Persistent Pulmonary Hypertension of Newborn(PPHN):Strategy for - - PowerPoint PPT Presentation

Persistent Pulmonary Hypertension

• f Newborn(PPHN):Strategy for

Diagnosis & Treatment

• Dr. Nargis Ara Begum

Consultant Neonatology United Hospital

Overview

• Background
• Fetal and transitional neonatal circulation
• Pathophysiology of PPHN
• Risk factors &Conditions associated with PPHN
• Clinical Presentation
• Diagnosis
• Management
• Outcome,Prognosis & Follow-up
• Outcome in our center

Background

New born with persistent pulmonary hypertension is a medical emergency with very high morbidity and mortality. It is therefore, essential to understand the etiopathogenesis, methods

• f

diagnosis, monitoring and available treatment modalities to ensure better outcome of this critical problem.

History of PPHN

1628 : 1st describe by Willim Harvey as : UNRIPE BIRTH OF MANKIND 1969: Gersony et al - as persistent fetal circulation

Current name : Persistent pulmonary hypertension in newborn

What is PPHN ?

 Persistent pulmonary hypertension of the newborn (PPHN) is defined as the failure of the normal circulatory transition that occurs after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left shunting of blood.

Epidemiology

• Incidence 1-6/1000 live birth
• Most common in term and near term
• Mortality nearly 40%(in absence of ECMO),

10-20 %(ECMO)

• Imp morbidity severe handicap , ICH,

deafness(>20%)

Source: M.T.R.Roofthooft et al, pulmonary medicine, 2011.

Fetal Circulation

Normal Pulmonary Vascular Transition

 In utero: – Pulmonary pressures are equivalent to systemic pressures due to elevated pulmonary vascular resistance (PVR). – Only 5% to 10% of cardiac output goes through the lungs.

In utero high pulm vascular tone

Compression of pulm arterioles by fluid filled alveoli. Presence of alveol & arteriolar oxygen tensions. Relative lack of vasodilators (NO, PGI2). Elevated level of vasoconstrictor endothelin-1 & thromboxane.

Oxygen, estrogen Ligand (ATP,VEGF) Receptor Endothelium L-Arginine eNOS L-Citrulline NO GTP Smooth Muscle cGMP

Guan Cyclase

GMP

No Pathway

Phosphodiesterases

Oxygen Lung distension Ligand (ATP etc) Receptor Endothelium Arachidonoic acid COX, PGI2 synthase Prostaglandins PGI2 ATP Smooth Muscle cAMP Aden Cyclase AMP

Phosphodiesterases

Prostacyclin Pathway

What happens at birth?

• The change from fetal to postnatal circulation

happens very quickly

• Changes are initiated by baby’s first breath
• Pulmonary arterial pressure decrease 50% of

systemic pressure

• Pulmonary blood flow increased to 10 folds

pulm vascular tone –maintained by(distens of the lung and rising PO2 , and oxygenation simulates the activity of eNOS and COX-1 directly.)

TRANSITIONAL CIRCULATION:

AT BIRTH

• Lung expansion causes establishment of adequate alveolar

ventilation and oxygenation, and successful clearance of fetal lung fluid

Rapid fall in PVR

• Removal of the placenta, the catechol surge , cold env

Increase in SVR Shunt through DA reverses & becomes L to R.

FACTORS AFFECTING PVR

Lower PVR:

• Oxygen, nitric oxide
• Prostacyclin, PG E1, D2
• Adenosine
• Magnesium
• Bradykinins
• Atrial natriuretic factor
• Alkalosis
• Histamine
• Acetylcholine
• Beta-adrenergic stimulation
• Potassium channel activation

Increase PVR:

• Hypoxia
• Acidosis
• Endothelin-1
• Eukotrienes, thromboxanes
• Platelet activating factors
• Prostaglandin F2- alpha
• Alpha-adrenergic stimulation
• Calcium channel activation

Pathophysiology

Risk Factors

• Male gender
• African or Asian maternal race
• Pre-conception maternal overweight
• Maternal diabetes, Maternal asthma
• Chorioamnionitis
• Antenatal exposure to SSRIs, NSAIDs
• Infection(mainly GroupB Streptococcus)
• Hypothermia
• Hypocalcemia
• Polycythemia
• Late preterm and large for gestational age
• IUGR

Classification

• 1. Parenchymal lung disease (meconium aspiration

syndrome, respiratory distress syndrome, sepsis)- Maladaptation

• 2. Idiopathic (or "black-lung") /Maldevelopment
• 3. Pulmonary hypoplasia (as seen in congenital

diaphragmatic hernia)-Underdevelopment.

