11

A concentração de angiopoetina 2 A concentração de angiopoetina 2 em crianças desenvolvendo em crianças desenvolvendo

displasia broncopulmonar: uma displasia broncopulmonar: uma atenuação pela dexametasonaatenuação pela dexametasona

Clube de RevistaClube de RevistaBrenda Carla Lima SilvaBrenda Carla Lima Silva

Janayana Oliveira AlmeidaJanayana Oliveira AlmeidaPablo Almeida RochaPablo Almeida Rocha

Orientação:Orientação: Dr Paulo R. Margotto Dr Paulo R. Margottowww.paulomargotto.com.brwww.paulomargotto.com.br

26/2//2008 – Hospital Regional da Asa Sul/SES/DF26/2//2008 – Hospital Regional da Asa Sul/SES/DF

Escola Superior de Ciências da Saúde (ESCS)/SES/DF

22

Angiopoietin 2 concentrations in Angiopoietin 2 concentrations in infants developing infants developing

bronchopulmonary dysplasia: bronchopulmonary dysplasia: attenuation by dexamethasoneattenuation by dexamethasone

ZH AghaiZH Aghai11, S Faqiri, S Faqiri11, JG Saslow, JG Saslow11, T Nakhla, T Nakhla11, S , S FarhathFarhath11, A Kumar, A Kumar11, R Eydelman, R Eydelman22, L Strande, L Strande22, G , G

StahlStahl11, P Leone, P Leone22 and V Bhandari and V Bhandari33 11Department of Pediatrics, Cooper University Hospital Robert Wood Johnson Medical Department of Pediatrics, Cooper University Hospital Robert Wood Johnson Medical School, UMDNJ Camden, NJ, USA; School, UMDNJ Camden, NJ, USA; 22Department of Surgery, Cooper University Hospital Department of Surgery, Cooper University Hospital

Robert Wood Johnson Medical School, UMDNJ Camden, NJ, USA and Robert Wood Johnson Medical School, UMDNJ Camden, NJ, USA and 33Division of Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New

Haven, CT, USA Haven, CT, USA

J Perinatol 2008; 28: 149-155J Perinatol 2008; 28: 149-155

33

IntroduçãoIntrodução DBP: importante causa de DBP: importante causa de

morbimortalidade em prematurosmorbimortalidade em prematuros Importante sequela: hiperreatividade Importante sequela: hiperreatividade

de vias aéreas e asmade vias aéreas e asma Incidência sem mudanças significativas Incidência sem mudanças significativas

na ultima décadana ultima década Patogenia complexa: injúrias (infecção Patogenia complexa: injúrias (infecção

intra-útero, por ventilação mecânica, intra-útero, por ventilação mecânica, hiperoxia) desencadeiam cascata hiperoxia) desencadeiam cascata inflamatória, que age em células inflamatória, que age em células imaturas do pulmãoimaturas do pulmão

44

IntroduçãoIntrodução Angiopoetina2:Angiopoetina2:

– Regulariza angiogênese e Regulariza angiogênese e integridade vascularintegridade vascular

– Na inflamação: citocinas induzem a Na inflamação: citocinas induzem a expressão de Ang2 nos sítios de expressão de Ang2 nos sítios de ativação endotelialativação endotelial

– Sua liberação: rápida Sua liberação: rápida desestabilização do endotélio, desestabilização do endotélio, disparando a resposta inflamatória disparando a resposta inflamatória

55

Incrementa resposta inflamatória e Incrementa resposta inflamatória e

desencadeia morte de células desencadeia morte de células pulmonares expostas à pulmonares expostas à hiperoxia!!!hiperoxia!!!

