Persistent Pulmonary Hypertension of the Newborn - Mattel ...

It is 4 AM in the morning -------You attend the delivery of M.L. at 40 weeks’ gestation. He iscovered with thick meconium. Endotracheal suctioning producesthick meconium from the trachea.‣The infant receives assisted ventilation and surfactant‣Inhaled nitric oxide is started at an OI of 15‣Echocardiogram on DOL 2 shows severe pulmonaryhypertension (PPHN)‣Cranial sonography shows parenchymal blood‣The OI is now 40WHAT ARE YOU GOING TO DO?

Beyond “NO” – Yes, Yes, Yes ---• PDE inhibitors – Sildenafil, Milrinone• ET receptor antagonists - Bosentan• Vasodilator Prostaglandins – PGI 2 , PGE 1• Magnesium sulfate• NO precursor – L-arginine, Citrulline• Free radical scavenger – superoxide dismutase• Rho-kinase antagonists

Off Label Drug Use• FDA regulates labeling of drugs; it does notregulate use of drugs by physicians• Off-label drug use• may benefit individual patients• is not improper, illegal or contraindicated• does not require an IND• is not research & does not require consent• Reluctance of off-label may deprive patients ofpotentially effective treatmentAAP, 2002

Off Label Drug Use• Off-label use of a drug should be:• based on sound evidence, expert medical judgment• done in good faith, in the best interest of the patient• discussed with the patient or parents• FDA encourages:• Publication of experience with off-label use of drugs• Report adverse events

Off Label Drug Use• New uses, doses, or indications will not beapproved by the FDA until substantial evidenceof safety and effectiveness – years, never??• Ethical & safety challenges• Neonates are constantly undergoing maturation –alter pharmacokinetics & end-organ responses• Therefore, clinical trials in adults or older childrencannot predict pharmacokinetics & end-organresponses of neonates

Off Label Drug Use• Should we accept off-label drug use without fullknowledge of safety, pharmacokinetics, orefficacy and risk therapeutic misadventures?

Post-INO Era• Questionnaire to220 neonatologistsin Canada,Australia, NewZealand• High Likelihoodof using othertreatments forPPHNShivananda, 2012

Beyond NOToxic MoleculeLife Threatening Effects ofDiscontinuing INOLack of Availability of INO &/ ECMODe-regionalized neonatal careResource poor countries↓eNOS↑ETLack of Response in 30-40%Not possible to predict responseInitial response is not a guarantee ofsustained responseALTERNATIVES ???Cost of INO is Exorbitant$10,142 initial charge, $10,142/day,max $25,000 per patient

Regulation of Pulmonary Vascular ToneBenza,2007

SELECTIVITYNO – Molecule of the 1990’sIMPACTNeonatal Respiratory ECLS casesNo effect on mortality

Regulation of Pulmonary Vascular ToneSILDENAFILDipyridamoleZaprinastPentoxyfylline

Sildenafil for PulmonaryHypertension inNeonatesShah, 2011

PO Sildenafil• 1 st dose - 1 mg/0.5 ml/kg per OGT• Dosing every 6 hours• Double dose if OI did not improve & BPstable after previous doseBaquero, 2006

Intravenous Sildenafil in PPHNSteinhorn, 2009

PDE-5 5 Inhibitor - Sildenafil• RCT to determine role of sildenafil in management ofPPHNDrug Sponsor NCT# Start Completion N Centers TypeInhaled Iloprost University of Chicago NCT00409526 12/2006 06/2009 40 2 PilotMilrinone CHOP NCT01088997 06/2010 03/2012 18 3 (US) PKSildenafil (iv) Pfizer NCT01069861 12/2010 04/2013 40 1 (UK) Phase 2Sildenafil (po)Third Military MedicalUniversity, ChinaNCT01373749 03/2011 03/2011 40 2 Phase 3Sildenafil (iv) NHLBI NCT01409031 06/2011 06/2012 50 7 (US) Phase 2Inhaled PGE1 NICHD NCT00598429 09/2011 05/2012 50 9 Phase 2Sildenafil (po)Hamad MedicalCorporation, QatarNCT01558466 11/2011 11/2015 1001 (Qatar) Phase 3Bosentan Actelion NCT01389856 12/2011 08/2013 30 17 Phase 3

