BEDSIDE ACTION BOX — The Labile, Hypoxaemic Term/Near-Term Infant
- Suspect PPHN when hypoxaemia is out of proportion to lung disease, with a preductal–postductal SpO₂ gap >10% (right hand higher than feet).
- Minimal handling, sedation/analgesia, normothermia, normal calcium/magnesium, correct anaemia and acidosis, and maintain systemic blood pressure.
- Optimise lung recruitment and ventilation first (disease-specific strategy); get an early echocardiogram to confirm PPHN and exclude cyanotic CHD.
- Start inhaled nitric oxide when the oxygenation index reaches ≥25 on two measurements (many units start at 15–20) in the ventilated infant above 34 weeks; escalate to a referral/ECMO centre early.
- If duct-dependent congenital heart disease is possible, start prostaglandin and get urgent cardiology input.
1. Overview & Definition
Overview
Persistent pulmonary hypertension of the newborn (PPHN) is a failure of the normal fall in pulmonary vascular resistance (PVR) after birth. High PVR sustains right-to-left shunting across the ductus arteriosus and foramen ovale, causing severe, often labile hypoxaemia. PPHN may be idiopathic or, more often, secondary to parenchymal lung disease, maldevelopment (e.g., CDH), or perinatal illness. Care centres on treating the cause, supporting oxygenation and systemic circulation, lowering PVR (chiefly with inhaled nitric oxide), and escalating early to a centre able to provide ECMO.
Why This Topic Matters
PPHN is a rapidly reversible-or-fatal emergency: infants can swing between adequate and critical oxygenation with minimal stimulation. Two errors are dangerous — mistaking PPHN for cyanotic heart disease (or vice versa), and delaying referral to an iNO/ECMO centre. A calm, protocolised approach with early echocardiography and early escalation saves lives.
Definition
PPHN is severe hypoxaemia due to persistently elevated PVR with extrapulmonary right-to-left shunting, in the absence of cyanotic structural heart disease, typically presenting in the first 12–24 hours in term/near-term infants.
2. Who This Guideline Applies To
Scope
- Term and near-term (≥34 weeks) infants with hypoxaemic respiratory failure and suspected/confirmed elevated PVR.
- Secondary PPHN complicating meconium aspiration, pneumonia/sepsis, RDS/surfactant deficiency, congenital diaphragmatic hernia, pulmonary hypoplasia, asphyxia, or severe anaemia/polycythaemia.
- Idiopathic PPHN (black-lung PPHN) and — cross-referenced — BPD-associated pulmonary hypertension (see 6.2).
- Note: iNO in preterm (<34 weeks) infants is not routine and is a specialist decision.
3. Key Definitions
Core Terminology
The concepts and numbers used to diagnose and grade PPHN severity.
| Term | Definition | Practical note |
|---|
| PVR | Pulmonary vascular resistance — normally falls sharply after birth. | Failure to fall is the core problem in PPHN. |
| Pre/post-ductal gap | Preductal (right hand) SpO₂ >10% higher than postductal (foot) SpO₂. | Indicates right-to-left ductal shunting; a key bedside clue. |
| Oxygenation index (OI) | OI = (mean airway pressure × FiO₂ × 100) / postductal PaO₂. | Quantifies severity and guides iNO/ECMO thresholds. (OSI is a non-invasive surrogate.) |
| iNO | Inhaled nitric oxide — a selective pulmonary vasodilator. | First-line targeted therapy for term/near-term PPHN. |
| ECMO / ECLS | Extracorporeal membrane oxygenation / life support. | Rescue for refractory PPHN; refer early via the transport service. |
4. Initial Assessment
Recognise PPHN
- Clinical: marked, labile hypoxaemia (often within the first 12 hours), a preductal–postductal SpO₂ difference >10%, and cyanosis that mimics cyanotic heart disease. Idiopathic PPHN may have minimal respiratory distress; secondary PPHN has the distress of the underlying lung disease.
- Cardiac signs: loud/single second heart sound, tricuspid regurgitant murmur, right ventricular heave, ± systemic hypotension.
- Attach pre- and post-ductal saturation monitoring (right hand and a foot) and follow the trend.
Investigations
- Blood gas — hypoxaemia (± hypercapnia) with a rising oxygenation index; disproportion between hypoxia and hypercapnia suggests idiopathic PPHN.
- Chest radiograph — variable; often clear/black lungs in idiopathic PPHN, or the pattern of the underlying lung disease.
- Echocardiography (early) — confirms elevated pulmonary pressures and right-to-left shunting, assesses ventricular function, and, crucially, excludes cyanotic congenital heart disease.
