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OBJECTIVE: To describe current treatment practices of preterm infants with early hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) and their association with patient outcomes. STUDY DESIGN: We developed a prospective, observational, multicenter clinical registry of preterm newborns <34 weeks' gestation with HRF and PH, based on either clinical or echocardiographic evidence during the first 72 hours of life, from 28 neonatal intensive care units in the US from 2017 through 2022. The primary end point was mortality among those who did or did not receive PH-targeted treatment, and the secondary end points included comparisons of major morbidities. Variables were compared using t tests, Wilcoxon rank-sum tests, Fisher exact tests, and χ² tests. RESULTS: We analyzed the results of 224 preterm infants enrolled in the registry. Of which, 84% (188/224) received PH-targeted treatment, most commonly inhaled nitric oxide (iNO). Early mortality in this cohort was high, as 33% (71/224) of this sample died in the first month of life, and 77% of survivors (105/137) developed bronchopulmonary dysplasia. Infants who received PH-targeted treatment had higher oxygenation indices at the time of enrollment (28.16 [IQR: 13.94, 42.5] vs 15.46 [IQR: 11.94, 26.15]; P = .0064). Patient outcomes did not differ between those who did or did not receive PH-targeted therapy. CONCLUSIONS: Early-onset HRF with PH in preterm infants is associated with a high early mortality and a high risk of developing bronchopulmonary dysplasia. iNO is commonly used to treat early-onset PH in preterm infants with HRF. In comparison with untreated infants with lower oxygenation indices, iNO treatment in severe PH may prevent poorer outcomes.

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Introducción. La hipertensión arterial pulmonar (HAP) es una enfermedad que presenta un elevado índice de mortalidad en la población pediátrica. Para su diagnóstico, el gold standard es la prueba de reactividad vascular pulmonar (PRVP), debido a que permite medir la respuesta vasodilatadora del lecho vascular pulmonar frente a la administración de moléculas con acción terapéutica, como el óxido nítrico inhalado (iNO). Esta prueba al ser positiva se asocia a un mejor pronóstico. En la actualidad existe incertidumbre y falta de consenso sobre la indicación y administración de iNO durante la PRVP. Objetivo. Describir el uso reportado en la literatura sobre iNO en PRVP en sujetos pediátricos con HAP. Métodos. Revisión sistemática exploratoria sensible en bases de datos PubMed, Epistemonikos, Cochrane, Scopus, Lilacs y Scielo, que describen el uso de iNO durante la PRVP en sujetos pediátricos con HAP. Resultados. se identificaron 8.906 artículos, de los cuales se seleccionaron 5 para la revisión cualitativa. La PRVP se realizó durante el cateterismo cardiaco derecho (CCD) en sujetosentre 2 semanas y 18 años de edad. Los diagnósticos fueron HAP primaria, idiopática y asociada a patología cardiaca congénita, cardiomiopatía y enfermedad pulmonar. Esta prueba fue realizada en sujetos sólo con soporte de oxígeno o con sedación profunda en ventilación mecánica invasiva, con dosis variables de oxígeno (21 y 100%) e iNO (3 y 80 ppm), o asociado a otras moléculas como iloprostol®, dilitiazem, sildenafil y/o epoprostenol. La administración de iNO disminuyó presión de arteria pulmonar y la resistencia vascular pulmonar, con mantención de presión arterial sistémica y gasto cardiaco y sin complicaciones asociadas a su uso. Conclusiones. Existen escasos estudios sobre iNO en PRVP pediátrica y con calidad metodológica limitada. El iNO se utiliza como método diagnóstico de vaso reactividad en sujetos pediátricos con HAP asociada a cardiopatía congénita, primaria o secundaria. Los protocolos para su uso son variables con dosis entre 20 y 40 ppm, con o sin uso de oxigeno adicional, con tiempos poco precisos y sin consenso en equipos de administración.

