Brief literature review for the use of inhaled Nitric Oxide (iNO) to treat pulmonary hypertension in the critical care setting

1. ICU management of Pulmonary
Hypertension
Literature review for the use of inhaled
Nitric Oxide (iNO)
Farooq Khan MDCM
PGY2 FRCP-EM
McGill University
Dec 3rd 2010

2. Mechanism of action of nitric oxide
• Potent inhaled vasodilator
• Dilates pulmonary vasculature in ventilated
lung units
– improves oxygenation
– reverses hypoxic pulmonary vasoconstriction
– reduces PAP
• Quickly inactivated by reaction with
hemoglobin in the pulmonary capillaries
– no significant systemic vasodilatory effects

3. Current WHO indications for therapy
• Group 1
– Stabilization of PAH crisis
– Hemodynamic support in OB patients
– Treatment of porto-pulmonary hypertension
• Groups 2-5
– PVH post cardiac surgery
– Rescue from refractory hypoxemia in acute lung
disease
– Hemodynamic support in acute thromboembolic
disease

4. Human physiological study
• Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT,
et al: Inhaled nitric oxide as a cause of
selective pulmonary vasodilatation in
pulmonary hypertension. Lancet 1991; 338:
1173–1174
– Inhaled NO vs prostacyclin in severe PAH patients
and control patients
– Predictable drop in PAP without concomitant drop
in SVR in both groups compared to placebo and
compared to prostacyclin

5. Clinical studies of effect on chronic
PAH
• Cockrill BA, Kacmarek RM, Fifer MA, et al:
Comparison of the effects of nitric oxide,
nitroprusside, and nifedipine on hemodynamics
and right ventricular contractility in patients with
chronic pulmonary hypertension. Chest 2001;
119:128–136
– Decreased PAP, PVR and RVEDP
– MAP unchanged, RV contractility unchanged
– SVI increased

6. Effect of iNO in RH syndrome
• Bhorade S, Christenson J, O’Connor M, et al:
Response to inhaled nitric oxide in patients
with acute right heart syndrome. Am J Respir
Crit Care Med 1999; 159: 571–579
– Increase in CO (36%), SV and MVO2 sat
– 38% decrease in PVR
– 28% increase in PaO2/FiO2
– Not designed to study mortality

7. iNO in other disease states
• iNO as treatment for severe ARDS
– Kaisers U, Busch T, Deja M, et al: Selective pulmonary
vasodilation in acute respiratory distress syndrome.
Crit Care Med 2003; 31: S337–S342
• reduce pulmonary hypertension
• improve matching of ventilation to perfusion and thus,
hypoxemia
– Taylor RW, Zimmerman JL, Dellinger RP, et al: Low-
dose inhaled nitric oxide in patients with acute lung
injury: A randomized controlled trial. JAMA 2004;
291:1603–1609
• Short term effect on increasing PaO2
• No effect on mortality or days spent off vent

8. iNO in other disease states
• iNO in severe heart failure
– Semigran MJ, Cockrill BA, Kacmarek R, et al:
Hemodynamic effects of inhaled nitric oxide in
heart failure. J Am Coll Cardiol 1994; 24:982–988
• Decrease in PAH caused by LV failure
• Identify patients with reversible pulmonary
vasocontriction where nipride can cause systemic
hypotension

9. iNO in other disease states
• iNO post MVR in chronic PAH patients
– Girard C, Lehot JJ, Pannetier JC, et al: Inhaled nitric
oxide after mitral valve replacementin patients
with chronic pulmonary artery hypertension.
Anesthesiology 1992;77:880–883
• Decrease in PAP, PVR
• Increase in MVO2 Sat, no change in MAP or PCWP

10. Adverse effects
• Methemoglobinemia
– Weinberger B, Laskin DL, Heck DE, et al: The toxicology of
inhaled nitric oxide. Toxicol Sci 2001; 59:5–16
• Oxidative stress due to combination with O2 creating NO2
– Wang T, El Kebir D, Blaise G: Inhaled nitric oxide in 2003: A
review of its mechanisms of action. Can J Anaesth 2003;
50:839–846
• Abrupt withdrawal can cause rebound Pah and
cardiovascular collapse
– Christenson J, Lavoie A, O’Connor M, et al: The incidence and
pathogenesis of cardiopulmonary deterioration after abrupt
withdrawal of inhaled nitric oxide. Am J Respir Crit Care Med
2000; 161:1443–1449