Not scheduled (administered inpatient only)

Inhalation (via mechanical ventilator)

• Inhalation gas: 800 ppm (parts per million) in nitrogen, supplied in pressurised cylinders for hospital use only

• Must be delivered via dedicated delivery/monitoring systems integrated with ventilators

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Persistent Pulmonary Hypertension of the Newborn (PPHN)

Eligibility: Term or near-term neonates (≥34 weeks gestation) with hypoxic respiratory failure and evidence of pulmonary hypertension; must be administered in tertiary NICU with ventilatory support and continuous NO/NO₂ monitoring

Parameter Details

Starting dose 20 ppm via ventilator circuit

Titration Once oxygenation improves (PaO₂ >60 mmHg or SpO₂ >90%), reduce by 5 ppm every 4–6 hours

Usual maintenance dose 5–10 ppm

Maximum dose 20 ppm (higher doses increase toxicity without additional benefit)

Clinical Notes:

• Trial lower starting doses (5–10 ppm) in milder cases

• Rule out structural cardiac causes with echocardiography before initiation

• Gradual weaning mandatory to prevent rebound pulmonary hypertension

1. Perioperative Pulmonary Hypertension During Cardiac Surgery (Neonates and Infants)

Parameter Details

Starting dose 10–20 ppm inhaled via ventilator

Titration Adjust by 5 ppm steps based on oxygenation and haemodynamic response

Usual maintenance dose 5–20 ppm

Maximum dose 20 ppm

Clinical Notes:

• Used in paediatric cardiac ICU settings

• Wean gradually once pulmonary pressures stabilise

Secondary Indications — Adults (Off-label, if any)

1. Acute Right Ventricular Failure Associated with Pulmonary Hypertension

Parameter Details

Indication RV failure with elevated pulmonary pressures in ICU

Starting dose 10 ppm inhaled

Titration Increase by 5–10 ppm based on response

Usual maintenance dose 10–20 ppm

Maximum dose 40 ppm

Duration Short-term ICU use only

Status OFF-LABEL; Specialist only

Evidence basis Clinical case series; Indian cardiac intensivist practice

1. Refractory Hypoxaemia in ARDS

Parameter Details

Indication Severe ARDS with refractory hypoxaemia despite optimal ventilation

Starting dose 5 ppm inhaled

Titration Increase by 5 ppm to maximum based on oxygenation response

Usual maintenance dose 5–10 ppm

Maximum dose 20 ppm

Duration Short-term; discontinue if no oxygenation improvement within 24 hours

Status OFF-LABEL; Specialist only

Evidence basis International RCTs show short-term oxygenation improvement; no mortality benefit demonstrated

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

1. Persistent Pulmonary Hypertension of the Newborn (PPHN)

Gestational Age Starting Dose Titration Usual Maintenance Dose Maximum Dose

≥34 weeks 20 ppm Reduce by 5 ppm every 4–6 hours once PaO₂ improves 5–10 ppm 20 ppm

<34 weeks 5–10 ppm Titrate by 1–2 ppm increments; use with extreme caution 5 ppm 20 ppm

Safety Monitoring:

• Continuous SpO₂ and heart rate monitoring

• MetHb levels: Check at 1 hour, then every 12–24 hours (maintain <5%)

• NO₂ levels: Continuous monitoring (maintain <2 ppm)

• Blood gas analysis for PaO₂ response

Weaning Protocol:

• Reduce by 5 ppm every 4–6 hours

• Final step: 1 ppm for 30–60 minutes before discontinuation

• Monitor closely for rebound hypoxaemia

Secondary Indications — Paediatric Doses (Off-label, if any)

1. Pulmonary Hypertension After Congenital Heart Surgery

Parameter Details

Indication Persistent pulmonary hypertension post-cardiac surgery

Starting dose 10–20 ppm inhaled

Titration Adjust by 5 ppm based on haemodynamics

Usual maintenance dose 5–10 ppm

Maximum dose 20 ppm

Duration ICU use; titrated to oxygenation and haemodynamic parameters

Status OFF-LABEL; Specialist only

Evidence basis Indian paediatric cardiac surgery protocols

Age/Weight Restriction:

Not recommended in infants <28 weeks gestation except under specialist neonatologist/cardiologist supervision with full parental consent

Mild to moderate impairment No dose adjustment required

Severe impairment/ESRD No dose adjustment required; use with caution due to potential for altered MetHb clearance

Haemodialysis Not dialysable; no supplemental dosing needed

• Known hypersensitivity to nitric oxide or nitrogen gas components

• Neonates dependent on right-to-left shunting (e.g., certain cyanotic heart defects)

• Left ventricular dysfunction with elevated pulmonary venous pressure

• Severe pre-existing methemoglobinaemia (MetHb >10%)

• Unintubated/non-ventilated patients (cannot be delivered without ventilator system)

• Risk of methemoglobinaemia — increased with prolonged use (>24 hours) or doses >20 ppm

• Abrupt discontinuation causes rebound pulmonary hypertension — always wean gradually

