isoflurane was administered after tracheal intubation in a differences among groups during surgery, probably because
concentration of 1 MAC for the control group, 0.6 MAC for the VO 2 was influenced by the anesthetic technique. Both
0.3 ng.ml-1 group and 0.3 MAC for the 0.6 ng.ml-1 group. Mo- clonidine and dexmedetomidine have promoted similar blood
tor response to skin incision was evaluated 15 minutes after. pressure and heart rate decrease, however one
In the presence or absence of reaction, isoflurane MAC was dexmedetomidine patient developed sinusoidal arrest during
adjusted 0.1% above or below, in the next patient. Isoflurane laryngoscopy.
MAC was 47% and 35% lower in the 0.6 ng.ml-1 and 0.3 Electroconvulsive therapy (ECT) is a treatment for severe
ng.ml-1 dexmedetomidine groups, respectively. There was a depressive disorders and is frequently associated to acute
17% to 30% decrease in thiopental need in the high and low hemodynamic responses (arterial hypertension and tachy-
dexmedetomidine dose groups as compared to controls. cardia) 38. Fu and White 39 have evaluated the benefit of
Lawrence and De Lange 35, have evaluated dexmedetomidine as preanesthetic medication for such pro-
dexmedetomidine effects in a single intravenous dose of 2 cedures. Twenty-four ECT treatments were evaluated in six
g.kg-1 as preanesthetic medication in patients submitted to elderly patients divided in three groups being one the control
minor orthopedic and general surgeries, as compared to pla- group (placebo) and the other two with 0.5 and 1 g.kg-1 intra-

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DEXMEDETOMIDINE IN ANESTHESIOLOGY

venous dexmedetomidine, 10 to 30 minutes before the pro- terectomy. Initially, in an open study, four dexmedetomidine
cedure. Anesthesia was induced with 0.1 to 0.2 mg infusion regimens were used starting 10 minutes after anes-
glycopyrrolate, 10 mg labetalol, 1 mg.kg-1 methohexital and thetic induction with doses varying between 120
1.3 to 1.5 mg.kg - 1 succinylcholine. There were no ng.kg-1.min-1 (initial dose) + 6 ng.kg-1.min-1 (maintenance
hemodynamic differences between treated and control dose) and 270 ng.kg-1.min-1 + 13.5 ng.kg-1.min-1. Anesthesia
groups before or after ECT. There was a mild time increase in was induced with fentanyl, thiopental, N2O/O2 (70%/30%)
convulsivant, motor and electroencephalographic activity in and isoflurane, according to the need, to maintain MAP be-
patients treated with dexmedetomidine. These patients also tween 30% and +15% and heart rate between -40% and
presented a higher degree of sedation and remained in +20% of baseline values. There has been a dose-dependent
PACU for a longer period. MAP increase after the initial dose. Patients receiving the
Peden et al. 40 have evaluated dexmedetomidine effects on highest doses had MAP increases above 30% of baseline
propofol plasma concentrations needed to suppress con- values. There has been a dose-dependent heart rate de-
sciousness and motor response during anesthesia with crease and the lowest heart rate was observed approxi-
propofol and sufentanil in patients submitted to superficial mately 8 minutes after beginning of infusion. There has been
general surgeries. Dexmedetomidine doses have to be in- a decrease in inhalational agent consumption in all patients.
creased twice due to adverse effects (sinusoidal bradycardia The second stage of the study compared 170 ng.kg-1.min-1
and sinusoidal arrest). Patients received an initial dose of dexmedetomidine (initial dose) + 8.5 ng.kg-1.min-1 (mainte-
0.45 g.kg-1 in 15 minutes, followed by 0.18 g.kg-1.h-1 infu- nance dose) to placebo, following the same anesthetic
sion until skin incision. These authors have found a 40% de- schedule of the first stage. There has been no need for
crease in total propofol dose needed to induce loss of con- complementation with isoflurane in 50% of
sciousness as compared to other authors who, in a similar dexmedetomidine patients. There has been more than 90%
model, have evaluated loss of consciousness with progres- isoflurane MAC decrease in the treated group and no patient
sive propofol doses. reported remembrances during anesthesia. There has been
Data of papers about dexmedetomidine as preanesthetic no significant MAP change after tracheal intubation, during
medication are shown in table I. surgery or one hour after surgery completion. Heart rate was
significantly decreased after the initial dose, after
Use in Anesthesia laryngoscopy and one hour after surgery in the treated group
and 40% of patients presented heart rate below 40 bpm,
Aho et al. 41 have reported the use of dexmedetomidine to needing treatment with atropine. There has been no emer-
maintain anesthesia in patients submitted to abdominal hys- gence time differences between groups.

