to view Dr Patel's speaker slides

Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia

Neil Patel Neonatologist

Royal Hospital for Sick Children, Glasgow

iNO 26th March 2015

iNO 26th March 2015

• Pathophysiology of PH in CDH

• PH therapies in CDH – iNO and friends

• Rationalising neonatal management in CDH

iNO 26th March 2015

CDH babies everywhere in world

iNO 26th March 2015

Congenital Diaphragmatic Hernia

• 3.5 per 10,000 pregnancies

• Defect in developing diaphragm – 85% left sided

• Herniation of abdominal contents into fetal chest

iNO 26th March 2015

iNO 26th March 2015

Pulmonary artery pressure and outcome in CDH

A second group consisted of 8 patients (17%) that

showed persistent systemic or suprasystemic pulmonary

artery pressure ratios (ratios 1.0) despite all attempts at

clinical management including nitrous oxide, ECMO,

and surgery (group 2). Even with veno-arterial ECMO,

the estimated pressures remained grossly abnormal over

time. In this group there were no survivors.

The third group was made up of 16 infants (34%) with

moderately elevated pressure ratios ranging from 0.5 to

0.9. In this group, 12 survived (75%), and 4 died. Seven

of the 12 survivors required ECMO support. The median

length of time to reach pulmonary artery pressure ratios

less than 0.5 in this group was 49 days.

Examining the survivors as a group, 46% had pulmo-

nary artery pressure ratios less than 0.5 within the first

week of life, and 66% reached this level within the first

3 weeks. One third of the survivors had elevated pulmo-

nary to systemic artery pressure ratios beyond 3 weeks of

therapy (Fig 3). By 2 and Fisher’s Exact test methods,

systemic ratios were associated with decreased survival

at all time-points when compared with normal-pressure

survivors. Within the first week of life, 60% of the

infants with systemic pulmonary artery pressure ratios

survived (P .003). By the third week, only 38% of

infants with systemic pulmonary artery pressures sur-

vived (P .007), and by the sixth week, there were no

survivors with systemic pulmonary artery pressure ratios

(P .02; Table 1).

ECMO support was required in 23 infants (49%). In

group I, 5 of 23 infants (22%) were placed on ECMO,

and all survived. In group III patients with intermediate

ratios, 11 of 16 (69%) required ECMO, and 7 survived

(64%). In group II patients with persistent systemic or

suprasystemic ratio estimates, all of the infants qualified

for ECMO support, and none survived (Table 2).

DISCUSSION

The clinical course of pulmonary hypertension and its

relationship to outcome in patients with congenital dia-

phragmatic hernia has never been documented in a large

study. The importance of pulmonary hypertension in

ultimately determining survival rates has always been

recognized, but establishing the boundary between re-

versible pulmonary hypertension and irreversible pulmo-

nary hypoplasia has been impossible clinically. To this

end, the acceptance and utilization of current clinical

treatments—delayed surgical repair, permissive hyper-

carbia, extracorporeal membrane oxygenation, and nitric

oxide—are strategies aimed at manipulating pulmonary

artery pressure and the pathophysiology associated with

its abnormal elevation.

The data presented in this report show that in the

context of current treatment strategies, CDH outcomes

can be divided into 3 clinical groups based on serial

echocardiographic analyses of pulmonary artery pressure

estimates. Almost half of all CDH patients will resolve

their pulmonary hypertension within the first 3 weeks of

life without a significant need for ECMO, and survival

rate in this group can be expected to approach 100%. A

smaller group of patients will show persistent systemic

or suprasystemic pulmonary pressures despite every at-

tempt to manage such pressures including nitric oxide,

high-frequency oscillation, ECMO, and delayed surgical

repair—or any combination of these interventions. Such

pressure profiles over time have been unresponsive to

Fig 2. Pulmonary artery pressure ratio and survival.

Fig 3. Time course of resolution of pulmonary hypertension in all

survivors

Table 1. Survival Rate with Pulmonary Artery Pressure Ratio > 1.0

(Systemic or Supra-Systemic)

Week % P value

1 60 .003

3 38 .007

6 0 .02

Table 2. Relationship of PAP:SAP Ratios to ECMO Use and Survival

Group No. of Patients (%) Survival (%)

I (PAP:SAP 0.5) 5 (22) 100

III (PAP:SAP 0.5-0.9) 11 (69) 64

II (PAP:SAP 1.0) 7 (100) 0

Total 23 (49)

