Acute effects of inhaled nitric oxide on inspiratory neural drive, dyspnea and exercise endurance in symptomatic patients post-pulmonary embolism

Following pulmonary embolism (PE), up to a third of patients develop persistent activity-related dyspnea without evidence of pulmonary hypertension (PH) at rest. In such individuals, dyspnea appears to be associated with relatively high inspiratory neural drive (IND, assessed via diaphragm electromyography) during exercise. Excessive IND is multi-factorial, but the effects of regional pulmonary capillary hypoperfusion and increased physiological dead space may be contributory. We aimed to determine the effect of iNO on IND, perceived dyspnea intensity and exercise endurance in patients post-PE. We undertook a randomized, double-blind, placebo-controlled crossover study where 14 symptomatic individuals post-PE completed constant work rate cycle exercise tests while breathing iNO (40 ppm) or placebo, on separate days. Detailed measurements of expired gas, respiratory neuromechanics and perceived dyspnea were acquired at rest and throughout exercise. iNO administration, compared with placebo, was associated with reduced isotime IND and breathing effort (esophageal pressure-time product of inspiratory muscles) by 9±8 and 19±35 %, respectively (both p<0.01), increased exercise endurance time by 27±12 % (p<0.001), and reduced isotime dyspnea ratings by 1±1 Borg units (p=0.011). The reduction in IND was related to reduced dyspnea (r=0.59, p<0.018), which in turn, correlated with increased exercise endurance time (r=-0.60, p<0.024). At standardized exercise times, iNO was associated with small reductions in ventilatory requirements for CO 2 and heart rate, and increased oxygen pulse, versus placebo (all p<0.05). This study demonstrated that excessive IND contributed to troublesome dyspnea and exercise intolerance in individuals post-PE and that these could be partially mitigated by selective pulmonary vasodilation.