Table I - Dexmedetomidine as Preanesthetic Medication. Dose, Administration Route, Surgical Procedure and Major Effects
Author and year of publication Dexmedetomidine dose Administration route and surgical Major effects
procedure
Aantaa et al., 1990 31 0.167; 0.33; 0.67 and 1 g.kg-1 IV, uterine curettage thiopental dose-dependent; BP
and HR
Aho et al., 1992 32 0.6; 1.2 and 2.4 g.kg-1 IM, laparoscopic, gynecologic of BP and HR increase after TI; of
surgeries 70% of plasma norepinephrine
Levanen et al., 1995 33 2.5 g.kg-1 IM, superficial elective surgeries Hemodynamic stability after TI;
bradycardia (55% of patients); inci-
dence of CNS changes
Aantaa et al., 1997 34 TPC of 0.3 and 0.6 ng.ml-1 IV, abdominal hysterectomy of isoflurane MAC in up to 47%; of
thiopental need in up to 30%

Lawrence et al., 1997 35 2 g.kg-1 IV, general and orthopedic surgeries Hemodynamic stability after TI;
isoflurane need; in 70% of plasma
norepinephrine and epinephrine;
need for analgesics and anti-emetics;
frequent bradycardia
Fragen et al., 1999 36 TPC of 0.3 and 0.6 ng.ml-1 IV, general surgery in 17% of sevoflurane MAC
-1
2.5 g.kg IM, plastic surgeries 8% VO2 before surgery; 17% post-
Taittonen et al., 1997 37
operative VO2; one case of sinusoidal
arrest
Fu et al., 1999 39 0.5 and 1 g.kg-1 IV, electroconvulsive therapy Without hemodynamic response pro-
tection; convulsivant activity time
Peden et al., 2001 40 0.45 g.kg-1 + 0.18 g.kg-1.h-1 IV, general superficial surgeries 40% in total propofol dose;
bradycardia and sinusoidal arrest
TPC = target plasma concentration, = increase, = decrease, BP = blood pressure, HR = heart rate, MAC = minimum alveolar concentration,
IM = intramuscular, IV = intravenous, VO2 = oxygen consumption, TI= tracheal intubation