66

Objetivo Objetivo Medir Ang2 na amostra de Medir Ang2 na amostra de

Aspirado Traqueal (TA) e associar Aspirado Traqueal (TA) e associar ao desenvolvimento de DBP ou ao desenvolvimento de DBP ou morte em prematuros ventiladosmorte em prematuros ventilados

Avaliar o efeito do uso de Avaliar o efeito do uso de dexametasona na concentração dexametasona na concentração de Ang2de Ang2

77

MétodosMétodos População:População:

– 39 leitos de UTI Neo do Cooper 39 leitos de UTI Neo do Cooper University Hospital in Camden, NJUniversity Hospital in Camden, NJ

– Março/2003 a outubro/2006Março/2003 a outubro/2006– Aprovado por comitê de ética; Aprovado por comitê de ética;

consentimento livre e esclarecidoconsentimento livre e esclarecido– Eleitos: IG< 32 sem e necessidade Eleitos: IG< 32 sem e necessidade

de VMde VM– DBP = ODBP = O22 por IGPC>=36 sem por IGPC>=36 sem

88

MétodosMétodos Coleta da amostra:Coleta da amostra:

– Dias 1, 3, 5 e 7, na vigência de VMDias 1, 3, 5 e 7, na vigência de VM– Amostra adicional: antes e 48h a 72h Amostra adicional: antes e 48h a 72h

depois de iniciar corticoterapiadepois de iniciar corticoterapia– Corticóide: 9 dias (0,3/0,2/0,1 Corticóide: 9 dias (0,3/0,2/0,1

mg/kg/dia)mg/kg/dia)– Instilação de 0,5ml de SF no tubo, e Instilação de 0,5ml de SF no tubo, e

sucção de resíduo após 3 ventilaçõessucção de resíduo após 3 ventilações– Processamento em 30 min em Processamento em 30 min em

laboratório: centrifugaçãolaboratório: centrifugação

99

MétodosMétodos Teste de ang2Teste de ang2

– Medido por Kit ELISAMedido por Kit ELISA– Detecção de 1,2 a 21,3 pg/ml Detecção de 1,2 a 21,3 pg/ml

(média:8,3)(média:8,3)– Sem reatividade cruzada com Ang1, Sem reatividade cruzada com Ang1,

Tie2 ou fator de crescimento Tie2 ou fator de crescimento endotelialendotelial

Teste de proteína:Teste de proteína:– Concentração de proteína foi medida Concentração de proteína foi medida

em cada amostra para correção da em cada amostra para correção da diluição durante a lavagemdiluição durante a lavagem

1010

MétodosMétodos Análise estatísticaAnálise estatística

– SigmaStat 3,1 (pacote estatístico do SigmaStat 3,1 (pacote estatístico do Windows)Windows)

– Valor mínimo de significância = 12 Valor mínimo de significância = 12 (alfa=0,05)(alfa=0,05)

– Dados continuos:Teste de T-Student, Dados continuos:Teste de T-Student, Mann-Witney, U-test,Mann-Witney, U-test,

– Dados categóricos: X2 ou FisherDados categóricos: X2 ou Fisher– Análise da curva: MedCalcAnálise da curva: MedCalc– Significância: P<= 0,05 Significância: P<= 0,05

1111

• 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)

ResultadosResultados

1212

• 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);

ResultadosResultados

1313

• 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);

ResultadosResultados

1414

ResultadosResultadosCaracterísticas dos gruposCaracterísticas dos grupos

1515

DiscussãoDiscussão Vários estudos utilizam vários Vários estudos utilizam vários

marcadores para a identificação de marcadores para a identificação de DBP em aspirados traqueais (AT) de DBP em aspirados traqueais (AT) de prematuros ventilados (TNFα, IL1, IL6, prematuros ventilados (TNFα, IL1, IL6, etc), com vários deles sendo propostos etc), com vários deles sendo propostos para o diagnóstico da DBP, mas os para o diagnóstico da DBP, mas os resultados foram inconclusivos por uso resultados foram inconclusivos por uso de diferentes metodologias e de diferentes metodologias e concentração-dependentes!concentração-dependentes!

1616

DiscussãoDiscussão O que os estudos mostram:O que os estudos mostram:

– IL1β, IL6, IL8, VEGF, fator de IL1β, IL6, IL8, VEGF, fator de crescimento de queratinócitos, crescimento de queratinócitos, proteína quimiotáxica de monócitos proteína quimiotáxica de monócitos estão relacionadas a injúria dos estão relacionadas a injúria dos pulmões, pulmões, in vitroin vitro

1717

DiscussãoDiscussão A maioria dos estudos teve um A maioria dos estudos teve um n n

diminuído, com coleta de AT em diminuído, com coleta de AT em períodos diferentes, sem períodos diferentes, sem padronização, com definições padronização, com definições variáveis de DBPvariáveis de DBP

-Aspirado traqueal X lavagem broncoalveolar-Padronização do aspirado traqueal

1818

DiscussãoDiscussão Neste estudo os valores de Ang2 Neste estudo os valores de Ang2

foram padronizadas pela correção foram padronizadas pela correção da diluição...da diluição...

