Rescue treatment with inhaled nitric oxide in preterm newborns with respiratory failure

Castleman disease or angiofollicular hyperplasia is a rare disorder included in the group of lymphoproliferative disorders. This entity was originally described by Castleman in 1956. The etiology remains unknown but it is postulated to be a reactive lymphoid hyperplasia due to chronic antigenic stimulation caused by a viral infection. The disease presents in young adults and is more frequent in women; it is exceptionally rare in the pediatric age group. It is classified into two clinical groups (localized disease and disseminated disease) and there are two histologic variants (hyaline-vascular and plasma cell Castleman disease). Localized disease is usually asymptomatic, has a good prognosis, and is the most common presentation in pediatric patients, usually corresponding to highly vascularized mediastinal masses. Resection of the mass, which is curative, is associated with a high risk of blood loss. Recently, preoperative arteriography with embolization has been used satisfactorily in the preoperative management of these tumors. We present a case of localized Castleman disease in a 12-year-old girl satisfactorily treated with embolization before curative resection.     

Echocardiographic outcome of infants treated as newborns with inhaled nitric oxide for severe hypoxemic respiratory failure

OBJECTIVE: To determine the cardiovascular outcome of a group of term newborns treated with inhaled nitric oxide (iNO) for severe hypoxemic respiratory failure with associated persistent pulmonary hypertension. STUDY DESIGN: We performed echocardiographic evaluations in 40 survivors treated for severe neonatal hypoxemic respiratory failure. Each of the 40 had at least 2 follow-up echocardiograms at 3 or 6 and 24 months. These studies were compared with echocardiograms done in infants in a normal, age-matched control group. RESULTS: Three of 31 infants met echocardiographic criteria for pulmonary hypertension at the 3-month examination. Two of the 3 had associated structural heart disease (1 with an atrial septal defect and 1 with a ventricular septal defect). At 24 months only 1 patient had pulmonary hypertension. This infant had an atrial septal defect that was surgically closed shortly after the 24-month echocardiogram because of the pulmonary hypertension. Group comparisons of 3- and 24-month echocardiographic variables showed no differences between the study and control groups. In the 31 infants in whom serial studies were completed, expected age-related changes were demonstrated between the 3- and 24-month examinations. CONCLUSIONS: The incidence of residual pulmonary hypertension in infants treated as newborns for severe hypoxemic respiratory failure is low. The group at highest risk is those with structural heart disease.     

Exhaled and nasal nitric oxide in mechanically ventilated preterm and term newborns

AIM: Nitric oxide (NO) is an important mediator required for neonatal pulmonary circulatory adaptation and for pulmonary defence. Both deficient and excessive NO production have been proposed to play a role in neonatal lung disease. This study aimed to establish a method that allows direct measurement of exhaled and nasal NO concentrations in newborn infants who require intubation and ventilation. METHODS: A rapid-response chemiluminescence NO analyser was used. Gas was sampled from the endotracheal intubation tube, and tidal volumes and flow rates were measured. The nasal NO was sampled from the non-intubated nostril. The accuracy of the method was validated using a lung model. NO levels from six preterm and six term/near-term newborns were studied. Measurements were performed on a daily basis during the first week. RESULTS: An expiration >0.2 s in duration with a flow rate >1.7 ml s(-1) could be accurately analysed for the presence of >1 parts per billion of NO. The very preterm infants with neonatal lung disease had a different postnatal NO output pattern from the lower and upper airways compared with the ventilated term/near-term infants. CONCLUSION: A novel method for measurement of exhaled NO of an intubated newborn is presented. The possible association of exhaled NO concentration with the development of chronic lung disease remains to be studied.     

