Speaker’fee’for’presentaons’ Treatmentof’PPHN’’ … · 2015. 4. 13. · 02.04.15 5...

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Treatment of PPHN in Premature Infants

Inhaled Nitric Oxide Therapy in Neonates 26th March 2015, Liverpool

1 Prof. Dr. H. Hummler

Disclosure

•  Speaker fee for presentaHons

2

3

•  ConstrucHon started in 1377 •  Highest tower of any church in the

world: 161.53 m,768 steps to a plaPorm 143 m

•  >2000 seats, 20.000 guests reported 4

* 14. March, 1879 Bahnhofstrasse 20, Ulm, Germany

Albert Einstein

Albert Einstein Memorial Ulm

Children‘s Hospital University of Ulm, Germany

•  Division of of Neonatology –  18 bed ICU –  24 bed Intermediate Care – CPAP –  6 bed special care unit with F/T Rooming of the mother –  VLBWI: n=120/year, ELBWI: n=60/year

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Pulmonary Hypertension in Neonates Mortality and Morbidity

•  Mortality –  Depending on underlying disease ■  GBS-‐Sepsis: up to 50%

–  Median (Min-‐Max): 11(4-‐33)%

•  Morbidity –  BPD –  Neurologic damage secondary to hypoxemia

6 Walsh-Sukys et al. Pediatrics 2000;105:14

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Generally Accepted Principles for Treatment of PPHN

•  Maintain physiology unHl PVR drops and/or underlying disease(s) improve

•  Correct severe metabolic acidosis -‐ do not alkalize –  By hypervenHlaHon – associated with BPD –  By giving excessive Na-‐Bicarbonate – associated with

increased organ damage –  Both are associated with brain damage and hearing

deficit •  Maintain blood pressure to limit R-‐L-‐ShunHng

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Targets for Current or Emerging Therapies in Pulmonary Arterial Hypertension

8 Humbert M et al. N Engl J Med 2004;351:1425

Treatments Described for Neonates with PPHN

•  Inhaled Nitric Oxide (iNO) •  Prostacyclin –  Intravenously –  via Aerosol

•  Sildenafil •  Milrinone •  Bosentan •  Magnesiumsulfate

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Proposed Effects of Nitric Oxide on the Respiratory System

10 Martin et al. NEJM 2005;353:82

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the infants in the trial by Mestan et al. and 35 per-cent in the trial by Van Meurs et al. were black. Raceor ethnic group is a very crude marker of potentialbiologic differences in drug response, known aspharmacogenomics.

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However, there are no previ-ous data in infants to suggest differential respon-siveness to nitric oxide between blacks and whites.

Whereas the trial by Mestan et al. was a single-center study, the study by Van Meurs et al. was largerand involved many centers. Drug delivery was per-formed by blinded personnel, and outcomes wereevaluated by observers blinded to therapy, minimiz-ing the chance of bias in the outcome assessments.

Even with these precautions, however, small trialshave been shown to overestimate the effects oftreatment, as compared with multicenter studies.

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It is likely that this is caused in part by the variationsin concomitant processes of care that occur amongcenters as opposed to the processes within a singlecenter.

In the study by Mestan et al., the finding of a de-crease in the rate of neurodevelopmental impair-ment at two years of age in patients who had beentreated with inhaled nitric oxide as infants, as com-pared with those who had been treated with placebo(24 percent vs. 46 percent, respectively), is impres-

Figure 1. Proposed Effects of Nitric Oxide on the Development of the Respiratory System.

Endogenously released and exogenously inhaled nitric oxide (NO) may influence many facets of perinatal lung develop-ment, including lung parenchyma, bronchi, and vascular structures. This schematic figure depicts a fetal or preterm lung during the transition from a saccular to an alveolar stage, corresponding to 25 to 28 weeks of gestation. Endogenous ni-tric oxide is released primarily from epithelial and endothelial cells that contain nitric oxide synthase, and it is implicated in the structural and functional aspects of the development of pulmonary vasculature and airway smooth muscle. Nitric oxide also contributes to growth of the lung parenchyma and to extracellular matrix deposition and may modulate sur-factant and inflammation in the developing lung. Animal models of bronchopulmonary dysplasia that have deficient lev-els of nitric oxide synthase show that inhaled nitric oxide can preserve lung growth. The implications of supplementation with inhaled nitric oxide in preterm infants are currently uncertain. The upward arrows indicate increased and the down-ward arrows decreased.

Neutrophil

Surfactant

Terminal sac(future alveoli)

Elastic fibersElastic fibers

FibroblastFibroblast

CapillaryCapillary

SmoothSmoothmuscle cellmuscle cell

ArterioleArteriole

Elastic fibers

Fibroblast

Epithelium

Capillary

Smooth-muscle cell

Arteriole

Growth

Elastin production

Inflammation

Surfactant function

Lung parenchyma

Vasorelaxation

Angiogenesis

Vasculature

Bronchodilation

Airway smooth-muscleproliferation

Bronchi

NO

NO

NO

NO

The New England Journal of Medicine Downloaded from nejm.org by HELMUT HUMMLER on March 26, 2015. For personal use only. No other uses without permission.

Copyright © 2005 Massachusetts Medical Society. All rights reserved.