Background. Pulmonary arterial hypertension (PAH) is a disease that has a high mortality rate among the pediatric population. For its diagnosis, the pulmonary vascular reactivity test (PVRT) is considered the "Gold Standard", because it allows to measure the vasodilator response of pulmonary vascular circulation with the administration of molecules with therapeutic action, such as inhaled nitric oxide (iNO). This test, when positive, is associated with a better prognosis of the disease. Currently, there's uncertainty and lack of consensus on the indication and administration of iNO during the PVRT. Objetives. to describe use of iNO in PVRT in pediatric users with PAH reported in the literature. Methods. Scoping review of studies published between 1992 and 2021 in PubMed, Epistemonikos, Cochrane, Scopus, Lilacs and Scielo databases, which describe the use of iNO during PVRT in pediatric users with PAH, in English and Spanish. Primary and secondary studies with a sensitive search strategy were considered. Results. 8,906 articles were identified, 40 were selected by title, 8 by full text, and 5 for final qualitative review. Of the total of articles selected, 3 were primary and 2 secondary studies. PVRT was performed during right heart catheterization (RHC) in a population between 2 weeks and 18 years old. Diagnoses were primary PAH, idiopathic PAH and PAH associated with congenital heart disease, cardiomyopathy and pulmonary disease. This test was carried out in subjects on spontaneous ventilation with oxygen support or with deep sedation in invasive mechanical ventilation, with variable oxygen doses between 21 and 100%, with exclusive use of iNO between 3 and 80 ppm, being more used between 20 and 40 ppm, or associated with other molecules such as iloprostol®, dilithiazim, sildenafil and / or epoprostenol. In all selected studies, administration of iNO decreased PAP (pulmonary artery pressure) and PVR (pulmonary vascular resistance), with maintenance of SBP (systemic arterial blood pressure) and cardiac output. The primary studies were made up of pre and post-test of serial or parallel interventions. The selected studies of iNO in PVRT did not report complications associated with its use. Conclusions. studies on iNO in pediatric PVRT are scarce in number of publications and methodological quality. iNO is used as a diagnostic method of vasoreactivity in pediatric users with PAH associated with congenital, primary, or secondary heart disease. The protocols for its use are variable with recommended doses between 20 and 40 ppm, with or without the use of additional O2, with imprecise times and without consensus in administration equipment. The response to PVRT serves as a guide for the treatment and prognosis of pediatric users with PAH.

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Abstract: Introduction: Among the patients infected with SARS-CoV-2, 14.6% were admitted to intensive care unit. this 29 to 75% required invasive mechanical ventilation with an associated mortality of 12 to 81%. Acute respiratory distress syndrome (ARDS) is the most serious form of presentation. The pathophysiology of ARDS secondary to SARS-CoV-2 differs from conventional causes. It presents dysregulation in hypoxic pulmonary vasoconstriction, secondary acute pulmonary hypertension and microthrombotic phenomena. The development of refractory severe hypoxemia (PaO2 < 60 mmHg or PaO2/FiO2 < 100 mmHg, with FiO2 80 to 100%, with PEEP > 10 to 20 cmH2O for at least 10 to 12 hours) constitutes the scenario of maximum severity with an associated mortality of 71 to 94%. The use of rescue strategies that impact on the specific pathophysiology of this entity such as the use of inhaled nitric oxide, neuromuscular blockade and prone ventilation have emerged as therapeutic targets of interest. Protective mechanical ventilation (plateau pressure [Pplat] < 27 cmH2O and driving pressure [DP] < 15 cmH2O) continues to be the cornerstone of the management. Objectives: To determine whether there is an association between the use of inhaled nitric oxide and prone ventilation with ventilatory mechanics in patients with severe refractory hypoxemia secondary to SARS-CoV-2 infection. Material and methods: A historical, retrospective, descriptive, comparative and retrolective cohort study was carried out. Data from the records of patients admitted to the Respiratory ICU of the ABC Medical Center with a diagnosis of ARDS secondary to SARS-CoV-2 infection who required iNO and mechanical ventilation in prone from April 1 to December 31, 2020 were analyzed. A univariate analysis was performed, the statistical analysis was performed in SPSS v 21, measures of trend, dispersion were analyzed as well as the analysis of risk factors with Student's t test and χ2. Results: A total of 108 patients were analyzed, of which 54 received iNO, neuromuscular blockade and prone and 54 only neuromuscular blockade and prone ventilation. 81.5% (n = 88) were men. The most common comorbidity was diabetes mellitus in 51.9% (n = 56). The increase in oxygenation (delta PaO2/FiO2) was with a median of 31.9 ± 15.2 mmHg in the iNO group and 52.9 ± 16.74 mmHg in the control group (p = 0.001). The postintervention Pplat in the iNO group was 26.3 ± 3 and 34.5 ± 1.9 cmH2O in the control group (p = 0.792). The preintervention DP in the iNO group was 17.2 ± 3.9 and 13.4 ± 2.8 cmH2O in control group vs 13.1 ± 1.29 and 12 ± 1.92 cmH2O after the intervention (p = 0.001). Conclusions: The use of iNO in patients with severe hypoxemia refractory to prone ventilation and neuromuscular blockade did not produce a statistically significant improvement in oxygenation, however it allowed to reprogram the ventilatory support to keep the patient in goals of alveolar protection.

