Pulmonary Hypertension

Jack is a 7-month-old ex-preterm infant presenting to the Emergency Department with a 2-day history of cough, coryza, and increasing respiratory effort.

He was born at 27 weeks’ gestation and had a complex neonatal course requiring prolonged intubation and ventilation. He received two courses of DART (dexamethasone for respiratory disease) to facilitate extubation and was subsequently diagnosed with chronic lung disease of prematurity. He was discharged home on 0.1 L/min of low-flow nasal oxygen.

Neonatal echocardiography showed a structurally normal heart with a small, haemodynamically insignificant PDA and mild to moderate right ventricular hypertrophy — findings attributed to pulmonary vascular changes secondary to prematurity.

At this current presentation, Jack is tachypnoeic with increased oxygen requirements. His capillary blood gas reveals:

pH: 7.18
pCO₂: 9.5 kPa
pO₂: 5.2 kPa
Base excess: +2.4
HCO₃⁻: 27 mmol/L
Lactate: 2.5 mmol/L
Ionised calcium: 1.02 mmol/L
Haemoglobin: 90 g/L

He appears to be tiring and remains hypoxic despite non-invasive respiratory support.

In a child like Jack, there are several potential causes for clinical deterioration. Could this be a lower respiratory tract infection exacerbating his chronic lung disease? Is there an evolving sepsis or cardiac decompensation at play? Or—critically—are we seeing the early signs of worsening pulmonary hypertension?

What is Pulmonary Hypertension?

Pulmonary hypertension (PH) is a progressive condition defined by elevated pulmonary arterial pressure (PAP), leading to right heart strain and, if untreated, right ventricular failure. In paediatrics, it is defined haemodynamically as a mean pulmonary artery pressure (mPAP) >20 mmHg, measured during right heart catheterisation.

In children, PH often presents with subtle, nonspecific symptoms—tachypnoea, poor feeding, failure to thrive, or desaturation—that can easily be attributed to other causes.

Who does it affect?

Paediatric pulmonary hypertension can occur at any age, from neonates with persistent pulmonary hypertension of the newborn (PPHN) to adolescents with connective tissue disease or idiopathic PAH. In contrast to adults, children more often have PH related to developmental lung disease, congenital heart defects, or genetic syndromes.

How common is it?

Pulmonary hypertension is rare but serious. Epidemiological data estimate an incidence of approximately 63.7 cases per million children, with significant variability depending on age group and underlying diagnosis.

What causes Pulmonary Hypertension?

The causes of pulmonary hypertension in children are diverse and differ significantly from adult populations. The Sixth World Symposium on Pulmonary Hypertension (WSPH) classifies PH into five major groups based on clinical and pathological characteristics:

1. Pulmonary Arterial Hypertension (PAH) – ~87% of paediatric cases

This group includes:

• Transient forms (82%)
  • Persistent Pulmonary Hypertension of the Newborn (PPHN)
  • PH secondary to congenital heart disease (CHD)
• Progressive forms (5%)
  • CHD-associated PH (72%)
  • Idiopathic PAH (23%)

2. PH due to left heart disease (~5%)

This includes:

• Left-sided obstructive lesions
• Cardiomyopathies
• Pulmonary venous hypertension

3. PH due to chronic lung disease and/or hypoxia (~8%)

A key group in neonates and infants, including:

• Chronic lung disease of prematurity (e.g. bronchopulmonary dysplasia)
• Interstitial lung disease
• Obstructive sleep apnoea
• High-altitude exposure

4. Chronic thromboembolic pulmonary hypertension (<1%)

Rare in children, but consider in adolescents with unprovoked or recurrent venous thromboembolism.

5. PH with multifactorial or unclear mechanisms

This is a “catch-all” category, including:

• Complex syndromes (e.g. trisomy 21, connective tissue disorders)
• Genetic mutations
• Haematological or metabolic disease

What is a Pulmonary Hypertensive Crisis?

A life-threatening complication of pulmonary hypertension where acute elevation in pulmonary vascular resistance (PVR) overwhelms right ventricular function. It leads to sudden cardiovascular collapse, profound hypoxia, acidosis and, if untreated, cardiac arrest.