Smooth Muscle Cell

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iNO is the Treatment of Choice in Full-‐term Neonates with PPHN

•  RaHonale: pulmonary vasodilataHon –  Treatment of pulmonary hypertension + extrapulmonary R-‐L Shunts (Higgenbojam et al. AJRCCM 1988;13:A107; Kinsella et al. Lancet 1992; 240:819, Roberts et al. Lancet 1992; 340:818)

–  Improvement of V/Q-‐Match (Rossaint et al. N Engl J Med 1993;328:399)

•  Reduces the need for ECMO –  12 RCT‘s: RR 0,65 (0,55-‐0,76) (www.nichd.nih.gov/

cochraneneonatal/Finer/Finer.htm)

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iNO for Treatment of PPHN in Term Newborns Death or ECMO

13 www.nichd.nih.gov/cochraneneonatal/Finer/Finer.htm

RR 0,65 (0,55-‐0,76)

RR 1,0 (0,53-‐1,90)

iNO for Treatment of PPHN in Term Newborns Change in PO2 aoer 30-‐60 min

14 www.nichd.nih.gov/cochraneneonatal/Finer/Finer.htm

RD +45 (35, 56)

RCT of Early vs. Delayed Use of iNO in Newborns with PPHN

•  Term infants (n=56) with moderate respiratory failure (OI 10-‐30) less than 48h of age were randomized to –  iNO 20 ppm –  Control group (rescue with iNO if OI >40)

•  Results: –  7/28 (25%) vs. 17/28 (61%) [iNO vs. Control-‐paHents]

developed an OI>40. –  OI decreased and was significantly lower in iNO vs.

Controls –  Deaths: 1 (early iNO) vs. 2 paHents (Control)

•  Conclusion: Early use of iNO in term infants with moderate respiratory failure improves oxygenaHon and decreases the probability of severe respiratory failure

15 Gonzales et al. J Perinatol 2010;30:420

PPHN ist not Limited to Full-‐term Neonates

•  FG 24+2 wks, 740 g •  IntubaHon, mech. VenHlaHon, Surfactant 2x •  SpO2 slowly ↓ to 37 % (PaO2: 18 mmHg)

16 Case University of Ulm

CXR

17 Case University of Ulm

Echo Use of iNO University of Ulm

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0 2 4 6 8 10 12 14 16 18 20

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Preterm

Full-‐term

No. of Infan

ts

•  There was a 6-‐fold increase (0.3 to 1.8%) in the use of iNO in infants <34 wks GA between 2000 and 2008. Largest increase occurred among infants with 23-‐26 wks GA (0.8 to 6.6%) (Clark et al. J Perinatol 2010;30:800)

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iNO in Preterm Infants for PPHN What’s the evidence?

•  1990’s: Case-‐reports and cohort studies (Rescue): –  OxygenaHon ↑ –  “High” mortality and/or –  “High” rate of IVH (IVH Grade ¾) ➜ However: selected paHent populaHon (high risk

for complicaHons)

•  30% of all newborns with PPHN do not respond to iNO (Travadi et al. Pediatr Pulmonol 2003;36:529)

19 Peliowski et al. J Pediatr 1995;126:450; Abman et al. Pediatrics 1993;92:606; Van Meurs et al. Pediatr Pulmonol 1997;24:319

Cochrane Review: iNO for Respiratory Failure in Preterm Infants Death

20 Barrington&Finer Cochrane Neonatal Reviews 13.10.2010, (www.nichd.nih.gov/cochrane_data/barringtonk_05)

RR (95% CI) 1.04 (0.90; 1.20)

Study entry <3d based on oxygenation

Study entry >3d based on BPD risk

RR (95% CI) 1.06 (0.64; 1.74) Studies on routine use in intubated infants

RR (95% CI) 0.91 (0.74; 1.11)

Cochrane Review: iNO for Respiratory Failure in Preterm Infants BPD @ 36 wks PMA


RR (95% CI) 0.89 (0.76; 1.04)


Study entry >3d based on BPD risk

RR (95% CI) 0.89 (0.78; 1.02) Studies on routine use in intubated infants

RR (95% CI) 0.94 (0.84; 1.05)

Cochrane Review: iNO for Respiratory Failure in Preterm Infants IVH Grade 3/4


RR (95% CI) 1.20 (0.98; 1.47)


Studies on routine use in intubated infants

RR (95% CI) 0.90 (0.74; 1.11)

Cochrane Review: iNO for Respiratory Failure in Preterm Infants Other Outcome Variables

(Study entry based on oxygenaHon)


Outcome Studies ParDcipants RR (95% CI) Death or BPD 8 958 0.94 (0.87, 1.01) IVH (all grades) 3 254 1.00 (0.73, 1.37) IVH or PVL 8 901 1.08 (0.88, 1.33) ROP (≥Stage 3) 3 261 0.97 (0.64, 1.47) Neurodev. disability 2 208 1.05 (0.78, 1.40) Cerebral Palsy 2 209 1.85 (0.93, 3.71) Conclusions: •  In very sick preterm infants who meet the criteria for poor oxygenaHon, rescue therapy with iNO does not improve their survival, survial without BPD, or brain injury… •  …there is some evidence of a potenHal increase in severe IVH or IVH+PVL. •  In view of these findings, iNO should not be rouHnely used for preterm infants as a rescued therapy in cases of hypoxic respiratory failure.