309PULMONARY ARTERY PRESSURE AND SURVIVAL IN CDH

Dillon et al, J Ped Surg 39 (3), 2004: 307-312

iNO 26th March 2015

Pulmonary vasculature in CDH

CDH Control

iNO 26th March 2015

Yamataka and Puri, J Ped Surg 32 (3), 1997, 387-390

iNO 26th March 2015

Pathophysiology of pulmonary hypertension

PULMONARY HYPERTENSION

RIGHT TO LEFT SHUNTING

• Within lungs • atrial septum • patent ductus

iNO 26th March 2015



REDUCED LV FILLING RIGHT TO LEFT SHUNTING


REDUCED LV OUTPUT

iNO 26th March 2015





REDUCED LV OUTPUT “CARDIAC FAILURE”

INCREASED RV

AFTERLOAD

iNO 26th March 2015

Normal RV structure and function

iNO 26th March 2015

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RV hypertrophy and effect on LV

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RV function

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Tissue Doppler imaging (TDI)

• Uses pulse wave Doppler to measure myocardial velocities as assessment of myocardial function

• Allows separate assessment of systolic (contractile) and diastolic (lusitropic) function

iNO 26th March 2015

Normal pulse wave TDI (PWTDI)

iNO 26th March 2015

IVV: Isovolumic contraction velocity

S: Systolic ejection velocity

E’: Early diastolic veloctiy (active relaxation)

A’: Late diastolic velocity (atrial contraction)

Pulse wave tissue Doppler in CDH

iNO 26th March 2015

Control infant CDH with PH

• Reduced systolic velocities (IVV and S)

• Loss of diastolic E’ velocity

• Abnormal “post-systolic contraction” *

* * *

iNO 26th March 2015

Pulse wave tissue Doppler in CDH

RV function in CDH

• Impaired early diastolic relaxation

• Impaired systolic contraction

iNO 26th March 2015

iNO 26th March 2015

Cardiac failure in CDH

• RV early diastolic and systolic dysfunction • RV dilatation and hypertrophy

– secondary myocardial ischaemia • LV compression and secondary dysfunction • Variable response to elevated PA pressure

iNO 26th March 2015

iNO 26th March 2015

Pathophysiology of PH in CDH



Intrapulmonary atrial septum patent ductus

REDUCED LV OUTPUT BIVENTRICULAR FAILURE

INCREASED AFTERLOAD

RV DIASTOLIC DYSFUNCTION AND DILATATION

HYPOXAEMIA HYPOTENSION HYPOPERFUSION ACIDOSIS

iNO 26th March 2015

Pathophysiology of PH in CDH



atrial septum and

patent ductus REDUCED LV OUTPUT BIVENTRICULAR

FAILURE

INCREASED AFTERLOAD



CLINICAL OUTCOMES iNO 26th March 2015

iNO 26th March 2015 PCCM October 2013

iNO 26th March 2015 PCCM October 2013

Copyright © 2013 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.Unauthorized reproduction of this article is prohibited

Neonatal Intensive Care

Pediatric Critical Care Medicine w w w .p c c m jo u rn a l.o rg 5

correlated with functional class and a reduced RV E′ predicted

adverse long-term outcome (10). The potential importance of

RV function as a predictor of outcome in CDH specifically is

supported by a recent study by Egan et al (14), who observed

that TDI RV E′ and S′ are impaired in long-term survivors up

to 6 years after CDH repair in the newborn period.

Insufficient antenatal data were available in this study to

allow comparison of TDI RV E′ to existing prenatal predictors

of outcome (observed to expected lung-head ratio and MR

fetal lung volumes) (15–17). Further studies are required to

compare TDI RV E′ with these and other postnatal measures,

including pulmonary artery diameter (e.g., McGoon Index)

and physiologic indices, which have previously been reported

to predict mortality in CDH (18, 19). The small cohort size

and incomplete data in the nonsurvivor group also prevented

meaningful investigation of the relationship between TDI

measures (including RV E′d1–2

) and survival. This will be an

interesting area for further study. However, with increasing

survival in CDH, as in our cohort, future interest is likely to

be in prediction of not only survival but also clinical severity,

early and long-term outcomes.

Does measuring RV function confer any benefit to measuring

PAP alone in CDH? Preoperative PSR has been demonstrated to

predict survival in CDH (20). We now additionally observed that

preoperative PSR also correlates with early outcome in survivors.

However, PSR unlike RV TDI was not measureable in 43% of

infants, due to the absence of TR. Furthermore, in the first 48

hours of life, only RV E′ correlated with outcome but PSR did

not. Nor did PSR as a measure of PAH correlate with RV func-

tion. This highlights the variable response of the RV to PAH but

also points to a key central role of RV function rather than abso-

lute PAP in determining illness severity and outcome in CDH.