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VILLELA AND NASCIMENTO JR

Talke et al. 42 have studied three dexmedetomidine doses in treated group. There were no differences in extubation or
plasma concentrations of 0.15 ng.ml-1, 0.30 ng.ml-1 and 0.45 emergence time between groups, but patients receiving
ng.ml-1 started one hour before anesthetic induction and dexmedetomidine remained more comfortable in the PACU
maintained for up to 48 postoperative hours, in patients sub- according to the nursing team evaluation.
mitted to major vascular procedures. Anesthesia was in- Ta l k e e t a l . 4 5 h a v e e v a l u a t e d t h e p o s s i b i l i t y o f
duced with alfentanil, thiopental, vecuronium, N 2 O/O 2 dexmedetomidine attenuating hemodynamic response dur-
(70%/30%) and isoflurane, according to the need to maintain ing anesthesia emergence in patients submitted to vascular
hemodynamic parameters within previously established lim- surgeries. Authors compared 19 patients receiving placebo
its. There has been a decrease in heart rate (lowest dose, to 22 patients receiving dexmedetomidine in the following in-
11%; intermediate dose, 5%; highest dose, 20%) and systolic fusion schedule starting 20 minutes before anesthetic induc-
blood pressure (lowest dose, 3%; intermediate dose, 12%; tion: 1.2 g.min-1 in the first 20 minutes; 0.8 g.min-1 from the
highest dose, 20%) in patients receiving dexmedetomidine 20th to the 60th minute; 0.35 g.min-1 from the 60th to the 300th
and they needed more perioperative vasoactive drugs to minute up to 48 hours after surgery. Anesthesia was induced
maintain hemodynamic stability. Forty-four percent of pa- with fentanyl, thiopental, vecuronium, N2O/O2 (50%) and
tients treated needed anticholinergic agents to treat isoflurane. During emergence heart rate and systolic blood
bradycardia during surgery against none on placebo group pressure were higher than baseline values for the control
patient. Treated groups presented less postoperative tachy- group but remained unchanged in the treated group. After
cardia and esmolol was needed for control and lowest tracheal extubation and admission to PACU, norepinephrine
dexmedetomidine dose groups. plasma concentrations were 2 to 3 times lower in the
Jalonen et al. 43 have studied dexmedetomidine as compared dexmedetomidine group. Epinephrine plasma levels were
to placebo in patients selected for myocardial l o w e r o n l y a f t e r e x t u b a t i o n . Tw o p a t i e n t s h a d
revascularization. Initial dexmedetomidine dose was 50 dexmedetomidine-related adverse effects: postoperative ar-
ng.kg-1.min-1 for 30 minutes before anesthetic induction and terial hypotension and sinusoidal arrest (10 seconds), during
7 ng.kg-1.min-1 until surgery completion. Patients received laryngoscopy.
scopolamine and morphine as preanesthetic medication and Bekker et al. 46 have reported the use of 1 g.kg-1.h-1
anesthesia was induced with fentanyl and isoflurane. dexmedetomidine during 30 minutes, followed by 0.4
Thirty-eight percent of treated patients and 82% of control g.kg-1.h-1 associated to N2O and sevoflurane for craniotomy
group patients presented muscular stiffness after fentanyl in- and speech cortical area mapping in a 38 year old patient.
fusion. During anesthetic induction, systolic blood pressure Cortical area mapping was performed after sevoflurane with-
and heart rate remained higher in the control group and after drawal and patient was maintained sedated only with 0.1
tracheal intubation they have significantly increased in the g.kg-1.h-1 dexmedetomidine infusion. The procedure was
control group. After skin incision, systolic and diastolic blood successful with the patient remaining relaxed and sleepy, but
pressure and heart rate remained higher in the control group. easily awakened and cooperative when required. After map-
During the first 60 minutes of cardiopulmonary bypass ping, brain tumor was resected, again under sevoflurane an-
(CPB), MAP was lower in the treated group. After CPB, sys- esthesia, without complications. Patient remembered the
tolic blood pressure remained lower in the dexmedetomidine period in which he remained sedated with dexmedetomidine
group without differences in heart rate between groups. Total but could not remember of any detail.
fentanyl dose and enflurane expired concentration were Epidural dexmedetomidine was described by Fukushima et
higher in the control group. Treated patients needed higher al. 27 who have studied 15 patients submitted to abdominal
fluid volumes to treat hypotension during surgery and also hysterectomy under general anesthesia, aiming at evaluat-
more vasopressants during CPB. Placebo group patients ing postoperative analgesia. Patients were divided in four
needed esmolol to treat bradycardia during surgery and groups with epidural administration of: saline solution; 1.5%
methoprolol in the postoperative period. There were no sta- lidocaine; 2 g.kg-1 dexmedetomidine; and 1.5% lidocaine
tistically significant differences in myocardial ischemia be- with 2 g.kg-1 dexmedetomidine. Dexmedetomidine has de-
tween groups. Postoperative shivering was present in 32.5% creased heart rate in 25% and blood pressure in 20%, coin-
of patients receiving dexmedetomidine and in 57.5% of con- ciding with a 35% decrease in plasma norepinephrine and
trol group patients. There has been more diuresis in the epinephrine. Analgesia in patients treated with
treated group. dexmedetomidine lasted more than 7 hours as compared to
Badner et al. 44 have evaluated 249 patients submitted to total only 3 hours in the lidocaine group.
knee arthroplasty, who were divided in two groups: placebo Data of papers on dexmedetomidine during anesthesia are
and dexmedetomidine in plasma concentrations of 0.6 summarized in table II.
ng.ml-1, started 15 minutes before anesthetic induction and
maintained for up to 2 hours after surgery. General anesthe- DEXMEDETOMIDINE ANTAGONISM
sia was induced with fentanyl continuous infusion. Patients
receiving dexmedetomidine reported being happier with pain As a2-adrenergic agonists, a2-adrenergic antagonists have
relief during the first 90 minutes they remained in PACU. been used in the veterinary practice for a long time. In ani-
Shivering, nausea and vomiting had a lower incidence in the mals, most popular drugs are ioimbine, tolazoline, idazoxan

110 Revista Brasileira de Anestesiologia


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DEXMEDETOMIDINE IN ANESTHESIOLOGY

Table II - Dexmedetomidine During Anesthesia. Dose, Administration Route, Surgical Procedure and Major Effects
Administration route and surgical pro-
Author and year of publication Dexmedetomidine dose Major effects
cedure
Aho et al., 1992 41 170 ng.kg-1.min-1 (initial dose) + IV, abdominal hysterectomy isoflurane MAC in 90%
8.5 ng.kg-1.min-1 (maintenance)