Inhaled Nitric Oxide for Premature Infants with Severe Respiratory Failure

•  NICHD network,420 VLBWI, <34 wks GA, OI >10 aoer surfactant Tx

•  RCT: iNO: 5 ppm vs. placebo, 10 ppm if response “incomplete” (∆PaO2 >20 mmHg), weaning acc. to protocol, duraHon max. 14d

•  Prim Outcome: death or BPD (O2 @36 wks GA) •  Trial closed aoer the second interim analysis (2/3 recruitment)… –  …incidence of IVH Grade 3/4 or PVL was significantly

higher in the iNO group (39% vs. 27%, p=0.02) –  420/440 infants were recruited at this Hme

24 Van Meurs et al. NEJM 2005;353:13

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nificant differences between treatment groups inthe baseline characteristics (Table 1) or status atthe time of randomization (Table 2). The distribu-tion by birth weight did not differ significantly be-tween the two treatment groups, with an overall dis-tribution of 47 percent in the infants who weighed401 to 750 g, 28 percent in those who weighed 751to 1000 g, and 25 percent in those who weighed1001 to 1500 g. The mean (±SD) oxygenation indexat randomization was 24.6±16.3 for the first oxy-genation-index stratum, and 20.4±17.4 for the sec-ond stratum.

The baseline characteristics for eligible infantswho did not undergo randomization were similarto those for enrolled infants. The reasons for notenrolling were refusal of the parent (31 percent);unavailability of the parent (5 percent); or consentnot being sought because of the recommendationof the attending physician (17 percent), unavail-ability of equipment (9 percent), use of high-fre-quency jet ventilation (8 percent), or other reasons(30 percent).

primary outcome

There was no difference between the incidence ofthe primary outcome (bronchopulmonary dyspla-sia or death) between the group given inhaled ni-tric oxide and the placebo group (80 percent vs. 82percent; relative risk, 0.97; 95 percent confidenceinterval, 0.86 to 1.06; P=0.52) (Table 3). The rate ofbronchopulmonary dysplasia was 60 percent in thegroup given inhaled nitric oxide and 68 percent inthe placebo group (relative risk, 0.90; 95 percentconfidence interval, 0.75 to 1.08; P=0.26), and therate of death was 52 percent in the group given in-haled nitric oxide and 44 percent in the placebogroup (relative risk, 1.16; 95 percent confidence in-terval, 0.96 to 1.39; P=0.11). There were no discern-ible differences between the group given inhalednitric oxide and the placebo group for the follow-ing variables: age at death (20 vs. 24 days, P=0.54)or cause of death (respiratory failure, 49 percentvs. 42 percent; neurologic insult, 4 percent vs. 1 per-cent; infection, 5 percent vs. 10 percent; necrotiz-ing enterocolitis, 8 percent vs. 2 percent; supportwithdrawn, 19 percent vs. 26 percent; or other, 16percent vs. 19 percent; P=0.13 for the equality ofthe distribution between the two treatment groups).

secondary outcomes

The frequency of severe intraventricular hemor-rhage or periventricular leukomalacia was not sig-

* Plus–minus values are means ±SD.† Race or ethnic group was self-reported.

‡ Data were not available for all infants.

Table 1. Baseline Characteristics of the Infants.*

CharacteristicInhaled Nitric Oxide

(N=210)Placebo (N=210)

Birth weight — g 840±264 837±260

Gestational age — wk 26±2 26±2

Male sex — no. (%) 133 (63) 127 (60)

Mother’s race or ethnic group — no. (%)†

White 95 (45) 96 (46)

Black 69 (33) 78 (37)

Hispanic 36 (17) 32 (15)

Other 10 (5) 4 (2)

Born at study hospital — no. (%) 165 (79) 159 (76)

Prenatal corticosteroids — no. (%)‡ 119 (70) 114 (67)

Delivery by cesarean section — no. (%) 144 (69) 139 (66)

Apgar scores <4 at 1 min — no. (%)‡ 92 (55) 87 (52)


Cause of respiratory failure — no. (%)

Respiratory distress syndrome 192 (91) 190 (90)

Sepsis or pneumonia 6 (3) 10 (5)

Aspiration syndromes 1 (<1) 0

Idiopathic persistent pulmonary hypertension of the newborn

6 (3) 5 (2)

Suspected pulmonary hypoplasia 5 (2) 5 (2)

* Plus–minus values are means ±SD.† The oxygenation index was calculated as 100 ¬ the fraction of inspired oxygen

¬ mean airway pressure (in centimeters of water) ÷ the partial pressure of ar-

terial oxygen (in millimeters of mercury).

