Dr Niha Peshimam, Dr David Cox; Illustrations Dr Simone Paulson

You are called to see an hour-old old term baby in the delivery suite with respiratory distress. You arrive to find a dusky, blue-tinged baby with significant respiratory distress. There is meconium staining of the skin and umbilical cord. You start face mask oxygen and call for help. Your consultant asks, do you think this could be PPHN?

Persistent pulmonary hypertension of the newborn (PPHN) is a relatively common condition that we treat in NICU.

It’s often used as a diagnosis, but if we’re going to be more accurate, it actually refers to a physiological state and can reflect a number of underlying pathologies. Some of these are quite common (sepsis, meconium aspiration) and some are rarer, for example congenital abnormalities of the heart or lungs (including congenital diaphragmatic hernia).

In PPHN there is systemic hypoxaemia, because of persistently high pulmonary vascular resistance with RIGHT-TO-LEFT shunting of blood from the relatively deoxygenated pulmonary arterial circulation to the systemic circulation.

A good management strategy for PPHN has two aims:

1. Reduce pulmonary arterial pressures (aiming to increase pulmonary blood flow)

How can we do this? A few ways – targeted oxygenation, lung protective ventilation, using a vasodilator (e.g. nitric oxide), correcting and preventing acidosis, and using adequate sedation (plus muscle relaxation if needed).

2. Support the systemic circulation – maintaining systemic arterial pressure, reducing the pressure-mediated shunting of blood at the atria and ductus arteriosus.

How can we do this? Maintain an adequate circulatory volume, including oxygen carrying capacity, and guided use of inotropes. Babies who are still hypoxemic despite all of these strategies are very sick, and probably heading towards extracorporeal membrane oxygenation (ECMO). The physiology of PPHN is basically the persistence of foetal circulation physiology (or in other words, failure to transition from foetal to neonatal circulation).

To understand PPHN better, let’s recap the foetal circulation.

Quick revision of foetal circulation

In utero, the placenta is where gas exchange happens. The foetus’s pulmonary vascular resistance is HIGH compared to the foetal systemic vascular resistance. There is pressure-mediated flow through foetal shunt pathways leading to reduced pulmonary blood flow.

The pulmonary and systemic circulations run in parallel rather than in series.

Blood flows from the placenta – through the umbilical vein – via the ductus venosus – to the right atrium (RA). Much of this blood (which is well-oxygenated as it comes from the placenta) is streamed into the left atrium (LA) through the foramen ovale, bypassing the lungs. This blood then flows into the left ventricle (LV) and is circulated to the rest of the body via the aorta.

Some of the blood entering the RA (from the IVC and SVC and coronary sinus) flows to the RV and into the pulmonary artery.

This blood gets directed away from the lungs and into the aorta through the ductus arteriosus (a connection between the pulmonary artery and the aorta).

At birth, the cord is clamped and the baby cries and fills their lungs with air. This marks the transition from foetal to neonatal circulation.

Clamping of the cord disconnects the placenta (which has the lowest resistance in foetal circulation) and so increases increasing the systemic vascular resistance. Once blood is no longer flowing through the umbilical vein, the ductus venosus closes, dropping the pressure in the RA.

When the lungs expand (filling with air instead of fluid for the first time) the pulmonary vascular capillaries, which have been coiled and collapsed, now open up. This lowers the pulmonary vascular resistance and increases the pulmonary blood flow. Pulmonary artery pressure then falls.

The increase in the pulmonary blood flow increases the pressure in the LA, and helps to close the foramen ovale. Increase in arterial oxygen saturation causes the closure of the patent ductus arteriosus (over the course of the next few hours to days).

In PPHN, pulmonary vascular resistance stays high rather than dropping just after birth. This causes persistent right-to-left shunting of blood through the patent foramen ovale (PFO) and patent ductus arteriosus (PDA), systemic cyanosis and labile hypoxaemia in the newborn baby.

What causes PPHN?

• Poor adaptation of lung parenchyma and vessels

Lung parenchymal diseases (meconium aspiration syndrome, respiratory distress syndrome, pneumonia, sepsis) 

• Underdeveloped lung parenchyma and vessels

Lung hypoplasia (congenital diaphragmatic hernia, renal agenesis, congenital pulmonary malformation (CPAM), foetal growth restriction)

• Poor development of pulmonary vessels

Idiopathic

Managing PPHN

While most babies affected by PPHN are term babies, PPHN can also happen in preterm babies. The key to successfully managing PPHN is recognising it early, and concentrating on therapies that help to lower pulmonary vascular resistance. This begins in the delivery room!

Neonates with risk factors for PPHN might need prolonged resuscitation and have a high oxygen requirement. Carry out resuscitation as per the NLS algorithm, but make sure you keep an eye on pre- and post-ductal saturation monitoring to help titrate the FiO2.