Pathophysiology of a Pulmonary Hypertensive Crisis

A pulmonary hypertensive crisis occurs when pulmonary vascular resistance (PVR) acutely rises, placing excessive strain on the right ventricle (RV) and triggering a rapid decline in cardiac output.

What happens during a crisis?

1. Pulmonary vasoconstriction is precipitated by triggers such as hypoxia, acidosis, agitation, infection, or pain. This abrupt increase in PVR significantly elevates the afterload on the RV.
2. The right ventricle, already operating under stress, begins to dilate. As it fails, the interventricular septum shifts leftwards, impairing left ventricular (LV) filling and reducing systemic perfusion.
3. Right ventricular failure results in a cascade of complications:
   • Reduced coronary artery perfusion
   • Progressive metabolic acidosis
   • Arrhythmias and myocardial ischaemia
   • V/Q mismatch and dead space ventilation, as distended pulmonary arteries compress small airways
   • Systemic hypotension and poor end-organ perfusion
4. In children with an atrial septal defect or patent foramen ovale, right atrial pressure may exceed left atrial pressure, resulting in right-to-left shunting and systemic desaturation. Although this maintains cardiac output, it worsens hypoxaemia.

The crisis rapidly self-perpetuates. Hypoxia and hypercapnia further raise PVR, exacerbating RV dysfunction. As cardiac output falls, tissue hypoxia and acidosis deepen, accelerating cardiovascular collapse. Without urgent intervention, this culminates in bradycardia, hypotension, and cardiac arrest.

Clinical Presentation of a Pulmonary Hypertensive Crisis

Children with pulmonary hypertension can deteriorate rapidly, and early recognition of a crisis is key to preventing cardiac arrest. The presentation is often nonspecific, especially early on, and may overlap with sepsis or respiratory failure.

Common clinical features include:

• Tachypnoea and increased work of breathing
• Tachycardia, which may progress to bradycardia as cardiac output fails
• Desaturation or cyanosis, often disproportionate to respiratory findings
• Hypotension
• Poor peripheral perfusion (cool peripheries, delayed capillary refill)
• Hepatomegaly or other signs of right heart failure (e.g. ascites, raised JVP in older children)
• New or changing cardiac murmur

In an intubated or sedated child, subtle signs such as a sudden drop in ETCO₂, oxygen saturation, or blood pressure may be the only early indicators.

Top tip: In a child with known or suspected pulmonary hypertension, any acute deterioration should raise concern for pulmonary hypertensive crisis, even in the absence of clear infective or cardiac pathology.

Jack now requires an FiO₂ of 0.80 on non-invasive ventilation, with only modest improvement in his oxygen saturations. He desaturates markedly with minimal handling and appears increasingly fatigued. Despite being commenced on broad-spectrum antibiotics to cover a possible respiratory infection, there are no clear features of sepsis.

His deterioration is raising serious concerns for an evolving pulmonary hypertensive crisis.

At this stage, it is essential to act quickly: identify the likely precipitant, stabilise the cardiopulmonary system, and consider early escalation.

Investigations in Suspected Pulmonary Hypertension

In a deteriorating child with suspected or known PH, investigations must be targeted, rapid, and geared towards risk stratification and identifying triggers. Many tests will need to run in parallel with initial resuscitation and supportive management.

Bedside Monitoring

• Continuous cardiorespiratory monitoring – observe for bradycardia, hypotension, arrhythmias
• Pulse oximetry and end-tidal CO₂ (ETCO₂) – sudden drops may precede cardiovascular collapse
• Arterial blood gas – assess for acidosis, hypercapnia, hypoxaemia
• Near-infrared spectroscopy (NIRS) (if available) – may help monitor end-organ perfusion

Blood Tests

• Capillary or arterial gas – look for:
  • Respiratory/metabolic acidosis
  • Rising lactate
• Full blood count and inflammatory markers – assess for infection or anaemia
• Electrolytes and glucose – correct hypocalcaemia, hypokalaemia, and hypoglycaemia
• NT-proBNP or BNP – raised in right ventricular strain, useful for trending
• Troponin – may be elevated in myocardial stress or ischaemia