Table 2. Status of Infants at Randomization.*

StatusInhaled Nitric Oxide


Age — hr 26±23 28±22

Oxygenation index† 23±17 22±17

Surfactant — no. of doses given 2±1 2±1

Type of ventilation — no. (%)

High-frequency oscillatory ventilation 116 (55) 116 (55)

High-frequency flow interruption 9 (4) 8 (4)

Conventional mechanical ventilation 85 (40) 86 (41)

Inotropic support — no. (%) 127 (60) 126 (60)

Sedation or analgesia — no. (%) 155 (74) 150 (71)

Paralytic agents — no. (%) 31 (15) 25 (12)

Postnatal corticosteroids — no. (%) 20 (10) 22 (10)

Pulmonary air leaks — no. (%) 26 (12) 31 (15)

Pulmonary hemorrhage — no. (%) 22 (10) 15 (7)

Seizures — no. (%) 8 (4) 6 (3)

Copyright © 2005 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at KIZ - ABT LITERATURVERWALTUNG on October 23, 2005 .

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nificant differences between treatment groups inthe baseline characteristics (Table 1) or status atthe time of randomization (Table 2). The distribu-tion by birth weight did not differ significantly be-tween the two treatment groups, with an overall dis-tribution of 47 percent in the infants who weighed401 to 750 g, 28 percent in those who weighed 751to 1000 g, and 25 percent in those who weighed1001 to 1500 g. The mean (±SD) oxygenation indexat randomization was 24.6±16.3 for the first oxy-genation-index stratum, and 20.4±17.4 for the sec-ond stratum.

The baseline characteristics for eligible infantswho did not undergo randomization were similarto those for enrolled infants. The reasons for notenrolling were refusal of the parent (31 percent);unavailability of the parent (5 percent); or consentnot being sought because of the recommendationof the attending physician (17 percent), unavail-ability of equipment (9 percent), use of high-fre-quency jet ventilation (8 percent), or other reasons(30 percent).

primary outcome

There was no difference between the incidence ofthe primary outcome (bronchopulmonary dyspla-sia or death) between the group given inhaled ni-tric oxide and the placebo group (80 percent vs. 82percent; relative risk, 0.97; 95 percent confidenceinterval, 0.86 to 1.06; P=0.52) (Table 3). The rate ofbronchopulmonary dysplasia was 60 percent in thegroup given inhaled nitric oxide and 68 percent inthe placebo group (relative risk, 0.90; 95 percentconfidence interval, 0.75 to 1.08; P=0.26), and therate of death was 52 percent in the group given in-haled nitric oxide and 44 percent in the placebogroup (relative risk, 1.16; 95 percent confidence in-terval, 0.96 to 1.39; P=0.11). There were no discern-ible differences between the group given inhalednitric oxide and the placebo group for the follow-ing variables: age at death (20 vs. 24 days, P=0.54)or cause of death (respiratory failure, 49 percentvs. 42 percent; neurologic insult, 4 percent vs. 1 per-cent; infection, 5 percent vs. 10 percent; necrotiz-ing enterocolitis, 8 percent vs. 2 percent; supportwithdrawn, 19 percent vs. 26 percent; or other, 16percent vs. 19 percent; P=0.13 for the equality ofthe distribution between the two treatment groups).

secondary outcomes

The frequency of severe intraventricular hemor-rhage or periventricular leukomalacia was not sig-

* Plus–minus values are means ±SD.† Race or ethnic group was self-reported.

‡ Data were not available for all infants.

Table 1. Baseline Characteristics of the Infants.*

CharacteristicInhaled Nitric Oxide


Birth weight — g 840±264 837±260

Gestational age — wk 26±2 26±2

Male sex — no. (%) 133 (63) 127 (60)

Mother’s race or ethnic group — no. (%)†

White 95 (45) 96 (46)

Black 69 (33) 78 (37)

Hispanic 36 (17) 32 (15)

Other 10 (5) 4 (2)

Born at study hospital — no. (%) 165 (79) 159 (76)

Prenatal corticosteroids — no. (%)‡ 119 (70) 114 (67)

Delivery by cesarean section — no. (%) 144 (69) 139 (66)



Cause of respiratory failure — no. (%)

Respiratory distress syndrome 192 (91) 190 (90)

Sepsis or pneumonia 6 (3) 10 (5)

Aspiration syndromes 1 (<1) 0

Idiopathic persistent pulmonary hypertension of the newborn

6 (3) 5 (2)

Suspected pulmonary hypoplasia 5 (2) 5 (2)

* Plus–minus values are means ±SD.† The oxygenation index was calculated as 100 ¬ the fraction of inspired oxygen

¬ mean airway pressure (in centimeters of water) ÷ the partial pressure of ar-

terial oxygen (in millimeters of mercury).

Table 2. Status of Infants at Randomization.*

StatusInhaled Nitric Oxide


Age — hr 26±23 28±22

Oxygenation index† 23±17 22±17

Surfactant — no. of doses given 2±1 2±1

Type of ventilation — no. (%)

High-frequency oscillatory ventilation 116 (55) 116 (55)

High-frequency flow interruption 9 (4) 8 (4)

Conventional mechanical ventilation 85 (40) 86 (41)

Inotropic support — no. (%) 127 (60) 126 (60)

Sedation or analgesia — no. (%) 155 (74) 150 (71)

Paralytic agents — no. (%) 31 (15) 25 (12)

Postnatal corticosteroids — no. (%) 20 (10) 22 (10)

Pulmonary air leaks — no. (%) 26 (12) 31 (15)

Pulmonary hemorrhage — no. (%) 22 (10) 15 (7)

Seizures — no. (%) 8 (4) 6 (3)


