Disclosures Long-term Consequences of No conflict of interest to - - PowerPoint PPT Presentation

6/21/2013 1

Sharon McGrath-Morrow, MD, MBA

Long-term Consequences of Bronchopulmonary Dysplasia and Pulmonary Hypertension

Disclosures

• No conflict of interest to disclose.
• Off-label use of sildenafil will be discussed

in this presentation.

Objectives

• Recognition of pulmonary hypertension as a complication in

infants with Bronchopulmonary Dysplasia (BPD)

• Risk factors for pulmonary hypertension in BPD.
• Approach to diagnosis and treatment of pulmonary

hypertension and BPD

• What we learned from our population of BPD infants with

pulmonary hypertension

Heron M et.al., Pediatrics, 2010. 1.5% 11% 87%

4,317,119 Live Births in the US in 2007 <32 Weeks 32-37 Weeks

Impact of prematurity in the US

About 60,000 infants born each year in the US are at risk for developing bronchopulmonary dysplasia

6/21/2013 2 Bronchopulmonary dysplasia

• Diagnosed in premature infants (<32 wk gestation) who

required supplemental oxygen for 28 days or greater

• BPD severity (mild, moderate, severe) based on need for

supplemental oxygen/PPV at 36 weeks post conception

10 20 30 40 50 60 510-750 751-1000 1001-1250 1251-1500

Birth weight (grams) % infants with BPD

Extremely low birth weight infants at highest risk for BPD

Ehrenkranz et.al. 2005

Extremely low birth weight infants- at highest risk for pulmonary hypertension

– Pulmonary hypertension affects at least 1 in 6 extremely low birth weight infants (<1000 grams)

• Prospective analysis of pulmonary hypertension in extremely low

birth weight infants. (Bhat R, Pediatrics, 2012)

• PH defined by ECHO

– Right ventricular hypertrophy, – Flattening of interventricular septum – Presence of tricuspid regurgitation in the absence of pulmonary stenosis, – Elevated right ventricular pressures as estimated by Doppler studies of tricuspid regurgitation jet.

Impact of BPD and PH in the US

• About 12,000 US infants develop BPD each year-

most are ELBW (American Lung Association Lung Disease Data: 2008).

• Estimated 1600 infants born each yr with BPD and

PH in the US

• Estimated 40 infants/yr born in Maryland with BPD

and PH

Chronic lung disease contributes to PH prevalence in children worldwide

• 31 centers, 19 countries, enrolled patients < 18 years of

age at time of PH diagnosis- 456 patients in TOPP registry

• 12% of patients had PH associated with lung disease-

– BPD most common cause of lung disease associated with PH

Berger et. al., Lancet, 2012

6/21/2013 3

Mortality is higher in infants with BPD and PH

• Boston Children’s Hospital

(Khemani E et al; Pediatrics; 2007).

Average gestational age 26 wks

• Seoul University

(Kim D et al; Neonatology; 2012).

21/34 20/25

Chronic respiratory symptoms

Abnormal growth of alveoli Abnormal airways Abnormal pulmonary vasculature What causes BPD and (PH)? Impaired alveolar growth in BPD

• gas exchange abnormalities

Thebaud and Abman, AJRCCM, 2007

Small airway abnormalities in BPD

• airflow obstruction

– Structural and reactive

– Postnatal dysanaptic airway growth due to prematurity

• Not responsive to anti-inflammatory meds

– Airway inflammation

• Likely responsive to anti-inflammatory meds

Kennedy, J. Paediatr Child Health, 1999.

Postnatal alveolar growth Growth of airways and blood vessels

Mechanisms and limits of induced postnatal lung growth. Am J Resp Crit Care Med, Vol170, 2004

6/21/2013 4

Impaired vascular growth in BPD

• pulmonary hypertension

Abman, S, Adv Exp Med Biol, 2010 Control VEGFR inhibitor (S5416) 3 week rat lung Adult rat lung

LeCras, et.al. 2002

VEGFR2 antibody (DC101) 2 week mouse lung Barium arteriograms Lung histology

McGrath-Morrow et.al., 2005

Rodent models of impaired vascular and alveolar growth in neonates with disruption of VEGF/VEGFR2 signaling Other Risk Factors associated with BPD and development of PH

• Small for gestational age
• Maternal preeclampsia
• Postnatal Infections
• Malnutrition
• Chorioamnionitis
• Oligohydramnios
• Abnormal lung physiology

– Ventilation/perfusion (V/Q) mismatch – Intermittent hypoxia/hypercarbia – Poor airway clearance/mucous plugs

• Cardiovascular shunts

– Atrial septal defects – Patent ductus arteriosus – Aorto-pulmonary collateral arteries

Role of genetics and epigenetics in BPD and PH children

• Genetic susceptibility accounts for approximately 50% of

BPD development (Bhandari et.al., 2006, Lavoie et. al., 2008).