Developing Lung Circulation Intrauterine Injury

Hemodynamic Stress Chronic Stress Inflammation Other (genetic)

Vascular Growth Abnormal Vascular Reactivity Altered Vascular Structure ↓ Angiogenesis ↓ Alveolarization ? ↓ Vasodilators (NO, PGI2, Adenosine) ↑ Vasoconstrictors (ET1, LT, TBX, PAF) Enhanced Myogenic Tone ↑ SMC Proliferation Altered Extracellular Matrix Adventitial thickening

Pathogenesis of PPHN

Pulmonary hypoplasia CDH RDS, MAS, GBS

Chronic IU hypoxia Idiopathic PPHN

Idiopathic PPHN

• Idiopathic (or "black lung") PPHN is most common in

term and near-term newborns. Remodeling of the pulmonary vasculature- vessel wall thickening and smooth muscle hyperplasia.

• constriction of the fetal DA in utero from exposure

to NSAIDs, Exposure to SSRI

• reactive oxygen species (ROS) ,Thrx, endothelin - the

vasoconstriction and vascular remodeling.

• genetic susceptibility, Down Syndrome

Meconium Aspiration Syndrome

• Mechanism of respiratory distress leading to

PPHN include

– blockage of the airway – inactivation of surfactant – direct damage to the lung parenchyma – atelectasis & V-Q mismatch

Perinatal Asphyxia

• In response to asphyxia in utero-fetus directs

blood flow to vital organs(heart, brain, adrenals). This leads to vasoconstriction of non vital vascular bed including pulm bed.

• Surfactant inactivation
• Cardiac dysfunction

Respiratory Distress Syndrome (RDS)

• Surfactant deficiency
• VQ mismatch

Congenital Diaphragmatic Hernia (CDH)

• Pulmonary hypoplasia and abnormal vascular

development with

– Decreased bronchial and pulmonary arterial branching – Pulmonary arterial muscle hyperplasia leading to PPHN

Clinical Presentation

• Most present within 1st 24 hours of life with signs
• f respiratory distress (eg, tachypnea, retractions,

and grunting) and cyanosis, low apgar scores

• There may be meconium staining of skin and

nails, which may be indicative of intrauterine stress.

• Differential cyanosis may appear in severe cases

(with a pink upper body and a cyanotic lower body)

Clinical Findings

• A prominent RV impulse and a single and loud S2
• Occasional gallop rhythm (from myocardial

dysfunction) and a harsh regurgitant systolic murmur of TR may be audible.

• Breath sounds may be normal (If pneumonia or

meconium staining exists, crackles or wheezes may be present)

• Severe cases of myocardial dysfunction may

manifest with systemic hypotension.

Pulse Oximetry

• A difference >10% between the pre- and

postductal (right thumb and either great toe)

• xygen saturation (d/t RL shunt through

PDA)

• However, absence of a pre- and postductal

gradient in oxygenation does not exclude the diagnosis of PPHN, since right-to-left shunting can occur predominantly through the foramen

• vale rather than the PDA.

Investigation

• ABG, Hyperoxia test-Obsolate
• BNP
• CXR
• Echo

Arterial Blood Gas

Arterial blood gas- PaO2 gradient of > 20 mmHg between pre-ductal (upper extremity

• r head) and post-ductal (lower extremity or

abdomen) ABGs

Hyperoxia Test

To distinguish PPHN & CHD, from parenchymal lung disease Give 100% O2 x 10-15 min. PPHN or CHD = PaO2 < 100 mmHg Parenchymal = PaO2 >100 mmHg ( CHD more or less ruled out )

Diagnosis

• Consider PPHN when hypoxemia is out of

proportion to the degree of parenchymal lung disease and there is no evidence of cyanotic CHD.

• Echo- diagnostic

Echocardiogram

• Gold standard

Level & direction of shunt Estimation of PAP

Assessment of severity of PPHN using

• xygenation index(OI)

Oxygen Index(OI)used to assess the severity of hypoxemia in PPHN and to guide the timing of interventions such as iNO administration or ECMO support.