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nificantly different between the group given in-haled nitric oxide and the placebo group accordingto concurrent local radiology readings (39 percentvs. 32 percent, respectively; relative risk, 1.25; 95percent confidence interval, 0.95 to 1.66; P=0.11)(Table 3) or by central reading performed after thetrial was terminated (37 percent vs. 38 percent; rel-ative risk, 0.97; 95 percent confidence interval, 0.74to 1.27; P=0.81). The local reading was based onthe worst results of evaluation among ultrasoundexaminations of the head performed during the ad-ministration of the study gas, at 28±3 days, and af-ter 28 days of age. Ultrasound examinations of thehead were not available for 86 infants, 93 percentof whom had died. Death occurred by 14 days in91 percent and before 28 days in 98 percent. Thecentral reading was based on the worst results ofevaluation among all ultrasound examinations ofthe head performed during hospitalization. Therewere no significant differences in the two treatmentgroups with respect to the days on oxygen, the

length of assisted ventilation, the length of hospi-talization, the incidence of air leak, threshold ret-inopathy of prematurity, or “physiological broncho-pulmonary dysplasia” for survivors (Table 3).

Thirty minutes after administration of the studygas, at a concentration of 5 ppm, the group giveninhaled nitric oxide had a significant increase inthe PaO

2

and a significant decrease in the oxygena-tion index as compared with the placebo group (Ta-ble 4). The PaO

2

and the oxygenation index showedno significant change in either group when the con-centration of the study gas was increased to 10 ppm.More than 70 percent of the infants in the placebogroup did not have a response to the study gas; theseinfants had a significantly shorter length of timeon the study gas (39 vs. 76 hours).

There were 26 deviations from the protocol. Fiveineligible infants were randomly assigned to a studygroup. One infant received the wrong study gas.Four incidents of unblinding occurred. Sixteen in-fants received open-label inhaled nitric oxide: sev-

* Plus–minus values are means ±SD. CI denotes confidence interval, IVH intraventricular hemorrhage, and PVL periven-tricular leukomalacia.

† Values were adjusted for center, birth-weight group, and oxygenation-index entry stratum.‡ The outcome of death or bronchopulmonary dysplasia is for 208 infants in the placebo group.§ This outcome is for infants who were alive at 36 weeks (109 in the group receiving inhaled nitric oxide and 127 in the

placebo group).¶ Results of ultrasound examinations of the head were available for 179 infants in the group receiving inhaled nitric oxide

and for 155 in the placebo group.¿ This outcome is for infants who survived (101 in the group receiving inhaled nitric oxide and 117 in the placebo group).** This outcome was defined according to the protocol of Walsh et al.,

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for 100 infants in the group receiving inhaled ni-tric oxide and for 115 infants in the placebo group.

††Examination for retinopathy of prematurity was performed in 98 infants in the group receiving inhaled nitric oxide and

112 infants in the placebo group.

Table 3. Primary and Secondary Outcomes.*

Outcome

InhaledNitric Oxide

(N=210)Placebo(N=210)

Relative Risk(95% CI)† P Value

Primary — no. (%)

Death or bronchopulmonary dysplasia‡ 167 (80) 170 (82) 0.97 (0.86–1.06) 0.52

Death 109 (52) 93 (44) 1.16 (0.96–1.39) 0.11

Bronchopulmonary dysplasia§ 65 (60) 86 (68) 0.90 (0.75–1.08) 0.26

Secondary

Grade 3 or 4 IVH or PVL — no. (%)¶ 69 (39) 50 (32) 1.25 (0.95–1.66) 0.11

Oxygen use — days¿ 84±63 91±61 0.91

Physiological bronchopulmonary dysplasia — no. (%)**

50 (50) 69 (60) 0.87 (0.68–1.10) 0.17

Length of hospitalization — days¿ 101±47 111±48 0.65

Duration of ventilation — days¿ 39±45 47±53 0.56

Incidence of air leak — no. (%)¿ 35 (35) 37 (32) 1.12 (0.78–1.61) 0.55

Threshold retinopathy of prematurity — no. (%)†† 29 (30) 36 (32) 1.16 (0.81–1.64) 0.42




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nitric oxide in premature infants have shown var-ied results. In a trial of 80 premature infants withsevere hypoxemic respiratory failure, Kinsella et al.reported a decrease in the number of days on a ven-tilator and a trend toward a decreased incidenceof bronchopulmonary dysplasia.

10

The Franco–

Belgian randomized trial of inhaled nitric oxideshowed no significant decrease in bronchopulmo-nary dysplasia or death in a cohort of premature in-fants with a median oxygenation index of approxi-mately 20.

11,12

A recent trial by Schreiber et al.studied a less critically ill cohort with a median oxy-

* Data were not available for all infants in the categories of bronchopulmonary dysplasia and grade 3 or 4 intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Some infants had bronchopulmonary dysplasia and died. CI denotes confidence interval.

† Values were adjusted for center, birth-weight group, and oxygenation-index stratum.