– Genes associated with PH development in BPD have not been identified. Future studies could include identifying modifiers genes thru candidate SNP studies of genes involved in familial PH, such as, BMPR2, ENG and ALK1

• The role of epigenetic changes that effect BPD infants

with PH needs to be explored

6/21/2013 5 Management and screening for PH in the preterm infant

• BPD Infant born at 26 weeks gestation with history of premature

rupture of membranes at 22 weeks gestation

• Briefly intubated in the NICU, but developed cystic emphysematous

lung disease and had ECHO evidence of PH at 6 months of age.

Lung CT at 6 months

Thurlbeck W.M. Thorax 37:564-571, 1982

PH in this BPD child may be structural due to inadequate postnatal lung growth

* Fewer number of alveoli and micro-vessels due to decreased surface area

Preterm Infant

But a component of PH in this BPD child may be reactive and respond to vasodilator medications

Figure concept from Humbert et.al., 2004

6/21/2013 6 Treatment of BPD child with PH

• Minimize further lung injury and decrease work of

breathing (aggressive supportive care)

• Minimize hypoxic/hypercarbic episodes
• Maximize nutrition to promote lung growth
• Consider other factors such as cardiac shunts,

pulmonary vein stenosis as contributing factors

• Consider trial of vasodilator medications if indicated

Screening of ELBW infants and infants with BPD for PH No guidelines exist for screening of ELBW or BPD infants for PH

• Bhat et.al.- 2/3 of ELBW infants with PH missed with ECHO at 1 month of

age

• Hopkins NICU guidelines to be tested:

– < 26 week gestation or <1000 grams at birth: ECHO at 8 to 10 wks of age – > 26 weeks gestation: ECHO if infant has moderate to severe BPD at 36 PCA – ECHOs obtained at the discretion of the Attending Neonatologist if child is felt to be at high risk for pulmonary hypertension due to clinical course/other risk factors

• Correlation of ECHO with catheterization in pediatric patients

– Mid-Atlantic Group of Interventional Cardiology and Mourani et.al., study

• Poor correlation of ECHO with catheterization in predicting severity of PH

Are there biomarkers to track disease progression

• BNP and NT-proBNP are adult biomarkers for PH

– Problematic in the BPD infant since BNP is a cardiac protein and is developmentally regulated

6/21/2013 7

Circulating NT-proBNP concentration is developmentally regulated and declines during the first 1-2 months of life

Nir A, et al. NT-pro-B-type natriuretic peptide in infants and children: reference values based on combined data from four studies. Pediatr Cardiol 2009 Jan;30(1):3-8.

• BNP and NT-proBNP may be useful for tracking

response to treatment in the preterm infant with PH

• Ongoing novel discovery projects, may provide

better biomarkers for infants and children with PH

Use of cardiac catheterization in patients with BPD and PH differs across centers

• Denver- most patients undergo catheterization before starting

chronic vasodilator medication Mourani PM, et al. J Pediatr 2009;154:378-384.

• Boston group reported catheterization of 31% of their patients

Khemani E, et al. Pediatrics 2007;120:1260-1269.

• Hopkins catheterizes about 11% of patients with BPD and PH.

– Before escalating/weaning vasodilator Rx in refractory PH – For evaluation/closure of CV shunts

Anesthesia in infants with BPD and PH

• Risk of perioperative cardiac arrest is 6-fold higher in children with
• PH. Carmosino, et al. Anesth Analg 2007;104:521-527.
• 50% of pediatric anesthetic-related deaths occur in children with PH.

van der Griend BF, et al. Anesth Analg 2011;112:1440-1447.- deaths-0.98/10,000 cases

• But, anesthesia can be performed safely.

Hill KD, et al. Catheter Cardiovasc Unterv 2010;76:865-873 Magic collaboration -

Adverse events were rare (n = 7) with no procedural deaths.

