Anders, M. Nitric oxide, Don't Forget the Bubbles, 2013. Available at:
Definition: nitric oxide (NO) is produced in the endothelium by eNOS (endothelial nitric oxide synthase). It works beside other chemical mediators, to regulate vascular tone. NO induces soluble guanylate cyclase to increase cGMP reducing cellular calcium levels and thus producing smooth muscle relaxation and pulmonary vasculature relaxation and a decrease in PAP.
Half-life is 15-30 secs when inhaled, at doses of 5-80 ppm. When it enters the bloodstream it binds to Hb producing nitrosylmethemoglobin (forming methemoglobin and nitrate), rendering it ineffective at producing systemic vasodilation.
It oxidises to form NO2 (nitrous dioxide) when exposed to oxygen, which can be toxic to the alveolar or vascular cells so levels of NO2 >2 ppm should be avoided.
- Conditions where pulmonary hypertension is present
- Hypoxic respiratory failure (e.g. meconium aspiration, ALI, ARDS)
Monitoring for effectiveness:
- PaO2 rise of >20% → improving V/Q mismatch
- Reduction in PAP (but doesn’t need to occur to produce PaO2 rise)
- Reduction of R → L shunt
If no significant beneficial effect is shown NO should be immediately discontinued prior to tolerance occurring. If benefit is shown this must be documented in the notes.
Monitoring for side effects:
- Systemic hypotension (with improved pulmonary venous return to a functionally impaired left ventricle)
- Daily measurements of methaemoglobin levels (ABG results) avoiding levels >2% (avoid NO >22 ppm)
Testing of the INOvent prior to use should be done by a person deemed competent by their institution. Once the unit has been shown to be working properly the following should be present:
- That the NO2 alarm should be set to an upper limit of 2 ppm
- That the anaesthetic bag is connected to the INOvent, whilst the patient is on iNO therapy.
- That the O2 and NO settings are reading what has been prescribed.
- Exhaust gases from the breathing circuit must be scavenged to minimise environmental pollution.
Higher doses of iNO up to 80 ppm have been described, but usually no more than 20 ppm is recommended, as higher doses showed increased side effects, but no improvement in outcome.
Weaning can result in rebound PHT and dose reductions should be made cautiously with some references recommending over 12-24 hrs, while other recommending reductions to be made every 2 hrs.
- Wean iNO every 30 min by 1 ppm
- When iNO is weaned to 2 ppm increase FiO2 to 60%
- Give sildenafil 0.4 mg/kg orally
- Cease iNO 60 min after sildenafil dose given
- Wean FiO2 to previous settings
In children, mean plasma levels 1h after doses of sildenafil 0.5-2.0 mg/kg are similar to the maximum plasma concentrations reported in adults receiving doses within the therapeutic range.
Sildenafil has also been used as a short term prophylactic therapy post-operatively in those undergoing palliative or definitive surgery for congenital heart disease with varying improvements in PAP and/or SpO2.
References: Am J Respir Crit Care Med. 2006 Nov 1;174(9):1042-7: Namachivayam et al: Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children.  Pediatr Cardiol. 2010 May;31(4):515-20. Epub 2010 Jan 7: Uhm et al: Postoperative use of oral sildenafil in pediatric patients with congenital heart disease.  Pediatric Cardiology. 31 pp 515 – 520. 2010: Uhm JY, Jhang W, Park J, Seo D, Yun S & Yun T. Postoperative use of oral sildenafil in pediatric patients with congenital heart disease.  Lancet. 1992 Oct 3;340(8823):819-20: Kinsella et al: Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn.  In: Up To Date. Available online at: . Accessed on: 11/1/2011: Taichman DB. Inhaled nitric oxide in adults with pulmonary hypertension.  Pediatr Crit Care Med. 2010 Mar;11(2 Suppl):S30-6: Barr et al: Inhaled nitric oxide and related therapies  Anesth Analg. 2010 Sep;111(3):693-702: Liu et al: Special article: rescue therapies for acute hypoxemic respiratory failure  Clin Chest Med. 2000 Sep;21(3):519-29: Payen: Inhaled nitric oxide and acute lung injury.  JAMA. 1996 Oct 9;276(14):1189-92: Murad et al: The 1996 Albert Lasker Medical Research Awards. Signal transduction using nitric oxide and cyclic guanosine monophosphate  J Perinatol. 2004 May;24(5):290-4: Guthrie: Initial dosing of inhaled nitric oxide in infants with hypoxic respiratory failure
 N Engl J Med. 2000 Feb 17;342(7):469-74: Clark et al: Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group