Resumo: Introdução: 14.6% dos pacientes infectados com SARS-CoV-2 são internados em terapia intensiva. Destes, 29 a 75% necessitam de ventilação mecânica invasiva com mortalidade associada de 12 a 81%. A síndrome do desconforto respiratório agudo (SDRA) é a forma mais grave de apresentação. A fisiopatologia da SDRA secundária ao SARS-CoV-2 difere das causas convencionais. Apresenta desregulação na vasoconstrição pulmonar hipóxica, hipertensão pulmonar aguda secundária e fenômenos microtrombóticos. O desenvolvimento de hipoxemia grave refratária (PaO2 < 60 mmHg ou PaO2/FiO2 < 100 mmHg, com FiO2 de 80 a 100%, PEEP > 10 a 20 cmH2O por pelo menos 10 a 12 horas) constitui o cenário mais grave com mortalidade associada de 71 a 94%. O uso de estratégias de resgate que impactam na fisiopatologia específica dessa entidade, como o uso de óxido nítrico inalatório (NOi), bloqueio neuromuscular e ventilação prona, surgiram como alvos terapêuticos de interesse. A ventilação mecânica protetora (Pressão de Platô [PPLAT] < 27 cmH2O e Pressão de Condução [CP] < 15 cmH2O) continua sendo a base de seu manejo. Objetivo: Determinar se existe associação entre o uso de óxido nítrico inalatório e ventilação prona prolongada com mecânica ventilatória em pacientes com hipoxemia refratária grave secundária à infecção por SARS-CoV-2. Material e métodos: Realizou-se um estudo de coorte histórico, retrospectivo, descritivo, comparativo e retroletivo. Analisaram-se dados dos prontuários de pacientes internados na UTI Respiratória do Centro Médico ABC com diagnóstico de SDRA secundária à infecção por SARS-CoV-2 que necessitaram de óxido nítrico inalatório e ventilação mecânica prona no período de 1o de abril a 31 de dezembro de 2020. Realizou-se uma análise univariada , a análise estatística foi realizada no SPSS v 21, foram analisadas as medidas de tendência e dispersão, assim como a análise dos fatores de risco com teste t de Student e χ2. Resultados: Analisaram-se 108 pacientes, dos quais 54 receberam NOi, bloqueio neuromuscular e prono e 54 apenas bloqueio neuromuscular e ventilação prona. 81.5% (n = 88) eram homens. A comorbidade mais comum foi diabetes mellitus em 51.9% (n = 56). O aumento da oxigenação (Delta PaO2/FiO2) foi com mediana de 31.9 ± 15.2 mmHg no grupo NOi e 52.9 ± 16.74 mmHg no grupo controle (p = 0.001). A PPLAT após a intervenção no grupo NOi foi de 26.3 ± 3 e 34.5 ± 1.9 cmH2O no grupo controle (p = 0.792). A PC antes da intervenção no grupo NOi foi de 17.2 ± 3.9 e 13.4 ± 2.8 cmH2O no grupo controle vs 13.1 ± 1.29 e 12 ± 1.92 cmH2O após a intervenção (p = 0.001). Conclusões: O uso de NOi em pacientes com hipoxemia grave refratária à ventilação em pronação e bloqueio neuromuscular não produziu melhora estatisticamente significativa na oxigenação, porém permitiu que o suporte ventilatório fosse reprogramado para manter as metas de proteção alveolar do paciente.

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OBJECTIVE: To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN. STUDY DESIGN: Part A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96 hours' old, >34 weeks of gestation, receiving iNO (10-20 ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15 to <60, were randomized (1:1) to intravenous (IV) sildenafil (loading: 0.1 mg/kg, over 30 minutes; maintenance: 0.03 mg/kg/h) or placebo, for up to 14 days. Coprimary end points were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary end points included time on ventilation and oxygenation measures. RESULTS: Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related. CONCLUSIONS: IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.