PDE5 Inhibitor - Sildenafil• In PPHN, sildenafil may:• facilitate weaning from INO• Decreases duration of mechanical ventilation,hospital stay• Sildenafil in combination with:• INO did not result in significant ↓ in systemic BP & actuallyimproved oxygenation• Milrinone (n=10) was not associated with hypotension orother adverse events

PDE-5 5 Inhibitor - Sildenafil• Potential AEs• delayed gastric emptying• hypotension• PDE6 inhibition - retinaldamage• Severe ROP - one PTinfant• Adults- CNS effects –emotional, psychologicaldisturbances, amnesia,loss of consciousness,aggressive behavior, ICH

Regulation of Pulmonary Vascular Tone, 3MILRINONE, 3

PDE-3 3 Inhibitor - Milrinone• Primary physiological disturbance in PPHN →↑RV afterload• Traditionally, physicians reluctant to treat PPHNwith afterload-reducing reducing agents because ofconcerns of systemic hypotension & desire tomaintain supranormal systemic BP• very high-dose vasopressors• dopamine or epinephrine may exacerbate PPHN• tachycardia, ↑ increasing myocardial O2 demand,McNamara, 2006, J Crit Care

Increased PDE3 activity in resistance PA after birthPDE-3 3 Inhibitor -MilrinoneMilrinone ↓ PVR and PAP in:•experimental models•adults•neonates- post cardiacsurgeryMilrinone inhibits NE-induced constriction inresistance PA from 1dSB and 100% O 2+iNO lambsChen, 2009

Milrinone Improves Oxygenationin Neonates With SeverePPHN• Routes of administration reported - IV, inhalation• Potential AEs:• Hypotension, thrombocytopenia, intra-cranial bleedMcNamara, 2006, J Crit Care

2005,Danhaive2006,Bassler,Kirpalani2006,McNamara2010,TziallaPDE-3 3 Inhibitor - MilrinoneType ofStudyCaseseriesCaseseriesCaseseriesCasereportDiseasePPHNPPHNPPHNPPHNrefractory toINOSubjectsIUGR

Regulation of Pulmonary Vascular ToneBOSENTANEndothelin system in vascular tissueET−1=endothelin−1,BIG–ET−1=proendothelin−1, ECE=endothelin–converting enzyme,NO=nitric oxide, PGI 2 =prostacyclin

Endothelin PathwayppET-1ET-AET-1ET-BIvy, 2000, AJP- Lung Cell Mol Phys

Regulation of Pulmonary Vascular TonePLA2=Phospholipase A2COX-1 = cyclooxygenase-1COX-2 = cyclooxygenase-2HPETE= Hydroperoxyeicosatetraenoic acidsHETE= Hydroxyeicosatetraenoic acidsDark outline boxes = vasoconstrictorsLight outline boxes = vasodilatorsPGD 2 has both vaso-constrictor & -dilator activity

Evidence in Neonates - PPHNSood, 2007

In utero exposure to PGSynthetase inhibitors

PGI 2 in the Treatment of PAH• IV Epoprostenol• Inhaled Iloprost• PO Beraprost Sodium• Adverse Effects• jaw pain, diarrhea, flushing,headaches, nausea, vomiting• Infection, thrombosisBarst, 1996, NEJM

Non-selective action:• Systemic & pulmonary circulation• Ventilated & non-ventilated regionsSystemic hypotension (30-60%)Venous admixture effect (11%)Siobal , 2004, Resp Care

“Old Wine in New Bottles”Non-selectivePGE 1PGI 2NitroprussideTolazolineSelective• Pulmonary• Ventilated regions

PGE 1 - Metabolism70-95%PGE 115-OH PGDHT 1/2 10 sec15-keto PGE 1PGΔ 13 reductase13, 14-dihydrodihydro-15 keto-PGE1(15-KD PGE 1 )13, 14-dihydrodihydro-PGE1(PGE 0 )De-activation byΩ- & β oxidationPolar dicarboxylic compoundsexcreted in urine

SPV – Inhaled VasodilatorsInactivationHalf-lifePhysical formBufferpKaOther effectsPlatelet aggregationBronchiInflammationProliferationCytotoxicityINO IPGE 1 IPGI 2Pulmonary Pulmonary Hepaticseconds

