Early iNO Research Articles

From WEMINO To WEBINO With Unilateral LMN Facial Palsy (P5-4.002)

<h3>Objective:</h3> To describe a case of progression from apparent trochlear nerve palsy, to wall-eyed monocular internuclear ophthalmoplegia (WEMINO), to wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) with unilateral lower motor neuron (LMN) facial palsy. <h3>Background:</h3> Various descriptions of INO with cranial nerve palsies are in the literature, but we report a patient with a remarkably instructive stepwise evolution. <h3>Design/Methods:</h3> Review of records of a patient with diplopia at our institution. <h3>Results:</h3> A 42-year-old woman presented acutely with oblique binocular diplopia worsening on right gaze and left head tilt, with left hypertropia. Trochlear nerve palsy was suspected but contrasted MRI brain with orbits, and initial CSF testing were unrevealing. On day 3, the hypertropia partly improved but she developed left eye adduction deficit. Given the fluctuation, myasthenia gravis was considered high in the differential diagnosis while test results were awaited. On day 7, she developed LMN left facial palsy and bilateral adduction deficit with abducting eye nystagmus, leading to the realization that a single progressing lesion in the pontine tegmentum could explain her entire sequence of events. Repeat MRI confirmed a minute enhancing lesion in the floor of the fourth ventricle corresponding to the dorsomedial surface of the left facial colliculus and bilateral medial longitudinal fasciculi (MLF), likely of demyelinating etiology. Her pending CSF tests returned with 7 oligoclonal bands. She received intravenous methylprednisolone and her symptoms nearly resolved by day 14. <h3>Conclusions:</h3> This patient presented with evolving symptoms that appeared to localize to the trochlear nerve initially, but lacked imaging correlate. It is clear in retrospect that her initial presentation represented a skew deviation from early INO, progressing to WEMINO and eventually WEBINO with unilateral fascicular facial palsy. The anatomical correlate was confirmed on repeated imaging. Her clinical course beautifully illustrates the importance of lesion localization for etiological diagnosis. <b>Disclosure:</b> Dr. Senthamarai Siddharthan has nothing to disclose. Dr. Witt has nothing to disclose. Dr. Kini has nothing to disclose. Dr. Vasireddy has nothing to disclose. The institution of Dr. Mathur Kumaraswamy has received research support from Woolsey Pharmaceuticals.

Early nitric oxide is not associated with improved outcomes in congenital diaphragmatic hernia.

Inhaled nitric oxide (iNO) is widely used for the management of infants with congenital diaphragmatic hernia (CDH); however, evidence of benefit is limited. This is a multicenter cohort study using data from the Congenital Diaphragmatic Hernia Study Group between 2015 and 2020. The impact of early iNO use in the first 3 days of life prior to ECLS use on mortality or ECLS use was explored using multivariate logistic regression models and subgroup analyses. Of the 1777 infants, 863 (48.6%) infants received early iNO treatment. Infants receiving iNO had lower birth weight, larger defect size, more severe pulmonary hypertension, and abnormal ventricular size and function. After controlling for these factors, early iNO use was associated with increased mortality (aOR 2.06, 95% CI 1.05-4.03, P = 0.03) and increased ECLS use (aOR 3.44, 95% CI 2.11-5.60, P < 0.001). Subgroup analyses after stratification by echocardiographic characteristics and defect size revealed no subgroup with a reduction in mortality or ECLS use. Use of iNO in the first 3 days of life prior to ECLS was not associated with a reduction in mortality or ECLS use in either the regression models or the subgroup analyses. The widespread use of iNO in this vulnerable population requires reconsideration. Evidence to support widespread use of iNO for infants with congenital diaphragmatic hernia is limited. The use of iNO in the first 3 days of life was associated with significantly increased mortality and ECLS use. Stratification by echocardiographic characteristics and defect size did not reveal a subgroup that benefited from iNO. Even the subset of patients with R-to-L shunts at both ductal and atrial levels, a surrogate for elevated pulmonary arterial pressures in the absence of significantly decreased LV compliance, did not benefit from early iNO use. Early iNO therapy was of no benefit in the management of acute pulmonary hypertension in infants with congenital diaphragmatic hernia, supporting reconsideration of its use in this population.

