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INO in neonatal PH and BPDWhy the impressive effects observed in animal models have not been translated in humans?

Jean-Christophe Mercier, 1 Anh-Tuan Dinh-Xuan, 2 Olivier Baud. 3

1 Department of Paediatric Emergency Medicine, Hôpital Robert Debré2 Department of physiology, Université Paris Descartes

3 Department of Neonatology, Hôpital Robert DebréINSERM U-1011 « Neuroprotect » Université Paris Diderot , Sorbonne Paris Cité

France

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Conflict of Interest Disclosure

• I received no honorarium for attending several meetings of the INOTherapeuticsAdvisory Board, but received travel grants from Ikaria, Inc.

• Our research group has also received a USD 100,000 gra nt from IKARIA, Inc. to study the effects on the brain of iNO in rat pups.

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Outline

1. From the ‘vascular hypothesis ’ of BPD to inhaled nitric oxide therapy .

2. Disappointment of iNO clinical trials to prevent BPD in preterm human babies.

3. Is there , however, a small room for usingiNO in preterm infants with PPHN/PROM?

4. INO, a selective pulmonary vasodilatorwhich has systemic effects on the brain …

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1. From the ‘vascular hypothesis ’ of BPD to inhaled nitric oxide therapy .

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The ‘new BPD ’: An arrest of lung development

IntrauterineLung development

PostnatalLung development

Cytokine exposure

Antenatal steroids

Preterm deliveryhormonal deprivation?

Initiation of ventilation Inhibition of

alveolar & vascular

development

Postnatal steroids

Nutrition

Cytokine exposure

Oxygen Ventilation Infection

Alan H Jobe. Pediatr Res 1999; 46:641-3

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Rationale for using INO to prevent BPD:the ‘vascular hypothesis ’

Thébaud B & Abman SH. AJRCCM 2007; 175:978-85.

Jakkula Am J Physiol 2000

Lassus AJRCCM 2001Bhatt AJRCCM 2001Abman AJRCCM 2001

Tang Am J Physiol 2004Thébaud Circulation 2005

McCurmin Am J Physiol 2005Balasubramanian Am J Physiol 2006

VEGF fulfills Koch’s alveolarization postulate:1. Inhibition of VEGF signaling impaired alveolariz ation2. Impaired alveolarization is associated with decre ased VEGF pathway3. Exogenous VEGF/NO restores normal alveolar devel opment

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2. Disappointment of iNO clinical trials to prevent BPD in preterm human babies

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NEJM 2003; 349:2099-107.

N Engl J Med 2006; 355:354-64.

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Lancet 2010; 376:346-54.

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Lancet 2010; 376:346-54.

11Pediatrics 2013; 132:695-703.

12Pediatrics 2013; 132:695-703.

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BPD or death @36 wksCognitive impairment

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1. The available evidence does not support use of iNO in early-routine, early-rescue, or late-rescue regimens in the care of preterm infants of <34 wks GA who require respiratory support.

2. The are rare clinical situations, including pulmonaryhypertension or hypoplasia that have been inadequately studiedin which iNO may have benefit in infants of <34 wks GA.

3. Future research should seek to understand the gap betweenbenefits on lung development and function in infants at high riskof BPD suggested by basic research and animal studies.

4. Predefined subgroup and posthoc analyses of previous tria ls showing potential benefit of iNO have generated hypotheses for future research for clinical trials .

5. On the basis of currently available data, hospitals, c linicians, and the pharmaceutical industry should avoid marketing iNO for premature infants of <34 wks GA

Pediatrics 2011; 127(2):363-9.

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INO and BPD: concerns about the design and interpretation of the meta-analysis

Steinhorn RH et al. Pediatrics 2011; 128(1):e255-6.

Mutiple doses for various lengths of treatment

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17Pediatrics 2011; 128(4):729-39.