Mas mesmo sem usar o método para corrigir a diluição,

os resultados se mostraram significativos!!

1919

DiscussãoDiscussãoConcentração de Ang2 (corrigida) em aspirados traqueais

2020

DiscussãoDiscussãoConcentração de Ang2 (não-corrigida) em aspirados

traqueais

2121

DiscussãoDiscussãoConcentração de Ang2 em ATs nos dias 1, 3, 5 e 7

2222

DiscussãoDiscussão Pontos fortes do estudo:Pontos fortes do estudo:

– Grande coorteGrande coorte– Múltiplas amostras em tempos Múltiplas amostras em tempos

clínicos relevantesclínicos relevantes– DBP definida a 36 semanas de IGpcDBP definida a 36 semanas de IGpc

2323

DiscussãoDiscussão Dexametasona foi associada com Dexametasona foi associada com

decréscimo significativo das decréscimo significativo das concentrações de Ang2 (com ou concentrações de Ang2 (com ou sem diluição), e com ou sem DBPsem diluição), e com ou sem DBP– Pequeno Pequeno nn (apenas 5 sem DBP) (apenas 5 sem DBP)

2424

DiscussãoDiscussãoConcentração de Ang2 (corrigida) antes e depois da Dex

2525

ConclusãoConclusão Concentração de Ang2 está Concentração de Ang2 está

significativamente aumentada em significativamente aumentada em bebês, na primeira semana de vida, bebês, na primeira semana de vida, que tiveram uma intercorrência (DBP que tiveram uma intercorrência (DBP e/ou morte)e/ou morte)

A terapia com dexametasona foi A terapia com dexametasona foi associada com uma diminuição nos associada com uma diminuição nos valores de Ang2 nos aspirados valores de Ang2 nos aspirados traqueaistraqueais

2626

AbstractAbstractObjectives:Objectives: To study the association between angiopoietin 2 (Ang2) concentrations in tracheal To study the association between angiopoietin 2 (Ang2) concentrations in tracheal

aspirates (TAs) and adverse outcome (bronchopulmonary dysplasia (BPD)/death) in aspirates (TAs) and adverse outcome (bronchopulmonary dysplasia (BPD)/death) in ventilated premature infants (VPIs) and modulation of Ang2 concentrations with ventilated premature infants (VPIs) and modulation of Ang2 concentrations with dexamethasone (Dex) use.dexamethasone (Dex) use.

Study Design:Study Design: Serial TA samples were collected on days 1, 3, 5 and 7, and Ang2 concentrations 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 were measured. Ang2 TA concentrations were compared prior to and after 48 to 72 h of using Dex.72 h of using Dex.

Result:Result: A total of 151 TA samples were collected from 60 VPIs. BPD was defined as the 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 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 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 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 (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) 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 (157, 16 and 218 pg mg-1) compared with those who developed BPD (234, 138 and 338 pg mg-1, 338 pg mg-1, PP=0.03) or BPD and/or death (234, 157 and 347 pg mg-1, =0.03) or BPD and/or death (234, 157 and 347 pg mg-1, PP=0.017), =0.017), in the first week of life. Twenty-six VPIs (BW 719 136 g, GA 25.1 1.3 weeks) received 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 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 278 pg mg-1 and significantly decreased to 144, 0 and 224 pg mg-1 after therapy ((PP=0.007).=0.007).

Conclusions:Conclusions:    Higher Ang2 concentrations in TAs are associated with the development of BPD or Higher Ang2 concentrations in TAs are associated with the development of BPD or

death in VPIs.Dex use suppressed Ang2 concentrations.death in VPIs.Dex use suppressed Ang2 concentrations.Keywords: Keywords: cytokines, premature, newborns, lung, inflammation, hyperoxia, tracheal aspiratescytokines, premature, newborns, lung, inflammation, hyperoxia, tracheal aspirates

2727

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Ddos Pablo, Brenda e Janayana e Dr. Paulo R. Margotto