Update on Persistent Pulmonary Hypertension of the Newborn (PPHN) - - PowerPoint PPT Presentation

Update on

Persistent Pulmonary Hypertension of the Newborn

(PPHN)

Abdulla Al Tuhami Consultant Neonatologist Dar Al Shifa Hospital

2nd KNC

Millennium Hotel & Convention Center 17-20 October 2018

Outline

Fetal circulation Pathophysiology Clinical presentation Management

• Fetal pulmonary circulation is a

high resistance, high pressure, low-flow system1-3

• Fetal PO2 is 32-35 mm Hg (with

an oxygen saturation ~80%)4

• The right ventricle (RV) and

left ventricle (LV) function in- parallel1-2,4

• Duct dependent circulation

Rudolph AM, Heymann MA. Circ Res. 1967;21:163-184.

High Pulmonary vasoconstrictors ( low

• xygen tension,

endothelin-1, leukotrienes) low basal production

• f vasodilators,

(prostacyclin and NO)

Selective Streaming of Oxygenated Blood to the Coronary and Cerebral Circulations

5

Selective Streaming Towards the Developing Brain

• Most blood from the inferior vena cava enters the

foramen ovale (FO) where it is channeled to the aorta1

• Oxygenated blood is preferentially channeled from

the aorta to the coronary and cerebral circulations instead of the lower body1,2

• Blood flow to the brain and lungs increases

throughout gestation2

Selective Streaming to the Right Ventricle

• Venous blood from the superior vena cava

bypasses the FO and enters the right ventricle1,2

• Due to high PVR, most of the right

ventricular output bypasses the lungs and is shunted into the aorta via the ductus arteriosus (DA)1,3

DA

DA, ductus arteriosus; FO, foramen ovale.

120.

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

BMJ 2013;348:f6932 doi: 10.1136/bmj.f6932

SSRI

Black lung PPHN , Clear lung PPHN

• 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

Pathology mainly in lung blood vessels Pathology mainly in lung airway and parenchyma

PPHN Hypothetical Model

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

TGA+PPHN TGA+IAA TGA+COA

TAPVR supracardiac

Yap SH et al , Pediaric Cardiol 2009

Neonatologist Performed Echocardiography (NPE)

Parameters for the assessment of PAP, PVR , RV performance and shunts

Willem P. et al; .Pediatric Research 2018

Less than 40 %

Less than 0.5 cm%

More than 1.2

LV Systolic Eccentricity Index LV-sEI more than 1

LV-sEI= D1(AP diameter)/D2(Septo-lateral diameter)

LV Configuration

Estimated RVP

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

Oxygenation index (OI) = FiO2 × MAP × 100 /PaO2 Oxygen Saturation Index (OSI ) MAP × FiO2 × 100/ Pre-ductal SpO2

Severity of HRF based on OI

• Mild

15

• Moderate 15 to 25
• Severe 25 to 40
• Very severe >40

Noninvasive OSI correlates with OI OI = ~ 2 X OSI

Severity of PPHN

P/F ratio = PaO2/ FiO2

use pre-ductal blood gases OI and P/F ratios P/F ratio

Mild Moderate Severe >200 to 300 >100 to 200 100 mm Hg

Pathology mainly in lung blood vessels Pathology mainly in lung airway and parenchyma

“PPHN”: Treatment

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 88-94%

PaO2 [50-80 mmHg]

PH 7.25 PCO2 45 -60 mmHg Lactate less than 3 UOP 1ml/kg/hr

Post ductal SPO2 ? 75%

MV

Gentle” 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

• Effective FDA-approved

therapy

• Selective pulmonary

vasodilator without decreasing SVR

• methemoglobin in

intravascular space

iNO

+/- improve V/Q mismatch by entering

• nly 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

CINRGI Study

(Clinical Inhaled Nitric Oxide

Research Group investigation)

Clark RH, al.. NEJM . Feb 2000

NINOS Study

(The Neonatal Inhaled Nitric Oxide Study)

