Variation in the definition of pulmonary hypertension and clinical indications for the use of nitric oxide in neonatal clinical trials

Abstract

Acta Paediatrica. 2020;109:930-934. wileyonlinelibrary.com/journal/apa | INTRODUC TI ONPulmonary hypertension (PH) complicating neonatal hypoxaemic respiratory failure occurs in approximately 0.4-6.8 cases per 1000 live births and is associated with significant morbidity and mortality. 1,2 The terms "pulmonary hypertension" and "persistent pulmonary hypertension of the newborn" (PPHN) are often used interchangeably, and this probably reflects the absence of clear case definitions.Unlike paediatric and adult pulmonary hypertension, there is no internationally accepted definition of PH in neonatal medicine. 3,4 The lack of a standardised definition precludes meaningful interpretation of clinical trials in this field, because it is difficult to compare trials with different entry criteria, perform subgroup analyses stratified by disease severity and adjust for confounding variables.Abbreviations: a/A ratio, alveolar to arterial oxygen tension ratio; BPD, bronchopulmonary dysplasia; iNO, inhaled nitric oxide; OI, oxygenation index; PAP, pulmonary arterial pressure; PH, pulmonary hypertension; PPHN, persistent pulmonary hypertension of the newborn; RCT, randomized controlled trial. Abstract Aim: Pulmonary hypertension (PH) frequently complicates neonatal hypoxaemic respiratory failure, but is inconsistently defined. We aimed to describe the variation among randomised controlled trials (RCTs) of inhaled nitric oxide (iNO), in relation to the definition of PH and/or hypoxaemic respiratory failure used to select patients for trial inclusion. Methods: PubMed, Cochrane Library and ClinicalTrials.gov were systematically searched for RCTs of iNO in neonates. Included studies were assessed for clinical and/or echocardiography criteria used to define PH/hypoxaemic respiratory failure. Results: Thirty-two trials were included in this review, of which 23 enrolled infants ≥34 weeks' gestation. Echocardiographic diagnosis was used in 21 studies, but there was considerable variation in the echocardiographic parameters used to diagnose PH. The most commonly used indices included markers of tricuspid regurgitation and extrapulmonary shunt. Conclusion: There is wide variation in the definition of PH used to select infants for inclusion into RCTs of iNO therapy in neonates. We recommend that an international consensus be reached on which parameters should be used and the thresholds defining severity of disease. K E Y W O R D S inhaled nitric oxide, neonatal, pulmonary hypertension, randomised controlled trial, systematic review This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland. | 931 HOYLE Et aL.Despite an absence of a clear definition of PH in this population, randomised controlled trials (RCTs) have frequently included neonates with hypoxaemic respiratory failure complicated by PH/ PPHN when evaluating the efficacy of pulmonary vasodilator therapies. Inhaled nitric oxide (iNO) is a licensed treatment for newborn infants ≥34 weeks gestation with hypoxic respiratory failure...

Pulmonary Vascular Remodeling in Pulmonary Hypertension

“…Alterations of PASMCs communicate with PAECs and play a major regulatory role in the pathological development of PH [ 90 ]. PAECs in PH lose the ability to modulate the appropriate moderate balance between vasoconstrictors, such as endothelin-1 (ET-1) and serotonin, and vasodilators, such as nitric oxide (NO) and prostacyclin [ 91 , 92 , 93 , 94 ]. The capacity of PAECs is to maintain a regular vascular network by secreting vasoactive factors, which affects the interactions between PAECs and PASMCs, and regulates multicellular contraction, proliferation, and survival.…”

Giant omphalocele associated pulmonary hypertension: A retrospective study

“…As the gold standard, right cardiac catheterization (RHC) should be performed when PH is clinically considered and cannot be accurately measured by echocardiography. PH was defined on echocardiography as the presence of tricuspid regurgitant jet with an estimated systolic pulmonary artery pressure (PAP) > 2/3 systemic systolic blood pressure and/or right-to-left or bidirectional flow at ductal and/or atrial level (17,18). Once PH was diagnosed, pulmonary vasodilators (PVDs) were administered individually that included inhaled nitric oxide (iNO), treprostinil, milrinone, sildenafil, or bosentan.…”

Inhaled nitric oxide in preterm neonates with preterm prelabour rupture of membranes, a systematic review

“…5 These concerns, coupled with the lack of a clear definition of PH and the heterogeneity in the baseline pathology of preterm infants recruited into previous randomised controlled trials (RCTs), have resulted in a potentially flawed conclusion that iNO is non-inferior to standard care, in a cohort who may in fact benefit from its use. [5][6][7][8] Despite the paucity of high-quality evidence, the use of iNO appears to be increasing in premature neonates as 'rescue therapy' from severe HRF when standard treatment has failed to show improvement. This has created an evidence-based versus pathophysiological-based divide amongst clinicians in terms of the perceived efficacy of iNO in this cohort.…”

“…There are concerns regarding the safety of iNO in extremely low birthweight neonates, with a higher mortality and increased risk of intraventricular haemorrhage (IVH) following its use 5 . These concerns, coupled with the lack of a clear definition of PH and the heterogeneity in the baseline pathology of preterm infants recruited into previous randomised controlled trials (RCTs), have resulted in a potentially flawed conclusion that iNO is non‐inferior to standard care, in a cohort who may in fact benefit from its use 5‐8 …”