- Screen for and treat contributors: sepsis (blood culture + antibiotics), hypoglycaemia, hypocalcaemia, hypomagnesaemia, anaemia, and polycythaemia.
5. Diagnostic Approach
PPHN vs Cyanotic Congenital Heart Disease
The single most important distinction — echocardiography is definitive. Do not withhold prostaglandin if a duct-dependent lesion is plausible.
| Feature | PPHN | Cyanotic CHD |
|---|
| Pre/post-ductal SpO₂ gap | Often present (>10%) | Variable; e.g., reverse differential in transposition + coarctation. |
| Response to oxygen/recruitment | May improve, often labile | Little improvement (fixed shunt). |
| Echocardiography | Structurally normal heart, high RV pressure, R→L shunts at PDA/PFO | Structural lesion identified. |
| Chest film | Clear/black lungs (idiopathic) or underlying lung disease | Lesion-specific (e.g., "egg on string", oligaemia). |
| Initial action | Lower PVR, support BP, iNO | Prostaglandin, urgent cardiology. |
Diagnostic Principle
If you cannot immediately exclude duct-dependent cyanotic heart disease in a severely cyanosed infant, start prostaglandin and obtain urgent echocardiography — the harm of missing a duct-dependent lesion outweighs the risk of a short prostaglandin course.
6. Management Algorithm
1
Recognise & stabilise
Labile hypoxaemia + pre/post-ductal gap → attach dual oximetry, minimal handling, sedation/analgesia, normothermia, correct Ca/Mg/glucose/anaemia, and support systemic BP. Involve the consultant immediately.
2
Exclude cyanotic CHD
Early echocardiography. If duct-dependent lesion possible, start prostaglandin and call cardiology.
3
Optimise lungs & oxygenation
Disease-specific ventilation: recruit parenchymal lung disease; gentle ventilation for CDH/black-lung PPHN. Consider surfactant when parenchymal disease. Target preductal SpO₂ 91–95%; tolerate postductal SpO₂ >70% and preductal PaO₂ ~7.3–10.6 kPa. Consider HFOV if high pressures needed. Monitor OI.
4
OI reaches threshold (commonly ≥15–25)?
Start inhaled nitric oxide at 1–20 ppm in the ≥34-week infant once lungs are recruited and reversible factors addressed. Assess response by improved oxygenation/OI.
5
Support the circulation
Maintain gestation-appropriate systemic BP (avoid supraphysiological targets); cautious volume (one 10 mL/kg bolus if hypotensive); vasoactive support and treat ventricular dysfunction per haemodynamics.
6
Refractory despite iNO?
Escalate to consultant; consider additional pulmonary vasodilators (sildenafil, magnesium sulphate) and refer to an ECMO/ECLS centre early via the neonatal transport service.
7
⚠ Do-not-miss
Do not miss duct-dependent CHD, pneumothorax (transilluminate), or ETT displacement/obstruction. Do not stop iNO abruptly (rebound). Avoid hyperoxia and hypocapnia.
7. Step-by-Step Management
General & Circulatory Measures
- Minimal handling and noise; cluster care; sedation/analgesia, with muscle relaxation reserved for high requirements or ventilator asynchrony.
- Maintain normothermia, normal biochemistry, and fluid balance; keep ionised calcium >1 mmol/L and magnesium adequate; keep haemoglobin high (e.g., ≥120 g/L) to optimise oxygen delivery.
- Secure arterial and central access; treat infection empirically until excluded.
- Maintain normal systemic blood pressure to reduce right-to-left shunting; avoid both hypotension and supraphysiological pressures.
Ventilation & Oxygenation
- Use a disease-specific strategy: recruit the atelectatic parenchymal lung; use gentle ventilation for CDH and idiopathic black-lung PPHN.
- Target preductal SpO₂ 91–95%; do not chase the pre/post-ductal difference as long as postductal SpO₂ stays >70%; avoid preductal desaturations <85% and preductal SpO₂ >97%.
- Aim PaCO₂ ~6–8 kPa and avoid hypocapnia (which reduces cerebral blood flow without durable PVR benefit).
- Consider HFOV when high pressures are needed to achieve adequate tidal volumes; monitor OI trends.
Pulmonary Vasodilatation
- Inhaled nitric oxide is the selective first-line vasodilator once the lung is recruited and reversible factors are addressed; start at the local OI threshold.
- For refractory disease, add other agents (sildenafil, magnesium sulphate) under consultant guidance while arranging ECMO/ECLS referral.
- Refer to the transport service for iNO/ECMO when FiO₂ remains >0.5 despite optimisation and all reversible factors (surfactant deficiency/displacement, tube obstruction, pneumothorax, equipment) have been excluded.