Management Practices During Perinatal Respiratory Transition of Very Premature Infants.

The present review considers some controversial management practices during extremely premature perinatal transition. We focus on perinatal prevention and treatment of respiratory distress syndrome (RDS) in immature infants. New concerns regarding antenatal corticosteroid management have been raised. Many fetuses are only exposed to potential adverse effects of the drug. Hence, the formulation and the dosage may need to be modified. Another challenge is to increase the fraction of the high-risk fetuses that benefit from the drug and to minimize the harmful effects of the drug. On the other hand, boosting anti-inflammatory and anti-microbial properties of surfactant requires further attention. Techniques of prophylactic surfactant administration to extremely immature infants at birth may be further refined. Also, new findings suggest that prophylactic treatment of patent ductus arteriosus (PDA) of a high-risk population rather than later selective closure of PDA may be preferred. The TREOCAPA trial (Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen) evaluates, whether early intravenous paracetamol decreases the serious cardiorespiratory consequences following extremely premature birth. Lastly, is inhaled nitric oxide (iNO) used in excess? According to current evidence, iNO treatment of uncomplicated RDS is not indicated. Considerably less than 10% of all very premature infants are affected by early persistence of pulmonary hypertension (PPHN). According to observational studies, effective ventilation combined with early iNO treatment are effective in management of this previously fatal disease. PPHN is associated with prolonged rupture of fetal membranes and birth asphyxia. The lipopolysaccharide (LPS)-induced immunotolerance and hypoxia-reperfusion-induced oxidant stress may inactivate NO-synthetases in pulmonary arterioles and terminal airways. Prospective trials on iNO in the management of PPHN are indicated. Other pulmonary vasodilators may be considered as comparison drugs or adjunctive drugs. The multidisciplinary challenge is to understand the regulation of pregnancy duration and the factors participating the onset of extremely premature preterm deliveries and respiratory adaptation. Basic research aims to identify deficiencies in maternal and fetal tissues that predispose to very preterm births and deteriorate the respiratory adaptation of immature infants. Better understanding on causes and prevention of extremely preterm births would eventually provide effective antenatal and neonatal management practices required for the intact survival.

Outcomes of early inhaled nitric oxide use in premature African American neonates.

Meta-analysis of individual-patient clinical trial data suggests that inhaled nitric oxide (iNO) improves respiratory outcomes in premature African American neonates. We hypothesized that early iNO therapy would be associated with lower mortality and less chronic lung disease (CLD) in extremely premature African American neonates. We conducted a retrospective cohort study of propensity score- and race-matched neonates 22-29 weeks gestation who were mechanically ventilated for treatment of respiratory distress and associated pulmonary hypertension (RDS + PPHN). We evaluated the association of iNO within 7 days of life with in-hospital mortality and CLD, using Cox proportional hazards regression and logistic regression, respectively. Among 178 matched pairs of African American patients, iNO was not associated with lower mortality (HR = 0.94, 95% CI 0.69-1.30) or less CLD (OR = 0.94, 95% CI 0.47-1.87). Early, off-label iNO use is not associated with improved outcomes in premature African American neonates with RDS + PPHN.

Current Practices and Attitudes Regarding Use of Inhaled Nitric Oxide in the NICU: Results From a Survey of Members of the National Association of Neonatal Nurse Practitioners.

Background:Excessive supplemental oxygen exposure in the neonatal intensive care unit (NICU) can be associated with oxygen-related toxicities, which can lead to negative clinical consequences. Use of inhaled nitric oxide (iNO) can be a successful strategy for avoiding hyperoxia in the NICU. iNO selectively produces pulmonary vasodilation and has been shown to improve oxygenation parameters across the spectrum of disease severity, from mild to very severe, in neonates with hypoxic respiratory failure associated with persistent pulmonary hypertension of the newborn.Purpose:An online survey was conducted among members of the National Association of Neonatal Nurse Practitioners to gain insight into the level of understanding and knowledge among neonatal nurse practitioners (NNPs) about optimizing supplemental oxygen exposure and the use of iNO in the NICU setting.Results:Of 937 NNP respondents, 51% reported that their healthcare team typically waits until the fraction of inspired oxygen level is 0.9 or more before adding iNO in patients not responding to oxygen ventilation alone. Among respondents with 1 or more iNO-treated patients per month, only 35% reported they know the oxygenation index level at which iNO should be initiated. Less than 20% of NNPs reported perceived benefits associated with early initiation of iNO for preventing progression to use of extracorporeal membrane oxygenation or reducing the length of hospital stay, and about one-third of respondents reported they believe early iNO use minimizes hyperoxia.Implications for Practice:More education is needed for NNPs regarding the negative effects of oxidative stress in neonates.Implications for Research:Additional clinical trials investigating the most beneficial strategies for avoiding neonatal hyperoxia are warranted.

