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.     

Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants

Background: Inhaled nitric oxide (iNO), commonly used for hypoxic neonates, may react with haemoglobin to form methaemoglobin (MetHb). MetHb monitoring during iNO therapy has been questioned since low doses of iNO are used. Aim: To evaluate the incidence of and identify risk factors associated with elevated MetHb in neonates treated with iNO. Methods: Neonates who were treated with iNO and had at least one MetHb measurement were included. Demographic characteristics and methods of iNO administration (dosage, duration) at the time of each MetHb measurement were analysed. Results: Four hundred and fifty‐two MetHb measurements from 81 premature and 82 term and near‐term infants were analysed. MetHb was above 5% in one‐term infant, and between 2.5–5% in 16 infants. A higher maximum dose of iNO (22.7 vs 17.7 p.p.m.), but not gestational age, was a significant risk factor for elevated MetHb. Significantly higher oxygen levels (75.5% vs 51.7%) were associated with higher MetHb in term infants. Preterm infants had no risk for high MetHb when iNO was kept below 8 p.p.m. These data suggest the possibility of limiting blood withdrawal when low doses iNO are used. Conclusion: High MetHb is exceptional in neonates treated with low dose iNO. Associated risk factors are related to high iNO dose and the simultaneous use of high concentrations of oxygen.     

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。     

A dose response study of inhaled nitric oxide in hypoxic respiratory failure in preterm infants

BACKGROUND: Inhaled nitric oxide (iNO) is used widely in newborn infants with hypoxic respiratory failure, despite the known and theoretical toxicity of iNO, and a relative lack of information about appropriate doses. AIM: To determine whether a dose-response relationship existed for iNO in preterm infants. DESIGN: A four-period, four-dose, cross-over design was used with iNO given for 15 min in a randomised sequence in concentrations of 5, 10, 20 and 40 parts per million (ppm), with a minimum 5 min wash-out period. Data on ventilatory, blood gas and other physiological measurements were recorded before and at the end of each period. The relationship of clinical response with iNO dose and period was analysed using multivariate regression. SUBJECTS: Infants with gestational age < 34 weeks and < 28 days postnatal age with hypoxic respiratory failure were recruited. OUTCOME MEASURE: A clinically significant dose-response was defined as a rise in the post-ductal arterial oxygen tension (PaO(2)) of at least 3 kPa. RESULTS: Thirteen infants were recruited. At trial entry, ten were < 3 days of age; 11 were being treated with high frequency oscillatory ventilation; median (inter-quartile range) gestational age 27 (25-29) weeks; birthweight 983 (765-1120) g; oxygenation index 27.1 (21.8-28.8). Six infants (46%) showed a clinically significant response. After adjusting for period and patient effect, no evidence for an overall dose effect was identified (likelihood ratio test, p=0.34). CONCLUSION: No evidence of a dose-response relationship with iNO was found in this study of very preterm infants with respiratory failure.     

Developmental outcomes in persistent pulmonary hypertension treated with nitric oxide therapy

Background:  The aim of the present study was to assess 3 year auditory and neurodevelopmental outcomes of persistent pulmonary hypertension of the newborn (PPHN) before and after introducing inhaled nitric oxide (i-NO) therapy, and to detect the clinical factors affecting poor outcome.
Methods:  A retrospective historical cohort study of 26 survivors with PPHN with oxygenation index (OI) ≥25 (13 infants without i-NO therapy, control group; 13 with i-NO therapy, i-NO group) was performed. Auditory brainstem response (ABR) at 6 and 12 months and neurodevelopmental outcomes at 3 years of age were evaluated.
Results:  ABR abnormalities at 6 months were observed in one infant in the i-NO group and six in the control group ( P  = 0.04). At 1 year, one infant in the i-NO group and two of six infants in the control group still had ABR abnormality. In the i-NO group, two children had abnormal neurodevelopmental outcomes, as compared with five children in the control group at 3 year follow up. Two children in the control group and no children in the i-NO group had hearing loss at 3 years of age. Hypocapnea ( P  = 0.04) and elevated creatine phosphokinase ( P  = 0.04) were found to be most predictive for neurodevelopmental abnormality.
Conclusion:  Avoidance of excessive hypocapnea via introduction of i-NO therapy might reduce both ABR and neurodevelopmental abnormalities.     

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.     