**Right hand = pre ductal** **Either lower leg = post ductal**

Investigations

1. Chest X-Ray: might have features of parenchymal disease such as meconium aspiration syndrome (MAS) or respiratory distress syndrome (RDS). CXR could also reveal a congenital diaphragmatic hernia. In primary PPHN, the lung fields may look suspiciously clear, due to lack of blood flow.
2. Arterial blood gas: Significant hypoxemia out of proportion to parenchymal disease.
3. Preductal (right hand) and post-ductal (either leg) saturations: A difference in oxygen saturation ≥ 5-10% is suggestive of PPHN. This difference may not be seen in babies with PPHN with no PDA. Absence of difference doesn’t mean ‘no PPHN’
4. Echocardiography: the gold standard of diagnosis. You will see right-to-left or bidirectional shunting of blood at the foramen ovale and/or the ductus arteriosus, as well as high pulmonary arterial/RV systolic pressure

Echocardiography is also important to rule out any duct dependent lesion. The echo gives you more information about the direction of shunting at ductal and atrial level. It also gives a visual assessment of ventricular function and can calculate the ejection fraction.

Management

The key principles in the management of PPHN are:

1. Reduce pulmonary vascular resistance to improve pulmonary arterial blood flow. Good alveolar recruitment is needed to achieve optimal V/Q ratio. (Especially important in secondary PPHN).
2. Prevent right-to-left shunting, by maintaining adequate systemic vascular resistance
3. Treat the underlying cause

Optimising oxygenation and preventing hypoxia-related acidosis are key!

Oxygenation and Ventilation

Use the Goldilocks approach – everything has to be ‘just right’! Optimising oxygen therapy is the mainstay of treating PPHN. When you suspect PPHN in the delivery suite, start with 100% oxygen and wean slowly and cautiously. Hypoxia makes pulmonary vascular resistance worse, but HYPERoxia will cause free radical injury, reduce the response to iNO and increase pulmonary vasoconstriction.

Keep pre-ductal saturations above 94% as you titrate the oxygen. Even better, monitor the arterial oxygen tension – the PaO2 should be kept at 8-12kPa while you are giving oxygen.

Use positive end expiratory pressure (PEEP) for lung recruitment – it reduces the pulmonary vascular resistance as well as helping iNO work better. Maintaining alveolar expansion, and avoiding overdistention, helps oxygen diffuse from the alveoli into the pulmonary capillaries.

Ventilation should be lung protective. If higher pressures are required to increase minute ventilation and CO2 clearance, consider switching to high frequency oscillatory ventilation (HFOV).

Oxygenation index (OI)

Monitoring the oxygenation trend helps guide when to start iNO, as well as indicating when a baby might need to be referred for ECMO.

When you are calculating OI, be aware of which units of measurement you use for the PaO2 – kPa or mmHg!

Medical therapies

Surfactant: If parenchymal lung disease is the likely underlying cause of PPHN, give surfactant early as it is achieves better outcomes – especially in milder disease.

Inhaled Nitric Oxide (iNO): This is a potent and selective pulmonary vasodilator which doesn’t have any effect on the systemic vasodilation. It selectively improves the blood flow to well-ventilated alveoli, reducing V/Q mismatch. There are several multicentre studies which show that using iNO is associated with a reduced need for ECMO.

1. Start iNO at a dose of 20 ppm when the oxygenation index is 15-20 with evidence of pulmonary hypertension on echocardiography.
2. iNO is contraindicated in duct dependent congenital heart disease, hence the importance of echocardiography to rule this out.
3. Take extreme caution with iNO doses higher than 20ppm – it can cause high levels of methaemoglobin and nitrogen dioxide. Other complications include platelet dysfunction and pulmonary oedema.
4. Monitor methaemoglobin levels at 2 hours and 8 hours once iNO has been started, then at least once a day.
5. Wean oxygen first. When FiO2 is below 0.4, wean the iNO.
6. Wean iNO gradually. Stopping it suddenly runs the risk of rebound pulmonary hypertension.
7. A suggested regime for weaning iNO is at a rate of 5 ppm every 4 hours. Once iNO dose is 5 ppm, wean gradually by 1 ppm every 2 to 4 hours.

Sildenafil: a phosphodiesterase (PDE) 5 inhibitor. If the echo shows right-to-left shunting and the baby is hypoxic with a stable blood pressure, sildenafil can be used.

Sildenafil is metabolised by the liver. Monitor very carefully if the baby has liver dysfunction/failure.

**Prostacyclin (PGI₂) and inhaled prostaglandin E1 (Alprostadil) are not discussed here as they are not routinely used**

Inotropes: Using inotropes to improve ventricular function and support systemic blood pressure is a common strategy in PPHN, which aims to reduce right-to-left shunting at the ductus arteriosus. However, the authors of this piece suggest that measures to reduce the pulmonary vascular pressures (optimising lung inflation and oxygenation, starting iNO) should be initiated – and the effects of these assessed, before starting inotropes. Inotropes can of course be started earlier, if there is clear evidence of systemic hypoperfusion.