Imaging and Cardiac Assessment

• Echocardiogram – essential to:
  • Assess right ventricular function and size
  • Estimate pulmonary artery pressures (via TR jet)
  • Detect structural heart disease, shunts, or tamponade
  • Evaluate septal position and RV-LV interaction
• Chest X-ray – may show:
  • Cardiomegaly
  • Prominent pulmonary arteries
  • Lung hyperinflation or signs of chronic lung disease
  • Evidence of intercurrent infection

Additional investigations (as child stabilises)

• High-resolution CT chest – if interstitial lung disease or pulmonary vein stenosis suspected
• Cardiac catheterisation – gold standard for diagnosis and classification, but high-risk during crisis
• Genetic testing – in selected cases of idiopathic or familial PAH
• ENT/respiratory review – consider airway malacia, particularly in chronic lung disease

Key principle: Echo remains the most important tool in the acute setting, but must be interpreted in the context of clinical findings and RV function, not just numbers.

Principles of Pulmonary Hypertension Management in the Acute Setting

Managing pulmonary hypertension—especially in crisis—requires anticipation, preparation, and physiological precision. Interventions should aim to:

• Optimise oxygenation and ventilation
• Minimise pulmonary vascular resistance (PVR)
• Support right ventricular function and perfusion
• Avoid triggers of decompensation

Start with a structured ABCDE approach, with early senior input and a low threshold for PICU involvement.

Initial Stabilisation

• Begin with oxygenation and gentle respiratory support: high-flow nasal cannula (HFNC), non-invasive ventilation (NIV), or trial of inhaled nitric oxide (iNO) or prostanoids where available.
• Avoid agitation, acidosis, and hypoxia — all potent triggers of a pulmonary hypertensive crisis.

Proceeding to Intubation: Weigh the Risks

Intubation and mechanical ventilation carry significant risk in PH due to the potential for sudden drops in systemic vascular resistance and cardiac output. Sedation and induction must be meticulously planned.

Intubation should be considered if:

• Oxygenation or ventilation remains inadequate
• Metabolic or respiratory acidosis is worsening despite therapy
• There is progressive respiratory failure or fatigue

If you must intubate:

• Use the most experienced clinician available
• Pre-oxygenate with 100% FiO₂ ± bagging with iNO
• Avoid agents that significantly reduce SVR (e.g. propofol)
• Prepare for post-intubation instability with fluid boluses, vasopressors, and inotropes

Once Ventilated

• Target SpO₂ >95% (or 75–85% in cyanotic heart disease)
• Avoid hypoxia — it increases PVR
• Use in-line suction to prevent alveolar derecruitment and V/Q mismatch
• Ensure adequate sedation, consider muscle relaxation to avoid agitation and sympathetic stimulation
• Aim for normocapnia (PaCO₂ 4.5–6.0 kPa)
  • Avoid hyperventilation, especially in those with chronic lung disease
• Avoid excessive PEEP — it impairs venous return and cardiac output
• Establish central venous and arterial access early if vasoactive support is required

Additional Key Considerations

• Aim for normal pH — acidosis worsens pulmonary vasoconstriction and reduces drug efficacy
  • Sodium bicarbonate may be considered if severe acidosis persists
• Fluids: Give cautious boluses (5 mL/kg)
  • Be particularly careful if there are signs of right heart failure
• Diuretics: Use judiciously — they may worsen a low cardiac output state
• Electrolytes: Correct any abnormalities, especially calcium, magnesium, and potassium
• Normothermia: Maintain body temperature to reduce metabolic demand

Clinical tip: Every intervention in PH management should be judged by its effect on oxygenation, PVR, and right heart function. Agitation, acidosis, and abrupt haemodynamic changes can be fatal.

Jack is transferred to paediatric intensive care where he is intubated and started on inhaled nitric oxide. Over the next 48 hours, he shows gradual improvement in oxygenation and haemodynamics. iNO is cautiously weaned, and repeat echocardiography shows persistently elevated but stable pulmonary artery pressures with moderate right ventricular dilation.

At this stage, the team considers transitioning to longer-acting pulmonary vasodilators to maintain pulmonary vascular tone and prevent rebound hypertension.

