Inhaled nitric oxide and extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn (PPHN) may occasionally require an invasive treatment with extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide (NO) has recently been introduced as a selective pulmonary vasodilator for treatment of PPHN. We describe a case of PPHN in which neither inhaled NO nor ECMO was effective in reversing pulmonary hypertension. The clinical course of the patient suggested a potential role of NO inhalation in predicting the outcome of ECMO treatment for PPHN.     

体外膜肺氧合技术在持续肺动脉高压新生儿救治中的临床应用北大核心CSCD

目的探讨体外膜肺氧合技术(extracorporeal membrane oxygenation,ECMO)在新生儿持续肺动脉高压(persistent pulmonary hypertension of the newborn,PPHN)救治中的临床应用价值。方法回顾性收集2015年1月至2021年12月在中山市人民医院新生儿重症监护室中应用ECMO支持的11例PPHN新生儿的临床资料,包括患儿的一般资料、临床诊断、实验室检查、ECMO支持时间及过程中各种并发症、住院时间、结局等,进行比较分析。结果11例患儿中有10例撤机成功,撤机成功率91%;存活8例,存活率73%。11例患儿ECMO治疗时间26~185 h,平均治疗时间(81±50)h;呼吸机治疗时间57~392 h,平均治疗时间(198±105)h;住院时间2~49 d,平均住院时间(22±15)d。11例患儿ECMO治疗24 h后氧合指数、血乳酸水平较ECMO治疗前均显著改善(P<0.05);其中10例患儿ECMO治疗24 h后肺动脉压力较ECMO治疗前均显著下降(P<0.05);1例患儿在EMCO治疗期间肺动脉压力呈进行性升高,最终死亡,结合尸检肺组织病理及全外显子测序结果,确诊为肺泡毛细血管发育不良。11例患儿ECMO治疗期间发生颅内出血5例,弥散性血管内凝血1例,胃出血1例,肺出血2例,肾功能不全1例,穿刺处出血3例。结论ECMO技术是一种有效应用于常规治疗无效的PPHN新生儿救治的心肺支持措施。应用ECMO技术的并发症发生率高,需严格掌握适应证、把握时机、提高ECMO管理水平,才能提高患儿的撤机率及存活率。     

先天性膈疝继发新生儿持续肺动脉高压的研究进展

先天性膈疝(CDH)继发新生儿持续性肺动脉高压(PPHN)是新生儿高病死率的重要原因之一,是导致CDH 患儿生后出现呼吸、循环衰竭的重要因素。CDH 继发PPHN 的病情危重,治疗困难,治疗预后差,故针对阻止CDH 病理进程的产前干预已成为研究热点,尤其是关于阻断PPHN 形成过程的病因治疗。鉴于PPHN 的病因尚不明确,治疗效果差,该文以国内外相关研究为基础,综述CDH-PPHN 的发病机制与治疗研究进展,以期为相关研究与临床治疗提供参考     

Persistent pulmonary hypertension of the term neonate: a strategy for management

The management of 32 consecutive term infants referred with persistent pulmonary hypertension of the newborn were reviewed. Despite indices suggesting severe cardiorespiratory failure with a median alveolar-arterial oxygen gradient of 591 torr (inter-quartile range 432–618) and oxygenation index of 31 (18–44), all but one patient responded to conventional treatment with inhaled nitric oxide and high frequency oscillatory ventilation. Conclusion Patients should be referred early to centres where maximal conventional support can be offered before consideration for extracorporeal membrane oxygenation. Received: 6 August 1998 / Accepted in revised form: 3 March 1999     

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.     