8. Medication Considerations
Drug Table (High-Risk — Verify All Doses Locally)
These agents are consultant/specialist-led. Confirm every dose against the Neonatal Formulary and your iNO/ECMO-network protocol before use.
| Agent | Role | Practical note | Cautions / monitoring |
|---|
| Inhaled nitric oxide | Selective pulmonary vasodilator (first-line) | Start at 1–20 ppm; wean gradually once stable. | Do not stop abruptly (rebound PH); monitor methaemoglobin and NO₂; assess response by OI/oxygenation. |
| Prostaglandin E1/E2 | Maintain ductal patency if duct-dependent CHD possible | Start while awaiting/at echocardiography. | Apnoea, hypotension, fever; have airway support ready. |
| Surfactant | When parenchymal lung disease/inactivation contributes | Consultant decision (e.g., MAS, pneumonia, surfactant deficiency). | Reassess ventilation after dosing. |
| Sildenafil | Adjunct/refractory pulmonary vasodilator | Specialist use; in BPD-associated PH start 0.25 mg/kg/dose every 6 h, titrated to 1 mg/kg/dose (6.2). | Systemic hypotension; consultant-led. |
| Magnesium sulphate | Adjunct vasodilator (where used) | Per Formulary/consultant. | Hypotension, sedation, neuromuscular effects. |
| Vasoactives (e.g., noradrenaline, dobutamine, milrinone, hydrocortisone) | Support systemic BP / cardiac function | Choose by haemodynamic phenotype and echo. | Titrate carefully; milrinone can cause systemic hypotension. |
| Sedation/analgesia (± muscle relaxant) | Reduce lability | Use for high requirements/asynchrony. | Monitor BP and respiratory drive. |
Evidence & Uncertainty
- iNO threshold: default OI ≥25 on two measurements above 34 weeks (section 8+); many units start at OI 15–20; iNO improves oxygenation and reduces ECMO need in term/near-term PPHN but not in most preterm infants.
- Targets: default pre-ductal SpO₂ 91–95%, pCO₂ 40–50 mmHg, pH >7.25, lactate <5 mmol/L (section 8+); the West Midlands kPa targets above are equivalent in intent.
- Consultant-led: acute sildenafil and magnesium dosing in PPHN, and milrinone use. Preterm iNO is not routine — only within an approved protocol (section 8+).
8+. Nitric Oxide Protocol, Dose by Dose (Baylor Ed. 33)
The generic advice to "start iNO and wean when stable" leaves the two decisions that actually matter — when to call a non-response, and how fast to come down — to improvisation. This is the operational protocol.
Starting
- Eligibility: gestational age above 34 weeks, mechanically ventilated, with an oxygenation index of at least 25 on two separate measurements.
- Recruit the lung first. iNO reaches only the alveoli that are open — giving it to an atelectatic lung wastes it and hides the real problem.
- Exclude congenital heart disease before starting. In a ductal-dependent or obstructed-left-heart lesion, pulmonary vasodilation makes the infant worse.
- Initial dose 1–20 ppm through the ventilator circuit. Doses above 20 ppm add no benefit and should not be used.
Oxygenation index
OI = (Mean airway pressure × FiO₂ ÷ PaO₂) × 100, with mean airway pressure in cmH₂O, FiO₂ as a percentage and PaO₂ in mmHg. Enter FiO₂ as a fraction and the result is 100-fold too small — a recurring arithmetic error at the bedside. Baylor's initiation threshold is OI ≥25 twice; many units start earlier, around 15–20.
Defining response at 30 minutes
A responder improves PaO₂ by at least 10 mmHg or saturation by at least 5% within 30 minutes of starting. Anything less, on optimized ventilation at 20 ppm, is a non-responder — and the answer is to reassess the diagnosis, not to increase the dose.
| Situation | Weaning schedule |
|---|
| Non-responder | Wean 20 → 10 → 5 ppm every 15 minutes. At 5 ppm, come down by 1 ppm every hour until off. |
| Responder, stable 4 hours | Wean FiO₂ first, by 2–5% at a time. Once FiO₂ reaches 60% with a stable infant, wean 20 → 10 → 5 ppm hourly; at 5 ppm come down by 1 ppm every 1–2 hours. |
| Before the last step off | Increase FiO₂ by 10% in anticipation of rebound, then discontinue and wean FiO₂ back to baseline within 2 hours. Discontinuation may require raising FiO₂ by as much as 15%. |
| On sildenafil | Time the discontinuation for one hour after a sildenafil dose. |
| Failed wean | Next attempt, step 1 ppm → 0.5 ppm before stopping. Below 5 ppm, wean cautiously — precipitous deterioration has been reported at these low concentrations. |
Toxicity monitoring
- NO₂ above 3 ppm: check the delivery system, circuit and detector, then cut the NO concentration by 50% every 15 minutes until NO₂ falls below 3 ppm. Above 5 ppm, consider stopping iNO.