This critical relationship between RV function and clinical

status was supported by our observation that RV E′ was lower

in those infants with more severe disease (requiring longer

respiratory therapy). This supports a potential critical role of

the RV in CDH pathophysiology in determining pulmonary

Figure 2. Correlation between averaged right ventricular early diastolic myocardial velocity on days 1 and 2 of lif e (RV E′

d1–2) and duration of

respiratory support (DRS). Receiver-operating characteristics curve for the prediction of DRS more than 21 days using RV E′

d1–2 Filled circle =

individual subject data point (RV E′d1-2

and DRS for each of 16 subjects).

Figure 3. Receiver-operating characteristics curve for the prediction of DRS more than 21 days using right ventricular early diastolic myocardial velocity on days 1 and 2 of lif e (RV E′

d1–2). An averaged RV E′

d1–2 less

than 4.6 cm/ s predicted duration of respiratory support more than 21 days with 100% sensitivity and 8 8% specificity (area under the curve = 0.9 6; SE = 0.04; 95% CI, 0.88–1.05; p = 0.002).

TABLE 2. Correlation Between Echocardiographic and Outcome Measures

Variable

Correlation

RV E′ Length of Stay Duration of Respiratory Support

r p r p r p

RV E′d1–2

–0.75 0.002 –0.84 0.0001

RV S′d1–2

–0.04 0.89 –0.19 0.50

PSRd1–2

a 0.17 0.68 0.28 0.46 0.49 0.19

RV E′preoperative

–0.39 0.19 –0.36 0.22

RV S′preoperative

0.22 0.47 0.14 0.65

PSRpreoperative

a 0.25 0.52 0.75 0.03 0.76 0.02

′ ′ = right ventricular systolic myocardial velocity, PSR = pulmonary:systemic peak pressure ratio.aPSR data obtained in n = 9 infants only, not measurable in remaining infants.

Copyright © 2013 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.Unauthorized reproduction of this article is prohibited

Neonatal Intensive Care

Pediatric Critical Care Medicine w w w .p c c m jo u rn a l.o rg 5

correlated with functional class and a reduced RV E′ predicted

adverse long-term outcome (10). The potential importance of

RV function as a predictor of outcome in CDH specifically is

supported by a recent study by Egan et al (14), who observed

that TDI RV E′ and S′ are impaired in long-term survivors up

to 6 years after CDH repair in the newborn period.

Insufficient antenatal data were available in this study to

allow comparison of TDI RV E′ to existing prenatal predictors

of outcome (observed to expected lung-head ratio and MR

fetal lung volumes) (15–17). Further studies are required to

compare TDI RV E′ with these and other postnatal measures,

including pulmonary artery diameter (e.g., McGoon Index)

and physiologic indices, which have previously been reported

to predict mortality in CDH (18, 19). The small cohort size

and incomplete data in the nonsurvivor group also prevented

meaningful investigation of the relationship between TDI

measures (including RV E′d1–2

) and survival. This will be an

interesting area for further study. However, with increasing

survival in CDH, as in our cohort, future interest is likely to

be in prediction of not only survival but also clinical severity,

early and long-term outcomes.

Does measuring RV function confer any benefit to measuring

PAP alone in CDH? Preoperative PSR has been demonstrated to

predict survival in CDH (20). We now additionally observed that

preoperative PSR also correlates with early outcome in survivors.

However, PSR unlike RV TDI was not measureable in 43% of

infants, due to the absence of TR. Furthermore, in the first 48

hours of life, only RV E′ correlated with outcome but PSR did

not. Nor did PSR as a measure of PAH correlate with RV func-

tion. This highlights the variable response of the RV to PAH but

also points to a key central role of RV function rather than abso-

lute PAP in determining illness severity and outcome in CDH.

This critical relationship between RV function and clinical

status was supported by our observation that RV E′ was lower

in those infants with more severe disease (requiring longer

respiratory therapy). This supports a potential critical role of

the RV in CDH pathophysiology in determining pulmonary

Figure 2. Correlation between averaged right ventricular early diastolic myocardial velocity on days 1 and 2 of lif e (RV E′

d1–2) and duration of

respiratory support (DRS). Receiver-operating characteristics curve for the prediction of DRS more than 21 days using RV E′

d1–2 Filled circle =

individual subject data point (RV E′d1-2

and DRS for each of 16 subjects).

Figure 3. Receiver-operating characteristics curve for the prediction of DRS more than 21 days using right ventricular early diastolic myocardial velocity on days 1 and 2 of lif e (RV E′

d1–2). An averaged RV E′

d1–2 less

than 4.6 cm/ s predicted duration of respiratory support more than 21 days with 100% sensitivity and 8 8% specificity (area under the curve = 0.9 6; SE = 0.04; 95% CI, 0.88–1.05; p = 0.002).