It’s a misconception that inotropes ‘always’ improve the function and contractility of the myocardium. They may manage to do this, but asking the myocardium to work harder means that it has a higher oxygen demand and energy requirement (especially if the heart is already working overtime against vasoconstricted pulmonary vessels). Inotropes also cause tachycardia, and a heart that is beating too fast will not function well. Less time for diastolic filling = reduced ventricular preload.

When using inotropes worsens rather than improves the ventricular function – causing poor cardiac output and reduced systemic perfusion – this is a losing game. Anaerobic activity increases, and the baby becomes more acidotic. Acidosis is terrible for the myocardium and also increases pulmonary vascular resistance.

In PPHN it’s crucial to think about the physiological impact of your interventions on the right ventricle. Whilst supporting the LV and systemic perfusion is important, PPHN and increased pulmonary arterial pressure often put the RV under a lot of strain. Using inotropes to raise systemic blood pressure and reduce right-to-left shunting can have the unintended effect of increasing the strain on the RV and worsening its performance. This is part of the reason ‘unnecessary’ inotrope use should be avoided, and Milrinone considered (see below).

A full discussion of the modes of action of commonly used neonatal inotropes would be an article in itself(!), but for the purposes of this article a sensible strategy is to use a combination of inotropes that increase myocardial function and cardiac output, whilst providing some vasoconstriction that helps to optimise systemic blood pressure. Any inotropes should be started at low infusion rates and titrated up. This is best done with regular echocardiograms, but this can be challenging in most NICUs.

Milrinone: an inodilator that inhibits PDE3 and increases the concentration of cyclic adenosine monophosphate in pulmonary and systemic arterial smooth muscle, and in cardiac muscle. It supports both cardiac ventricles and increases ventricular output. One of its main advantages in PPHN is that it causes diastolic relaxation of the RV and so improves its diastolic function. If the echo shows LV dysfunction with high LA pressures, using iNO can cause or worsen pulmonary oedema and so milrinone is usually the drug of choice.

Caution – milrinone is a systemic vasodilator, watch out for hypotension.

Consider giving a fluid bolus if a baby is hypotensive when starting milrinone. Monitor the blood pressure closely. To balance out the effect on blood pressure, milrinone is often used along with a drug that increases systemic vascular resistance.

Supportive Measures

1. Target mean systemic arterial pressures that reduce right-to-left shunting at the ductus arteriosus. Be guided by the equalising of pre- and post-ductal O2 saturations. If the baby remains hypotensive or poorly perfused despite fluid boluses, blood pressure should be supported using inotropic agents like dopamine, dobutamine or adrenaline.
2. Correct electrolyte and metabolite abnormalities; keep blood glucose above 2.6mmol/L and ionized calcium above 1mmol/L
3. Stimulation and sudden movements may worsen oxygenation due to shunting. Minimise this by using opioids (e.g. morphine). Avoid continuous infusions for muscle relaxation; consider intermittent doses of pancuronium.
4. Acidosis worsens pulmonary hypertension (by causing severe pulmonary vasoconstriction). Aim for a normal pH, or at least above pH7.28.

Extracorporeal membrane oxygenation (ECMO): If the baby is still hypoxemic despite all of these strategies, they probably need to be referred for ECMO. There isn’t a specific OI cut-off point, but generally speaking, babies with OI above 30 should be discussed with referral centres. Babies with OI above 40 are considered candidates for ECMO (if there are no contraindications).

What NOT to do – practices that have been discontinued

DON’T use alkali infusions or hyperventilation to correct acidosis – this can cause sensorineural deafness, impaired cerebral blood flow and increased need for ECMO.

If this all feels like a lot of information, just remember your A B C’s

A: (Airway): Correct sized ET tube, with minimal leak and in optimal position.

B: (Breathing)

• Lung protective ventilation, strategies to optimise oxygenation.
• If high PIP required to achieve minute ventilation, consider switching from conventional ventilation to HFOV
• Early surfactant for underlying parenchymal disease
• Inhaled nitric oxide when OI 15-20

C: (Circulation)

• Maintain normal blood pressure using inotropes if needed. Use invasive blood pressure monitoring to titrate inotropes
• Echocardiography for diagnosis and to guide treatment

D: (Disability/neuro): Sedation using morphine infusion. Paralysis as needed (boluses of pancuronium) – stimulation and movement may worsen oxygenation.

E: (Exposure): Keep a normal body temperature

F: (Fluids: input/output): Correct hypovolaemia, aim for urine output above 1ml/kg/hr

G: (GI): Maintain normal blood glucose levels. Parenteral nutrition to optimise nutrition

H: (Haematology and biochemistry): Correct polycythaemia and electrolyte or metabolite abnormalities

I: (Infection): Antibiotics to treat for sepsis

L: (Lines): Central venous access (UVC) to safely give inotropes. Arterial access (UAC or peripheral arterial line) to measure PaO2 and monitor blood pressure

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Dr Niha Peshimam, Paediatric Registrar; Dr David Cox, Consultant Neonatologist, Imperial College NHS Trust