- Methaemoglobin at 24 hours after starting. Above 7%, wean iNO if possible; if levels stay high despite weaning or stopping, consider red-cell transfusion, IV methylene blue or IV vitamin C according to the clinical picture. At 20 ppm, levels above 5–10% are uncommon and rarely cause acute symptoms.
- Never stop abruptly — rebound pulmonary hypertension can be severe.
Targets in the first hours, and the limits of iNO
- Preductal saturation 91–95%, pCO₂ 40–50 mmHg, pH above 7.25, lactate below 5 mmol/L.
- Beyond vasodilators: recruit the lung, prevent acidosis, and minimize agitation with sedation and, if needed, neuromuscular blockade. Raising haemoglobin by transfusion raises arterial oxygen content and so oxygen delivery.
- If the left ventricle is working normally, norepinephrine or vasopressin raise systemic resistance while lowering pulmonary resistance. If it is not, augment output with dobutamine, dopamine or epinephrine; milrinone is the lusitrope of choice when either ventricle fails against a high pulmonary resistance.
- PGE₁ may be considered to unload a high-pressure right ventricle by reopening or maintaining a duct, in preterm and term infants without a VSD (very low certainty, weak recommendation).
- Preterm infants: iNO to prevent chronic lung disease, or to treat pulmonary hypertension associated with it, is not routinely recommended and should be limited to an IRB-approved protocol. A trial may be considered once ventilation, oxygen delivery and surfactant have been optimized and the echo shows pulmonary hypertension.
- ECMO is not recommended below 34 weeks or under 2 kg.
8++. Pulmonary Hypertension in Developmental Lung Disease — BPD and CDH (Baylor Ed. 33)
A different disease from PPHN
- Prevalence is estimated at 17–50% in these lung diseases, with inconsistent criteria and screening timing. It does not track BPD severity neatly: about 2% of extremely preterm infants without BPD develop PH, so prematurity itself injures the pulmonary vasculature.
- PH with BPD differs from pulmonary arterial hypertension (lifelong) and PPHN (transient, with acute parenchymal disease). Prenatal factors (hypertensive pregnancy, growth restriction, infection, genetics) and postnatal factors (hyperoxia, ventilation, infection, hypoxia, cardiac dysfunction, shunts) reduce angiogenesis and alveolarization and raise vascular tone.
- CDH: most infants have some PH at birth, driven by endothelial dysfunction and vascular remodelling. No antenatal test reliably predicts its severity or persistence — fetal lung volume and liver herniation included.
Who to screen and how
- At risk: BPD and CDH, plus oligohydramnios, growth restriction, poor postnatal growth, congenital heart disease needing escalating or persistent support, interstitial lung disease, prolonged PPHN, and chronic respiratory failure.
- AHA/ATS guidance: echocardiographic screening for moderate and severe BPD at 36 weeks PMA. Echo signs include more tricuspid regurgitation, a higher RVET:PAAT ratio, lower TAPSE, RV dilation or shape change, a flattened or bowed septum, and right-to-left shunting.
- Cardiac catheterization is the gold standard but invasive. Recommend it when significant PH persists despite optimal treatment of lung disease, when long-term PH therapy is planned, or when there is unexplained recurrent pulmonary oedema. It defines anatomy, shunts, collaterals, pulmonary vein disease, ventricular function and drug response.
Management in the NICU
- Treat the respiratory failure first — it can be curative. Avoid both under- and over-inflation, since each raises PVR (strong recommendation, high-quality evidence).
- Oxygen: intermittent hypoxaemia drives PH. Target SpO₂ 92–95%, and avoid desaturation below 85% and hyperoxia above 97% (strong, high).
- Diuretics titrated to effect, particularly with shunts, provided preload is adequate. Pressors may be needed alongside PH therapy; data are thin, though vasopressin has been suggested.
- iNO 1–20 ppm when PaO₂ is <100 mmHg on 100% oxygen or OI >25, ideally after an echo confirms raised right-heart pressure and excludes left-heart disease or dysfunction (strong, high). iNO can also be first-line for acute RV dysfunction.
- Refractory disease → PH team. None of these drugs is well studied in preterm infants:
- Sildenafil (PDE-5 inhibitor; oral or IV, weight-based, 3–4 times daily; hypotension and reflux) — the most used agent in BPD. Starting dose in section 9+ of chapter 6.2.
- Bosentan (endothelin receptor antagonist; oral twice daily; monitor liver enzymes; anaemia and oedema).