• NO₂ accumulation risk — continuous monitoring required; levels >2 ppm cause pulmonary toxicity

• Bleeding disorders — nitric oxide inhibits platelet aggregation

• Preterm neonates (<34 weeks) — higher sensitivity; use lower doses with close monitoring

• Ventilator-integrated NO delivery and monitoring system mandatory

Parameter Details

Safety category Not established; limited human data

Preferred alternatives Not applicable — no equivalent therapy

When it may be used Perioperative use by cardiac anaesthetists in exceptional circumstances (OFF-LABEL, Specialist only)

What to monitor Maternal oxygenation, MetHb levels, foetal heart rate monitoring

Parameter Details

Compatibility Not applicable

Rationale Drug is exclusively used in neonates/ICU patients; no maternal systemic exposure when used for neonatal therapy

Expected levels in milk Not relevant

What to monitor Not applicable

Parameter Recommendation

Starting dose 5–10 ppm (lower than standard)

Titration Slower; increase by 5 ppm based on haemodynamic response

Extra risks Increased risk of hypotension, reduced pulmonary reserve, age-related renal impairment affecting MetHb clearance

Monitoring More frequent blood gas analysis and MetHb levels

Note: Use in elderly is rare and limited to ICU settings for RV failure or refractory ARDS (OFF-LABEL)

Interacting Drug Effect Recommendation

Nitroglycerin / Nitrates Additive hypotension and increased methemoglobinaemia risk Avoid concurrent use or use with extreme caution; monitor MetHb frequently

Sildenafil / PDE5 inhibitors Enhanced systemic vasodilation; severe hypotension Avoid concurrent use in adults

Prilocaine / Benzocaine (topical anaesthetics) Additive methemoglobinaemia Avoid; if used, monitor MetHb closely

Interacting Drug Effect Recommendation

Milrinone Additive vasodilation; potential hypotension May be co-used in ICU with haemodynamic monitoring

Anticoagulants (heparin, warfarin) Additive bleeding risk due to platelet inhibition Monitor for bleeding; adjust anticoagulation if needed

Pulmonary surfactant (neonates) May alter NO delivery/distribution Ensure proper timing and synchronisation of administration

High FiO₂ Increased NO₂ production Monitor NO₂ levels continuously; keep <2 ppm

• Methemoglobinaemia (dose-dependent; usually <5% at standard doses)

• Transient hypotension

• Rebound hypoxaemia on withdrawal

• Mild thrombocytopaenia

Adverse Effect Clinical Action

Severe methemoglobinaemia (MetHb >25%) Discontinue NO; administer methylene blue 1–2 mg/kg IV

Nitrogen dioxide (NO₂) toxicity Discontinue NO; supportive pulmonary care

Severe rebound pulmonary hypertension Restart NO at previous dose; wean more gradually

Significant bleeding (platelet inhibition) Supportive management; consider platelet transfusion in neonates

During therapy Continuous: SpO₂, heart rate, NO concentration, NO₂ concentration (<2 ppm); Serial: MetHb (at 1 hour, then every 12–24 hours), blood gases

During weaning Oxygenation parameters; observe for rebound hypoxaemia; reduce by 5 ppm every 4–6 hours

Long-term Not applicable (short-term therapy only)

• INOmax® (Mallinckrodt) — imported via select tertiary hospitals

• Generic nitric oxide cylinders — supplied under contract to tertiary NICUs and cardiac centres

Note: Requires proprietary delivery and monitoring system (e.g., INOvent, INOblender)

Parameter Cost

Per day treatment cost ₹25,000–80,000 (depending on dose and duration)

Supply model Hospital block purchase agreements; not available for retail purchase

Government availability Available at tertiary public institutions (e.g., AIIMS, major medical colleges) under reimbursement models

Insurance coverage Generally not covered under routine health insurance policies

• Never administer without a certified NO delivery system and continuous NO/NO₂ monitoring — unmonitored use can cause fatal pulmonary toxicity

• Always wean gradually (reduce by 5 ppm every 4–6 hours) — abrupt discontinuation causes severe rebound pulmonary hypertension

• Perform echocardiography before initiating therapy to rule out structural cardiac lesions dependent on right-to-left shunting

• Monitor MetHb daily — accumulation occurs with prolonged therapy; keep below 5%

• Lack of oxygenation response within 30–60 minutes suggests non-responder status — consider alternative therapies

• In ARDS, use is primarily for transient oxygenation improvement; no mortality benefit has been demonstrated

nitric oxide; iNO; PPHN; persistent pulmonary hypertension; neonatology; NICU; inhaled vasodilator; ARDS; RV failure; methemoglobinaemia

RxIndia v1.0 — 06 May 2025

• CDSCO product information

• Indian Pharmacopoeia (IP)

• National Neonatology Forum (NNF) India — PPHN Management Guidelines

• AIIMS NICU Protocols

• ICMR Guidelines on Neonatal Care

• Indian paediatric cardiac ICU protocols

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th Edition

• International RCTs/meta-analyses on ARDS (cited for off-label indications only)