Use of inhaled nitric oxide in the preterm infant

PURPOSE OF REVIEW: Inhaled nitric oxide is established therapy for term infants with hypoxemic respiratory failure. Laboratory studies demonstrate that inhaled nitric oxide improves lung function and morphology in animal models of bronchopulmonary dysplasia, creating a rationale for clinical studies in premature infants. Four large multicenter randomized trials have now completed enrollment, and one trial has reported neurodevelopmental outcomes at 18-22 months. The purpose of this review is to summarize the results of the most recent preclinical studies and clinical trials. RECENT FINDINGS: In 2006, short-term outcomes from two large multicenter randomized trials were published. These studies differed in their target population and study design. Early use of inhaled nitric oxide was associated with a decrease in brain injury, and decreased chronic lung disease in infants over 1000 g. Inhaled nitric oxide use in older infants (7-21 days) was associated with decreased chronic lung disease, particularly if started early. SUMMARY: Neurodevelopmental outcomes after discharge are still needed from three large multicenter randomized trials. These results will help confirm the long-term implications of the benefits reported in the two most recent trials.     

Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide

Inhaled nitric oxide (iNO) is used to treat preterm infants with hypoxaemic respiratory failure. In this study we describe the long-term survival and neurodevelopmental status of high-risk preterm infants enrolled into a randomized controlled trial of iNO therapy. Information regarding long-term outcome was available for all 25 children enrolled in the original trial who survived until discharge from hospital. Formal, blinded, developmental assessment and neurological examinations were performed in 21 out of 22 children still alive at 30 mo of age, corrected for prematurity. No significant differences were found in long-term mortality (12/20 vs 8/22, RR 1.65, 95% CI 0.87-3.3), neurodevelopmental delay (4/7 vs 9/14, RR 0.89, 95% CI 0.37-1.75), severe neurodisability (0/7 vs 5/14, p = 0.12) or cerebral palsy (0/7 vs 2/14, p = 0.53) between iNO-treated and control infants. CONCLUSION: In this study there was no evidence of a significant effect on either survival or long-term neurodevelopmental status in infants treated with iNO.     

Uncertainties about the use of inhaled nitric oxide in preterm infants

Respiratory failure in the premature neonate is frequently complicated by pulmonary hypertension. When conventional therapies including administration of exogenous surfactant, conventional mechanical ventilation or high-frequency oscillatory ventilation using an appropriate high-volume strategy have failed, one should assess the pulmonary circulation status with colour-coded Doppler echocardiography. There is now considerable evidence that the regulation of foetal and postnatal pulmonary circulation occurs via nitric oxide (NO), and that persistent pulmonary hypertension of the neonate may be related to a relative deficiency in NO release. Low-dose (10–20 ppm), short-duration (1–2 d) inhaled NO has generally been shown to improve the oxygenation and relieve pulmonary hypertension in premature neonates with severely hypoxaemic respiratory failure. Whether this therapy (eventually prolonged >1-3 wk?) would improve survival and lessen morbidity (e.g. intracranial haemorrhage and chronic lung disease) remains to be proven by appropriately designed controlled trials. Until these issues can be clarified, NO therapy for premature neonates should be still considered as an experimental drug, and its use restricted to clinical studies.     

Uncertainties about the use of inhaled nitric oxide in preterm infants

Respiratory failure in the premature neonate is frequently complicated by pulmonary hypertension. When conventional therapies including administration of exogenous surfactant, conventional mechanical ventilation or high-frequency oscillatory ventilation using an appropriate high-volume strategy have failed, one should assess the pulmonary circulation status with colour-coded Doppler echocardiography. There is now considerable evidence that the regulation of foetal and postnatal pulmonary circulation occurs via nitric oxide (NO), and that persistent pulmonary hypertension of the neonate may be related to a relative deficiency in NO release. Low-dose (10-20 ppm), short-duration (1-2 d) inhaled NO has generally been shown to improve the oxygenation and relieve pulmonary hypertension in premature neonates with severely hypoxaemic respiratory failure. Whether this therapy (eventually prolonged >1-3 wk?) would improve survival and lessen morbidity (e.g. intracranial haemorrhage and chronic lung disease) remains to be proven by appropriately designed controlled trials. Until these issues can be clarified, NO therapy for premature neonates should be still considered as an experimental drug, and its use restricted to clinical studies.     