Talke et al., 1995 42 PTC of 0.15; 0.3 and 0.45 ng.ml-1 IV, major vascular surgeries BP and HR in 20%; need for
vasoactive dr ugs; fr e q u e n t
bradycardia; incidence of tachy-
cardia
Jalonen et al., 1995 43 50 ng.kg-1.min-1 (initial dose) + IV, myocardial revascularization Lower incidence of stiffness after
7 ng.kg-1.min-1 (maintenance) 1 fentanyl; need for vasoactive
drugs, incidence of postoperative
shivering;
Badner et al., 1999 44 PTC of 0.6 ng.ml-1 IV, knee arthroplasty incidence of postoperative shiv-
ering and vomiting; postoperative
comfort
Talke et al., 2000 45 1.2 g.min-1 and progressive decrease IV, vascular surgeries Hemodynamic stability at anesthe-
to 0.15 g.min-1 up to 48 hours after surgery sia emergence; in 2 to 3 times
plasma norepinephrine after
extubation; 1 case of postoperative
hypotension and 1 case of sinusoi-
dal arrest during laryngoscopy
Bekker et al., 2001 46 1 g.kg-1.min-1 (initial dose) + IV, craniotomy and cortical area Cortical area mapping with patient
0.4 g.kg-1.h-1 mapping sedated only wi th
dexmedetomidine
Fukushima et al., 1997 30 2 g.kg-1 Epidural, abdominal hysterectomy Prolonged postoperative analgesia
PTC = plasma target concentration, = increase, = decrease, BP = blood pressure, HR = heart rate, MAC = minimum alveolar concentration,
IV = intravenous

and atipamezole 47. They differ in a2-adrenergic receptors reverted with atipamezole in a dose-dependent manner. The
specificity and selectivity and vary in their ability to bind to dose of 150 g.kg-1 has increased plasma norepinephrine
imidazoline receptors. levels above baseline values. Authors have concluded that,
Atipamezole is a potent and selective a2-adrenergic antago- probably, the most adequate atipamezole dose to revert
nist without major activity on imidazoline receptors. It has an dexmedetomidine effects should have a ratio with its dose of
8500:1 selectivity ratio with a2:a 1 receptors 48. 20:1 to 60:1.
Karhuvaara et al. 49 have evaluated the effects of three differ- Aho et al. 51 have studied the effects of atipamezole (50
ent atipamezole doses (6.7 g.kg -1 , 27 g.kg -1 and 67 g.kg-1) after dexmedetomidine (2 g.kg-1) or midazolam
g.kg-1) in volunteers receiving 0.67 g.kg-1 (0.15 mg.kg-1) in patients submitted to uterine curettage.
dexmedetomidine. For all patients, dexmedetomidine has Atipamezole has totally reverted dexmedetomidine-induced
promoted sedation, systolic and diastolic blood pressure de- sedation but had no effect on midazolam.
crease and 80% decrease in plasma norepinephrine. Only 27
g.kg-1 and 67 g.kg-1 atipamezole doses were effective in to-
tally reverting sedation and dexmedetomidine-related CONCLUSION
hemodynamic changes.
Scheinin et al. 50 have studied the atipamezole dose needed Dexmedetomidine is a potent a2-adrenergic agonist which
to revert sedation obtained with 2.5 g.kg -1 muscular may be used as a coadjuvant in Anesthesiology. It has major
dexmedetomidine in healthy volunteers. Alpha-2 adrenergic analgesic, sedative, anxiolytic and sympatholytic action. As
infusion was started one hour after dexmedetomidine. Low- preanesthetic medication, during anesthesia or in the post-
est and highest atipamezole doses needed to revert operative period, it promotes good hemodynamic stability.
dexmedetomidine effects were 50 and 163 g.kg-1. In a sec- There is a decrease in drug consumption during anesthesia.
ond stage, authors have evaluated three atipamezole doses Patients sedated with dexmedetomidine may be awakened
(15 g.kg-1, 50 g.kg-1 and 150 g.kg-1) as compared to pla- when required and become cooperative. Even high doses do
cebo and administered 1 hour after 2.5 g.kg-1 muscular not cause respiratory depression. Bradycardia is the most
dexmedetomidine, in 8 healthy volunteers. Sedation was to- frequent side-effect and may be minimized by slow drug infu-
tally reverted with the two highest doses, however with the 15 sion. So, this new a2-agonist - dexmedetomidine - is an im-
g.kg-1 dose there were no differences as compared to pla- portant additional resource for Anesthesiology and may be
cebo. Blood pressure decrease after dexmedetomidine was used in different patients and surgical procedures.

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VILLELA AND NASCIMENTO JR

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41. Aho M, Erkola O, Kallio A et al - Dexmedetomidine infusion for RESUMEN


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