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 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 multifactorial, 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 CO₂ and heart rate, and increased oxygen pulse, vs. 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.NEW & NOTEWORTHY The current study confirmed that excessive inspiratory neural drive contributed to troublesome dyspnea and exercise intolerance in individuals with a history of pulmonary embolism and that these could be partially mitigated by acute selective pulmonary vasodilation via inhaled nitric oxide. This study increased our understanding of the complex mechanisms of exertional dyspnea in individuals post-PE with persistent abnormal physiological responses during CPET.