Critically evaluate the use of inhaled nitric oxide in the ICU.

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College answer

Indications:
Nitric oxide is used as a rescue therapy for ARDS with refractory hypoxemia and right ventricular dysfunction in ICU. Evidence for its use in ICU is limited. However, because of the immediate physiological benefits, it continues to be one of the agents used in ICU in these scenarios.

Mechanism of Action of iNO
o    Causes selective pulmonary arteriolar vasodilatation
o    This leads to a reduction in pulmonary artery pressure and pulmonary vascular resistance.
o    Reduction in PVR leading to reduced afterload on RV→ improvement in right ventricular cardiac output and organ perfusion.
o    Dilates pulmonary vessels in better ventilated areas of the lung which in turn reduces V/Q mismatch and improves oxygenation.

Advantages:
o    Quick onset of effect
o    Minimal systemic hypotension

Disadvantages:
o    Can cause methaemoglobinemia in patients with methaemoglobin reductase deficiency
o    Very expensive
o    Needs specialized/complex equipment to deliver
o    Needs to be weaned slowly as can cause rebound pulmonary hypertension
o    Air filtration rates of 10-12 air exchanges per hour are necessary to prevent accumulation of NO/ NO2 in the ambient air in ICU
o    Decrease platelet aggregation.
 

Evidence
For hypoxemia in ARDS:

Despite obvious physiological benefits iNO has not been shown to change ICU outcomes of mortality, ventilator-free days in large randomised control trials in adult and paediatric patient groups. In a Cochrane Review published in 2016, there were no statistically significant effects of iNO on longest follow-up mortality, 28-day mortality in both adults and children- moderate quality of evidence. There was a statistically significant improvement in P/F ratio and oxygenation index at 24 hours- moderate quality of evidence. There was a statistically significant increase in renal failure in iNO groups- high quality evidence.

For right ventricular dysfunction:
Only small randomised control trials and case series are available. Most of them have been conducted in post-cardiac surgery patients with right heart dysfunction, patients on LVAD, heart transplantation with primary graft dysfunction and patients with pulmonary arterial hypertension. Again all the studies demonstrate a physiological reduction in pulmonary artery pressure and ?increase cardiac output. No randomised trials have demonstrated mortality benefit with iNO.

Other studies on LVAD and heart transplantation are case series only, and there are no randomised clinical trials. Theoretical benefit for ischaemia-reperfusion injury post- lung transplant (decreased leucocyte and platelet aggregation) but no difference in clinical outcomes.

Summary statement
Inhaled nitric oxide in ICU provides short-term physiological benefits to the patients in ICU with refractory hypoxemia and right heart dysfunction. However, none of the studies has shown any mortality benefit. When used for refractory hypoxemia in ARDS, there is strong evidence that it is associated with renal failure. Also, it is an expensive therapy. Candidates might state that they use alternative selective pulmonary vasodilators like inhaled epoprostenol instead of iNO. This is also acceptable.

Examiners Comments:

Some insightful, thoughtful and well-balanced answers. However, there are quite a few candidates who have minimal knowledge of a mainstream agent used in intensive care practice. A structured approach to this type of question i.e. " Critically evaluate " was quite variable; some have practiced this template well whilst others have not thought about this prior to the exam.

Discussion

Somebody at CICM must have a subscription to the British Journal of Pharmacology. After ignoring nitric oxide for over a decade (the last SAQ was Question 14 from the first paper of 2006), the college had decided to spring this topic on its final exam candidates in 2019. Totally coincidentally, the BJP published a special themed issue celebrating the 20th anniversary of  Furchgott Ignarro and Murads' Nobel Prize for the discovery of nitric oxide's role in cell signalling. In this issue, the excellent article by Yu et al (2019) has served as the main source of information for this answer.

