Update on Persistent Pulmonary Hypertension of the Newborn (PPHN) Abdulla Al Tuhami Consultant Neonatologist Dar Al Shifa Hospital 2 nd KNC Millennium Hotel & Convention Center 17-20 October 2018
Outline Fetal circulation Pathophysiology Clinical presentation Management
• Fetal pulmonary circulation is a High Pulmonary low basal production vasoconstrictors ( low high resistance, high pressure, oxygen tension, of vasodilators, low-flow system 1-3 endothelin-1, (prostacyclin and NO) • Fetal P O2 is 32-35 mm Hg (with leukotrienes) an oxygen saturation ~80%) 4 • The right ventricle (RV) and left ventricle (LV) function in- parallel 1-2,4 • Duct dependent circulation Rudolph AM, Heymann MA. Circ Res . 1967;21:163-184. 2 Rudolph AM. Circulation . 1970;61:343-359 . 3 Hislop A, Reid L. J Anat. 1972;113:35-48. 4 Lautt WW. Hepatic Circulation: Physiology and Pathophysiology . San Rafael (CA): Morgan & Claypool Life Sciences; 2009.
Selective Streaming of Oxygenated Blood to the Coronary and Cerebral Circulations Selective Streaming Towards Selective Streaming to the DA the Developing Brain Right Ventricle • • Venous blood from the superior vena cava Most blood from the inferior vena cava enters the foramen ovale (FO) where it is channeled to the bypasses the FO and enters the right aorta 1 ventricle 1,2 • Oxygenated blood is preferentially channeled from • Due to high PVR, most of the right the aorta to the coronary and cerebral circulations instead of the lower body 1,2 ventricular output bypasses the lungs and • is shunted into the aorta via the ductus Blood flow to the brain and lungs increases throughout gestation 2 arteriosus (DA) 1,3 DA, ductus arteriosus; FO, foramen ovale. 1 Rudolph AM. Circulation . 1970;61:343-359. 5 2 Rudolph AM. Fetal Cardiography: Embryology, Genetics, Physiology, Echocardiographic Evaluation, Diagnosis and Perinatal Management of Cardiac Diseases . London: Martin Dunitz; 2003:107- 120. 3 Rasanen J, et al. Circulation. 1996;94:1068-1073.
Which segment of the fetal circulation contains the highest O2? A. Right atrium B. Right ventricle C. Left ventricle D. Umbilical artery E. Pulmonary artery
Which segment of the fetal circulation contains the highest O2? A. Right atrium B. Right ventricle 53 C. Left ventricle 65 D. Umbilical artery 55 E. Pulmonary artery
Circulatory Changes During Transition 8 Rudolph AM. Circulation . 1970;61:343-359.
PPHN Failure of normal postnatal adaptation with persistent high PVR leading to right ventricular failure and right to left shunting
NICHD Cohort Meconium aspiration syndrome – 41% Pneumonia- 14% Respiratory distress syndrome- 13% Pneumonia and/or RDS- 14 % Congenital diaphragmatic hernia -10% Pulmonary hypoplasia 4% Idiopathic 17% Persistent Pulmonary Hypertension of the Newborn in the Era Before Nitric Oxide: Practice Variation and Outcomes, Michele C, Pediatrics 2000 Jan
SSRI Black lung PPHN , Clear lung PPHN BMJ 2013;348:f6932 doi: 10.1136/bmj.f6932
• The risk for PPHN of the newborn in infants exposed to SSRIs during late pregnancy is small although significantly increased • NNH 286 to 351 women would need to be treated with an SSRI during late gestation to result in one case of PPHN
NSAID & PPHN No Association Linda et al , pediatrics 2012
PPHN Hypothetical Model Pathology mainly Pathology mainly in lung airway and in lung blood vessels parenchyma Pulmonary Parenchymal Feature Pulmonary Vascular Meconium or Risk of Sepsis History Nothing or range of pregnancy complications Opacified CXR Clear Difficult Ventilation Easier Difficult Oxygenation Variable Variable Pulm Press Very high Small and variable shunt Ductus Patent and right to left
Clinical Presentation
• 3.2kg infant born at 37 wks GA • CS - fetal distress • Thick MSAF , apnea with CR 20-30/min. – Intubated IPPV with CPR for 5min. Apgar scores 2/5 / 7 • ABG within 1 hour pH 7.1, pO2 40mmHg, HCO3 15 mmol/L, BE – 14 mmol/L • SPO2 88% right arm / 78% right leg Choose the possible underlying etiology of this case A. HLHS B. IAA C. PPHN D. TGA+IAA E. TGA with PPHN F. A , B & C
• 3.2kg infant born at 37 wks GA • CS - fetal distress • Thick MSAF , apnea with CR 20-30/min. – Intubated IPPV with CPR for 5min. Apgar scores 2/5 / 7 • ABG within 1 hour pH 7.1, pO2 40mmHg, HCO3 15 mmol/L, BE – 14 mmol/L • SPO2 88% right arm / 78% right leg Choose the possible underlying etiology of this case A. HLHS B. IAA C. PPHN D. TGA+IAA E. TGA with PPHN F. A , B & C
