Recent advances in diagnosis and management of pulmonary hypertension in chronic lung disease

Pulmonary hypertension with elevated pulmonary vascular resistance is a common cardiovascular complication associated with increased morbidity and mortality in preterm infants with chronic lung disease. Injury to the developing pulmonary circulation results in structural and functional abnormalities of the pulmonary vasculature. Animal studies have demonstrated that disruption of angiogenesis may contribute to the failure of normal alveolarisation in chronic lung disease. Levels of vascular endothelial growth factor in bronchoalveolar lavage fluid are lower in infants with chronic lung disease compared to preterm controls. Supplemental oxygen is commonly used to prevent and treat pulmonary hypertension, although optimal arterial oxygen saturation levels remain uncertain. Other vasodilators such as inhaled nitric oxide appear promising, but as yet have not been evaluated in the form of randomised controlled trials. Further studies are required to investigate the long-term effectiveness of pulmonary vasodilator therapy.     

Perinatal factors and the development of chronic lung disease in preterm infants: A case control study

A case control study of neonates was performed to determine those factors contributing to the development of chronic lung disease (CLD). During the 5 years 1981 -84 there were 487 neonatal survivors at gestations of 25–32 weeks; 391 of these developed respiratory failure (oxygen therapy required for more than 6 h). Fifty-six of the latter developed CLD (oxygen therapy required for more than 28 days and a coarse reticular pattern on chest X-ray). These neonates were predominantly of the shortest gestational ages, regardless of the initial chest X-ray diagnosis. Forty-three of these infants with CLD were matched for gestation and initial chest X-ray appearance (respiratory distress syndrome, n = 20; normal, n = 15; non-specific, n = 8) with 42 control infants.
The mean duration of oxygen therapy ( P < 0.001), maximum FiO₂ ( P < 0.001), incidence ( P < 0.01) and duration of intermittent positive pressure respiration (IPPR; P < 0.05) and peak IPPR ( P < 0.05) were significantly greater in the CLD group. Mean birthweight ( P < 0.001), arterial cord pH ( P < 0.05) and base excess ( P < 0.05) were significantly lower in the CLD group. Factors that were not statistically significant in the development of CLD included antenatal fetal heart rate abnormality, hypertensive disease of pregnancy, acute intrauterine infection (chorioamnionitis or umbilical vasculitis). administration of antenatal steroids, sex, patent ductus arteriosus and pneumothorax.     

Assessment of pulmonary function in resolving chronic lung disease of prematurity

AIM—To investigate the longitudinal changes of interstitial and airways disease in resolving chronic lung disease of prematurity (CLD).METHODS—Thirty three infants were studied between 35 and 40 weeks of postconceptional age, and then at three monthly intervals throughout their first year. Measurements of mean arterial oxygen saturation (MSaO₂) and its variability (δMSaO₂) were recorded. PaCO₂ and PaO₂ were determined while the infants breathed steady state 50% oxygen via a hood. From these, the alveolar arterial difference (A-a) Do₂⁵⁰ was calculated. Airway disease was assessed by the measurement of partial forced expiratory flow volume curves (PEFC) to give V?_max Frc.RESULTS—The cohort mean +/- 95% confidence intervals measured between 35 and 40 weeks were for MSaO₂ (89·25 +/- 1·87%, range 75-96·5%) and δMSaO₂ (4·79 +/- 0·8%, range 0·16-9·64%), PaCO₂ (5·89 +/- 0·56 kpa, range 4·2-10·11 kpa), (A-a) Do₂⁵⁰ (22·7 +/- 2·56 kpa, range 6·67-31·4 kpa) and V?_maxFrc (41·5 +/- 8·65 mls/second, range 8·5-103·7 ml/second). The most significant improvement in all measurements occurred within the first three months (P = 0·05). An MSaO₂ of less than 90% in room air at 1 year of age was predicted between 35 and 40 weeks postconceptional age by an (A-a) Do₂⁵⁰ of greater than 29 kpa, with a sensitivity of 0·85 and a specificity of 0·88, and a PaCO₂ greater than 7 kpa predicted a specificity of 0·78 and a sensitivity of 0·88. Predictions were strengthened by combining the above criteria and these then gave a sensitivity and specificity of 1.CONCLUSION—Measurements of (A-a) Do₂⁵⁰ and PaCO₂ taken between 35 and 40 weeks can be used to assess the degree of pulmonary dysfunction at 1 year. Quantification of the severity of CLD could be used as a measurable end point for early neonatal intervention studies.     