Inhaled nitric oxide in term/late preterm neonates with hypoxic respiratory failure: estimating the financial impact of earlier use

Objective:We reported recently that early use of inhaled nitric oxide therapy (iNO) for term and late preterm infants with hypoxic respiratory failure (HRF) at an oxygenation index (OI) of ≥15 and <20 is associated with earlier discharge from the hospital, relative to babies treated at OI ≥25. The objective of the present analysis is to determine whether earlier use of iNO in this cohort leads to lower cost of medical care.Methods:We used a decision-analytic model, which was developed to compare hospital resource use and costs associated with early versus standard use of iNO in HRF. The model population included infants with moderate HRF caused by primary pulmonary hypertension with an OI ≥15 and <20. A hypothetical case population of 1000 patients was assumed and probabilistic sensitivity analyses were completed where all the clinical inputs into the model were varied. Two deterministic sensitivity analyses were also completed, one surrounding the hospital cost inputs and another surrounding the cost of iNO.Results:Early iNO was associated with fewer hospital days, fewer days of ventilation and fewer hours on extracorporeal membrane oxygenation (ECMO). In probabilistic sensitivity analyses, total costs per patient were $88,518 ± $7574 and $92,581 ± $9664 for early iNO and standard iNO, respectively. The probability of early iNO being cost-effective was approximately 72%, based on a willingness to pay $100,000 or less to prevent ECMO therapy and/or death. In both deterministic sensitivity analyses, early iNO was cost-saving.Conclusion:Our analysis shows that early use of iNO at an OI of ≥15 and <20 may be associated with shorter hospitalizations and a decreased cost of care for term/late preterm infants with HRF associated with pulmonary hypertension. Our results are based on clinical data from a single trial; future research using data from real-world practice is warranted.

Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure

Objective:We conducted a post-hoc analysis of early inhaled nitric oxide (iNO)-randomized controlled trial data to identify associations pertinent to the management of moderate hypoxic respiratory failure in term/late preterm infants.Study design:Univariate and multivariate logistic regression analyses were used to determine risk factors for the progression of respiratory failure and extracorporeal membrane oxygenation (ECMO)/death.Result:Among the 299 enrolled infants, oxygenation index (OI) <20 at enrollment (odds ratio 0.52, confidence interval (CI) 0.27 to 0.97) and surfactant use before randomization (odds ratio 0.47, CI 0.24 to 0.91) were associated with decreased ECMO/death rates. Early surfactant use for respiratory distress syndrome, perinatal aspiration syndrome and pneumonia/sepsis was associated with lower risk of ECMO/death (P<0.001). Early iNO (OI 15 to 25) decreased the progression of respiratory failure to OI >30 (P=0.002) and to composite outcome of OI >30 or ECMO/death (P=0.02).Conclusion:This post-hoc analysis suggests that early use of surfactant and iNO in moderate respiratory failure is associated with improved outcomes.

Randomized controlled trial of early compared with delayed use of inhaled nitric oxide in newborns with a moderate respiratory failure and pulmonary hypertension