Rationale for the use of inhaled nitric oxide:

  • To decrease pulmonary vascular resistance:
    • This decreases right ventricular afterload and may improve the performance of a failing right ventricle
  • To improve V/Q matching (for severe ARDS):
    • Only ventilated regions of lung receive the inhaled agent
    • Therefore pulmonary vessels will only be dilated in the well-ventilated regions of the lung
    • Therefore blood flow will be preferentially directed to those regions
    • In heterogeneous lung disease (eg. ARDS) this may improve shunt

Administration

  • via a uniquely designed gas mixer
  • from its own tank
  • start at 5-10 ppm, go up to 160ppm as needed

Monitoring

  • Monitor PA pressures with PAC and serial TTE
  • monitor response with arterial oxygenation
  • regular CXR, watch for pulmonary haemorrhage
  • Monitor for toxicity, particularly methaemoglobin levels and NO2
  • Observe strict handling safeguards, including gas scavenging and ventilation precautions

Mechanism of action:

  • Nitric oxide is a potent vasodilator; it inhibits vasoconstriction by increasing the amount of cyclic GMP (cGMP) in the cytosol, thus decreasing the amount of cytosolic calcium ions available to sustain smooth muscle contraction.

Advantages

  • Relatively non-toxic
  • Does not require scavenging technology (though if it were used in higher concentration, it would require scavenging)
  • Short-acting (thus, no systemic vasodilation - only pulmonary)
  • Small molecule:
    • diffuses easily to the site of action
    • penetrates well into the alveoli (where aerosols do not)

Disadvantages

  • Expensive
  • Can actually decrease the oxygen-carrying capacity of the blood
  • Though scavenging is not required, a high air flow rate in the room is called for.

Complications

  • Methemoglobinaemia
  • Hypotension
  • Rebound hypoxia after abrupt withdrawal
  • Thrombocytopenia (in as many as 10% of patients)
  • Increased susceptibility to pulmonary infections probably due to NO2 formation
  • Renal failure

Contraindications

  • Left ventricular failure
  • Left to right intracardiac shunt
  • Uncontrolled haemorrhage 
  • Existing methaemoglobinaemia

Evidence

In short, there is little high-quality evidence. What we do know is that there is no benefit in mortality. However:

  • It is an effective pulmonary vasodilator (Sim et al, 2010)
  • It improves oxygenation in ARDS (Albert et al, 2017) 
  • There does not appear to be a surival benefit. One of the papers quoted by the CICM examiners was the 2016 Cochrane review by Gebistorf et al, which looked at ARDS and concluded that the evidence was "insufficient to support INO in any category of critically ill patients". The same study found that nitric oxide caused an apparent increase in the risk of renal failure (RR was ~ 1.59). However, many of the older trials on this application of nitric oxide were performed in the bad old days, before the advent of lung-protective ventilation. 

Other applications:

  • Haemolysis:  Lei et al (2018) were able to demonstrate a marked improvement in the rates of renal failure (from 63% to 50%) among post-cardiac surgical patients receiving inhaled nitric oxide.
  • Post-cardiac surgery pulmonary hypertension: iNO is at least as effective as inhaled prostacycline (McGinn et al, 2015).
  • Sickle cell disease: a single trial did not demonstrate much improvement in symptoms (Gladwin et al, 2011)
  • Cerebral malaria: iNO does not seem to have much of an effect on the outcomes in this disease (Hawkes et al, 2015)

References

References

Ikaria, the only company which produces this stuff in Australia, has an excellent product information pamphlet.

Barker, Steven J., and John J. Badal. "The measurement of dyshemoglobins and total hemoglobin by pulse oximetry." Current Opinion in Anesthesiology21.6 (2008): 805-810.

Afshari, Arash, et al. "Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults." Cochrane Database Syst Rev 7 (2010).

Gebistorf, Fabienne, et al. "Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults." Cochrane database of systematic reviews 6 (2016).

Yu, Binglan, et al. "Inhaled nitric oxide." British journal of pharmacology 176.2 (2019): 246-255.

Sim, Ji-Yeon. "Nitric oxide and pulmonary hypertension." Korean journal of anesthesiology 58.1 (2010): 4.

Albert, Martin, et al. "Comparison of inhaled milrinone, nitric oxide and prostacyclin in acute respiratory distress syndrome." World journal of critical care medicine 6.1 (2017): 74.