Outcome predictors in nitric oxide treated preterm infants

Our aim was to identify factors predictive of death in preterm infants in whom inhaled nitric oxide was administered in response to poor oxygenation (oxygenation index ≥15). Of the 23 (median gestational age 28 weeks, range 24–36) infants consecutively so treated, 15 died. Non-survival was commoner in infants with air leaks (12 of 12, P < 0.002) and/or a change in their oxygenation index of less than 30% in response to inhaled nitric oxide administration (P < 0.05). Conclusion In preterm infants given inhaled nitric oxide because of poor oxygenation, a diagnosis of airleak and a lack of initial response are predictive of death. Received: 18 June 1998 / Accepted in revised form: 4 November 1998     

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.     

Nitric oxide in preterm infant with pulmonary hypoplasia

Premature infants with hypoplastic lungs may have elevated pulmonary vascular resistance with right to left shunt across ductus arteriosus and/or foramen ovale. Inhaled nitric oxide (NO) being selective pulmonary vasodilator without significant effects on systemic circulation can potentially reverse this shunt. The authors herewith report a case of a premature infant with severe hypoxemic respiratory failure after preterm premature prolonged rupture of membranes leading to oligohydramnios and pulmonary hypoplasia that was treated successfully with NO and describe the neurodevelopmental outcome at 1 year of age.     

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     

Neurodevelopmental outcome in very-low-birth-weight infants with or without periventricular haemorrhage and/or leucomalacia

The aim of the study was to verify the predictive value of ultrasound performed in the neonatal period for short-term neurodevelopmental prognosis in 122 preterm very-low-birth-weight infants followed-up at 36 months. Neuromotor development was favourable in 53 (87%) subjects with normal ultrasound findings and in 21 (81%) subjects presenting uncomplicated haemorrhage. However, sensory and/or cognitive sequelae developed in 13% and 19% of the two groups, respectively. Outcome was unfavourable in 14 (50%) of 28 patients with ultrasound findings of complicated cerebral haemorrhages and in 5 (71%) of those (7) with ultrasound findings of parenchymal lesions without haemorrhage. Neonatal ultrasound examination seems to be fundamental in predicting neuromotor, but not cognitive, outcome in very-low-birth-weight infants.     

吸入一氧化氮治疗足月或近足月儿低氧性呼吸衰竭的循证医学证据

目的：通过对吸入一氧化氮（iNO）治疗足月或近足月儿低氧性呼吸衰竭（HRF）的临床研究进行循证分析,综合评价iNO治疗足月或近足月儿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治疗足月或近足月儿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治疗足月或近足月儿HRF的随机对照试验（RCT）研究进行Meta分析。结果：共检索出162篇文献,对符合标准的15篇RCT研究进行Meta分析,其中11篇为多中心研究,4篇为单中心研究。 结果表明经过iNO的治疗,能够在30 min到60 min显著降低患儿的氧合指数(OI) (P<0.05)、升高动脉血氧分压（PaO2）(P<0.05),减少使用体外膜肺 (P<0.05),长期神经系统的发育随访和对照组比较没有统计学差异(P>0.05);先天性膈疝患儿经过iNO的治疗不能改善患儿的氧合和减少死亡率(P>0.05)。结论：经用Meta分析认为对于患有HRF的足月或近足月儿,除了先天性膈疝外,当OI＞25或吸入FiO2达到100％,PaO2<13.3 kPa时,可以进行iNO的治疗,但对患儿长期神经系统发育的影响还需要进行随访。     

Variable oxygenation response to inhaled nitric oxide in severe persistent pulmonary hypertension of the newborn

The causes of variable responsiveness to inhaled nitric oxide (NO) in Persistent Pulmonary Hypertension of the Newborn (PPHN) are unknown. The changes in the severity of respiratory failure after the onset of inhaled NO (maximal dose 20ppm) were studied in 13 consecutive neonates with severe PPHN. Response was defined as a sustained decrease of alveolar-arterial oxygen gradient (AaD0₂) by > 20%, or a decrease in oxygenation index (OI) by > 40%. Six neonates had a rapid response within 30min, three had an intermediate response within 8h, and three had a delayed response within 12 h after the onset of NO. Three infants with birth asphyxia responded rapidly to inhaled NO. One infant with sepsis did not respond, and two with suspected sepsis had a delayed response. The infants with Meconium Aspiration Syndrome and idiopathic PPHN had a variable response time. Twelve neonates required 4 to 14 days of mechanical ventilation and survived. Infants with PPHN may benefit from a trial of inhaled NO therapy that exceeds 30min. The variability of the response time to inhaled NO is likely to be multifactorial and dependent on the disease process associated with PPHN.     