TABLE 2. Correlation Between Echocardiographic and Outcome Measures

Variable

Correlation

RV E′ Length of Stay Duration of Respiratory Support

r p r p r p

RV E′d1–2

–0.75 0.002 –0.84 0.0001

RV S′d1–2

–0.04 0.89 –0.19 0.50

PSRd1–2

a 0.17 0.68 0.28 0.46 0.49 0.19

RV E′preoperative

–0.39 0.19 –0.36 0.22

RV S′preoperative

0.22 0.47 0.14 0.65

PSRpreoperative

a 0.25 0.52 0.75 0.03 0.76 0.02

′ ′ = right ventricular systolic myocardial velocity, PSR = pulmonary:systemic peak pressure ratio.aPSR data obtained in n = 9 infants only, not measurable in remaining infants.

iNO 26th March 2015

RV diastolic function is associated with adverse outcome in CDH

Early RV function appears to be a better predictor of outcome than PAP

RV function, rather than absolute PAp may determine outcome in CDH

iNO 26th March 2015

Patterns of PH and RV function in CDH

0

2

4

6

8

10

12

Age 2 3 4 6 7 8 9 10 14 16 18 19 20 21 22 23 24 26 28 33 35 36 37 37.5 39 43 44 47 51 60

RV S

RV E

ECMO weaning iNO + cardiotropes off

iNO + cardiotropes

extubation

repair

weaning sedation

Sepsis

0

1

2

3

4

Age 2 3 4 6 7 8 9 10 14 16 18 19 20 21 22 23 24 26 28 33 35 36 37 37.5 39 43 44 47 51 60

PDA flow ratio Rl:Lr

R->L

L->R

iNO 26th March 2015

RV function in the first week of life in CDH

• RV diastolic velocities can stratify illness severity • RV early diastolic velocities increase from day 1-2 to day 3-4

iNO 26th March 2015

Moenkemeyer & Patel, PCCM October 2013

RV function after CDH repair

• In more severely affected infants RV early diastolic velocities are

lower at day 3-4 post op

iNO 26th March 2015

Moenkemeyer & Patel, PCCM October 2013

TREATMENT OF PH in CDH

iNO 26th March 2015

TREATMENT OF PH IN CDH

INCREASED PVR


atrial septum and

patent ductus REDUCED LV OUTPUT BIVENTRICULAR

FAILURE



CLINICAL OUTCOMES iNO 26th March 2015

Pulmonary vasodilator therapies in CDH

iNO 26th March 2015

iNO and oxygenation in CDH

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Haemodynamic effects of iNO in CDH

iNO 26th March 2015

RCTs iNO in CDH

NINOS study (1997) • 53 subjects, > 34 weeks, <14 days

• iNO at 20ppm, increased to max 80ppm

• Used hyperventilation, no standardization of ventilation

Clark et al (2000) • >34 weeks, < 4 days

• Inclusion at OI >25, randomization at OI>40

• iNO weaned to 5ppm after 24 hours, for max 96 hours

iNO 26th March 2015

iNO 26th March 2015

Analysis 1.13. Comparison 1 Inhaled NO versus control, Outcome 13 Bayley PDI more than 2 SD below the

mean.

Review: Nitric oxide for respiratory failure in infantsborn at or near term

Comparison: 1 Inhaled NO versuscontrol

Outcome: 13 Bayley PDI more than 2 SD below the mean

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI

Davidson 1997 2/35 16/94 34.4 % 0.34 [ 0.08, 1.39 ]

Ninos1996 9/75 17/79 65.6 % 0.56 [ 0.27, 1.17 ]

Total (95% CI) 110 173 100.0 % 0.48 [ 0.25, 0.94 ]

Total events: 11 (Treatment), 33 (Control)

Heterogeneity: Chi2 = 0.40, df = 1 (P= 0.53); I2 =0.0%

Test for overall effect: Z = 2.16 (P= 0.031)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 2.1. Comparison 2 Inhaled NO versus control in infants with diaphragmatic hernia, Outcome 1

Death or need for ECMO.

Review: Nitric oxide for respiratory failure in infantsborn at or near term

Comparison: 2 Inhaled NO versuscontrol in infantswith diaphragmatic hernia

Outcome: 1 Death or need for ECMO

Study or subgroup iNO Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI

Ninos1997 24/25 23/28 60.3 % 1.17 [ 0.97, 1.41 ]

Clark 2000 12/13 17/18 39.7 % 0.98 [ 0.81, 1.19 ]

Total (95% CI) 38 46 100.0 % 1.09 [ 0.95, 1.26 ]

Total events: 36 (iNO), 40 (Control)

Heterogeneity: Chi2 = 1.77, df = 1 (P= 0.18); I2 =43%

Test for overall effect: Z = 1.25 (P= 0.21)