Studies of Inhaled Prostaglandins in PulmonaryHypertension - AnimalsAuthor, yrWelte, 1993Zobel, 1995Booke, 1996Habler, 1996Habler, 1996Walmrath, 1997Krieg, 1998Ikeda, 1999Kumar, 2010PatientDrug6 dogs IPGI , INO212 piglets IPGI , 2 i.v. PGI 2 , iNO6 ewes IPGI , INO214 Healthy lambs IPGI 215 healthy lambs IPGI 2Rabbit lungINO, IPGI , IPGE 2 1 , i.v PGI 2 , i.vPGE 124 pigs INO, IPGE , 1 INO + IPGE 1Anesthetized catsINO, IPGI , 2 INO + IPGI 2 ,IPGI L2after L-NAME,Papaverine 2 mg/kgNewborn lambsIPGI 2Inhaled MilrinoneIPGI 2 + Inhaled Milrinone

Studies of Inhaled Prostaglandins in PulmonaryHypertension – Human AdultsAuthor, YearWalmrath, 1993Bein, 1994PatientDrugARDS - 3 adults IPGI , 2 i.v. PGI 21 adult IPGI 2Walmrath, 1995 12 adults IPGI 2Bein, 1996Eichelbronner, 1996Haraldsson, 1996Olschewski, 1996Walmrath, 1996Webb, 1996Van Heerden, 1996Van Heerden, 1996Haraldsson, 1998O’Hare, 1998Meyer, 1998Putensen, 1998Olschewski, 1998Olschewski, 2000Della Rocca, 20088 adults IPGI 2Exposure period 15 min16 adult with PHT INO, IPGI 29 adults with PHT IPGI 2Exposure period 10 min6 adults with PHT IPGI , 2 i.v. PGI 2, INO, Aerosolized iloprost16 adults - ARDSINO, IPGI 2– for 15 min65 yr, M, PE, PHT IPGI 2for 24 hours2 adults IPGI 25 adults, ARDS IPGI 2, INO Exposure for 30 min10 adults IPGI 2, INO for 10 minPregnant womanIPGI 215 adults with ALI IPGE 110 adults, ARDS INO, IPGE , 1 i.v PGE 1no intervention45 yr, F, PHT Aerosolized iloprost, INO19 adults with PHT Inhaled iloprost18 adults, lung transplantation IPGE 1

Studies of Inhaled Prostaglandins in PulmonaryHypertension – Humans – Children & NeonatesAuthor, yrBindl, 1994Pappert, 1995Santak, 1995Zwissler, 1995Soditt, 1997Kelly, 2002Sood, 2004Hsiao, 2004Patient2 newborns - PPHNThree 8 yr old-ARDS4-month old - PPHTerm neonate with CHDPreterm, 28 weeks, HMD, PPHN, 34 hTerm infants, refractory to INODrugIPGI 2IPGI 2, INO for 30 mini.v PGI 2, iPGI 220 minIPGI 2, INO 40 ppmIPGI 2IPGI 220 term infants, PPHN IPGE 13 preterm infants, PPHN IPGI 2Summary of Clinical studies: evidence for safety & efficacy ofinhaled PGs

Is IPGE 1 Efficacious?

Phase I Clinical Trial of IPGE 1 in NHRFSood et al, Ped Res, 2004

Phase I Trial: Change in P a O 2Δ P a O 264.4±71.6 0.038 Δ P a O 243.5±51.8 NSΔ OI -14.6±10.0 0.004 OI -9.0±11.9 NSSood et al, Ped Res, 2004

Phase I Trial: Dose ResponseDoseng/kg/minGroup In=8Full Response (%)Group IIn=42550 50 25150 87.5 50300 87.5 75Weaning 100 75The findings of this small unblinded study needto be validated in large-scale prospectiverandomized controlled trialsSood et al, Ped Res, 2004

Is IPGE 1 Safe?