• RCT, Multicenter
• 235 term/near term

with HRF unresponsive to conventional therapy

• End points :
• composite
• utcome of Death
• r ECMO
• Death
• ECMO

Neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS). The Journal of pediatrics. May; 2000

• RCT, Multicenter
• 186 term/near term

with HRF unresponsive to conventional therapy

• End points :
• Need for ECMO

Left Pulmonary Artery Blood Flow and response to Nitric Oxide. Roze et al, Lancet

1994

Prior to iNO 12 hr After iNO

Sharma, V et al Matern. Health Neonatol. Perinatol. 2015

Protocol at Women & Children’s Hospital of Buffalo

Rule Triple 20 Triple 60

Poor lung inflation Myocardial dysfunction Systemic hypotension Severe pulmonary vascular structural disease Missed anatomic cardiovascular lesions such as

TAPVR COA alveolar capillary dysplasia CDH

iNO Refractory PPHN 40%

PDE3 inhibitor Milrinone cAMP vasodilation PDE5 inhibitor Sildenafil cGMP vasodilation

Phosphodiesterase inhibitors be aware of non selective ……..

In a Cochrane meta-analysis

• 37 newborns from centers that lacked NO and high frequency ventilation,

significant improvement in oxygenation was observed in the group receiving sildenafil1

• In a Cochrane review of 3 placebo-controlled RCTs (total n=77) found oral

sildenafil statistically significantly reduced mortality and improved the

• xygenation index and partial pressure of oxygen 2

1Sildenafil for pulmonary hypertension in neonates, Cochrane Database Syst Rev, 2007 2 Shah PS, Ohlsson A: Cochrane Database Syst Rev 2011.

Milrinone

PDE3 inhibitor (cardiac myocytes and vascular smooth muscle) No RCT

• Retrospective
• Nine term

iNO refactory cases

• OI more than 20
• n iNO for the

preceding 4 hr

• Primary Outcome :

 Oxygenation  BP over a 72-hr

Milrinone led to improvement in OI in iNO refractory PPHN without inducing systemic hypotension

(OI more than 20 on at least 2 consecutive ABG , at least 20 minutes apart)

TREND OF RISE OF SBP,MBP &DBP

• In babies with iNO resistant PPHN, milrinone resulted in improved LVO, RVO,

and ultimately a reduction in iNO requirement

Conclusions: Milrinone use was associated with an improvement in systolic and diastolic function in the RV, corresponding to an improvement in clinical status.

Neonatology 2012;102:130–136

Prostaglandins

• Activate adenylate

cyclase

• Increases cAMP
• IV prostacyclins can

cause hypotension and worsening of V-Q mismatch

• Ventavis (Iloprost)
• Flolan

(Epoprostenil)

• Remodulin

(Trepostinil)

• Tyvaso (Trepostinil)

Inhaled Prostacyclin

Inhaled prostacyclin + iNO

Augmented vasodilator effect prevent rebound hypertension during weaning case reports

Endothelin Receptor Blockers

Bosentan  Dual endothelin (ETA and ETB) receptor blocker  Case reports of success as an adjunct to iNO and

• ral sildenafil

 Very seldom used in newborns

Cardiovascular Support

• Cause of

hypotension

• Myocardial

performance

Cardiovascular Support

Normal LV & RV function LV & or RV systolic dysfunction

CONCLUSION

• PPHN is an acute neonatal disorder with complex underlying

pathophysiology, which has a high mortality rate

• Clinically suspected by labile hypoxemia and differential

cyanosis

• NPE/TnEcho is crucial to confirm PH , assess cardiac

function , shunts and exclude CHD prior to starting pulmonary vasodilator therapy in infants presenting with HRF

CONCLUSION

• Gentle” ventilation strategies with optimal PEEP, relatively low

PIP or tidal volume and a degree of permissive hypercapnia are recommended

• iNO is effective selective pulmonary vasodilator in the majority of

patients, but is not always available

• Oral sildenafil is a relatively safe alternative option
• Appropriate hemodynamic assessment and use of inotropes
• iNO refractory cases could be managed by combination therapy but

after optimizing lung recruitment and exclusion of underlying causes e g LV dysfunction and TAPVR,CDH