Table 5. Post Hoc Analysis According to Birth Weight, Type of Ventilation, and Oxygenation Index.*

VariableInhaled Nitric

Oxide PlaceboRelative Risk

(95% CI)† P Value

no. (%)

Birth weight

≤1000 g 158 158

Death or bronchopulmonary dysplasia 141 (89) 133 (85) 1.04 (0.96–1.13) 0.29

Death 98 (62) 76 (48) 1.28 (1.06–1.54) 0.01

Bronchopulmonary dysplasia 49 (73) 65 (73) 1.02 (0.85–1.23) 0.84

Grade 3 or 4 IVH or PVL 55 (43) 39 (33) 1.40 (1.03–1.88) 0.03

>1000 g 52 52


Death 11 (21) 17 (33) 0.65 (0.36–1.18) 0.16



Type of ventilation

Conventional mechanical ventilation 85 86


Death 53 (62) 34 (40) 1.46 (1.10–1.92) 0.01



High-frequency ventilation 125 124


Death 56 (45) 59 (48) 0.96 (0.75–1.24) 0.75



Oxygenation index

≤17 100 110


Death 45 (45) 40 (36) 1.27 (0.96–1.68) 0.09



>17 110 100


Death 64 (58) 53 (53) 1.11 (0.88–1.40) 0.39








•  Conclusions –  The use of iNO in criHcally ill premature infants weighing less than 1500g does not decrease the rates of death or BPD

–  Further trials are required to determine whether inhaled nitric oxide benefits infants with a BW of 1000g or more

NIH Consensus Conference Statement: Inhaled Nitric-‐Oxide Therapy for Premature Infants

•  “… the available evidence does not support use of iNO in early-‐rouHne, early-‐rescue, or later-‐rescue regimens in the care of premature infants of <34 weeks gestaHon who require respiratory support.

•  There are rare clinical situaHons, including pulmonary hypertension or hypoplasia, that have not been inadequately studied in which iNO may have benefit in infants of <34 weeks ‘ gestaHon. In such situaHons, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainHes.

29 Cole et al. Pediatrics 2011;127:363

Use of Inhaled Nitric Oxide in Preterm Infants AAP Commijee on Fetus and Newborn

•  “The results of randomized controlled trials, tradiHonal meta-‐analyses, and an indiviualized paHent data meta-‐analysis study indicated that neither rescue nor rouHne use of iNO improves survival with respiratory failure” (Evidence quality, A, grade of recommendaHon, strong)

30 Kumar and Committee on Fetus and Newborn. Pediatrics 2014;133:164

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Infants aoer Prolonged Preterm Rupture of Membranes (PPROM) with respiratory failure

•  Decreased proinflammatory cytokines and nitrite + nitrate levels were low, but increased during iNO treatment (Aikio et al. J Pediatr 2012;161:397) –  SuggesHng that there may be a transient deficiency in the inflammatory response including a defect in nitric oxide generaHon in the airspaces.

31

Inhaled Nitric Oxide in Preterm Infants: An Individual-‐PaHent Data Meta-‐analysis of RCTs (MAPPiNO) •  Significant heterogeneity in paHent populaHons between

trials and within trials •  Individual paHent data Meta-‐analysis provides more

uniformity •  Data from 3298 infants in 12 trails

32 Askie et al. Pediatrics 2011;128:729

Inhaled Nitric Oxide in Preterm Infants: An Individual-‐PaHent Data Meta-‐analysis of RCTs (MAPPiNO)




Conclusions: •  RouHne use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. •  The use of a higher starHng dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examinaHon.



Off-‐Label Use of Inhaled Nitric Oxide Aoer Release of NIH Consensus Statement

Pediatrix Medical Group 2009-‐2013 •  iNO use in preterm infants 23-‐29 wks GA: 5.03% to 6.19% (23% increase)

36 Elisworth et al. Pediatriacs 2015;135 (April) currently online

Among all neonates ,34 weeksadmitted to level III or IV PMG NICUsin 2013, iNO utilization rates wereinversely proportional to gestationalage (Fig 2). For example, 13.9% ofall 23- to 24-week infants weretreated with iNO, compared with0.6% of 33-week neonates. Of allneonates who received iNO therapyin 2013, nearly half (46%; Fig 3)were ,34 weeks’ gestation and thus

received this drug off-label. Becauseonly 1.3% of iNO-exposed patientswere treated at level II NICUs, datafor these patients were not includedin the above analyses.

Specifics regarding the age atinitiation for all neonates andduration of use (first course) forthose with complete data aredisplayed in Tables 2 and 3,respectively. There were no

significant differences in eitherpattern of use within gestational agecohorts from 2009 to 2013. Infants,34 weeks’ gestation accounted formore than half of all iNO days eachyear of the study period.

