Nitric Oxide for Refractory Hypoxaemia in ARDS

Nitric Oxide for Refractory Hypoxaemia in ARDS

A 65 year old woman developed a hospital acquired pneumonia 24 hours after a multilevel spinal fixation. She became progressively more hypoxic and required intubation. She remained profoundly hypoxic despite FiO2 1.0, paralysis, lung protective ventilation and inverse ratios. She was established on inhaled nitric oxide therapy as anticoagulation for ECMO was felt to be contraindicated. This resulted in an rapid but modest increase in SpO2. Over the next days, her recovery was complicated by pneumothoraces requiring chest drains, but she remained on iNO for several days, and weaned off the ventilator at around day 10.

Does nitric oxide have a role to play in hypoxemia secondary to ARDS?

David Garry


Nitric oxide is a potent endogenous vasodilator that can be administered by inhalation, providing selective pulmonary vasodilatation in well-ventilated lung units, improving ventilation perfusion (V/Q) mismatch and reducing the elevated pulmonary vascular resistance and pulmonary hypertension seen in ARDS (1,2). It also plays a role in protection from oxidative lung injury and in the regulation of immune and inflammatory responses (3,4). The use of iNO has previously been shown (2,5,6) to lead to a modest transient improvement in oxygenation but with no mortality benefit.

A meta-analysis was published in 2011 looking at the effects of iNO in patients with ARDS (7). A total of 14 trials were included in the final dataset (1303 patients). Three were pediatric trials, the others mixed populations of critically ill adults with acute lung injury (ALI) and ARDS. Sample sizes of the individual trials varied from 14 to 385 participants. Duration of iNO varied from < 24 hours to 4 weeks with a median length of 7 days. Eight trials applied a fixed dose of iNO (median 10 parts per million), 5 used the lowest dose to achieve an oxygenation response and 1 trial used different doses of iNO. Various co-interventions were applied including recruitment manoeuvres, prone positioning, and corticosteroids.

The primary outcome was survival at 28 days and at longest follow up. The secondary outcomes were duration of mechanical ventilation, ventilator-free days, Pao2/Fio2 ratio, oxygenation index, length of stay in (ICU) and hospital and adverse events (such as bleeding and renal dysfunction). The results showed that:
• There was no statistically significant effect of iNO on mortality (265/660 deaths (40.2%) in the iNO group vs 228/590 deaths (38.6%) in the control group (RR 1.06, 95% CI 0.93 to 1.22; I2=0%)).
• There was no beneficial effect of iNO on ventilator free days or the duration of mechanical ventilation. There was a transient but statistically significant improvement in oxygenation in the first 24 hours, expressed as the ratio of PaO2 to fraction of inspired oxygen (mean difference [MD] 15.91, 95% CI 8.25 to 23.56; I2=25%).
• In terms of adverse effects, renal failure was reported in 4 of the studies. There was no increase in the risk of bleeding or methaemoglobin/nitrogen dioxide formation.

The lack of a mortality benefit could be multifactorial. Reversal of hypoxic pulmonary vasoconstriction could cause vasodilatation of the poorly ventilated areas of the lungs, increasing the V/Q mismatch and resulting in a worsening of oxygenation. Importantly, oxygenation is only a surrogate outcome. The lack of mortality benefit in patients who have an improvement in their oxygenation could be because the improvement in oxygenation is not due to resolution of the lung pathology, the underlying cause of the ARDS and the often coexisting multiorgan failure that the majority of patients with ARDS die from.

Prolonged exposure to iNO and its toxic metabolites can lead to tachyphylaxis and override the possible benefits. Of note the meta-analysis showed an association with renal failure. NO is an important regulator of renal vascular tone and a modulator of glomerular function, so changes in NO production could potentially cause acute renal failure by altering the function of mitochondria, enzymes, DNA, and membranes.


1. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K Jr, Hyers TM, Papadakos P. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study group. Crit Care Med 1998;26:15–23
2. Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute hypoxic respiratory failure in children and adults: a meta- analysis. Anesth Analg 2003;97:989–98
3. McAndrew J, Patel RP, Jo H, Cornwell T, Lincoln T, Moellering D, White CR, Matalon S, Darley-Usmar V. The interplay of nitric oxide and peroxynitrite with signal transduction path- ways: implications for disease. Semin Perinatol 1997;21:351– 66
4. Prodhan P, Noviski N. Pediatric acute hypoxemic respiratory failure: management of oxygenation. J Intensive Care Med 2004;19:140 –53
5. Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults. Cochrane Database Syst Rev 2003;1:CD002787
6. Adhikari NK, Burns KE, Friedrich JO, Granton JT, Cook DJ, Meade MO. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 2007;334:779
7. Arash Afshari, MD, Jesper Brok, Ann M. Møller, MD, Jørn Wetterslev. Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome and Acute Lung Injury in Adults and Children: A Systematic Review with Meta-Analysis and Trial Sequential Analysis. Anesth Analg 2011;112:1411–21

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