0.5 0.7 1 1.5 2

Favors iNO Favors control

35Nitric oxide for respiratory failure in infants born at or near term (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Nitric oxide for respiratory failure in infants born at or near

term (Review)

Finer N, Barrington KJ

Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary

2006, Issue4

http://www.thecochranelibrary.com

Nitric oxide for respiratory failure in infants born at or near term (Review)



term (Review)


Thisisareprint of aCochranereview, preparedandmaintained byTheCochraneCollaboration andpublished in TheCochraneLibrary

2006, Issue4



Copyright © 2009 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

iNO 26th March 2015


term (Review)


Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary

2006, Issue4





term (Review)


Thisisareprint of aCochranereview, preparedandmaintained byTheCochraneCollaboration andpublished in TheCochraneLibrary

2006, Issue4



Copyright © 2009 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

“Infants with diaphragmatic hernia do not appear to share the benefit of iNO; indeed ……outcomes may be worse in infants with CDH who received inhaled NO compared to controls.”

iNO 26th March 2015

• 57% of infants received iNO

• INO use ranged from 34-92%

• Peak iNO use on day 2 (38%)

• 48% iNO pre op, 40% iNO post op

• Age at iNO: 11%>30days, 3% >60days

Why are we using (more!) iNO in CDH?

• Limitations of existing RCTs – conducted in older treatment eras

– Small populations

– Short durations of treatment

– Didn’t account for variable patterns / timing of PH in CDH

• INO may improve oxygenation and haemodynamics and buy time e.g. for ECMO or for repair of CDH

• iNO may be more effective in combination with new therapies

iNO 26th March 2015

iNO 26th March 2015

Sildenafil

• PDE-5 inhibitor

• Oral preparations introduced first to allow weaning of iNO

• IV preparation now available

iNO 26th March 2015

iNO 26th March 2015

iNO 26th March 2015

• 2005-2012, single centre experience

• 112 CDH infants • 19 (17%) discharged on oral

sildenafil

Pediatric Cardiology 2013

iNO 26th March 2015

Milrinone: “inodilator”

iNO 26th March 2015

Lakshminrusimha and Steinhorn, PCCM 2013

• Pulmonary vasodilator

• Improved diastolic function (lusitropy)

• Improved systolic function (inotropy)

• (systemic vasodilatation)

iNO 26th March 2015

Fax +41 61 306 12 34E-Mail [email protected]

Original Paper

Neonatology 2012;102:130–136

DOI: 10.1159/000339108

Use of Milrinone to Treat Cardiac Dysfunction in Infants with Pulmonary Hypertension Secondary to Congenital Diaphragmatic Hernia:A Review of Six Patients

Neil Patel

Royal Children’s Hospital, Melbourne, Vic. , Australia

there was a significant increase in early diastolic myocardial

velocities in the RV, accompanied by increasing systolic ve-

locities in the RV and IVS. Oxygenation index was significant-

ly reduced, blood pressure unchanged, and ductal shunt ve-

locity minimally altered over the same time period. Conclu-

sions: Milrinone use was associated with an improvement in

systolic and diastolic function in the RV, corresponding to an

improvement in clinical status.

Copyright © 2012 S. Karger AG, Basel

Introduction

In infants with pulmonary hypertension (PHT), in-cluding those with congenital diaphragmatic hernia (CDH), elevated pulmonary vascular resistance increases afterload on the right ventricle (RV) leading to systolic and diastolic ventricular dysfunction [1, 2] . Milrinone is a phosphodiesterase-3 inhibitor which has been proposed to be of benefit in this setting. The rationale for the use of milrinone is threefold: as a direct pulmonary vasodilator, as an inotrope to improve systolic function, and as a lu-sitropic agent to improve diastolic function [3] . In infants with persistent PHT of the newborn, milrinone has been demonstrated to improve oxygenation index (OI) [4] .

Key Words

Pulmonary hypertension Congenital diaphragmatic

hernia Milrinone Phosphodiesterase 3 inhibitor

Newborn infants Tissue Doppler imaging

Abstract

Background: Pulmonary hypertension and secondary car-

diac dysfunction are important contributors of morbidity

and mortality in infants with congenital diaphragmatic her-

nia (CDH). Milrinone, a phosphodiesterase-3 inhibitor, may

be useful in this setting for its combined actions as a pulmo-

nary vasodilator and to improve systolic and diastolic func-

tion. Objectives: This study aimed to assess the effects of

milrinone on cardiac function and pulmonary artery pres-

sure in infants with CDH. Methods: A retrospective review of

echocardiograms performed on infants with CDH who re-

ceived milrinone was performed. Tissue Doppler imaging

velocities were used to assess systolic and diastolic function.