- Prostacyclins (iloprost, treprostinil, epoprostenol) for severe disease, as add-on or for the unstable infant.
Involve interventional cardiology as indicated.
- Prognosis: PH raises NICU mortality, with the highest risk in the first 2 years. Growth, shunts and pulmonary vein stenosis must be sought and addressed. Few children need PH drugs beyond early childhood, but acute PH with respiratory infections remains a risk for years, and abnormal vascular reactivity can persist in survivors.
8+++. Neonatal ECMO — Selection, Running and Weaning (Baylor Ed. 33)
Who, and when
- Outcomes: ECMO improves survival in term and late-preterm infants with hypoxic respiratory failure despite high support. Survival to discharge in the ELSO registry is about 75%, lowest with CDH and acquired pneumonia. In Baylor's centre, CDH accounts for most neonatal runs (with PPHN, meconium aspiration, RDS, sepsis and other lung malformations making up the rest).
- Indices linked to ≥80% mortality (not validated for CDH): OI >35–60 for 0.5–6 h; AaDO₂ >605–620 mmHg for 4–12 h; PaO₂ <35–60 mmHg for 2–12 h. Refractory septic shock (ESPNIC-based working definition): arterial lactate ≥8 mmol/L, or a rise of ≥1 mmol/L after 6 h of resuscitation, despite high vasoactive support.
- General inclusion:
- ≥34 weeks, ≥2 kg, under 1 month old.
- No significant coagulopathy or uncontrolled bleeding, and no major intracranial haemorrhage.
- Reversible lung disease with ventilation for less than 10–14 days.
- No uncorrectable heart defect, lethal anomaly or irreversible brain injury.
Individualize for some preterm infants, FETO patients, severe air leak and viral pneumonia. Occasionally an infant needs both cooling for HIE and ECMO.
- Baylor's primary indication: severe hypoxic respiratory failure despite optimized care — 100% FiO₂, iNO, and PIP ≥28 or HFOV MAP ≥17 — or OI >40 on two measurements, or PO₂ persistently <40 mmHg or lactate >3.0. Surfactant may be tried first, though it is unproven in CDH (see chapter 11.7).
Mode and physiology
- Venoarterial (VA) is the most common mode — right internal jugular to right atrium plus right common carotid to the aortic arch — and is needed for infants requiring circulatory support or too small for VV cannulation. Venovenous (VV) uses a double-lumen cannula in the right internal jugular vein with its tip in the right atrium; circulatory dysfunction does not rule out a VV trial, since function often improves once support starts. Consult the PH team when PH is the indication.
- VA: PaO₂ reflects mixing of circuit blood with left-ventricular output. It rises with more circuit flow, lower native output (beware tamponade, haemothorax, pneumothorax, cardiac failure) or recovering lungs, and falls with higher native output or lower circuit flow. Flow is non-pulsatile, so more flow lowers systolic but not mean pressure.
- VV: delivery depends on native cardiac output. SpO₂ is seldom above 95% and PaO₂ of 40–50 is expected. Falling PaO₂ usually means recirculation — improve it by gently repositioning the cannula under echo guidance. Raising flow can worsen recirculation. The arterial waveform stays pulsatile.
- CO₂ removal depends on membrane area, sweep gas flow and CO₂ content, and is highly efficient even at low blood flow.
Starting bypass
- Before cannulation: check prime potassium and ionized calcium, and give 1–3 doses of calcium gluconate or chloride just before starting if iCa is very low. Obtain a STAT head ultrasound and start cerebral NIRS.
- Flow: increase over 15–30 minutes to 100–125 mL/kg/min. On VV, flows above 125–140 mL/kg/min may worsen oxygenation through recirculation. If flow cannot rise or the pump cuts out, give volume in 10–15 mL/kg aliquots, then check cannula position.
- Adequate flow: pre-ductal SaO₂ ≥90%, SvO₂ 65–75% (unreliable on VV), lactate ≤3.0, capillary refill <3 s.