Pharmacological Management of Pulmonary Hypertension

Pulmonary hypertension is driven by an imbalance of vasoconstrictor and vasodilator forces within the pulmonary circulation. Modern treatments target three key biological pathways implicated in this imbalance:

• The nitric oxide–cGMP pathway, which promotes pulmonary vasodilation
• The endothelin pathway, a major contributor to vasoconstriction and vascular remodelling
• The prostacyclin pathway, which facilitates vasodilation and inhibits platelet aggregation

Most therapies work by enhancing vasodilation or inhibiting vasoconstriction, with some used acutely in crisis and others for longer-term disease control. These pathways form the basis for selecting targeted pharmacological agents.

Nitric Oxide–cGMP Pathway

The nitric oxide–cGMP pathway plays a central role in regulating pulmonary vascular tone. In the healthy lung, nitric oxide (NO) is produced by endothelial cells and diffuses into adjacent smooth muscle, activating guanylate cyclase and increasing intracellular cyclic GMP (cGMP). This promotes smooth muscle relaxation and vasodilation.

In pulmonary hypertension, impaired nitric oxide production and increased phosphodiesterase activity reduce cGMP levels, contributing to sustained vasoconstriction. Therapeutic strategies target this pathway to restore pulmonary vasodilation and reduce right ventricular afterload.

Inhaled Nitric Oxide (iNO)

Inhaled nitric oxide is often the first-line treatment for acute pulmonary hypertensive crises. As a selective pulmonary vasodilator, it improves oxygenation by acting only on ventilated lung units, thereby enhancing ventilation–perfusion matching. Its effects are immediate and short-acting, making it suitable for rapid control in critical illness.

However, abrupt withdrawal can lead to rebound pulmonary hypertension and cardiovascular collapse. It should be weaned gradually and with care.

Avoid iNO in children with pulmonary venous hypertension (e.g. left heart obstruction or elevated left atrial pressure), as this may precipitate pulmonary oedema.

Inhaled nitric oxide is typically initiated at a starting dose of 20 parts per million (ppm).

It should be weaned gradually, using a stepwise approach to avoid rebound pulmonary vasoconstriction, which can precipitate sudden cardiovascular deterioration.

Monitoring should include methemoglobin levels, aiming to keep them below 1%. Elevated concentrations, though uncommon, can reduce oxygen delivery and complicate management.

Sildenafil

Sildenafil is most commonly introduced during the weaning phase from inhaled nitric oxide or as part of maintenance therapy for ongoing pulmonary hypertension. It can be administered orally or intravenously, and both routes have been shown to be equally effective provided gut perfusion is adequate.

Its effect on systemic vasodilation means blood pressure should be closely monitored during initiation and titration.

Sildenafil Dosing (BNFc 2025)

<1 year: 250–500 micrograms/kg every 6–8 hours (max 30 mg/day)

1–17 years:
– 20 kg: 10 mg TDS
– ≥20 kg: 20 mg TDS

Prostacyclin Pathway

Prostacyclins are potent vasodilators that also inhibit platelet aggregation and smooth muscle proliferation. In children with moderate to severe pulmonary hypertension—particularly those who remain symptomatic despite initial therapies—prostacyclins are an important part of escalation.

Eporostenol

Epoprostenol is the most commonly used intravenous prostacyclin analogue. It has a very short half-life and requires continuous infusion via central venous access. While effective, its delivery demands careful monitoring and robust safety measures. Abrupt interruption of the infusion can result in rebound pulmonary hypertension and rapid clinical deterioration.

Epoprostenol dosing:

Neonates: Start at 2 nanograms/kg/min
Children: Up to 40 nanograms/kg/min (typically titrated gradually)

Iloprost

Inhaled iloprost may be considered in non-intubated children for short-term support or as a bridge in chronic management, though it requires frequent dosing and close observation.

Endothelin Pathway

Endothelin-1 is a powerful vasoconstrictor that also promotes vascular remodelling and smooth muscle proliferation. Agents that block this pathway may benefit children with chronic or progressive pulmonary hypertension.

Bosentan, an oral endothelin receptor antagonist (ERA), is commonly used in paediatric PAH under the guidance of a specialist pulmonary hypertension team. It acts on both ETA and ETB receptors to reduce vasoconstriction and mitigate disease progression.