Phase I Trial: Adverse Effects:No exacerbation of hypotension, hyperthermia,dysrhythmias, or bleeding tendencyTestBefore IPGE 1Mean (SD)After IPGE 1Mean (SD)Alanine aminotransferase* 26.3 (10.2) 25.3 (14.1) NSAspartate aminotransferase* 74.7 (65.6) 47.2 (29.4) 0.04Alkaline phosphatase* 193.4 (272.5) 93.6 (54.9) NSBilirubin** 4.6 (2.9) 5.3 (4.3) NSBlood urea nitrogen** 7 (3.3) 9.9 (5.5) 0.011Creatinine** 0.7 (0.18) 0.7 (0.23) NSHematocrit (%) 46.8 (6.4) 40.1 (6.6) 0.001Platelets† 219.3 (116.7) 187 (77.5) NSTotal leukocyte count† 16.2 (6.8) 12.6 (6.4) 0.039* U/L, ** (mg/dL), † 10 3 /mm 3 Sood et al, Ped Res, 2004P

Animal Toxicity Studies:• Ten mechanically ventilated anesthetized piglets• High dose IPGE 1 (1200 ng/kg/min) or nebulized NS for 24 hNormal bronchus andadjacent alveoli in apiglet who receivedIPGE 1for 24 hFew neutrophils andred blood cells in thebronchus (arrow) andminimal alveolaredema (arrowhead)• No evidence of adverse cardio-respiratory respiratory effects,bronchial irritation or hypernatremia related to IPGE 1• No evidence of severe toxic injury:• Hyaline membranes• Diffuse/severe neutrophilic infiltration• Diffuse/severe ulceration• Distinct histologic findings in IPGE 1 animals:• Focal ulceration• Focal flattening of the bronchial epithelium• Focal loss of cilia of moderate to severe degreeSood et al, Pulm Pharm Ther, 2008

Effect on Ductus Arteriosus• Echocardiograms obtained before andafter study in 5 animals• High dose IPGE 1for 24 hrs did notopen a functionally closed DA• In one animal with small DA,administration of IPGE 1did not changethe size of the DATable 3: Morphometry of the DA at AutopsyControl(n=6)IPGE 1(n=9)Length 0.47 (0.05) 0.49 (0.06)Circumference (Aortic) 0.33 (0.08) 0.34 (0.09)Circumference (Pulmonary) 0.33 (0.08) 0.33 (0.11)Values represent mean (SD) in mm. Group differences not significantControlIPGE 1Gittenberger-de Groot, 1980Sood et al, POLM, 2009

Is IPGE 1 Stable Upon Aerosolization?What is the Emitted Dose?What is the APSD?

Stability and Emitted DoseModified Wet Lung ModelExpiratorylimb ofventilatorInspiratory limb ofventilatorExtensiontubingconnected toinfusion pumpdelivering PGE 1solution @ 4ml/hrClosed glasscontainer for“wet”collection ofcondensateOxygen flowto nebulizer@ 2 LPMNebulizerchamberprimed with 2ml of PGE 1solution at startof continuousaerosol therapySood et al, Pharm Res, 2007

Stability – LC-MSPGE 1 500 μg/ml ethanolDissolved in normal salineOHOOHOPGE 1 and its potentialdegradation productsOHCOOHProstaglandin E 1 (PGE 1 )O15-keto PGE 1COOHOOHOMass spectral fragmentationpattern of PGE 1 and itsmetabolites13,14-dihydro-15-keto PGE 1 Chemical Formula: C 20 H 31 O - 5 Exact Mass: 351.22OCOO -HOOHProstaglandin E 1COOHChemical Formula: C 20 H 33 O - 5Exact Mass: 353.23OCOO -OCOO -OHProstaglandin A 1OHProstaglandin A 1Chemical Formula: C 14 H 19 O - 3Chemical Formula: C 20 H 31 O - 4Exact Mass: 235.13Exact Mass: 335.22Molecular Weight: 235.30COOHOCOO -OOHOO15-keto Prostaglandin E 1OHOCOO -Chemical Formula: C 20 H 29 O 4-Exact Mass: 333.21Molecular Weight: 333.44COO -Chemical Formula: C 14 H 21 O 4-Exact Mass: 253.14Molecular Weight: 253.31OSood et al, Pharm Res, 2007

ResultsLC-MS Chromatograms Following JetNebulizationLC-MSBaselineResolutionPGE 1PGA 115-keto PGE 1Sood et al, Pharm Res, 2007