Predictors of chronic lung disease in the 'CPAP era'

OBJECTIVE: To assess predictors of chronic lung disease (CLD), in infants requiring nasal continuous positive airway pressure (CPAP) support in the first 4 weeks of life. METHODS: A retrospective case note audit of infants of birthweight 1250 g or less was undertaken. RESULTS: Of 290 infants identified, 50% were initially treated with ventilation, 41% with CPAP, 4% required no support, and 5% had care withdrawn. Of infants initially treated with CPAP, 23% subsequently required ventilation. Overall mortality was 19%, with a further 21% of infants developing CLD. For infants requiring CPAP support, requirement for supplementary oxygen at between 10 and 21 days predicted increased risk of CLD, and receiver operating characteristic curves suggest requirement for supplementary oxygen at 14 days to be the most reliable cut-off (area under curve = 0.72). Positive predictive values for future CLD or death for FiO2 .25, .30 and .40 while on CPAP at 14 days were 0.56, 0.61 and 0.76, respectively. CONCLUSIONS: CLD remains prevalent in very low birthweight infants in the CPAP era. Oxygen requirement at 14 days is the strongest predictor of CLD. Infants requiring 30% oxygen or more while on CPAP at 14 days have a 60% risk of subsequent CLD or death.     

Pentoxyfylline in and prevention and treatment of chronic lung disease

The anti-inflammatory effects of pentoxfylline are associated with a number of clinical benefits. These include reduction in mortality in patients who have undergone bone marrow transplants or suffer peritonitis. In infants with sepsis, a reduction in mortality has also been associated with pentoxyfylline administration. The anti-inflammatory effects of pentoxyfylline, as well as its bronchodilator, diuretic and respiratory muscle stimulant effects suggest it may have a useful role in BPD. Interim analysis of a prophylactic trial suggests pentoxyfylline may reduce treatment requirements after the neonatal period and that, in established BPD, pentoxyfylline and dexamethasone may be of similar efficacy.     

Vitamin A status in preterm neonates with and without chronic lung disease

It has been proposed that there is an association between vitamin A (VA) deficiency and the development of chronic lung disease (CLD) in preterm infants. This study was designed to measure the VA status in preterm infants and to compare the results in the group of babies who developed CLD with the group who did not. Vitamin A status was assessed by measuring plasma VA, retinol binding protein (RBP) and the plasma VA:RBP molar ratio in 25 infants of less than 31 weeks gestation during the first 28 days of life. Eleven babies developed CLD and 14 did not. There was no significant difference in plasma VA levels between the CLD and non CLD groups during the first 28 days. The majority of infants had adequate VA status, with a subgroup being deficient.     

新生儿支气管肺发育不良诊治进展

支气管肺发育不良（bronchopulmonarydy splasia,BPD）是一种慢性肺部疾病,常见于长期氧疗和机械通气的早产儿。BPD由Northway于1967年首次报道,近年来其发生率有逐年增加的趋势,并成为NICU最为棘手的问题之一以及婴儿期慢性肺疾病（CLD）的主要病因。产前糖皮质激素和出生后外源性表面活性物质的应用,以及保护性通气策略实施,使BPD表现形式发生了很大变化,更为常见的是一种轻型BPD（又称为“neWBPD”）,这种“newBPD”与40年前的“oldBPD”从病因、病理改变及临床表现等方面均有很大区别。文章对BPD最新定义、诊断标准及治疗进展作一介绍。     

Development of chronic lung disease in preterm infants treated with surfactant

BACKGROUND: Chronic lung disease (CLD) is generally known to develop among preterm infants who have severe respiratory distress syndrome (RDS) at birth. Many clinical trials have established the efficacy of surfactant replacement therapy to treat RDS at birth with differing doses. In this study, the preterm infants diagnosed to have RDS at birth and treated with one or two doses of surfactant, depending on the severity of the RDS, were studied to evaluate the effect of surfactant on the later development of CLD. METHODS: A retrospective examination of case records of preterm infants who were born at < or = 28 weeks gestation period were studied. The subjects received a natural surfactant product (survanta) between September 1994 and April 1996 at the Monash Medical Center, Australia. RESULTS: Despite less severe initial lung disease, the subsequent respiratory outcome of infants who received one dose of surfactant, showed a trend towards being poorer compared to those who were diagnosed as having severe RDS at birth and received two doses of surfactant. At the corrected gestational age of 36 weeks, 54% of those infants began with mild RDS required oxygen, while only 44% of those who started with a severe RDS required supplemental O2. CONCLUSION: This study reports the infants with severe RDS at birth had responded slightly better or equally, compared to those with mild RDS, in terms of later development of CLD under surfactant treatment proportional to the severity.     