Bosentan is generally introduced as part of longer-term therapy rather than acute crisis management. Liver function abnormalities are a known side effect, and regular monitoring is essential.

Other ERAs include ambrisentan (selective ETA antagonist) and macitentan, both of which are less commonly used in children but may be considered in specialist centres.

Supporting the Right Ventricle: Milrinone

In pulmonary hypertension, the right ventricle often fails due to the sudden increase in afterload. Milrinone, a phosphodiesterase-3 inhibitor, plays a key role in supporting the right heart by improving contractility (inotropy), enhancing myocardial relaxation (lusitropy), and reducing afterload through systemic vasodilation.

It is particularly useful in right ventricular dysfunction, especially when combined with agents targeting pulmonary vascular tone. However, milrinone can cause hypotension, so close haemodynamic monitoring is required during initiation and dose escalation.

Milrinone dosing:

Loading dose: 50–75 micrograms/kg over 30–60 minutes (omit if hypotensive)

Maintenance: 30–45 micrograms/kg/hour as a continuous infusion

Common side effects include tachyarrhythmias, hypotension, and occasional thrombocytopenia. It also has mild antiplatelet effects, so caution is advised in patients at risk of bleeding.

Despite maximal medical therapy—including inhaled nitric oxide, sildenafil, milrinone, and careful ventilation—Jack’s condition is not improving. His pulmonary pressures remain high, and he shows ongoing signs of right ventricular strain.

At this point, it’s vital to step back, review, and consider next steps in refractory pulmonary hypertension.

What else should be considered when a child isn’t improving?

Managing refractory pulmonary hypertension requires a systematic, collaborative approach:

• Reassess for reversible triggers
  Common culprits include infection, acidosis, pain, hypoxia, or fluid overload. Correct what you can, and stabilise what you can’t.
• Don’t forget the airway
  Tracheobronchomalacia can worsen ventilation and increase PVR in children with chronic lung disease, especially ex-prems. Request input from the Respiratory and ENT teams, and consider airway imaging or bronchoscopy.
• Rule out pulmonary venous hypertension
  Elevated left atrial pressure or pulmonary vein stenosis can mimic or worsen PH. Advanced cardiac imaging (e.g. cardiac MRI or CT) may help clarify this.
• Involve the MDT early
  Complex PH cases benefit from multidisciplinary team discussion, including cardiology, respiratory, intensive care, and the regional pulmonary hypertension team. This is also a time to consider parallel planning and revisit goals of care.
• Consider referral for ECMO
  If Jack’s deterioration is potentially reversible—such as sepsis, infection, or post-operative PH—then ECMO may provide a bridge to recovery or further intervention. Timing is crucial.
• Specialist interventions
  For selected patients with suprasystemic pulmonary pressures and refractory right heart failure, a balloon atrial septostomy may offer short-term haemodynamic improvement. Sometimes, a reversed Potts shunt might be discussed for longer-term palliation or a bridge to transplant.

Take Home Messages

Pulmonary hypertension is a medical emergency — early recognition and senior involvement are essential.

Consider PH in any child with unexplained hypoxia, respiratory distress, or signs of right heart failure, particularly if they have chronic lung disease or a history of prematurity.

Stabilise physiology: correct acidosis, support cardiac function, and optimise preload and afterload.

Identify and treat triggers such as infection, pain, or hypovolemia.

Avoid agents that reduce systemic vascular resistance, such as propofol, which can precipitate cardiovascular collapse.

Escalate early — timely ventilation, vasodilator therapy, and specialist input can be lifesaving.

About PICSTAR

PICSTAR is a trainee-led research network open to all doctors, nurses and allied health trainees within Paediatric Intensive Care.  We are the trainee arm of the Paediatric Critical Care Society – Study Group (PCCS-SG) and work with them on research, audit and service evaluation.

If you would like to join PICSTAR and get involved in projects, have ideas you would like to propose or get advice/mentorship via PCCS-SG, don’t hesitate to contact us at picstar.network@gmail.com. See their website for more: https://pccsociety.uk/research/picstar/

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