Escola Superior de Ciências da Saúde (ESCS)/SES/DF
A concentração de angiopoetina 2 em
crianças desenvolvendo displasia
broncopulmonar: uma atenuação pela
dexametasona
Clube de Revista
Brenda Carla Lima Silva
Janayana Oliveira Almeida
Pablo Almeida Rocha
Orientação: Dr Paulo R. Margotto
www.paulomargotto.com.br
26/2//2008 – Hospital Regional da Asa Sul/SES/DF
1
Angiopoietin 2 concentrations in
infants developing bronchopulmonary
dysplasia: attenuation by
dexamethasone
ZH Aghai1, S Faqiri1, JG Saslow1, T Nakhla1, S
Farhath1, A Kumar1, R Eydelman2, L Strande2, G
Stahl1, P Leone2 and V Bhandari3
1Department
of Pediatrics, Cooper University Hospital Robert Wood Johnson Medical School,
UMDNJ Camden, NJ, USA; 2Department of Surgery, Cooper University Hospital Robert Wood
Johnson Medical School, UMDNJ Camden, NJ, USA and 3Division of Perinatal Medicine,
Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
J Perinatol 2008; 28: 149-155
2
Introdução




DBP: importante causa de morbimortalidade
em prematuros
Importante sequela: hiperreatividade de
vias aéreas e asma
Incidência sem mudanças significativas na
ultima década
Patogenia complexa: injúrias (infecção intraútero, por ventilação mecânica, hiperoxia)
desencadeiam cascata inflamatória, que age
em células imaturas do pulmão
3
Introdução

Angiopoetina2:
– Regulariza angiogênese e integridade
vascular
– Na inflamação: citocinas induzem a
expressão de Ang2 nos sítios de ativação
endotelial
– Sua liberação: rápida desestabilização do
endotélio, disparando a resposta
inflamatória
4
Incrementa resposta inflamatória e
desencadeia morte de células
pulmonares expostas à hiperoxia!!!
5
Objetivo


Medir Ang2 na amostra de Aspirado
Traqueal (TA) e associar ao
desenvolvimento de DBP ou morte em
prematuros ventilados
Avaliar o efeito do uso de
dexametasona na concentração de
Ang2
6
Métodos

População:
– 39 leitos de UTI Neo do Cooper
University Hospital in Camden, NJ
– Março/2003 a outubro/2006
– Aprovado por comitê de ética;
consentimento livre e esclarecido
– Eleitos: IG< 32 sem e necessidade de VM
– DBP = O2 por IGPC>=36 sem
7
Métodos

Coleta da amostra:
– Dias 1, 3, 5 e 7, na vigência de VM
– Amostra adicional: antes e 48h a 72h
depois de iniciar corticoterapia
– Corticóide: 9 dias (0,3/0,2/0,1 mg/kg/dia)
– Instilação de 0,5ml de SF no tubo, e
sucção de resíduo após 3 ventilações
– Processamento em 30 min em
laboratório: centrifugação
8
Métodos

Teste de ang2
– Medido por Kit ELISA
– Detecção de 1,2 a 21,3 pg/ml
(média:8,3)
– Sem reatividade cruzada com Ang1, Tie2
ou fator de crescimento endotelial

Teste de proteína:
– Concentração de proteína foi medida em
cada amostra para correção da diluição
durante a lavagem
9
Métodos

Análise estatística
– SigmaStat 3,1 (pacote estatístico do
Windows)
– Valor mínimo de significância = 12
(alfa=0,05)
– Dados continuos:Teste de T-Student,
Mann-Witney, U-test,
– Dados categóricos: X2 ou Fisher
– Análise da curva: MedCalc
– Significância: P<= 0,05
10
Resultados
• Foram coletados 151 amostras de 60 prematuros
ventilados;
• 12 crianças não apresentaram DBP ( IG: 26,5 +/- 2,1
semanas e peso ao nascer: 913 +/- 230g);
• 32 crianças desenvolveram DBP ( IG: 25,8 +/-1,4
semanas e peso ao nascer: 768 +/- 157g);
• 16 crianças foram a óbito antes de 36 semanas da
IGpc ( IG: 24,5 +/- 1,1 semanas e peso ao nascer:
710 +/- 143g)
11
Resultados
• Na primeira semana de vida, a concentração de
angiopoetina 2 foi significativamente baixa nas
crianças sem DBP (157, 16 e 218 pg/mg), quando
comparada aos que desenvolveram DBP (234, 138
e 338pg/mg, P= 0,03) ou aos que morreram
(234, 157 e 347 pg/mg, P= 0,017);
12
Resultados
• 26 crianças (Peso ao nascer: 719 +/- 136g e
IG: 25,1 +/-1,3 semanas) , receberam terapia
com corticóide – 27 doses de Dexametasona;
• a concentração de angiopoetina 2
antes de
iniciar a corticoterapia foi 202, 137 e 278
pg/mg;
• esta
concentração
foi
significativamente
diminuída após o fim da terapia : 144, 0 e 224
pg/mg (p=0,007);
13
Resultados
Características dos grupos
14
Discussão