Role of angiotensin-converting enzyme gene polymorphism in persistent pulmonary hypertension of the newborn

Aim: To evaluate the association of angiotensin‐converting enzyme (ACE) gene polymorphism with risk/severity of persistent pulmonary hypertension of the newborn (PPHN) among at risk infants. Methods: Infants ≥34 weeks with respiratory distress at birth were recruited. PPHN was diagnosed clinically and by cardiac echocardiogram. Control group consisted of infants with respiratory distress who did not develop PPHN. ACE genotyping (DD, II, DI genotypes) and serum ACE levels were determined. Results: A total of 120 infants were included (PPHN = 44; control = 76). Frequency of ACE DD genotype was not different between the two groups of infants (25% versus 33%). Among PPHN infants, severity of illness did not differ between genotypes. Mean (SD) serum ACE levels [15 (9) versus 24 (13) versus 29 (14) U/L] were positively associated with the number of D alleles and inversely associated with infants’ gestational age (GA) and level of cardiovascular support. Conclusion: Angiotensin‐converting enzyme gene polymorphism did not impact the risk or severity of PPHN among infants ≥34 weeks GA.     

Alternative treatment may lower the need for use of extracorporeal membrane oxygenation

Access to artificial surfactant and high frequency oscillatory ventilation (HFO) in Japan seems to affect the actual indications for extracorporeal membrane oxygenation (ECMO). The relation between the methods of treatment and survival and/or neurological sequelae of 27 neonates with servere respiratory failure who would have met the US ECMO entry criteria in the Neonatal Intensive Care Unit of National Children's Hospital, Tokyo between January 1988 and May 1992 were retrospectively analyzed. Out of 27 neonates, conventional treatment including artificial surfactant was successful in 6 cases (22%). High frequency oscillatory ventilation was used for the 21 cases who did not respond to conventional treatment and it was effective in 5 cases (19% of total). Extracorporeal membrane oxygenation was used on 11 (40% of total) of 16 cases who did not respond to HFO. Eight (29% of total or 73% of ECMO cases) of these cases survived and 3 cases (11% of total) died. The remaining 5 cases (19% of total) who met the exclusion criteria of ECMO died. No patient with respiratory distress syndrome (RDS) became ill enough to meet the US ECMO entry criteria. Six out of 8 congenital diaphragmatic hernia cases were saved on a delayed surgery protocol with HFO. Only about 1% of the neonates who were admitted to our NICU during the last 4 years needed ECMO treatment. Forty-one per cent of the patients who would have met the US ECMO entry criteria were treated successfully without ECMO. The necessity for ECMO is less in Japan than in the US because other methods can often be used successfully to treat severe respiratory disorders.     

高频振荡通气治疗新生儿肺出血的临床研究

目的探讨高频振荡通气(HFOV)治疗新生儿肺出血的有效性及安全性。方法回顾性分析高频和常频通气(CMV)治疗肺出血患儿62例的临床效果,比较两组患儿的肺氧合功能、肺出血时间、住院时间、上机时间、氧疗时间、合并症及转归。结果 HFOV组治疗后1、6、12、24、48、72 h氧合指数(OI)明显低于CMV组,动脉/肺泡氧分压(a/APO2)明显高于CMV组,差异有统计学意义(P<0.05)。HFOV组呼吸机相关性肺炎(VAP)发生率明显低于CMV组(P<0.05),治愈率增高(P<0.05)。HFOV组气胸、颅内出血、消化道出血、血糖异常、败血症、肾功能损害的发生率与CMV组比较差异无统计学意义(P>0.05)。存活患儿中,HFOV组在肺出血时间、住院时间、上机时间、氧疗时间较CMV组明显缩短(P<0.05)。结论 HFOV能更好地改善肺出血患儿氧合功能,降低VAP的发生率,缩短病程,提高治愈率,与CMV组比较并不增加不良反应的发生率。     

Entry criteria for extracorporeal membrane oxygenation In neonates with congenital diaphragmatic hernia treated with high-frequency oscillatory ventilation