吸入低浓度一氧化氮对胎粪吸入综合征患儿机体抗氧化能力的影响

目的 探讨吸入低浓度一氧化氮(iNO)对胎粪吸入综合征(MAS)患儿机体氧化-抗氧化平衡的影响.方法 将我院新生儿科病房的55例MAS患儿随机分为机械通气+iNO组(A组,n=25)、机械通气组(B组,n=30),并选择我院同期的健康足月新生儿为对照组(C组,n=30).iNO前A、B组均接受气管插管、气管内吸痰、机械通气及静脉滴注抗生素等一般治疗.A组于入院后1～2 h给予iNO治疗,分别在0、24、72 h监测各组患儿静脉血血清中超氧化物歧化酶(SOD)、丙二醛(MDA)、总抗氧化能力(T-AOC)水平.结果 三组患儿一般情况比较差异无显著性.随着NO吸入.A组SOD、T-AOC渐增高,MDA含量降低(P＜0.05).B组SOD在24 h降低,而在72 h呈增高改变,MDA含量变化与之相反,T-AOC呈渐增高改变(P＜0.05).A组机械通气时间及氧暴露时间分别为(77.38±13.97)h与(158.70±47.23)h,明显低于B组[(104.27±10.53)h与(202.15±61.92)h],差异有显著性(P＜0.05),但两组患儿病死率及气漏、肺出血、颅内出血(Ⅱ～Ⅳ级)的发生率差异无显著性(P＞0.05).结论 iNO可减少机械通气及氧暴露时间.MAS患儿体内存在不同程度的氧化-抗氧化失衡,iNO多显示抗氧化活性,有助于机体氧化-抗氧化平衡的调节,对机体具有保护性作用.     

一氧化氮对脑室周围白质软化早产儿神经发育的影响

目的探讨一氧化氮(NO)在合并脑室周围白质软化(PVL)的早产儿神经发育中的作用。方法采用随机、对照实验,对合并PVL的106例早产儿,在出生后24h内随机分成吸入NO组(第1天10×10-6,以后改为5×10-6继续用6d)和对照组(吸入氧气7d),在纠正胎龄18个月时采用贝利发育量表评估其神经发育。结果吸入NO组贝利评分明显高于对照组(P<0.05),贝利评分低于70分的发生率明显低于对照组(P<0.05)。结论合并脑室周围白质软化早产儿采用吸入NO治疗,有利于促进其神经发育。     

CPAP combined with inhaled nitric oxide for treatment of lung hypoplasia and persistent foetal circulation due to prolonged PPROM

Background

Second trimester preterm premature rupture of the membranes (PPROM) before 24 weeks of gestation is associated with a high morbidity and mortality rate.

Aim

To demonstrate the efficacy of early continuous positive airway pressure (CPAP) combined with inhaled nitric oxide (iNO) for treatment of preterm infants with lung hypoplasia and persistent foetal circulation (PFC) due to very early PPROM and prolonged severe oligohydramnios.

Methods

Seven infants with prolonged PPROM, lung hypoplasia, respiratory distress and persistent foetal circulation were intubated in the delivery room for subsequent surfactant and iNO application. As our new treatment strategy was to keep the period of mechanical ventilation as short as possible, all infants were switched on nasal CPAP combined with iNO within the first 24 hours.

Results

Mean gestational age at PPROM was 19 + 6 weeks (range 14 + 2 to 23 + 6 weeks) and the average latency period between rupture of membranes and delivery was 10 + 3 weeks (7 + 3 to 16 + 4 weeks). Infants were born at 30 + 3 weeks of gestation (28 + 3 to 33 + 1 weeks) with an average birth weight of 1468 g (884 to 2200 g). In all neonates CPAP combined with iNO reversed PFC and 6 patients stabilised without the need for reintubation and mechanical ventilation. One infant had to be reintubated following 12 hours of CPAP combined with iNO due to respiratory insufficiency. All seven infants survived to discharge.

Conclusion

CPAP combined with iNO might be a promising approach for therapy of preterm infants with lung hypoplasia and persistent foetal circulation due to very early PPROM.