Persistent Pulmonary Hypertension of the Newborn (PPHN)

Summary
Introduction
Differential Diagnosis
Investigation
Management
Areas of Uncertainty in Clinical Practice

Summary

diagnosis should be confirmed by cardiac echo as soon as feasible
appropriate support of ventilation with liberal oxygenation is important
early consultation with NETS is advisable
support of systemic BP with inotropes is useful
nitric oxide is safe and usually effective in PPHN up to a dose of 20ppm

Introduction

One of the main tasks facing a fetus making the transition to the extra-uterine environment is that of cardio-pulmonary adaptation. Central to this process is a dramatic drop in pulmonary vascular resistance. This is due to a number of influences including:

mechanical stretching of the lungs
increased oxygen levels in the blood
vascular endothelial factors including nitric oxide

Delayed relaxation of the pulmonary vascular bed and consequent PPHN is seen in association with many neonatal respiratory diseases including:

lung hypoplasia (e.g. diaphragmatic hernia)
meconium aspiration syndrome
pneumonia
surfactant deficiency
The syndrome may also be seen in the absence of triggering diseases.

Right to left shunting across the ductus arteriosus and foramen ovale characterizes PPHN, hence the alternate name Persistent Fetal Circulation. A "vicious cycle" of worsening hypoxia causing increasing pulmonary vascular resistance in turn reducing oxygen uptake provides a substantial therapeutic challenge.

Therapies for PPHN are largely untested in randomized controlled trials and many controversies about management strategies remain.

Differential Diagnosis

Structural heart disease needs to be excluded when PPHN is considered a likely diagnosis.

echocardiography is the definitive diagnostic tool but is not always available
clinical examination is of limited value. A single second heart sound is present in many cyanotic heart defects and clinical or radiological evidence of cardiac failure suggests structural cardiac disease
the use of pre-ductal and post-ductal oxygen concentrations to make the diagnosis of PPHN is readily available but has limitations. Normal right arm oxygen levels with low oxygen levels taken from an umbilical artery or left arm/lower limb is the classic finding but may not be present if atrial right to left shunting is prominent. In addition the combination of patent ductus arteriosus with coarctation of the aorta may produce differential cyanosis, mimicking PPHN
the clinical course of the disease and response to therapy may be the most useful diagnostic tool particularly where resources are limited

Investigation

In addition to conventional echocardiography, Doppler studies of ductal and tricuspid regurgitation in conjunction with simultaneous blood pressure measurements provide an accurate indication of right-sided cardiac pressures and physiology.

Management

The primary goal of therapy is to selectively reduce pulmonary vascular resistance and thereby improve oxygenation.

In the level II nursery

urgent echocardiogram (if available) to exclude cyanotic congenital heart disease (where Prostin may be life saving)
oxygen
warmth
correction of hypoglycaemia and acidosis
early consultation with NETS regarding
- need to transfer
- diagnosis/differential diagnosis
- level III management advice (see below)

Level III Management

Nitric oxide is the only specific therapy shown to reduce pulmonary vascular resistance. The reviewers for the Cochrane Library identified twelve RCTs evaluating the use of nitric oxide in term infants. They concluded "on the evidence presently available, it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 parts per million for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia".

Other appropriate management strategies depend on the underlying disease process

if surfactant deficiency is present, exogenous surfactant should be given. The use of exogenous surfactant in conditions characterised by surfactant inactivation eg meconium aspiration syndrome and pneumonia is less clear-cut but may be considered in individual cases
high frequency ventilation is frequently used in PPHN. Maintaining a respiratory alkalosis may be useful but the association of low CO2 levels (e.g. < 30 mmHg) with poor neurodevelopmental outcome has resulted in a more cautious approach to this line of treatment
judicious use of bicarbonate in conjunction with mild hypocapnia to maintain a pH of 7.4 to 7.5 is currently common practice
muscle relaxation with pancuronium and liberal use of sedation (e.g. morphine) may assist in achieving adequate ventilation
support of systemic blood pressure with inotropes such as dopamine and dobutamine (dose ranges from 5 - 20 mcg/kg/min) is useful in reducing right to left shunting
other drugs such as tolazoline, and magnesium sulphate are less commonly used now than in previous years
provision of liberal supplemental oxygen is beneficial. The risks of hyperoxia are much lower in the population of term infants compared with preterms

Once adequate oxygenation is achieved weaning of oxygen and other ventilator settings should be done in tiny increments to prevent a return to a fetal circulation pattern.

Areas of Uncertainty in Clinical Practice

the management of diaphragmatic hernia remains controversial
nitric oxide and exogenous surfactant remain unproven therapies in this condition.
recent expert advice has tended towards an approach characterized by permissive hypercapnia and less aggressive oxygenation.

References

Kinsella JP, Abman SH. Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 1995; 126:853-864.

Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term (Cochrane Review). Cochrane Database Syst Rev 1902; 4:CD000399