Pulmonary artery pressure was assessed from the pattern

and velocity of ductal shunting. Results: Six infants with

CDH and severe pulmonary hypertension were identified.

Systolic and diastolic myocardial velocities were reduced in

the right ventricle (RV) and interventricular septum (IVS) at

baseline. In the 72 h after commencement of milrinone,

Received: February 7, 2012

Accepted after revision: April 10, 2012

Published online: June 16, 2012

Dr. Neil Patel, BA, MB ChB, MRCPCH, MD Royal Children’s Hospital Flemington Road Melbourne, VIC 3052 (Australia) Tel. +61 3 9345 5008 or +61 413 417 011, E-Mail nei l.patel @ rch.org.au

© 2012 S. Karger AG, Basel1661–7800/12/1022–0130$38.00/0

Accessible online at:www.karger.com/neo


Original Paper

Neonatology 2012;102:130–136

DOI: 10.1159/000339108


Neil Patel











Introduction


Key Words




Abstract






















Dr. Neil Patel, BA, MB ChB, MRCPCH, MD Royal Children’s Hospital Flemington Road Melbourne, VIC 3052 (Australia) Tel. +61 3 9345 5008 or +61 413 417 011, E-Mail neil.patel @ rch.org.au

© 2012 S. Karger AG, Basel1661–7800/12/1022–0130$38.00/0



Original Paper

Neonatology 2012;102:130–136

DOI: 10.1159/000339108


Neil Patel











Introduction


Key Words




Abstract






















Dr. Neil Patel, BA, MB ChB, MRCPCH, MD Royal Children’s Hospital Flemington Road Melbourne, VIC 3052 (Australia) Tel. +61 3 9345 5008 or +61 413 417 011, E-Mail neil.patel @ rch.org.au

© 2012 S. Karger AG, Basel1661–7800/12/1022–0130$38.00/0


iNO 26th March 2015

Rationalising therapies in CDH

• Understanding of pathogenesis of PH in CDH

• Multiple pulmonary vasodilators + inodilators

• Some evidence of haemodynamic benefits

• Lack of RCT support

iNO 26th March 2015

A rationale approach…

iNO 26th March 2015

(Early) RV dysfunction / hypertrophy

INCREASED PVR

Severity and survival

iNO 26th March 2015

hypoxia LVO / BP


INCREASED PVR

Severity and survival

iNO 26th March 2015

hypoxia LVO / BP

REARLY AND REGULAR ASSESSMENT


INCREASED PVR

iNO 26th March 2015

hypoxia LVO / BP

REARLY AND REGULAR ASSESSMENT

TARGETED, SYSTEMATIC, EARLY

THERAPY

REDUCED SEVERITY IMPROVED SURVIVAL

Clinical assessment of PH and RV function

• Simple

• Quantifiable

• Accurate

iNO 26th March 2015

Echocardiography

iNO 26th March 2015

iNO 26th March 2015


Original Paper

Neonatology 2008;94:22–30

DOI: 10.1159/000112641

N-Terminal-pro-B Type Natriuretic Peptide as a Useful Tool to Evaluate Pulmonary Hypertension and Cardiac Function in CDH Infants

Maria J. Baptistaa, c Gustavo Rocha a Fátima Clementea Luís F. Azevedo b

Dick Tibboel d Adelino F. Leite-Moreira b Hercília Guimarães a José C. Areias a

Jorge Correia-Pinto a, c

a Divisions of Pediatric Cardiology, Neonatology and Pediatric Surgery, Department of Pediatrics,

Hospital S. João, b Serviços de Fisiologia, Bioestatistica e Informática Médica, Faculdade de Medicina da

Universidade do Porto, Porto , and c Life and Health Sciences Research Institute, School of Health Sciences, University

of Minho, Braga , Portugal; d Department of Pediatric Surgery, Erasmus Medical Center,

Sophia Children’s Hospital, Rotterdam , The Netherlands

ly correlated with estimated pulmonary artery pressure,

right ventricular Tei index, and tricuspid E/A ratio. Addition-

ally, we found that CDH infants with NT-proBNP 1 11,500 pg/

ml experienced a worse prognosis. Conclusions: We dem-

onstrated that PH is associated with NT-proBNP elevation

and diastolic impairment in CDH infants. Early elevations in

NT-proBNP levels seem to alert for a subset of CDH infants

with worse prognosis. Copyright © 2007 S. Karger AG, Basel

Introduction

Despite many advances in the management of con-genital diaphragmatic hernia (CDH), the outcome of af-fected infants remains unpredictable and varies from year to year even in experienced teams with predeter-mined treatment protocols. Its morbidity and mortality is largely dependent of pulmonary hypertension (PH) and hypoplasia [1] . Pulmonary hypoplasia installs during prenatal development [2–4] and limited possibilities exist to attenuate it [5, 6] . PH is likely secondary to pulmonary