Emitted DoseSood et al, Pharm Res, 2007

Aerosol Particle Size DistributionAerodynamicExpiratory limbof ventilatorInspiratorylimb ofhumidifiedventilatorcircuitExtensiontubingconnected toinfusion pumpdeliveringPGE 1solution@ 4 ml/hrSix-stagecascadeimpactorOxygen flowto nebulizer@ 2 LPMNebulizer chamberprimed with 2 mlof PGE 1solutionat start ofcontinuousaerosol therapyTo VacuumSood et al, Pharm Res, 2007

Aerosol Particle Size DistributionAerosol particle size•> > 5 µm oropharynx•1 - 5 µm m pulmonary delivery•< < 1 µm m too small to adhere torespiratory epitheliumDunbar, 2005Sood et al, Pharm Res, 2007

Pharmacokinetics of IPGE 1 ?

PPHNCongenital Heart diseasePigletsNo difference in LungTissue Concentrationsof PGE1 and itsmetabolites – Data notshownSolid Line = PGE 1Dotted line = 15-keto PGE 1

Nominal DoseAerosolizedRemain in deviceInhaledVentedDepositedExhaledPulmonaryExtrapulmonary< 40%< 1%AlveolarBronchialMucociliaryclearanceExcretionO’Riordan et al., 1999

Is Aerosol Generated by the MiniHeartNebulizer Deposited in the Alveoli?

Aerosol Delivery Assessed by MRIExpiratory limbInspiratory limbO 2at 2 LPMMiniHEARTjet nebulizerGd-DTPA• Prime 4 ml/hr• Rate 8 ml/hrRoom AirSood et al, Ped Res, 2008

Aerosol Delivery Assessed by MRI• Contrast wasvisualized in thekidneys 30 minafter aerosolinitiation in allanimalsBefore Gd After 30min of Gd Sood et al, Ped Res, 2008

Aerosol Delivery Assessed by MRI450Change in SI Over TimeChange in SI (%)40035030025020015010050Left LungRight LungKidney0-500 10 20 30 40 50 60 70 80 90 100Time (min)Sood et al, Ped Res, 2008

Aerosol Delivery Assessed by MRI35Change in SI Over TimeChange in SI (%)30252015105Left LungRight LungKidney00 5 10 15 20 25Time (minutes)Sood et al, Ped Res, 2008

Aerosol Delivery During HFOVSood et al,Respirol,2010

Bob Galli, RRTSood, 2012

Preliminary Data - Conclusions• Potentially efficacious• Pulmonary selectivity with lack of systemic AE• Potentially safe• Stable• Favorable ED, APSD• Pulmonary Deposition

Pilot Randomized Clinical Trial ofInhaled PGE 1in Neonates with Sub-optimalResponse to Inhaled Nitric Oxide

Specific AimsPrimary Aims:‣ Evaluate feasibility of performing a RCT of IPGE 1 in NHRF‣ 50 patients in 9 mo, ≤ 20% protocol violations‣ To establish safety of IPGE 1Secondary Aims:given over a longer duration‣ Identify optimal dose of IPGE 1in treatment of NHRF‣ Define optimal duration of therapy with IPGE 1in NHRF‣ Evaluate the efficacy of IPGE 1 in NHRF• Progression of OI, need for ECMO, mortality, duration ofINO/MV/O2/Hospitalization

Progress• Recruitment halted after 6 months• Data Analysis ongoing• What went wrong?? What Next??

Challenges: RCTs in PPHN• Small number of subjects?• ↓ post-term term & late preterm births• De-regionalized NICU care• Study Design Issues:• eligibility criteria - arterial line• consent• relevant outcome measures• Timeline• IND• IRB approvals

Challenges: RCTs in PPHN• Alternatives:• Study designs:• Fully sequential• Adaptive• Pragmatic trials• Opportunistic• Endpoints• Duration of intensive care, hospitalization, cost-effectiveness• Resource poor settings - Networks/Registry

Thank YouDiscussion

PGE 1 or PGE 2 ?PGE1:•stimulates stimulates cAMP production more effectively•more more powerful anti-inflammatory inflammatory properties•more more potent vasodilator•inhibits inhibits collagenase activity•inhibits inhibits platelet aggregation whereas PGE2 either doesnot affect aggregation or sometimes enhances it•inhibits inhibits vascular smooth-musclemuscle-cell cell proliferationLevin, 2002