To evaluate whether early treatment with inhaled nitric oxide (iNO) will prevent newborns with moderate respiratory failure from developing severe hypoxemic respiratory failure (oxygenation index (OI)>or=40). A total of 56 newborns with moderate respiratory failure (OI between 10 and 30) were randomized before 48 h after birth to early treatment with 20 p.p.m. of iNO (Early iNO group, n=28) or conventional mechanical ventilation with FiO(2) 1.0 (Control group, n=28). Infants received iNO and/or high-frequency oscillatory ventilation (HFOV) if they developed an OI>40. 7 of 28 early iNO patients (25%) compared to 17 of 28 control patients (61%) developed an OI>40 (P<0.05). In the Early iNO group mean OI significantly decreased from 22 (baseline) to 19 at 4 h (P<0.05) and remained lower over time: 19 (12 h), 18 (24 h) and 16 at 48 h. In contrast, OI increased in the Control group and remained significantly higher than the Early iNO group during the first 48 h of study: 22 (baseline), 29, 35, 32 and 23 at 4, 12, 24 and 48 h, respectively (P<0.01). Of 17, 6 control patients who developed an OI>40 were successfully treated with iNO. Nine of the remaining eleven control patients and six of seven Early iNO patients who had an OI>40 despite use of iNO responded with the addition of HFOV. One patient of the Early iNO group and two of the Control group died. Median (range) duration of oxygen therapy was significantly shorter in the Early iNO group: 11.5 (5 to 90) days compared to 18 (6 to 142) days of the Control group (P<0.03). Early use of iNO in newborns with moderate respiratory failure improves oxygenation and decreases the probability of developing severe hypoxemic respiratory failure.

Early inhaled nitric oxide treatment decreases apoptosis of endothelial cells in neonatal rat lungs after vascular endothelial growth factor inhibition

Vascular endothelial growth factor (VEGF) receptor blockade impairs lung growth and decreases nitric oxide (NO) production in neonatal rat lungs. Inhaled NO (iNO) treatment after VEGF inhibition preserves lung growth in infant rats by unknown mechanisms. We hypothesized that neonatal VEGF inhibition disrupts lung growth by causing apoptosis in endothelial cells, which is attenuated by early iNO treatment. Three-day-old rats received SU-5416, an inhibitor of VEGF receptor, or its vehicle and were raised in room air with or without iNO (10 ppm). SU-5416 reduced alveolar counts and lung vessel density by 28% (P < 0.005) and 21% (P < 0.05), respectively, as early as at 7 days of age. SU-5416 increased lung active caspase-3 protein by 60% at 5 days of age (P < 0.05), which subsided by 7 days of age, suggesting a transient increase in lung apoptosis after VEGF blockade. Apoptosis primarily colocalized to lung vascular endothelial cells, and SU-5416 increased endothelial cell apoptotic index by eightfold at 5 days of age (P <0.0001). iNO treatment after SU-5416 prevented the increases in lung active caspase-3 and in endothelial cell apoptotic index. There was no difference in alveolar type 2 cell number between control and SU-5416-treated rats. We conclude that neonatal VEGF receptor inhibition causes transient apoptosis in pulmonary endothelium, which is followed by persistently impaired lung growth. Early iNO treatment after VEGF inhibition reduces endothelial cell apoptosis in neonatal lungs. We speculate that enhancing endothelial cell survival after lung injury may preserve neonatal lung growth in bronchopulmonary dysplasia.

Early Inhaled Nitric Oxide Therapy for Term and Near-Term Newborn Infants with Hypoxic Respiratory Failure: Neurodevelopmental Follow-Up

To report the neurodevelopmental outcome of infants enrolled in a randomized multicenter trial of early inhaled nitric oxide (iNO) in term and near-term neonates with hypoxic respiratory failure and pulmonary hypertension. Neonates born at > or = 34 weeks gestation who required assisted ventilation and had an oxygenation index > or = 15 and < 25 were randomized to an early iNO group or a control group. A comprehensive neurodevelopmental assessment of survivors was performed at age 18 to 24 months. The trial enrolled 299 infants, of which 266 (89%) survived to age 18 to 24 months (136 in the early iNO group and 130 in the control group). Follow-up evaluations were done on 234 (88%) of surviving infants. There were no differences between the 2 groups in the incidence of neurodevelopmental impairment (early iNO, 27%; control, 25%) and hearing impairment (early iNO, 23%; control, 24%). Mental development index scores were similar in the 2 groups; however, psychomotor developmental index scores were significantly higher in the control group (early iNO, 89 +/- 17.7; control, 93.5 +/- 18.4). Early iNO therapy for hypoxic respiratory failure in term and near-term infants is not associated with an increase in neurodevelopmental impairment or hearing loss at 18 to 24 months postnatal age.