| Anticoagulation (Baylor) | Detail |
|---|
| At cannulation | Heparin 50 units/kg (100 units/kg in selected cases). Consult transfusion medicine for every ECMO patient. |
| Maintenance | Once ACT is <200–240 s (about 1 h) with no bleeding, start bivalirudin 0.15 mg/kg/h — preferably into the patient (PICC or midline) rather than the circuit. It is a direct thrombin inhibitor with a half-life of about 15 minutes and no reversal agent. Check a bivalirudin coagulation panel and ROTEM 1 h after starting. |
| Targets | Default PTT (heparinase-corrected) 60–90 s with bivalirudin level 1.0–2.0 µg/mL; if clot forms in the circuit, PTT 80–100 s with the same level. Recheck 2 h after any dose change. There is no need to raise the dose for platelet transfusions. Low urine output raises levels. |
| Routine labs (drawn from the circuit) | Coagulation panel with bivalirudin level every 6 h; plasma free haemoglobin daily (lipid off 4 h beforehand); CBC and factor XIII daily; von Willebrand panel weekly; ROTEM daily if bleeding or thrombosis; ACT as needed (starting anticoagulation, surgery, plasma exchange). |
| General targets | Platelets ≥100,000; fibrinogen >200 mg/dL; PT ≤17 s; PTT 70–100 s; ACT 160–200 s (transfusion medicine may adjust). |
Care on ECMO
- Lung rest: rate 10–20, PIP 20–22, Ti 0.4 s, PEEP 10. Wean iNO off during rest on VA ECMO and restart it for recruitment; on VV it may be weaned off in non-responders. Oxygen delivery is managed with pump flow and haemoglobin, not the ventilator. Targets: SvO₂ 65–75% (VA); post-oxygenator PO₂ 200–250 and PCO₂ 35–40 by adjusting sweep gas; pre-ductal SpO₂ 90–95%.
- Fluids and ultrafiltration:
- Concentrate drugs, minimize flushes and limit blood products. Restrict IV fluids to 50 mL/kg/day on day 1.
- Within 6–12 h, start slow continuous ultrafiltration at a background rate equal to the daily volume of drugs, drips, flushes and line maintenance fluids ÷ 24.
- On day 2 give PN 50 + lipid 5 mL/kg/day. Remove any nutrition volume above that 55 mL/kg/day with an added alimentation rate. Example: 3 kg infant, desired PN 100 + lipid 15 mL/kg = 345 mL/day, minus 165 mL baseline = 180 mL ÷ 24 = 7.5 mL/h.
- Remove volume given as blood products for haemoglobin or factor replacement, but not volume given for expansion. Nutrition goals are 90–100 kcal/kg, protein 3–4 g/kg, lipid 15 mL/kg and carbohydrate 10–16 g/kg per day.
- Watch preload, BUN, creatinine and urine output; the ideal rate is not always achievable.
- Analgesia: morphine 0.01 mg/kg/h is preferred — tolerance develops within 3–5 days on fentanyl versus 5–7 days on morphine, and fentanyl is lost to the circuit. If inadequate, give a 1-hour-equivalent bolus and raise the infusion by 0.01–0.02 mg/kg/h every 30–60 minutes, reassessing 30–60 minutes after each change. If fentanyl is used, start at 1 mcg/kg/h and titrate by 0.5–1; up to 20 mcg/kg/h may be needed by day 6.
- Circulation: VA flow of 100–130 mL/kg/min usually lets pressors be weaned; VV depends on native output, so pressors are more often needed. Keep haematocrit >40% with periodic transfusion.
- Neuromonitoring: head ultrasound and NIRS before cannulation; neurocritical care consultation with continuous EEG started within 6 h and continued for at least 72 h (watch the scalp); NIRS until decannulation; serial neurological examinations; a non-contrast brain MRI before discharge and developmental clinic referral.
| Hypertension on ECMO | Definition, work-up and drugs |
|---|
| Definition (VA) | Term: sustained MAP >55 or systolic >80 mmHg. Late preterm (34–36 weeks): MAP >50. Treat promptly, because prolonged hypertension risks intracranial bleeding. |
| Look for causes while treating | Inadequate sedation; seizures (EEG, head ultrasound); fluid overload (more ultrafiltration, fewer products); renal artery or vein thrombosis (renal Doppler, urinalysis); circuit occlusion (pressure change); UAC-related aortic thrombus (aorta/IVC Doppler) |
| As-needed doses | Hydralazine 0.1 mg/kg IV every 6–8 h first, rising by 0.1 mg/kg to 0.5 mg/kg and up to every 4 h (tachycardia) while the infusion is prepared. Second: labetalol 0.1 mg/kg IV, rising by 0.1 to 1 mg/kg (caution with bronchospasm or heart failure). |
| Infusions |
- 1st: nitroprusside 0.5 mcg/kg/min, up by 0.5 every 15–20 min to a maximum of 10, with sodium thiosulfate against cyanide. Still hypertensive at 4 → add nicardipine.
- Use nicardipine first if sodium is >145 or there is renal impairment.
- 2nd: nicardipine 0.5 mcg/kg/min, up by 0.5 to a maximum of 2. At 2 → add esmolol.
- 3rd: esmolol 50 mcg/kg/min, up by 25–50 to a maximum of 500.