• Ways to minimize anesthesia risk-

– Cardiac anesthesiologist – Preoperative consultation – Prepare for management of a PH crisis, i.e., NO/milrinone/prostanoids/PICU bed availability

6/21/2013 8 Multi-disciplinary Approach

• Monthly meetings of pulmonologists, cardiologists,

intensivists/anesthesiologists, neonatologists and pharmacists to discuss diagnosis, treatment and follow-up of PH patients

• Inpatients and outpatients are cared for by

multidisciplinary group of specialists with an interest in PH (started in 2009)

• Yearly regional pulmonary hypertension conferences –

Expert in the treatment of pediatric pulmonary hypertension invited as a keynote speaker to help educate healthcare providers in the region who care for these children

The Johns Hopkins Outpatient BPD Clinic

Clinic population:

• Preterm infants (<37 weeks gestation) diagnosed with BPD

– Referred from area NICUs or pediatricians – Clinic staffed by 2 pediatric pulmonologists

• Families are approached to participate in a clinical database

– Recruitment began in January 2008 – 98% of those approached agree to participate – Data collected through chart review/questionnaires – Data have been used to examine daycare, sleep studies, SES, compliance, quality of life, pulmonary hypertension, smoke exposure, etc. in this population

6/21/2013 9

BPD Database n = 423

(as of May 2013)

Characteristic Mean ± S.D. Sex (% male) 59.8 Race/Ethnicity (% non-white) 67.1 Gestational Age (weeks) 26.9 ± 3.0 Birth Weight Percentile (%) 40.1 ± 22.7 (n = 408) Home Supplemental Oxygen (%) 36.6 Home Ventilator (%) 2.4 GT (%) 23.6 Nissen (%) 15.8

BPD & PH: HEALTHCARE UTILIZATION

A Retrospective Chart Review

BPD Clinic and ECHOs

No Echo Data, (121)

Indeterminate, 4 Congenital Heart Disease, 4

No PH, (43) PH prior to 2 months, (47) PH after 2mo, (19) Echo Data, (117)

Stuart BD et al. J. Perinatology, 2013.

Clinical Risk Factors associated with PH after 2 Months of Age

BPD Only BPD and PH prior to 2 months only BPD and PH after 2 months of age p Value n 43 47 19

• Gestational Age (weeks)

26.8 ± 2.4 26.1 ± 1.9 25.2 ± 1.5 0.014 Birth Weight Percentile (%) 35 ± 22 46 ± 25 40 ± 24 0.08

6/21/2013 10

Persistent PH associated with greater need for home respiratory support

Odds Ratio Compared to BPD Only Group BPD Only (n = 43) BPD and PH Prior to 2 Months Only (n = 47) BPD and PH After 2 Months Old (n = 19) Home Respiratory Support Unadjusted 1.00 1.04 p = 0.93 5.74 p = 0.007 Adjusted for gestational age 1.00 0.95 p = 0.92 4.47 p = 0.025 Gastrostomy Tube Unadjusted 1.00 0.70 p = 0.47 3.55 p = 0.028 Adjusted for gestational age 1.00 0.65 p = 0.40 2.66 p = 0.11 Stuart BD et al. J Perinatol 2013.

Longer length of initial hospitalization in BPD infants with persistent PH

• After correction for gestational age, PH that persists after

2 months of age is associated with 2.2 months longer initial hospitalization stay (p=0.016)

NICU NICU NICU Home Home Home

2 4 6 8 10 12

BPD + PH after 2 mos BPD + PH prior to 2 mos BPD Only Age (Months)

Stuart BD et al. J Perinatol 2013.

Caring for BPD infants with PH costs at least $300,000 more during 1st year of life

Costs ($) BPD Only ($) BPD + Persistent PH ($) Notes NICU Stay 411,000 703,000 Based on $3000 per day Home Oxygen 500 700 Based on time at home and risk of requiring oxygen GT Supplies 5500 6600 Based on time at home and risk of requiring GT Sildenafil 6700 Based on 10 months of therapy for PH

Total 417,000 717,000

• Probably an underestimate of costs.
• Does not include costs for surgeries, catheterizations, additional outpatient visits, etc.