Key Words

N-terminal-pro-B type natriuretic peptide Congenital

diaphragmatic hernia Pulmonary hypertension

Cardiac function Diastole

Abstract

Objective: In congenital diaphragmatic hernia (CDH) the se-

verity of pulmonary hypertension (PH) is considered, by sev-

eral authors, determinant of clinical outcome. Plasmatic N-

terminal-pro-B type natriuretic peptide (NT-proBNP) might

be useful in diagnosis and management of PH in newborns,

although its interest in CDH infants remains to be defined.

Early NT-proBNP levels were assessed in CDH infants and

correlated with cardiovascular echocardiographic parame-

ters. Patients and Methods: 28 newborns, CDH and age-

matched controls were enrolled in a prospective study. Clin-

ical condition, NT-proBNP plasmatic levels, echo parameters

of PH and biventricular function were assessed at 24 h after

delivery as well as survival outcome. Results: Estimated

mean pulmonary pressure and NT-proBNP were significant-

ly higher in CDH than control infants. NT-proBNP significant-

Received: June 4, 2007

Accepted after revision: September 24, 2007

Published online: December 21, 2007

formerly Biology of the Neonate

Maria João Baptista Escola de Ciências da Saúde, Universidade do Minho Campus de Gualtar, CPII (piso 3) PT–4709-057 Braga (Portugal) Tel. +351 253 604 807, Fax +351 253 604 831, E-Mail [email protected]

© 2007 S. Karger AG, Basel1661–7800/08/0941–0022$24.50/0



Original Paper

Neonatology 2008;94:22–30

DOI: 10.1159/000112641

N-Terminal-pro-B Type Natriuretic Peptide as a Useful Tool to Evaluate Pulmonary Hypertension and Cardiac Function in CDH Infants

Maria J. Baptistaa, c Gustavo Rocha a Fátima Clementea Luís F. Azevedo b

Dick Tibboel d Adelino F. Leite-Moreira b Hercília Guimarães a José C. Areias a

Jorge Correia-Pinto a, c

a Divisions of Pediatric Cardiology, Neonatology and Pediatric Surgery, Department of Pediatrics,

Hospital S. João, b Serviços de Fisiologia, Bioestatistica e Informática Médica, Faculdade de Medicina da

Universidade do Porto, Porto , and c Life and Health Sciences Research Institute, School of Health Sciences, University

of Minho, Braga , Portugal; d Department of Pediatric Surgery, Erasmus Medical Center,

Sophia Children’s Hospital, Rotterdam , The Netherlands

ly correlated with estimated pulmonary artery pressure,

right ventricular Tei index, and tricuspid E/A ratio. Addition-

ally, we found that CDH infants with NT-proBNP 1 11,500 pg/

ml experienced a worse prognosis. Conclusions: We dem-

onstrated that PH is associated with NT-proBNP elevation

and diastolic impairment in CDH infants. Early elevations in

NT-proBNP levels seem to alert for a subset of CDH infants

with worse prognosis. Copyright © 2007 S. Karger AG, Basel

Introduction

Despite many advances in the management of con-genital diaphragmatic hernia (CDH), the outcome of af-fected infants remains unpredictable and varies from year to year even in experienced teams with predeter-mined treatment protocols. Its morbidity and mortality is largely dependent of pulmonary hypertension (PH) and hypoplasia [1] . Pulmonary hypoplasia installs during prenatal development [2–4] and limited possibilities exist to attenuate it [5, 6] . PH is likely secondary to pulmonary

Key Words

N-terminal-pro-B type natriuretic peptide Congenital

diaphragmatic hernia Pulmonary hypertension

Cardiac function Diastole

Abstract

Objective: In congenital diaphragmatic hernia (CDH) the se-

verity of pulmonary hypertension (PH) is considered, by sev-

eral authors, determinant of clinical outcome. Plasmatic N-

terminal-pro-B type natriuretic peptide (NT-proBNP) might

be useful in diagnosis and management of PH in newborns,

although its interest in CDH infants remains to be defined.