Response to nitric oxide in term and preterm infants

The response to three levels (10 ppm, 20 ppm and 40 ppm) of nitric oxide (NO) was assessed in 30 infants, median gestational age 30 (range 24–42) weeks. All the infants required an inspired oxygen concentration of more than 0.5, despite receiving surfactant where appropriate. All but one infant had a positive response to NO (median reduction in the oxygenation index (OI) was 33%, range −9%–90%), but only 20 infants showed a greater than 20% reduction in the OI. There was no obvious relationship of the optimum NO level (i.e. that associated with the maximum reduction in OI) and either diagnosis (congenital diaphragmatic hernia, meconium aspiration syndrome, respiratory distress syndrome, pulmonary interstitial emphysema (PIE), hydrops and sepsis) or maturity, except that five of six infants with PIE responded best to 40 ppm, as did eight of nine infants less than 28 weeks gestational age. We conclude NO dosage should be individualized and NO levels up to 40 ppm should be considered in very immature infants. Received: 15 March 1996 / Accepted: 5 February 1997     

Disease-related response to inhaled nitric oxide in newborns with severe hypoxaemic respiratory failure

Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10–80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51 ± 21 vs 23 ± 17, P < .0001) or term infants with idiopathic or acute respiratory distress syndrome (45 ± 20 vs 20 ± 17, P < .0001), `idiopathic' PPHN (39 ± 14 vs 14 ± 9, P < .0001), and sepsis (55 ± 25 vs 26 ± 20, P < .0001) provided there was no associated refractory shock. Improvement in oxygenation was less significant and sustained (OI = 41 ± 16 vs 28 ± 18, P < .001) in term neonates with meconium aspiration syndrome and much less (OI = 58 ± 25 vs 46 ± 32, P < .01) in those with congenital diaphragmatic hernia. Only 21 of the 129 term newborns (16%) required extracorporeal membrane oxygenation (57% survival). Survival was significantly associated with the magnitude in the reduction in OI at 30 min of iNO therapy, a gestational age ≥34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants. Received: 24 April 1997 / Accepted in revised form 3 January 1998     

Changes in oxygenation and pulmonary haemodynamics in preterm infants treated with inhaled nitric oxide

AIM—To investigate changes in various cardiorespiratory variables with inhaled nitric oxide (NO), as part of a randomised controlled trial.METHODS—Infants were treated with inhaled NO for 72 hours. Changes in oxygenation were assessed using the oxygenation index (OI). Serial changes in pulmonary artery pressure (PAP) were assessed using the Doppler derived acceleration time to right ventricular ejection time ratio (AT:RVET). Doppler measurements of right ventricular output, pulmonary blood flow, and systolic PAP was performed in a subset of infants.RESULTS—Twenty infants received inhaled NO and 22 acted as controls. Infants were treated at a median dose of 5 (range 5 to 20) ppm. There was a fall in median OI by 17% in treated infants within 30 minutes of treatment. The fall in OI in treated infants was significantly different from the response in controls until 96 hours. Infants treated with inhaled NO showed a rapid response with a median rise in AT:RVET of 0.04 (range ?0.06 to 0.12) within 30 minutes. The change in AT:RVET was significantly different from controls until 4 hours. Median systolic PAP also fell in treated infants by 6.1 (range ?14.4 to ?4.4) mm Hg within 1 hour. Changes in OI were significantly associated with changes in PBF (r = 0.44), but not with changes in AT:RVET.CONCLUSION—Treatment with inhaled NO rapidly improves oxygenation and lowers PAP in preterm infants. However, these effects are transient and treatment does not influence long term outcome.     

Endogenous nitric oxide production in the airways of preterm and term infants

Few studies have measured endogenous nitric oxide exhaled from the respiratory system of newborn infants. We measured exhaled nitric oxide (eNO) in the first 48 h of life in 24 (13 preterm, 11 term) spontaneously breathing (online method) newborns using a chemoluminescence analyzer. There was a significant difference in the eNO concentration between term and preterm healthy infants in the first 2 days of life (repeated measures analysis of variance, p < 0.05). In term infants there is a peak eNO production in the first hours of life, suggesting a potential role in postnatal adaptation, while in preterm infants eNO production is almost absent at birth, and then gradually increases.     