TAPVR TGA+PPHN supracardiac TGA+IAA TGA+COA Yap SH et al , Pediaric Cardiol 2009
Neonatologist Performed Echocardiography (NPE) Parameters for the assessment of PAP, PVR , RV performance and shunts Less than 0.5 cm % Less than 40 % More than 1.2 Willem P. et al; .Pediatric Research 2018
LV Systolic Eccentricity Index LV-sEI more than 1 LV-sEI= D1(AP diameter)/D2(Septo-lateral diameter)
Estimated RVP LV Configuration O shaped LV 50% of LVP D – shaped LV 50%---100% of LVP C – shaped LV 100 % of LVP
Low LPA flow
Echocardiographic evaluation of neonatal hypoxemia based on ductal and atrial shunts Lakshminrusimha et al : Pediatr Res.2006
Severity of PPHN Severity of HRF based on OI Oxygenation index (OI) = Mild 15 Moderate 15 to 25 FiO2 × MAP × 100 /PaO2 Severe 25 to 40 Very severe >40 Oxygen Saturation Index (OSI ) MAP × FiO2 × 100/ Pre-ductal SpO2 OSI OI = ~ 2 X Noninvasive correlates OSI with OI
Severity of PPHN P/F ratio = PaO2/ FiO2 P/F ratio OI and P/F ratios Mild >200 to 300 Moderate >100 to 200 use pre-ductal blood Severe 100 mm Hg gases
“ PPHN ” : Treatment Pathology mainly Pathology mainly in lung airway and in lung blood vessels parenchyma Pulmonary Parenchymal Pulmonary Vascular Optimise Ventilation Inhaled Nitric Oxide Surfactant Inhaled Nitric Oxide Milrinone if not hypotensive Noradrenaline if hypotensive Sildenafil????
More recently, it has been found that brief exposure to 100% oxygen in newborn lambs results in • Increased contractility of pulmonary arteries • Reduces response to iNO, • Peroxynitrite produce VC & surfactant inactivation Lakshminrusimha et al Pediatr Res. 2006 Lakshminrusimha Set al Pediatr Res. 2009
What is your Oxygen Saturation Targets??? Pre-ductal SpO 2 PaO2 [50-80 mmHg] 88-94% PH 7.25 PCO2 45 -60 mmHg Post ductal SPO2 ? 75% Lactate less than 3 UOP 1ml/kg/hr
MV G entle ” ventilation strategies with optimal PEEP, relatively low PIP or tidal volume and a degree of permissive hypercapnia are recommended to ensure adequate lung expansion limiting barotrauma and volutrauma Wung JT, et al Pediatrics. 1985. Gupta A, et al J Perinatol. 2002
• Meta-analysis of the results of four RCTs of surfactant administration in MAS - PPHN – significant reduction in the need for ECMO (RR 0.64, 95% CI 0.46 to 0.91)
Pulmonary Vasodilators
iNO • Effective FDA-approved therapy • Selective pulmonary vasodilator without decreasing SVR • methemoglobin in intravascular space
+/- improve V/Q mismatch by entering only ventilated alveoli
iNO may reduce the need for ECMO in infants with PPHN 2 randomized trials 248 neonates < 4 days old (gestational age > 34 weeks) with PPHN were randomized to low-dose nitric oxide (20 ppm for maximum of 24 hours, then 5 ppm for maximum 96 hours) vs control group comparing vs. control need for ECMO in 39.3% vs. 61.9% (p = 0.001, NNT 4) chronic lung disease in 7% vs. 20% (p = 0.02, NNT 8) 30-day mortality 7% vs. 8% (not significant) N Engl J Med 2000
NINOS Study CINRGI Study (The Neonatal Inhaled Nitric ( Clinical Inhaled Nitric Oxide Oxide Study) Research Group investigation ) o RCT, Multicenter o RCT, Multicenter o 235 term/near term o 186 term/near term with HRF unresponsive with HRF unresponsive to conventional therapy to conventional therapy o End points : o End points : o composite • Need for ECMO outcome of Death or ECMO • Death • ECMO Neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS). Clark RH, al.. NEJM . Feb 2000 The Journal of pediatrics. May; 2000
Left Pulmonary Artery Blood Flow and response to Nitric Oxide. Roze et al, Lancet 1994 Prior to iNO 12 hr After iNO
Protocol at Women & Children ’ s Hospital of Buffalo Rule Triple 20 Triple 60 Sharma, V et al Matern. Health Neonatol. Perinatol. 2015
iNO Refractory PPHN 40% Severe Missed pulmonary Poor lung Myocardial Systemic anatomic vascular inflation dysfunction hypotension cardiovascular structural lesions such as disease alveolar capillary TAPVR COA CDH dysplasia
PDE3 inhibitor PDE5 inhibitor Milrinone Sildenafil cAMP cGMP vasodilation vasodilation
Phosphodiesterase inhibitors be aware of non selective …… ..
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