Prenatal predictors of chronic lung disease in very preterm infants

OBJECTIVE: To identify prenatal risk factors for chronic lung disease (CLD) at 36 weeks postmenstrual age in very preterm infants. POPULATION: Data were collected prospectively as part of the ongoing audit of the Australian and New Zealand Neonatal Network (ANZNN) of all infants born at less than 32 weeks gestation admitted to all tertiary neonatal intensive care units in Australia and New Zealand. METHODS: Prenatal factors up to 1 minute of age were examined in the subset of infants born at gestational ages 22-31 weeks during 1998-2001, and who survived to 36 weeks postmenstrual age (n = 11 453). Factors that were significantly associated with CLD at 36 weeks were entered into a multivariate logistic regression model. RESULTS: After adjustment, low gestational age was the dominant risk factor, with an approximate doubling of the odds with each week of decreasing gestational age from 31 to less than 25 weeks (trend p<0.0001). Birth weight for gestational age also had a dose-response effect: the lower the birth weight for gestational age, the greater the risk, with infants below the third centile having 5.67 times greater odds of CLD than those between the 25th and 75th centile (trend p<0.0001). There was also a significantly increased risk for male infants (odds ratio 1.51 (95% confidence interval 1.36 to 1.68), p<0.0001). CONCLUSIONS: These population based data show that the prenatal factors low gestational age, low birth weight for gestational age, and male sex significantly predict the development of chronic respiratory insufficiency in very preterm infants and may assist clinical decision about delivery.     

Awake daytime oximetry measurements in the management of infants with chronic lung disease

OBJECTIVE: To assess the value of 1-h daytime awake oximetry as a means of weaning oxygen flows in infants with oxygen dependent chronic lung disease. METHODS: A cohort study of oxygen dependent infants enrolled in a 3-month period. One hour of awake oximetry data were compared with equal time periods defined within a polysomnographic study and at the same oxygen flow rate. Sensitivity results were derived from the decision to wean oxygen to a lower flow or air. RESULTS: Twenty-two infants were enrolled and 27 studies were performed. The infants that could be weaned had an awake median of mean oxygen saturations of 97% and spent 14% of the time < or = 95% but only 2% < or = 92%, while for those not weaned, the awake median of mean oxygen saturations was 94% with 43% of their time < or = 95% and 26.8% < or = 92% saturation. CONCLUSIONS: Daytime oximetry can predict the outcome of polysomnography with a sensitivity of 100% and a specificity of 65%, and could be used to wean oxygen or as a screening tool for polysomnographic studies in infants with chronic lung disease provided there are reasonably long periods of monitoring and mean oxygen saturations above 95%.     

早产儿慢性肺部疾病13例报告

目的　探讨早产儿慢性肺部疾病 (CLD)的临床表现形式、病因、治疗和预后。方法　对 1998年 10月至2 0 0 2年 3月在我院NICU住院的 13例CLD患儿的临床表现形式、病因、治疗和预后进行观察和总结。结果　①13例中 8例以感染性肺炎入院 ,5例胸片未见异常 ;② 6例应用机械通气 ,除 1例外 ,持续时间为 3～ 4d ,设置的PIP、FiO2 参数值均较低 ;其余患儿给予CPAP或面罩给氧 ,辅助用氧时间为 (48 38± 2 0 47)d[(30～ 92 )d];③ 10例合并“婴儿肝炎”综合征 ,5例死亡 ,5例治愈 ;④生后 3～ 4周时 5例胸片仍异常 ,8例胸片未见异常 ,后者行胸部CT检查 ,符合BPD特征性影像学改变 ;⑤ 6例生后第 4周应用地塞米松治疗 ,其中 1例存活 ;⑥ 6例CLD存活 ,其中 2例出院后易患呼吸系统感染 ;7例死亡。结论　CLD的非典型表现形式是其最常见形式 ;肺部CT在诊断CLD中具有重要价值 ;该病病死率高 ,寻找有效的治疗方案是亟待解决的问题。     