Three-year follow up of term and near-term infants treated with inhaled nitric oxide

BACKGROUND: The present study describes the outcome at 3 years in term and near-term infants treated with inhaled nitric oxide (iNO) for persistent pulmonary hypertension of the newborn (PPHN). METHODS: The study population consisted of 18 infants delivered at 34 weeks by best obstetric estimate who were admitted to the neonatal intensive care units with a diagnosis of PPHN. RESULTS: Eighteen infants (mean gestational age 38.5 +/- 2.6 weeks, mean birthweight 3015 +/- 587 g) were treated with iNO. The mean oxygenation index before iNO was 27.2 +/- 15.2. Responses to iNO were classified into three groups: (i) early response in eight infants; (ii) late response in two; and (iii) poor response in eight infants. Three infants died within seven postnatal days. Fifteen surviving infants were followed up to 3 years. The mean developmental scale was 98.4 +/- 9.0. One infant was diagnosed with severe neurodevelopmental disability due to cerebral palsy. Another infant was diagnosed with mild neurodevelopmental disability because of a low developmental scale. No infant showed significant hearing loss. Five infants had reactive airway disease (RAD) at 18 months, these infants required a significantly longer duration of mechanical ventilation in their neonatal period than non-RAD infants (P = 0.02). The frequency of survival with normal neurodevelopmental outcome was significantly higher in the early response group than the late or poor response groups (P = 0.03). CONCLUSION: In iNO-treated PPHN, mortality and neurodevelopmental outcome were associated with response to iNO, and pulmonary outcome was associated with duration of mechanical ventilation.     

吸入一氧化氮治疗早产儿低氧性呼吸衰竭的Meta分析

目的 总结国内、外吸入一氧化氮（iNO）治疗早产儿低氧性呼吸衰竭（HRF）的研究结果，采用Meta分析方法综合评价iNO治疗早产儿HRF的临床效果，为临床应用提供指导。方法 制定原始文献的纳入标准、排除标准及检索策略，检索PubMed、EMBASE、Ovid、Springer和中国期刊全文数据库等，获得iNO治疗早产儿HRF的临床文献。使用国际Cochrane中心推荐的方法进行文献质量评估后，采用Review Manager 4.2软件对满足纳入标准的有关iNO治疗早产儿HRF的RCT研究进行Meta分析。选取iNO治疗组和对照组用氧时间、住院时间、机械通气时间、住院期间的病死率作为近期观察指标；支气管肺发育不良（BPD）、颅内出血或脑白质软化（PVL）、早产儿视网膜病（ROP）的发生率、1岁时随访脑瘫、Bayley 精神发育指数（MDI）或精神运动发育系数（PDI）＜2个标准差（s）的发生率为终点疗效观察指标，得出合并后疗效的优势比（OR）及其95％CI进行定性、定量综合评估。结果 共检索出883篇文献，对符合标准的9篇RCT文献进行Meta分析，漏斗图检验未发现发表偏倚。Meta分析结果显示治疗后的近期观察指标：3项RCT研究：用氧时间:iNO治疗组（n=259）低于对照组（n=259），P＜0.05；机械通气时间：iNO治疗组（n=259）和对照组（n=259）差异无统计学意义；住院时间：iNO治疗组（n=259）低于对照组（n=259），P＜0.05；6项住院期间患儿病死率的RCT研究:iNO治疗组（n=1 084）和对照组（=1 096）差异无统计学意义。治疗后的终点疗效观察指标：5项BPD发生率的RCT研究:iNO治疗组（n=618）低于对照组（n=621），P＜0.05；5项颅内出血（所有级别）发生率的RCT研究：iNO治疗组（n=787）和对照组（n=806）差异无统计学意义；4项颅内出血（3级或4级）发生率的RCT研究：iNO治疗组（n=767）发生率低于对照组（n=784），P＜0.05；5项颅内出血（3级或4级）或PVL发生率的RCT研究：iNO治疗组（n=1 021）和对照组（n=1 012）差异无统计学意义；2项阈值ROP发生率的RCT研究：iNO治疗组（n=608）和对照组（n=605）差异无统计学意义；4项ROP发生率的RCT研究：iNO治疗组（n=474）和对照组（n=463）差异无统计学意义；1项需要手术治疗ROP发生率的RCT研究：iNO治疗组（n=294）和对照组（n=288）差异无统计学意义；3项随访至1岁时脑瘫发生率的RCT研究：iNO治疗组（n=168）和对照组（n=184）差异无统计学意义；2项Bayley MDI＜2s发生率的RCT研究：iNO治疗组（n=156）和对照组（n=110）差异无统计学意义；2项Bayley PDI＜2s发生率的RCT研究：iNO治疗组（n=155）和对照组（n=167）差异无统计学意义。结论 现有的RCT研究结果还不支持iNO作为早产儿HRF的常规治疗方法，仍需要大样本、多中心RCT研究和远期神经系统发育情况随访来探讨iNO治疗早产儿HRF的确切疗效。     