Persistent PH was not associated with outpatient respiratory morbidities

Odds Ratio for Clinical Outcome* BPD Only (n = 33) BPD and PH Prior to 2 Months Only (n = 33) BPD and PH After 2 Months Old (n = 18) Emergency Department Visits 1.00 0.81 p = 0.73 0.40 p = 0.23 Hospital Readmission 1.00 1.09 p = 0.88 0.18 p = 0.09 Respiratory Symptoms 1.00 1.71 p = 0.34 0.57 p = 0.56 Activity Limitations 1.00 0.73 p = 0.61 0.29 p = 0.24 *Odds ratios derived via clustered logistic regression adjusted for age and gestational age. Stuart BD et al. J Perinatol 2013.

6/21/2013 11

Cautious weaning of supplemental oxygen may be warranted in BPD children with PH-

EEG Nasal flow O2 sat EKG Thor Abd CA (5.2 sec) CA (5.3 sec)

86% 84% 98% 96% McGrath-Morrow et.,al. Ped Pulm 2012

BPD & PH: MORTALITY

A Retrospective Chart Review 16% mortality associated with PH and BPD at Johns Hopkins (n = 82)

Alive (n = 69) Deceased (n = 13) P Value

Sex (% male) 56.5 61.5 0.74 Race/Ethnicity (% non-white) 81.5 61.5 0.12 Gestation (weeks) 26.4 ± 3.3 28.7 ± 4.5 0.03 Cardiac Catheterization (% yes) 13.0 0.0 0.17 Gastrostomy Tube (% yes) 71.0 23.1 0.001 Nissen (% yes) 46.4 15.4 0.037

Of the 13 deaths, 8 occurred during the initial hospitalization, 4 occurred during a re-hospitalization, and 1 occurred at home

Unpublished Data

0% 100% 75% 50% 25%

Probability of Survival

18 12 6 24 30 36

Age (Months)

Survival with Pulmonary Hypertension and BPD

Seoul Univ.: N = 25 Boston Children’s: N = 34

JHH: Unpublished; Boston: Khemani et al. Pediatrics 2007; Seoul: Kim et al. Neonatology 2012.

JHH: N = 82

6/21/2013 12

SILDENAFIL USE

Johns Hopkins Hospital

Sildenafil Use

• Population identified via inpatient pharmacy records
• Records identify sildenafil orders, not necessarily

administration

• Records include a 72 month period from January 2007 to

January 2013

• 216 pediatric patients were prescribed Sildenafil at least
• nce

Discharge Diagnoses (n = 216)

Cardiac* CDH

Preterm 72

1 2 14 9 63 33

PPHN Other

4 18 *Does not include PDA, ASD, or VSD

N = 71 Preterm Infants

5 10 15

Number of Patients

1 2 3 4 5 6 7

Sildenafil Dose (mg/kg/day)

6/21/2013 13

Initial sildenafil dose not associated with mortality

Mean ± SD Alive (n = 58) Deceased (n = 13) P value Sildenafil Dose (mg/kg/day) 1.53 ± 1.26 2.00 ± 1.55 0.25 Sildenafil Dose (mg/kg/dose) 0.43 ± 0.33 0.62 ± 0.39 0.09 Sildenafil Frequency (times per day) 3.5 ± 0.8 3.5 ± 1.1 0.84

Future Directions

• Establishing guidelines for screening BPD infants for PH

– Determining best timing for screening and interval screening – Identifying biomarkers for screening – Identifying biomarkers to follow treatment response

• Establishing guidelines for treatment and follow-up of BPD infants

with PH using a multidisciplinary approach

• Identifying non-invasive ways to quantify severity of PH in infants

and children with BPD

• Identifying which infants with PH and BPD can benefit from

phosphodiesterase type 5 inhibitors

Multidisciplinary Pulmonary Hypertension Working Group

Anesthesiology/Critical Care

• Anna Brown
• Lew Romer

Neonatology

• Ned Lawson
• Larry Nogee

Cardiology

• Joel Brenner
• John Coulson
• Allen Everett
• Melanie Nies
• Priya Sekar

Pulmonary

• Sharon McGrath-Morrow
• Bridget Stuart
• J. Michael Collaco

Data Coordinators

• Angela Aherrera
• Jen Choi
• Tim Ryan

Pharmacy

• Dave Procaccini

Funding Source: FAMRI (SM, JMC), Thomas Wilson Grant (SM, JMC)