Doppler assessment of pulmonary artery pressure in neonates at risk of chronic lung disease

AIM—To evaluate the pulmonary artery pressure (PAP) change in very low birthweight (VLBW) infants at risk of chronic lung disease (CLD).
METHODS—The time to peak velocity:right ventricular ejection time (TPV:RVET) ratio calculated from the pulmonary artery Doppler waveform, which is inversely related to PAP, was used. The TPV:RVET ratio was corrected for different heart rate (TPV:RVET(c)). Seventy three VLBW infants studied on days 1, 2, 3, 7, 14, 21 and 28 were enrolled for the analysis.
RESULTS—Twenty two infants developed CLD with a characteristic chest radiograph at day 28. Fifty one did not, of whom 17 were oxygen dependent on account of apnoea rather than respiratory disease, and 34 were non-oxygen dependent. The TPV:RVET(c) ratio rose progressively in all three groups over the first three days of life, suggesting a fall in PAP. In the oxygen and non-oxygen dependent groups, the mean (SD) ratio rose to 0.53 (0.09) and 0.57 (0.09), respectively, on day 7, then remained relatively constant thereafter. The CLD group rose more slowly after day 3 and had a significantly lower mean ratio from day 7 onwards compared with the other two groups (day 7: P<0.001, days 14-28: P<0.0001), and fell significantly from 0.47 (0.11) on day 7 to 0.41 (0.07) on day 28 (P=0.01), suggesting a progressive rise in PAP. The mean (SD) ratios at day 28 of all infants were: CLD group 0.41 (0.07); oxygen dependent group 0.66 (0.15); and the non-oxygen group 0.67 (0.11). The CLD group had a significantly lower ratio than the oxygen dependent group and the non-oxygen group (P<0.0001). Using the TPV:RVET(c) ratio of <0.46, infants at risk of developing CLD could be predicted on day 7 (predictive value 82.8%, sensitivity 54.5%, specificity 94.1%).
CONCLUSION—The non-invasive assessment of PAP using the TPV:RVET(c) ratio may be useful in the longitudinal monitoring of PAP change in VLBW infants, and for prediction of chronic lung disease.

     

Effect of hydrocortisone therapy on severe leaky lung syndrome in ventilated preterm infants

Background: The aim of this study was (i) to determine the incidence and risk factors of severe leaky lung syndrome (sLLS), persistent pulmonary edema characterized by massive tracheal secretions and resistance to surfactant therapy, in extremely low gestational age newborns requiring ventilatory support; and (ii) to evaluate the effects of hydrocortisone (HC) therapy for sLLS on tracheal aspirate fluid (TAF) volume and β2‐microglobulin levels in TAF. Methods: Infants born at <28 weeks gestation requiring ventilation beyond day of life (DOL) 7 were included. Daily TAF volume changes were assessed using a TAF scoring system. Levels of TAF β2‐microglobulin, an indicator of capillary leakage, were measured at DOL0, 7, before, and 4 days after starting HC therapy (started at 4 mg/kg/day; tapered for 1–3 weeks). Results: Of the 54 infants enrolled, 24 (44%) were diagnosed with sLLS. Lower gestational age, lower birthweight, and higher TAF β2‐microglobulin levels at DOL7 were independent risk factors for sLLS. Seventeen infants with sLLS received HC therapy starting at DOL17 (median), with subsequent decreases in TAF volume and β2‐microglobulin levels. Conclusions: The incidence of sLLS, as defined in this study, was 44% in extremely low gestational age newborns requiring ventilator support beyond a week. HC therapy effectively reduced TAF volume and β2‐microglobulin levels, suggesting suppression of increased permeability of pulmonary capillaries in infants with sLLS.     

吸入一氧化氮治疗先天性心脏病术后肺动脉高压的疗效观察

目的 探讨吸入一氧化氮(NO)治疗先天性心脏病术后肺动脉高压患儿的疗效.方法 选择32例先天性心脏病术后传统治疗无效的、难治的、反应性肺动脉高压或肺动脉高压危象患儿,吸入NO(10～25)×10-6,定时记录各项血流动力学和呼吸功能指标,定期监测二氧化氮、高铁血红蛋白含量.结果 吸入NO后,平均肺动脉压(mPAP)从(38.0±3.2)mm Hg(1 mm Hg=0.133 kPa)降至(28.0±2.1)mm Hg,肺血管阻力从(62.2±6.7)kPa/(L·S)降至(49.9±5.6)kPa/(L·S),氧合指数从(67.0±30.1)mm Hg升至(92.6±25.0)mm Hg,动脉血氧饱和度从0.78±0.14升至0.84±0.09,差异均有非常显著性(P＜0.01).吸入NO期间,二氧化氮和高铁血红蛋白含量均在安全范围.结论 NO可以明显降低先天性心脏病术后肺动脉压力和肺血管阻力,是一种安全且理想的肺血管扩张剂.     