DISCUSSION

We demonstrate that off-labelprescription of iNO to pretermneonates has not declined in theyears after the NIH statementdiscouraging routine use in thispopulation.22 Similar to NRN-affiliated clinicians,24 we detecteda small decrement in iNO use in 2011among premature infants, though thischange was not statisticallysignificant. By extending our analysisthrough 2013, we were able todetermine that the overall rate of off-label iNO use among all gestationalage subgroups persisted at itsbaseline level and the rate increasedamong neonates ,30 weeks’gestation. Between 2009 and 2013,for the 79 434 infants 23 to 29 weekscared for at the 703 hospitals in theUnited States participating in the

TABLE 1 Distribution of iNO Use in PMG NICUs

Discharge Year P

2009 2010 2011 2012 2013

Total patients in CDW, n 79 883 82 778 85 149 85 994 86 767iNO-treated patients, n (%) 1049 (1.3) 1120 (1.4) 1085 (1.3) 1159 (1.3) 1263 (1.5) .2EGA, median (10th–90th) 35 (24–40) 35 (24–40) 36 (24–40) 34 (24–40) 34 (24–40) .6EGA group, n (%), wka .223–29 392 (37) 397 (35) 366 (34) 441 (38) 476 (38) —

30–33 99 (9) 97 (9) 86 (8) 107 (9) 106 (8) —

$34 556 (53) 621 (55) 630 (58) 602 (52) 674 (53) —

Birth weight, median (10th–90th) 2.27 (0.62–3.71) 2.42 (0.60–3.80) 2.59 (0.62–3.75) 2.20 (0.59–3.79) 2.27 (0.60–3.78) .01Boy, n (%) 614 (59) 666 (59) 638 (59) 684 (59) 721 (57) .4Race/ethnicity, n (%)a .1White 504 (48) 548 (49) 498 (46) 560 (48) 631 (50) —

Hispanic 223 (21) 251 (22) 261 (24) 227 (20) 224 (18) —

African American 211 (20) 221 (20) 222 (20) 263 (23) 258 (20) —

Asian 29 (3) 31 (3) 20 (2) 30 (3) 32 (3) —

American/Alaska Native 15 (1) 16 (1) 10 (1) 10 (1) 19 (2) —

Pacific Islander 3 (0) 3 (0) 5 (0) 6 (1) 11 (1) —

Other 64 (6) 50 (4) 69 (6) 63 (5) 88 (7) —

Cesarean delivery, n (%) 704 (67) 772 (69) 731 (67) 768 (66) 858 (68) .9Outborn, n (%) 419 (40) 445 (40) 404 (37) 416 (36) 456 (36) .4Disposition, n (%)a .7Alive 586 (56) 604 (54) 604 (56) 634 (55) 713 (56) —

Died 231 (22) 246 (22) 213 (20) 264 (23) 261 (21) —

Transfer 232 (22) 270 (24) 268 (25) 261 (23) 289 (23) —

a Based on 2-tailed x2 testing evaluating the group.

FIGURE 1Change in percentage of infants treated with iNO at PMG NICUs within 3 gestational age groupingsfrom 1997 to 2013.

PEDIATRICS Volume 135, number 4, April 2015 3 by Helmut Hummler on March 22, 2015pediatrics.aappublications.orgDownloaded from

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Off-‐Label Use of Inhaled Nitric Oxide Aoer Release of NIH Consensus Statement

37 Elisworth et al. Pediatriacs 2015;135 (April) currently online

Vermont Oxford Network, the rate ofiNO utilization increased from 6.7%to 6.9% (unpublished data providedby the Vermont Oxford Network).

iNO use within PMG has acceleratedmost rapidly among extremelypreterm neonates, a subgroup thatnow accounts for nearly half of all

iNO use in the NICU despite thepotential for morbidities in thispopulation.11,28 Given increased iNOutilization in higher-acuity units,24 itmay be that iNO is directed at morecritically ill neonates for whichevidence of benefit and safety of useis most limited.6–16 The observationthat neonatologists wouldincreasingly prescribe iNO ina manner contrary to clinicalevidence and expert opinion22,23 isfascinating and provocative.

We suspect that off-label iNOutilization is driven by the idea thatiNO promotes increased survival.Despite no clear evidence that there isimproved survival in iNO-exposedpremature infants, the immediatephysiologic effect of iNO is welldescribed, with an increase in oxygensaturation being readily apparent inmany infants who are exposed toiNO.6,29,30 We speculate that thisphysiologic effect likely leads manyneonatologists to attribute thesurvival of iNO-exposed neonates toiNO therapy, when in fact a number ofother factors could have led to thatinfant’s outcome. We acknowledgethat it is possible that iNO may betherapeutic in the premature neonate,but clearly its role has not beendelineated. For example, there may bea role for use in infants withpremature rupture of membranes,oligohydramnios, and pulmonaryhypoplasia, but currently there are noprospective studies in thispopulation.31 Perhaps the history ofiNO eventually will resemble that ofanother 1-time controversial therapy,extracorporeal membraneoxygenation. Once regarded as unsafeand founded on suboptimal clinicalevidence,32,33 extracorporealmembrane oxygenation is nowregarded as lifesaving therapy witha clear role for utilization in selectgroups of neonates.34

Until that time, we must consider theincreased costs that the use of iNOtherapy contributes to caring forcritically ill neonates. Among the 456

FIGURE 2Percentage of infants treated with iNO at PMG (level III or IV) NICUs stratified by gestational age in2013.

FIGURE 3Distribution of total iNO use by gestational age in PMG (level III or IV) NICUs in 2013.