Death or CLDaccording to subgroup

Severe neurologic eventsaccording to subgroup

Favors iNO

Favors control

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3. Is there , however, a small room for using iNO as a rescue therapy in

preterm babies with PPHN/PROM?

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Aikio O et al. J Pediatr 2012; 161(3):397-403.

iNO

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HFR + iNO PROM

Spontaneous birth w/o PROM Preeclampsia

Aikio O et al. J Pediatr 2012; 161(3):397-403.

[Nitrite+Nitrate] in airway specimens shortly after bir th

iNO supply

22Pediatrics 2015; 135(4):ahead of print

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• So why this continued use of iNO?– Lack of awareness of the evidence?

– Evidence is not generalizable to a particular situation?

– Very likely, neonatal intensivists’ instinct to attempt to normalize physiology when facedwith a hypoxic ventilated baby?

• Speculation: iNO is mainly used in 2 clinical senarios:– During acute crises of oxygenation in the first week or two of life;

– In infants with evolving chronic lung disease with suspected PH, despite the negativeresults of the recently completed trial ‘INO for the prevention of BPD in preterm infants’(also known as NEWNO) (Hot Topics in Neonatology, Washington DC, 2014)

• The risk for iNO appears to be the highest and efficacy l owest for infants weighing <1000g at birth.

– However, there is still a need for specifically focused trials of iNO on preterm infants with evidence of PH,

– Or other specific conditions such as prolonged oligohydramnios.

Pediatrics 2015; 135(4):ahead of print

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1. The results of RCTs, traditional and individualized patient data meta-analyses indicate that neither rescue nor routine use of INO improvessurvival in preterm infants with respiratory failure (Evidence q uality A, strong recommendation).

2. Evidence does not support treating preterm infants who have RF w ith INOfor the purpose of preventing/ameliorating BPD, sever e IVH, and otherneonatal morbidities (A, strong recommendation).

3. The results of one multienter RCT suggest that treatm ent with a high dose of INO (20ppm) beginning in the second postnatal wee k may provide a small reduction in BPD. However these results need to be c onfirmed by other trials.

4. An individual-patient data meta-analysis that inclu ded 96% of preterminfants enrolled in all published INO trials found no statistically significantdifferences in INO effect according to any patient-level characteristics, including GA, race, OI, postnatal age at enrollment, e vidence of PPHN, and mode of ventilation.

5. There are limited data and inconsistent results regarding the effects of INO treatment on pulmonary outcomes of preterm infants in earlychildhood.

FAAP and Committee on Fetus and Newborn. Pediatrics 2014; 133(1):164-70.

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4. INO, a selective pulmonary vasodilatorwhich has systemic effects on the brain …

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INO mediates the redistributionof CBF during brain ischemia INO offers neuroprotection

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Impact of hyperoxia (FiO 2=0.8) on the developing brain

ED1: microglial activationCC3: hemispheric cell death

Ki67: proliferating cellsO4, NG2: developing oligo

GFAP: mature astrocytesAPC: mature oligoMBP: myelin density

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INO reduced inflammation & cell death in the developin g brain after postnatal hyperoxia

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3-nitrotyrosine immunostaining at P7Negative Ctrl Ctrl rats in room air 5-ppm INO 20-ppm IN O

31Duong-Quy S. et al. Nitric Oxide 2014; 38:8-16.

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Conclusions• Definitely, INO has systemic effects ,

at least on the brain and lung.

• Complexity of nitrite/nitrate and S-nitrosothiol biology (NO transport)

• Why such effects observed in animals do not translate into humanbeings?– Rat P0 P7 P9-10

– Human 22-24 34-36 40 wks

– Is it a matter of dosage (20 vs 5ppm)?

• Genetic background (~same# genes) vs. major influence of epigenetics in humans, as well as the complexity of human diseases?

Unraveling the reactions of NO,Nitrite, and Hemoglobin

In physiology and therapeutics

Atherioscleros Thromb Vasc Biol2006; 26:697-705.