Nitric Oxide

Reviewed and revised 12 September 2014

CLASS

• inhalational agent (inhaled nitric oxide, iNO)
• an inorganic gas

MECHANISM OF ACTION

• diffuses to vascular smooth muscle layer from the alveoli
  -> stimulates gluanylate cyclase
  -> increase in cGMP –
  > activates a phosphorylation cascade
  -> smooth muscle relaxation
  -> vasodilation results
• hence iNO is a potent, selective pulmonary vasodilator of those area of the lung being ventilated
  -> improves V/Q mismatch
  -> decreased pulmonary vascular resistance
  -> decreased pulmonary artery pressure

PHARMACEUTICS

• aluminium or stainless steel cylinders
• 100 to 2000 ppm NO
• typically 40L capacity

DOSE

• 5-80 ppm INH

INDICATIONS

1. controversial role in ARDS (see evidence)
2. pulmonary hypertension of the newborn
3. pulmonary hypertension in adults
4. right heart failure (e.g. post-cardiac surgery, post-VAD insertion, heart transplant)
5. primary graft failure post-lung transplant

ADVERSE EFFECTS

• hypotension
• platelet inhibition and prolonged bleeding time
• rebound pulmonary hypertension and hypoxia on withdrawal
• increased blood flow to left atrium may precipitate acute pulmonary oedema if LV dysfunction
• renal failure
• inhalation of toxic higher oxides of nitrogen by patient and staff (ie. nitrogen dioxide -> worsens ARDS, bronchiolitis and may cause pneumonitis)
• mutagenicity

OTHER ISSUES

• complicated circuitry may increase risk of disconnection
• complex equipment
• complex monitoring for NO and nitrogen dioxide concentrations
• some patients appear to be non-responders
• dose-dependent effects not well defined
• minimal additional hemodynamic effects above 20 ppm iNO

PHARMACOKINETICS

• Absorption – INH, highly lipid soluble and diffuses freely across cell membranes
• Metabolism – rapidly converted to nitrates and nitrites in presence of O2, and readily reacts with oxidised Hb to form methaemoglobin
• Elimination  t1/2 = 5sec

EVIDENCE

• several studies suggest transient improve in oxygenation in ARDS with NO therapy
• no study has found clinically meaningful benefits in mortality or duration of mechanical ventilation in ARDS patients
  • if multi-organ failure is the main cause of death in ARDS, then iNO to correct hypoxia is unlikely to improve mortality and may expose the patient to systemic side effects
• In neonates, shown to increase oxygenation, decrease PHT and reduce the need to go onto ECMO

Adhikari NK et al, 2014

• Systematic review of 9 trials, with overall ‘good methodological quality’, that met inclusion criteria
• n = 1,142 patients, patient level data was used
• No reduction in mortality in severe ARDS (PF ratio <100) or moderate-mild ARDS (PF ratio 100-300), no threshold of PF ratio at which NO showed benefit
• further studies addressing the role of NO in ARDS not expected to be available in the foreseeable future

AN APPROACH

• established use in neonates
• use as a ceiling of care
• to use as a bridge to another treatment (HFOV, VV ECMO, proning, prostacycline)
• assess whether responder
• wean slowly
• monitor closely for complications (risk of bleeding, renal failure, methHb, nitrogen dioxide formation) -> if they develop cease

References and Links

Journal articles

• Adhikari NK, Dellinger RP, Lundin S, Payen D, Vallet B, Gerlach H, Park KJ, Mehta S, Slutsky AS, Friedrich JO. Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit Care Med. 2014 Feb;42(2):404-12. PMID: 24132038.
• Creagh-Brown BC, Griffiths MJ, Evans TW. Bench-to-bedside review: Inhaled nitric oxide therapy in adults. Crit Care. 2009;13(3):221. doi: 10.1186/cc7734. PMC2717403.
• De Cruz SJ, Kenyon NJ, Sandrock CE. Bench-to-bedside review: the role of nitric oxide in sepsis. Expert Rev Respir Med. 2009 Oct;3(5):511-21. PMID: 20477340.
• Hollenberg SM, Cinel I. Bench-to-bedside review: nitric oxide in critical illness–update 2008. Crit Care. 2009;13(4):218. PMC2750127.
• Ichinose F, Roberts JD Jr, Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation. 2004 Jun 29;109(25):3106-11.PMID: 15226227. [Free Full Text]
• Pasero D, Martin EL, Davi A, Mascia L, Rinaldi M, Ranieri VM. The effects of inhaled nitric oxide after lung transplantation. Minerva Anestesiol. 2010 May;76(5):353-61. PMID: 20395898.
• Weitzberg E, Hezel M, Lundberg JO. Nitrate-nitrite-nitric oxide pathway: implications for anesthesiology and intensive care. Anesthesiology. 2010 Dec;113(6):1460-75. PMID: 21045638. [Free Full Text]