- Needing a third agent calls for a multidisciplinary discussion, including cardiology.
|
Weaning, trial off and surgery on ECMO
- Recovery signs: oxygenation holds as support falls. A 10–15 minute hyperoxia challenge raising PaO₂ to 150–200 mmHg or more suggests PVR has fallen below systemic. Wean flow in steps guided by PaO₂, SpO₂ and echo, but not below 50–60 mL/kg/min or 100 mL/min absolute. Trial off VA for 15–30 minutes with increased ventilator support; for VV, simply disconnect and cap the sweep gas.
- Clamping (trial off):
- Check ACT and give heparin 25 units/kg to the patient; recheck at 10 minutes. Once ACT has risen 30–50 s above baseline, clamp — repeat the bolus once if needed. Consider this even on bivalirudin, to protect the circuit; discuss with transfusion medicine if there is intracranial bleeding.
- Release the clamp every 5 minutes, total clamp time under 30 minutes, and inspect the circuit for clot.
- Stop bivalirudin at decannulation.
- Surgery on ECMO (e.g., CDH repair):
- 8–12 h before: fibrinogen >200 and platelets >150,000.
- Blood products at the bedside: 1 unit red cells, 2 units platelets, 1 unit FFP, plus emergency blood. Also have extra analgesia and sedation, saline, 5% albumin, a chest drain system, and a peripheral IV for the anaesthetist.
- Aminocaproic acid goes into the patient by peripheral IV (not the circuit, not a UVC in CDH): 100 mg/kg bolus 30 min before incision, then 30 mg/kg/h, usually for about 48 h. Give 25% of the dose in renal failure (creatinine >1.2 or urine output <2 mL/kg/h).
- Bivalirudin: cut to 0.08–0.1 mg/kg/h 15–60 min before incision, aiming for ACT 150–180 s before incision. After surgery, ACT ranges are 130–150 s for 0–24 h and 160–180 s for 24–48 h, with the surgical team setting final targets.
- After surgery: hold a huddle; start at a bivalirudin level of 0.5–1.0 µg/mL. Increase by 10–20% steps if not bleeding, to reach PTT 60–90 s and level 1–2 µg/mL by 24 h. Stop aminocaproic acid at 24–48 h.
- No trial off during aminocaproic acid or for 12 h after it stops.
- Decisions for CDH, preterm infants ≤34 weeks and complex anomalies are individualized, often at an urgent joint meeting of the medical, surgical and ECMO teams.
| Hypoxic respiratory failure at a referring unit (Baylor Ch 18.6) | Call the ECMO centre to discuss (any one) | Transfer (any one) |
|---|
| Oxygenation index | >15 | >20 |
| A–a gradient | >400 mmHg | >600 mmHg |
| FiO₂ | >60–80% | >80–100% |
| Support | Switch to HFOV; starting iNO; hypotension needing a vasopressor; suspected cyanotic heart disease | Dopamine >15 mcg/kg/min, epinephrine >0.2 mcg/kg/min, or a second vasopressor; no echo available to exclude heart disease; no response to iNO or a rising OI after an initial response |
Early transfer of possible ECMO candidates avoids delay and instability in transport.
9. Monitoring
Monitoring Table
Continuous, trend-based monitoring is essential in the labile PPHN infant.
| Parameter | Frequency | Target | Action if abnormal |
|---|
| Pre- & post-ductal SpO₂ | Continuous | Preductal 91–95%; postductal >70% | Optimise recruitment/BP; adjust iNO; escalate. |
| Oxygenation index | With each gas | Downward trend | Rising OI → start/escalate iNO; refer for ECMO. |
| Blood gas / lactate | Frequent | Improving oxygenation, PaCO₂ ~6–8 kPa, resolving acidosis, falling lactate | Adjust ventilation; avoid hypocapnia. |
| Blood pressure / perfusion | Continuous (arterial) | Gestation-appropriate, not supraphysiological | Volume/vasoactives; echo-guided. |
| Ca²⁺ / Mg²⁺ / glucose / Hb | Regular | Ionised Ca >1 mmol/L; normoglycaemia; Hb ≥120 g/L | Correct promptly. |
| Methaemoglobin / NO₂ (on iNO) | Per iNO protocol | Within safe limits | Reduce iNO; treat methaemoglobinaemia. |
| Echocardiography | Early & serial | Falling RV pressure, good function | Guide vasoactive/vasodilator choices. |
10. Contraindications & Precautions
Safety Cautions
- Do not stop inhaled nitric oxide abruptly — wean gradually to avoid rebound pulmonary hypertension.
- Do not label an infant "PPHN" without excluding cyanotic congenital heart disease; if in doubt, start prostaglandin.
- Avoid excessive handling and noise — stimulation can precipitate acute deterioration.