Vários estudos utilizam vários marcadores
para a identificação de DBP em aspirados
traqueais (AT) de prematuros ventilados
(TNFα, IL1, IL6, etc), com vários deles
sendo propostos para o diagnóstico da DBP,
mas os resultados foram inconclusivos por
uso de diferentes metodologias e
concentração-dependentes!
15
Discussão

O que os estudos mostram:
– IL1β, IL6, IL8, VEGF, fator de crescimento
de queratinócitos, proteína quimiotáxica
de monócitos estão relacionadas a injúria
dos pulmões, in vitro
16
Discussão

A maioria dos estudos teve um n
diminuído, com coleta de AT em
períodos diferentes, sem
padronização, com definições variáveis
de DBP
-Aspirado traqueal X lavagem broncoalveolar
-Padronização do aspirado traqueal
17
Discussão

Neste estudo os valores de Ang2
foram padronizadas pela correção da
diluição...
Mas mesmo sem usar o método
para corrigir a diluição, os
resultados se mostraram
significativos!!
18
Discussão
Concentração de Ang2 (corrigida) em aspirados traqueais
19
Discussão
Concentração de Ang2 (não-corrigida) em aspirados traqueais
20
Discussão
Concentração de Ang2 em ATs nos dias 1, 3, 5 e 7
21
Discussão

Pontos fortes do estudo:
– Grande coorte
– Múltiplas amostras em tempos clínicos
relevantes
– DBP definida a 36 semanas de IGpc
22
Discussão

Dexametasona foi associada com
decréscimo significativo das
concentrações de Ang2 (com ou sem
diluição), e com ou sem DBP
– Pequeno n (apenas 5 sem DBP)
23
Discussão
Concentração de Ang2 (corrigida) antes e depois da Dex
24
Conclusão


Concentração de Ang2 está
significativamente aumentada em bebês, na
primeira semana de vida, que tiveram uma
intercorrência (DBP e/ou morte)
A terapia com dexametasona foi associada
com uma diminuição nos valores de Ang2
nos aspirados traqueais
25
Abstract
Objectives:
To study the association between angiopoietin 2 (Ang2) concentrations in tracheal aspirates
(TAs) and adverse outcome (bronchopulmonary dysplasia (BPD)/death) in ventilated premature
infants (VPIs) and modulation of Ang2 concentrations with dexamethasone (Dex) use.
Study Design:
Serial TA samples were collected on days 1, 3, 5 and 7, and Ang2 concentrations were
measured. Ang2 TA concentrations were compared prior to and after 48 to 72 h of using Dex.
Result:
A total of 151 TA samples were collected from 60 VPIs. BPD was defined as the oxygen
requirement at 36 weeks postmenstrual age (PMA). Twelve infants (mean s.d.) (gestational age
(GA) 26.5 2.1 weeks, birth weight (BW) 913 230 g) had no BPD, 32 infants (GA 25.8 1.4 weeks,
BW 768 157 g) developed BPD and 16 infants (GA 24.5 1.1 weeks, BW 710 143 g) died before
36 weeks PMA. Ang2 concentrations were significantly lower in infants with no BPD (median,
25th and 75th percentile) (157, 16 and 218 pg mg-1) compared with those who developed BPD
(234, 138 and 338 pg mg-1, P=0.03) or BPD and/or death (234, 157 and 347 pg mg-1,
P=0.017), in the first week of life. Twenty-six VPIs (BW 719 136 g, GA 25.1 1.3 weeks)
received 27 courses of Dex. Ang2 concentrations before starting Dex were 202, 137 and
278 pg mg-1 and significantly decreased to 144, 0 and 224 pg mg-1 after therapy (P=0.007).
Conclusions:
Higher Ang2 concentrations in TAs are associated with the development of BPD or death in
VPIs.Dex use suppressed Ang2 concentrations.
Keywords:
cytokines, premature, newborns, lung, inflammation, hyperoxia, tracheal aspirates
26
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Obrigado!
Ddos Pablo, Brenda e Janayana e Dr. Paulo R. Margotto
34