TABLE 2 Age at Initiation of First Course of Therapy

EGA Group DOL iNO Started, d 2009 2010 2011 2012 2013

23–29 wk 0–7 227 (58) 208 (52) 200 (55) 252 (57) 261 (55)8–28 104 (27) 117 (29) 97 (27) 96 (22) 130 (27).28 61 (16) 72 (18) 69 (19) 93 (21) 85 (18)

30–33 wk 0–7 87 (88) 80 (82) 71 (83) 91 (85) 90 (85)8–28 5 (5) 6 (6) 5 (6) 7 (7) 8 (8).28 7 (7) 11 (11) 10 (12) 9 (8) 8 (8)

$34 wk 0–7 532 (96) 588 (95) 597 (95) 565 (94) 641 (95)8–28 20 (4) 22 (4) 16 (3) 26 (4) 20 (3).28 4 (1) 11 (2) 17 (3) 11 (2) 13 (2)

Data presented as n (%). DOL, day of life.

4 ELLSWORTH et al by Helmut Hummler on March 22, 2015pediatrics.aappublications.orgDownloaded from

Vermont Oxford Network, the rate ofiNO utilization increased from 6.7%to 6.9% (unpublished data providedby the Vermont Oxford Network).

iNO use within PMG has acceleratedmost rapidly among extremelypreterm neonates, a subgroup thatnow accounts for nearly half of all

iNO use in the NICU despite thepotential for morbidities in thispopulation.11,28 Given increased iNOutilization in higher-acuity units,24 itmay be that iNO is directed at morecritically ill neonates for whichevidence of benefit and safety of useis most limited.6–16 The observationthat neonatologists wouldincreasingly prescribe iNO ina manner contrary to clinicalevidence and expert opinion22,23 isfascinating and provocative.

We suspect that off-label iNOutilization is driven by the idea thatiNO promotes increased survival.Despite no clear evidence that there isimproved survival in iNO-exposedpremature infants, the immediatephysiologic effect of iNO is welldescribed, with an increase in oxygensaturation being readily apparent inmany infants who are exposed toiNO.6,29,30 We speculate that thisphysiologic effect likely leads manyneonatologists to attribute thesurvival of iNO-exposed neonates toiNO therapy, when in fact a number ofother factors could have led to thatinfant’s outcome. We acknowledgethat it is possible that iNO may betherapeutic in the premature neonate,but clearly its role has not beendelineated. For example, there may bea role for use in infants withpremature rupture of membranes,oligohydramnios, and pulmonaryhypoplasia, but currently there are noprospective studies in thispopulation.31 Perhaps the history ofiNO eventually will resemble that ofanother 1-time controversial therapy,extracorporeal membraneoxygenation. Once regarded as unsafeand founded on suboptimal clinicalevidence,32,33 extracorporealmembrane oxygenation is nowregarded as lifesaving therapy witha clear role for utilization in selectgroups of neonates.34

Until that time, we must consider theincreased costs that the use of iNOtherapy contributes to caring forcritically ill neonates. Among the 456

FIGURE 2Percentage of infants treated with iNO at PMG (level III or IV) NICUs stratified by gestational age in2013.

FIGURE 3Distribution of total iNO use by gestational age in PMG (level III or IV) NICUs in 2013.

TABLE 2 Age at Initiation of First Course of Therapy

EGA Group DOL iNO Started, d 2009 2010 2011 2012 2013

23–29 wk 0–7 227 (58) 208 (52) 200 (55) 252 (57) 261 (55)8–28 104 (27) 117 (29) 97 (27) 96 (22) 130 (27).28 61 (16) 72 (18) 69 (19) 93 (21) 85 (18)

30–33 wk 0–7 87 (88) 80 (82) 71 (83) 91 (85) 90 (85)8–28 5 (5) 6 (6) 5 (6) 7 (7) 8 (8).28 7 (7) 11 (11) 10 (12) 9 (8) 8 (8)

$34 wk 0–7 532 (96) 588 (95) 597 (95) 565 (94) 641 (95)8–28 20 (4) 22 (4) 16 (3) 26 (4) 20 (3).28 4 (1) 11 (2) 17 (3) 11 (2) 13 (2)

Data presented as n (%). DOL, day of life.

4 ELLSWORTH et al by Helmut Hummler on March 22, 2015pediatrics.aappublications.orgDownloaded from

Inhaled Nitric Oxide for the Preterm Infant: Evidence vs. PracHce

•  Three possibliHes –  Lack of awareness of the evidence (-‐) –  Neonatologists’ view that the evidence may not be generizable

in a parHcular situaHon (+) –  Neonatologists’ insHnct to ajempt to normalize physiology (++)

•  Need for focused trials –  iNO on preterm infants with evidence of PH (robust entry

criteria using ABG, echo …) –  iNO in preterm infants aoer PPROM

•  Some quesHons may be answered using large databases –  Call for registering paHents undergoing off-‐label treatment to

databases such as the exisHng “European Inhaled Nitric Oxide Registry” (www.medscinet.net/ino )

38 Finer & Evans Pediatrics 2015;135 April, currently online

Conclusions

•  No rouHne use of iNO in preterm infants with respiratory failure

•  Individualized approach –  Severe hypoxic respiratory failure (based on applied

pathophysiology) ■  PPHN should be proven (by echocardiography) in preterm infants ■  Preterm infants born aoer PPROM? ■  Preterm infants with early onset sepsis?

•  Parents should be informed/involved if iNO is used in preterm infants

•  PaHents should be treated within the context of RCTs and/or registered in a database –  Database should include long-‐term outcomes

39

Thank you very much!

40

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