Early NT-proBNP levels were assessed in CDH infants and

correlated with cardiovascular echocardiographic parame-

ters. Patients and Methods: 28 newborns, CDH and age-

matched controls were enrolled in a prospective study. Clin-

ical condition, NT-proBNP plasmatic levels, echo parameters

of PH and biventricular function were assessed at 24 h after

delivery as well as survival outcome. Results: Estimated

mean pulmonary pressure and NT-proBNP were significant-

ly higher in CDH than control infants. NT-proBNP significant-

Received: June 4, 2007

Accepted after revision: September 24, 2007

Published online: December 21, 2007

formerly Biology of the Neonate

Maria João Baptista Escola de Ciências da Saúde, Universidade do Minho Campus de Gualtar, CPII (piso 3) PT–4709-057 Braga (Portugal) Tel. +351 253 604 807, Fax +351 253 604 831, E-Mail [email protected]

© 2007 S. Karger AG, Basel1661–7800/08/0941–0022$24.50/0


iNO 26th March 2015

Plasma vascular endothelial growth factor A and placental growth factor: novel biomarkers of pulmonary hypertension in congenital diaphragmatic hernia

Neil Patel , Florian Moenkemeyer , Susie Germano , Michael M. H. Cheung

AJP Lung Feb 2015

iNO 26th March 2015

Regu

lar assessmen

t of p

ulm

on

ary pressu

re & card

iac (RV

) fun

ction

BIRTH

Discharge and beyond

iNO 26th March 2015

Regu

lar assessmen

t of p

ulm

on

ary pressu

re & card

iac (RV

) fun

ction

BIRTH


First line:

Evidence of effects of PH: HYPOXIA / BP / RV dysfunction

Optimise ventilation, sedation, acid-base, Ca/Mg, sepsis

iNO 26th March 2015

Regu

lar assessmen

t of p

ulm

on

ary pressu

re & card

iac (RV

) fun

ction

BIRTH


Second line:

hypoxia RV dysfunction

First line:



iNO 26th March 2015

Regu

lar assessmen

t of p

ulm

on

ary pressu

re & card

iac (RV

) fun

ction

BIRTH


Second line:


Worsening hypoxia or RV dysfunction

Third line:

First line:



iNO 26th March 2015

Regu

lar assessmen

t of p

ulm

on

ary pressu

re & card

iac (RV

) fun

ction

BIRTH


Second line:


First line:



PGE1 to maintain PDA if PAP>SBP / PDA closing / RV dilated

iNO 26th March 2015

Regu

lar assessmen

t of p

ulm

on

ary pressu

re & card

iac (RV

) fun

ction

BIRTH


Second line:


Worsening hypoxia or RV dysfunction

Third line:

First line:



PGE1 to maintain PDA if PAP>SBP / PDA closing / RV dilated

BP First line: Treat PH

Dopamine (max 10 mcg/kg/min)

-hydrocortisone -low dose Adr (if LV fx) -low dose NA (if SVR)

BP

BP

Targeted timing of procedures inc surgery

0

2

4

6

8

10

12

Age 2 3 4 6 7 8 9 10 14 16 18 19 20 21 22 23 24 26 28 33 35 36 37 37.5 39 43 44 47 51 60

RV S

RV E

ECMO weaning iNO + cardiotropes off

iNO + cardiotropes

extubation

repair

0

1

2

3

4

Age 2 3 4 6 7 8 9 10 14 16 18 19 20 21 22 23 24 26 28 33 35 36 37 37.5 39 43 44 47 51 60

PDA flow ratio Rl:Lr

R->L

L->R

iNO 26th March 2015

A new RCT?

iNO 26th March 2015

Early and regular assessment of PAp and cardiac (RV) function

Targeted: • Systematic pulmonary vasodilator

/ cardiotrope use.

• Timing of procedures: surgery, weaning, extubation

Newborn with CDH

CONTROL (current therapy)

OUTCOMES: DEATH, ECMO, DISABILITY

VS.

iNO 26th March 2015

Morgan, Farah Eaton, Jason R. Dyck, Stephen L. Archer and Bernard ThébaudDon Walker, Kathryn G. Todd, Pierre Gressens, Zamaneh Kassiri, Khurram Nadeem, Beverly Christina Luong, Juliana Rey-Perra, Arul Vadivel, Greg Gilmour, Yves Sauve, Debby Koonen,

Congenital Diaphragmatic HerniaAntenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2011 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/CIRCULATIONAHA.108.845909

2011;123:2120-2131; originally published online May 2, 2011;Circulation.

http://circ.ahajournals.org/content/123/19/2120

World Wide Web at: The online version of this article, along with updated information and services, is located on the

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Take home message

iNO 26th March 2015

iNO 26th March 2015

iNO 26th March 2015

Staff and patients of the : Royal Hospital for Sick Children, Glasgow Royal Children’s Hospital, Melbourne Murdoch Childrens Research Institute Florian Moenkemeyer Michael Cheung Michael Stewart Joanne Behrsin Anja Bialkowski John Mills

Thanks to

to view Dr Patel's speaker slides

Documents

Transcript of to view Dr Patel's speaker slides