The effect of inhaled nitric oxide therapy on thromboelastogram in newborns with persistent pulmonary hypertension

Studies about the effects of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation in newborns are limited in number and have inconclusive results. Thromboelastogram (TEG) shows the combined effects of coagulation factors and platelet functions. In this preliminary study, we aimed to evaluate the effects of iNO on coagulation using TEG in newborns with persistent pulmonary hypertension (PPH). TEG assays were performed in 10 term infants receiving iNO treatment for PPH and 32 healthy term infants. Samples of the iNO group were collected before and during iNO. Clot reaction time (R), clot kinetics (K), maximum amplitude (MA), and alpha angle were obtained from the TEG tracing. TEG-R values were statistically higher during iNO treatment (7.75?±?3.34) when compared to the values before iNO (4.83?±?1.38) and the healthy controls (3.75?±?0.98). The alpha angle was lower in iNO treated infants at both periods (before iNO, 55.33?±?8.58; during iNO, 42.90?±?18.34) compared to the control group (64.95?±?6.88). MA values before iNO treatment were the lowest (44.43?±?14.09) and improved with the iNO treatment (48.40?±?9.49) despite still being lower compared to the controls (53.67?±?5.56). Conclusion: Both PPH and iNO may negatively effect in vitro coagulation tests. Therefore, newborns with PPH requiring iNO treatment should be closely monitored for coagulation problems.     

Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide

OBJECTIVE: To determine the medical and neurodevelopmental outcome of children with moderately severe persistent pulmonary hypertension of the newborn (PPHN) treated with or without inhaled nitric oxide (I-NO). STUDY DESIGN: Term infants with PPHN and a baseline oxygenation index of 24 +/- 9 at study entry were randomly assigned to early treatment with placebo or initial doses of I-NO (5, 20, and 80 ppm). Outcome was measured at approximately 1 year by frequency of hospitalization, growth, and neurodevelopmental and audiologic evaluation. RESULTS: Of 155 children enrolled, 144 survived, and there was follow-up for 133. No significant differences between the placebo and the I-NO groups were seen in any long-term outcome. Rehospitalization occurred in 22%, and growth did not differ. The composite neurodevelopment and audiologic outcome showed impairment in 46% of the infants. There were major neurologic abnormalities in 13%, cognitive delays in 30%, and hearing loss in 19% of the infants. CONCLUSIONS: Moderately severe PPHN at 24 hours after birth is associated with high rates of rehospitalization and disability at 1 year. Adverse outcomes were the same in I-NO and control groups.     

吸入一氧化氮治疗早产儿低氧性呼吸衰竭的应用

动物实验表明,吸入一氧化氮（inhaled NO,iNO）可减少早产动物肺部炎症发生率,提高表面活性物质功能,促进肺生长。自20世纪90年代初iNO首次被用于治疗持续性肺动脉高压以来,已逐渐在新生儿重症监护病房得到应用。虽然多项研究结果均证实iNO治疗早产儿低氧性呼吸衰竭（hypoxic respiratory failure,HRF）的有效性,但至今尚无确切证据表明对早产儿可常规使用iNO治疗。本文结合国内外近年文献,就目前iNO治疗早产儿的作用机制、治疗的临床方案、iNO的有效性及安全性做一综述,以期为临床提供参考。