Total steroid dose given to ventilated newborn infants with chronic lung disease

AIM: There are currently two dexamethasone regimes used in our nursery. We aimed to retrospectively compare the cumulative dose of dexamethasone that infants on each regime received and the requirement for further courses. METHODS: Infants receiving dexamethasone between 1 January 2000 and 31 December 2004, with a gestational age of <30 weeks or a birthweight of <1000 g, were identified and then a chart review of these infants was undertaken. Demographic data were obtained and compared as was the total dose of dexamethasone and number of courses that each infant received. Some clinical outcome measurements were also obtained. RESULTS: A total of 119 infants were identified. The total dexamethasone dose received was 1.92 mg/kg less for infants commencing on the 2-week course compared with the 6-week course (difference between medians, Mann-Whitney test, P=0.005). Infants having the 2-week course had 17 days less steroid treatment (difference between medians, Mann-Whitney test, P=0.0001). Seventeen (46%) subjects who started on a 2-week course of steroids and 18 (22%) who started on a 6-week course required at least one further course of steroids (Fisher's exact test, P=0.01). There were no significant differences in the short-term outcome measures of neonatal chronic lung disease. CONCLUSION: Infants who received the 2-week course of dexamethasone had a 27% reduction in total steroid dose compared with infants receiving a 6-week course with similar short-term outcomes. However, our study was limited by its retrospective nature and possible confounding factors.     

早产儿慢性肺疾病的高危因素和预后分析

目的探讨早产儿慢性肺疾病(CLD)的患病危险因素及预后分析。方法统计我院新生儿重症监护病房(NICU)12年间收治的CLD患儿,总结患儿的出生体重、性别、有否围生期窒息、孕周、原发疾病、机械通气时间、用氧浓度、吸气峰压、呼吸暂停、并发症及预后。结果(1)12年间NICU收治的922例早产儿中,发生CLD52例,发生率为5·64%。出生体重1501~2500g早产儿、极低出生体重儿(1001~1500g)和超低出生体重儿(≤1000g)CLD发生率分别为2·37%、12·09%和23·52%,有非常显著性差异(χ2=42·92,P<0·01)。(2)出生体重≤1500g,有围生期窒息,胎龄≤32周,呼吸窘迫综合征机械通气,吸氧浓度≥60%,动脉导管未闭,呼吸暂停,气胸,感染是CLD的高危因素,而性别,吸气峰压与CLD无明显关系。结论早产儿CLD是由多种因素所致,需综合治疗。     

Severe pulmonary arterial hypertension in type 1 glycogen storage disease

Pulmonary arterial hypertension is characterised by the presence of pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg at rest or >30 mmHg during exercise) and normal pulmonary wedge pressure (<12 mmHg). Several risk factors for pulmonary arterial hypertension have been described. In the absence of any factor or condition suspected to play a causal or facilitating role in the process, pulmonary hypertension is “unexplained” (primary pulmonary hypertension, PPH). PPH is a rare condition, with an estimated incidence of 2 per million people. Recent genetic studies have identified mutations in the bone morphogenetic protein receptor-II (BMPR-II) gene, a receptor member of the transforming growth factor-beta family, in a majority of familial cases of PPH. Interestingly, 25% of patients displaying sporadic PPH may also have mutations in theBMPR-II gene, emphasising the relevance of genetic susceptibility for this severe condition. Other molecular and biochemical processes behind the complex vascular changes associated with pulmonary arterial hypertension are currently investigated. Type 1a glycogen storage disease caused by a deficiency of glucose-6-phosphatase has an estimated incidence of 1 per 100,000 with a few reported cases of unexplained severe pulmonary hypertension. The occurrence of pulmonary arterial hypertension in type 1a glycogen storage disease could be due to vasoconstrictive amines such as serotonin, a pulmonary vasoconstrictor and growth factor for vascular smooth muscle cells stored in platelets. Published online: 31 July 2002