• OI = [mean airway pressure x FiO2 ÷ PaO2] x 100
• OI>25-iNO
• OI>40-ECMO

( high OI indicates severe hypoxemic respiratory failure)

Severity of PPHN

• Patients with OI ≥25 should receive care in a center

where high-frequency oscillatory ventilation (HFOV), iNO, and ECMO are readily available

• In patients with OI <25, general supportive care is

typically adequate and no further invasive intervention is usually required

MANAGEMENT

Aims of Management

The treatment strategy for PPHN aimed at-

• Lower pulmonary vascular resistance.
• Maintain systemic blood pressure

Reverse right-to-left shunting.

• Improve arteriolar oxygen saturation and
• xygen delivery to the tissues.
• Minimize barotrauma &
• Ensure adequate sedation and pain relief.

General Management

• Minimum handling/stimulation of the

newborn.

• Minimal use of invasive procedures.
• Continuous monitoring of oxygenation, blood

pressure & perfusion.

• Maintaining of normal body temperature.
• Nutritional support.
• Correction of electrolytes & glucose

abnormalities.

• Correction of metabolic acidosis.

Oxygenation

High flow oxygenation by oxyhood

• This will help to maintain arterial
• xygen levels and will act as a

pulmonary vasodilator.

• Maintain saturations in the normal

range (95‐100%), aiming to maintain paO2 between 60‐100 mmHg in term infants.

Specific Therapies

Mechanical ventilation

100% O2

• Always start with 100% oxygen and reduce

the FiO2, rather than starting on 25% and

• increasing. Aim to maintain normal pCO2 in

the range 35 to 40 mmHg, pCO2 lower than this may cause cerebral vasoconstriction. Hypercarbia leads to pulmonary vasoconstriction and should be avoided.

Specific Therapies

Mechanical ventilation

• Ventilatory strategies include conventional

positive pressure ventilation with initial increased rates ,PEEP of 4 cm H2O, and sufficient peak pressure to achieve a PaCO2

• f not greater than 35-40 mmHg with the

pH between 7.35 and 7.45.

• The PaO2 should be maintained 50-60

mmHg once stable

• Weaning should be gradual; pressures are

to be decreased before decreasing the FiO2.

Specific Therapies

HFOV

• Consider HFOV to reduce barotrauma &

associated air leak syndrome in newborn who require high PIP (>30 cm H2O) or MAP (>15 cm H2O)

• HFOV allowed for better oxygenation by

allowing better lung inflation and "alveolar recruitment.

• Use of HFOV, particularly in combination

with inhaled Nitric Oxide, has been shown to reduce the need for ECMO.

Specific Therapies

INO

Pulmonary vasodilators

• I nhaled nitric oxide (iNO) is the

vasodilator of choice.

• 1999, potient selective pulm vasodil without

dec sys vsc tone.

• It dec VQ mismatch.
• iNO should be started at 20ppm and reduced

to 5ppm as able, according to response and to stability.

• Methaemoglobin levels should be monitored.
• Nitrogen dioxide (NO2) levels should be

monitored and kept below 1ppm.

• Contra‐indications
• Major Cardiac anomalies
• Lethal congenital anomalies

Pulmonary vasodilators

• Sildenafil has been reported to reduce

mortality where in centres where iNO/ECMO is not available.

• Sildenafil is a potent and selective inhibitor
• f cGMP-specific phosphodiesterase 5

(PDE5). This isoenzyme metabolizes cGMP which is the second- messenger of NO and a principle mediator of smooth muscle relaxation and vasodilatation. By inhibiting the hydrolytic breakdown of cGMP , sildenafil prolongs the action of cGMP .

• This results in augmented smooth muscle

relaxation and cause pulmonary vasodilatation.

Reffelmann et al. Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease. Circulation 2003;108 :239-244.

• Sildenafil is safe and easy to administer; it

is available in an IV and oral preparation and is relatively inexpensive.

• Enteral administration and gastro‐intestinal

absorption may be impaired in critically ill patients.

• Dose: 0.5mg/kg/dose P/O 8 hrly

(2mg/kg/day) Humbert et al. Treatment of pulmonary arterial hypertension in newborn. N Engl J Med 2004;351:1425-36.

SILDENAFIL cGMP PATHWAY MODULATION

Pulmonary vasodilators Milrinone

• Milrinone causes pulmonary vasodilation

by inhibiting phosphodiesterase 3.

• It has inotropic effects and is also effective

in reducing the afterload by improving right sided cardiac output.