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The endogenous free radical nitric oxide (NO) plays a pivotal role in the immunological system. NO has already been reported as a potential candidate for use in the treatment of human coronavirus infections, including COVID-19. In fact, inhaled NO has been used in clinical settings for its antiviral respiratory action, and in the regulation of blood pressure to avoid clot formation. In this mini-review, we discuss recent progress concerning the antivirus activity of NO in clinical, pre-clinical and research settings, and its beneficial effects in the treatment of clinical complications in patients infected with coronaviruses and other respiratory viral diseases, including COVID-19. We also highlight promising therapeutic effects of NO donors allied to nanomaterials to combat COVID-19 and other human coronavirus infections. Nanomaterials can be designed to deliver sustained, localized NO release directly at the desired application site, enhancing the beneficial effects of NO and minimizing the side effects. Challenges and perspectives are presented to open new fields of research.

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OBJECTIVE: To assess the prognostic accuracy of early cumulative supplemental oxygen (CSO) exposure for prediction of bronchopulmonary dysplasia (BPD) or death, and to evaluate the independent association of CSO with BPD or death. STUDY DESIGN: We performed a secondary analysis of the Trial of Late Surfactant, which enrolled 511 infants born at ≤28 weeks gestational age who were mechanically ventilated at 7-14 days of life. Our primary outcome was BPD or death at 36 weeks postmenstrual age, as determined by a physiological oxygen/flow challenge. Average daily supplemental oxygen (fraction of inspired oxygen - 0.21) was calculated. CSO was calculated as the sum of the average daily supplemental oxygen over time periods of interest up to 28 days of age. Area under the receiver operating curve (AUROC) values were generated to evaluate the accuracy of CSO for prediction of BPD or death. The independent relationship between CSO and BPD or death was assessed in multivariate modeling, while adjusting for mean airway pressure. RESULTS: In the study infants, mean gestational age at birth was 25.2 ± 1.2 weeks and mean birth weight was 700 ± 165 g. The AUROC value for CSO at 14 days was significantly better than that at earlier time points for outcome prediction (OR, 0.70; 95% CI, 0.65-0.74); it did not increase with the addition of later data. In multivariate modeling, a CSO increase of 1 at 14 days increased the odds of BPD or death (OR, 1.7; 95% CI, 1.3-2.2; P < .0001), which corresponds to a 7% higher daily supplemental oxygen value. CONCLUSION: In high-risk extremely low gestational age newborns, the predictive accuracy of CSO plateaus at 14 days. CSO is independently associated with BPD or death. This index may identify infants who could benefit from early intervention to prevent BPD.

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JUSTIFICATIVA E OBJETIVOS: O objetivo desse estudo foi rever a literatura sobre a utilização de óxido nítrico inalatório em crianças com síndrome do desconforto respiratório agudo. CONTEÚDO: Revisão bibliográfica e seleção de publicações mais relevantes sobre óxido nítrico inalatório, utilizando a base de dados MedLine e Cochrane de Revisões Sistemáticas. A revisão incluiu descrição de aspectos da definição, fisiopatologia e tratamento ventilatório da síndrome do desconforto respiratório agudo, assim como o metabolismo, efeitos biológicos e aplicação clínica do óxido nítrico inalatório, comentando dose, administração e retirada do gás, precações, efeitos adversos e contra-indicações. CONCLUSÕES: O óxido nítrico, vasodilatador pulmonar seletivo, tem efeitos benéficos sobre as trocas gasosas e ventilação em crianças com hipóxia grave. É seguro quando administrado em ambiente de tratamento intensivo sob rigorosa monitorização. Estudos aleatórios e controlados devem enfocar a administração precoce do gás na síndrome do desconforto respiratório agudo, quando essa é potencialmente reversível.

BACKGROUND AND OBJECTIVE: The objective of this study was to review the literature on inhaled nitric oxide to children with acute respiratory distress syndrome. CONTENTS: A review of literature and selection of the most important publications on inhaled nitric oxide, using the MedLine and Cochrane Systematic Review Databases. This review was organized as follows: introduction; metabolism and biological effects; clinical applications; dosage, gas administration and weaning process; warnings and side-effects. Inhaled nitric oxide use was described in acute respiratory distress syndrome. CONCLUSIONS: Inhaled nitric oxide as the first vasodilator to produce selective pulmonary vasodilation has beneficial effects on gas exchange and ventilation, improving outcome in children with severe hypoxia. It is safe when administered in intensive care units under strict surveillance and monitoring. Further studies should be concentrated on early treatment, when acute respiratory distress syndrome is potentially reversible.

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