- Avoid hyperoxia (oxidative injury, paradoxical vasoconstriction) and hypocapnia (cerebral ischaemia without durable PVR benefit).
- Give volume cautiously; over-resuscitation worsens ventricular function.
- Watch for pneumothorax and tube problems in any sudden deterioration (transilluminate, DOPE).
- iNO is not routine in preterm (<34-week) infants — specialist decision only.
11. Escalation Criteria
Escalate / Refer for iNO or ECMO When…
- FiO₂ >0.5 with persistent hypoxaemia despite optimal ventilation once reversible factors are excluded.
- Rising oxygenation index despite iNO and haemodynamic optimisation.
- Refractory hypotension or ventricular dysfunction, or need for support beyond local capability.
- Any concern for duct-dependent CHD (start prostaglandin, urgent cardiology).
- Refer early — ECMO outcomes are better before multi-organ decline.
Parent Counselling Points
- "Your baby's lung blood vessels have not relaxed as they should after birth, so oxygen levels are low and can change quickly. This is called pulmonary hypertension."
- "We are keeping your baby calm, supporting the breathing and blood pressure, and can give a special gas (nitric oxide) that opens the lung blood vessels."
- "Some babies need transfer to a centre that can provide a heart-lung support machine (ECMO). We will explain each step and keep you closely informed."
12. Key Pearls
High-Value Clinical Pearls
- A preductal–postductal SpO₂ gap >10% with labile hypoxaemia is PPHN until proven otherwise — attach dual oximetry early.
- Recruit the lung before, and alongside, giving iNO — iNO cannot reach a collapsed lung.
- Systemic blood pressure is therapeutic: keeping it normal reduces right-to-left shunting.
- Echocardiography does two jobs — confirms PPHN and excludes cyanotic CHD; if unsure, start prostaglandin.
- Never wean iNO abruptly; taper to avoid rebound.
- Refer for ECMO early — before multi-organ failure — when OI keeps climbing despite iNO.
13. Common Mistakes to Avoid
Pitfalls & Better Practice
The recurring errors in PPHN care.
| Mistake | Why it harms | Better practice |
|---|
| Assuming cyanosis is lung disease and missing duct-dependent CHD. | Fatal delay in prostaglandin. | Early echo; start prostaglandin if any doubt. |
| Starting iNO into an atelectatic lung. | iNO fails to reach alveoli; poor response. | Recruit the lung (± surfactant/HFOV) first. |
| Excessive handling/stimulation. | Precipitates acute hypoxaemic crises. | Minimal handling, sedation, cluster care. |
| Chasing 100% saturations / hyperventilating. | Hyperoxia and hypocapnia cause injury. | Preductal SpO₂ 91–95%; PaCO₂ ~6–8 kPa. |
| Abruptly stopping iNO. | Rebound pulmonary hypertension. | Wean gradually per protocol. |
| Late ECMO referral. | Worse outcomes after multi-organ injury. | Refer early when OI rises despite iNO. |
14. Board-Style High-Yield Summary
Key Takeaways
- PPHN = failure of PVR to fall → right-to-left shunt at PDA/PFO → severe labile hypoxaemia; preductal > postductal SpO₂ (>10% gap).
- Echocardiography confirms PPHN and excludes cyanotic CHD; start prostaglandin if duct-dependent lesion possible.
- Foundations: minimal handling, sedation, normothermia, normal Ca/Mg/glucose/Hb, systemic BP support, and treat the cause/infection.
- Recruit the lung (± surfactant, HFOV) then start iNO at the local OI threshold (commonly ≥15–25) in ≥34-week infants.
- Targets: preductal SpO₂ 91–95%, postductal >70%, PaCO₂ ~6–8 kPa; avoid hyperoxia and hypocapnia.
- Refractory disease → sildenafil/magnesium and early ECMO referral; never wean iNO abruptly.
15. References
- 1.Bedside Clinical Guidelines Partnership / West Midlands Neonatal ODN. Acute Pulmonary Hypertension of the Newborn; Nitric Oxide. Neonatal Guidelines 2025–28.
- 2.Baylor College of Medicine, Division of Neonatology. Guidelines for Acute Care of the Neonate, Edition 33, 2025–2026.
- 3.Ministry of Health Belize. Neonatal Clinical Practice Guidelines 2018–2021.
- 4.American Academy of Pediatrics. Use of inhaled nitric oxide in the neonate (clinical guidance). https://publications.aap.org/
- 5.Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants; and term/near-term infants. Cochrane Database Syst Rev. https://www.cochranelibrary.com/
- 6.Extracorporeal Life Support Organization (ELSO). Neonatal respiratory failure guidelines. https://www.elso.org/
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