• Intravenous milrinone leads to better
• xygenation and improvements in

pulmonary and systemic hemodynamics in patients with suboptimal response to iNO.

• Dose: 0.25-1 microgram/kg/min

McNamara et al. Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide. Pediatr Crit Care Med 2013;14:74-84.

Pulmonary vasodilators

• Magnesium sulphate
• MgSO4 could be used as a first-line

vasodilator in developing countries because of its low cost and high efficacy.

• Is an endothelin rc antagonist. It promotes

vasodil by antagonizing entry of calcium in cell.

• Hypotension is a common side effect

might need inotrop support.

Chandran et al. Use of magnesium sulphate in severe persistent pulmonary hypertension of the newborn. J Trop Pediatr 2004 Aug;50(4):219-23.

Pulmonary vasodilators Bosentan

• Bosentan is an orally active dual

endothelin receptor antagonist which reduces PVR and pulmonary arterial pressure in pulmonary hypertension.

• A recent randomised controlled trial

demonstrated that bosentan was superior to placebo (p<0.0001) as an adjuvant therapy of PPHN in neonates in low‐income settings where iNO and ECMO are not readily available.

Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903.

Therapy Mechanism of Action Doses Side Effects Inhaled NO Increased cGMP levels via stimulation of sGC activity 5 -20 ppm through ventilator Methemoglobinemia,inhib ition of platelet aggregation Sildenafil Increased cGMP levels via specific PDE-5 inhibition PO 0.5 - 2 mg/kg/ dose every 6 hours. Hypotension impaired retinal vascular growth, thrombocytopeni Milrinone Increased cAMP levels via specific PDE-3 inhibition 0.33 - 0.99 μg/kg/min IV infusion Systemic hypotension, Intraventricular hemorrhage (IVH) Magnesium Sulphate affecting calcium influx thereby inhibits SMC depolarization and promotes vasodilation IV 200 mg/kg loading

• ver 20 min

f/b 20 - 150 mg/kg/h infusion Bradycardia, hypotension, respiratory depression Adenosine Release of endogenous NO, stimulation of K+-ATP ,channels, and decreasedcalcium influx 30-90 μg/kg/min IV infusion Bosentan Increased cGMP levels via ET-1 receptor antagonism PO 1 mg/kg/dose Systemic hypotension

ECMO

ECMO : Baseline ECMO criteria

 ≥ 34 weeks

 Wt > 2000g (‘cannulas fit’)  No major ICH on HUS (no > Gr II)  Reversible lung disease  No evidence of lethal congenital anomalies or inoperable cardiac disease

Emerging Therapies for Treatment of PPHN

• Soluble guanylate cyclase (cGS) activators
• Recombinant superoxide dismutase
• Antinatal steroids

(potential future therapy currently under invest)

Source:Seminar Perinatol,2014;78-92

Differential Diagnosis

• Congenital Heart Disease

– PAPVR */ TAPVR – PA with intact ventricular septum – Transposition of Great Arteries (TGA) – Tricuspid Atresia

• Pulmonary Alveolar Capillary Dysplasia

– failed formation & growth of alveolar capillaries and medial musculature hypertrophy

Follow-Up Care

• Neurodevelopmental follow-up:
• Upto 2 years ,as 25% chance of neurodevelopmental

impairment.

• Hearing test :
• Before discharge , at 6 months of age & again as the

result indicated as chance of sensorineural hearing loss is very high.

• Pulmonary hypertension clinic follow-up:
• Comprehensive evaluation & treatment plan for patients

with persistence of any level of pulmonary hypertension.

Source: Seminar Perinatol, 2013

Last But Not the Least

• The sophisticated and expensive treatment

modalities of PPHN such as iNO, ECMO are limited in developing countries like Bangladesh.

• Current evidence indicates that sildenafil,

bosentan, magnesium sulphate or milrinone may improve oxygenation in PPHN. Awareness of predisposing conditions and proper identification along with less expensive treatment leads to better outcome in PPHN in countries with limited resources.

Last 6 years review of PPHN cases in

• ur Unit ( N=142)

Type Number %

Mild 100 70 Moderate 24 17 Severe 18 13

Treatment modalities

RX Number %

O2 + Supportive care 142 100 MgSO4 31 21 Sildenafil 27 19 Milrinone 5 4 HFOV 3 2

• Optimal approach to PPHN mx still

remains controversial.

• Future high quality RCT, needed to

develop Strong, evidence based guideline for PPHN mx

THANK YOU