Although respiratory management with high-frequency oscillatory ventilation (HFOV) has generally been used for neonates with congenital diaphragmatic hernia (CDH), entry criteria for extracorporeal membrane oxygenation (ECMO) based on data from patients who underwent HFOV have not yet been reported. To establish entry criteria for ECMO in such patients, we retrospectively studied 36 neonates with CDH treated by HFOV in our institutions between 1986 and 1994. From the admission records, preductal and postductal arterial blood gas data and HFOV ventilation conditions for 72 h after admission were extracted. Oxygenation index (01) and alveolar-arterial oxygen gradient (A-aD02) time interval combinations were calculated. Patients were divided into two groups: candidates for ECMO (n = 22) who underwent ECMO (n = 18) or died without ECMO (n = 4); and non-candidates (n = 14), who survived without ECMO. Blood gas data in patients placed on ECMO were comparable to those in patients who died without ECMO: mean pre- and postductal OI for 4 h > 30, postductal A-aD02 ≥620 mmHg for 4 h, postductal A-aD02 ≥580 mmHg for 8 h, and postductal A-aD02 ?550 mmHg for 12 h showed better sensitivity with a specificity of more than 90% compared to entry criteria that had previously been used in our institutions: a postductal OI >40 for 4 h and postductal A-aDO₂ ≥610 mmHg for 8 h. In addition, a combination of preand postductal OI >30 for 4 h indicated a sensitivity of 95.5% and a specificity of 92.9%.     

常频通气联合一氧化氮吸入治疗新生儿持续肺动脉高压

目的 探讨常频通气联合一氧化氮吸入(iNO)治疗新生儿持续肺动脉高压(PPHN)的疗效.方法 对22例确诊为PPHN且入院时采取常频通气疗效不满意的患儿给予iNO.NO初始吸入浓度上,20例为(10～20)×10-6,2例为(20～40)×10-6.当SpO2≥93%并已经稳定20min以上,开始下调呼吸机参数,并逐渐下调NO吸入浓度.当NO吸入浓度降至(5～10)×10-6时,再持续2～3h后,若PaO2>55mm Hg(1 mm Hg=0.133 kPa)、SpO2>93%时停止吸入.在NO吸入前和吸入后1～6 h分别进行血气分析,连续记录生命体征、SpO2和监测NO2值等.结果 20例在吸人NO后5～20 min左右SpO2逐渐升高,临床缺氧状态逐步改善.有效率达91%.吸入NO 1～6 h,SpO2、PaO2分别由吸入前的(76.3±13.3)%、(46.4±10.1)mm Hg升到(94.4±2.9)%和(92.8±24.7)mm Hg,FiO2由(0.9±0.1)降至(0.6±0.1),差异均有非常显著性(P<0.001).患儿生命体征平稳,未发现急性合并症.全组治愈18例,治愈率达82%,自动放弃4例.结论 iNO能有效地缓解PPHN患儿的乏氧状态.提高氧分压和治愈率.NO吸入不良反应小、易操作.iNO初始吸人浓度以(10～20)×10-6开始为宜,极个别病例可以(20～40)×10-6开始.     

Successful treatment of persistent pulmonary hypertension of the newborn with bosentan

The sophisticated and expensive treatment modalities of persistent pulmonary hypertension of the newborn (PPHN), such as nitric oxide, are limited in developing countries. Alternative (less expensive) treatments are being sought and bosentan, an oral dual endothelin-1 receptor antagonist, may be an option for the treatment of PPHN. We report our experience of using bosentan in a neonate with severe PPHN.
Conclusion:  Bosentan may be a useful adjuvant therapy in neonates with PPHN, providing significant improvement in oxygenation, and thus may be particularly useful in the treatment of PPHN in countries with limited resources.     

Endogenous nitric oxide and endothelin-1 in persistent pulmonary hypertension of the newborn

We studied changes in endogenous nitric oxide (NO) synthesis and endothelin-1 (ET-1) production in infants with persistent pulmonary hypertension of the newborn (PPHN). We determined concentrations of serum NO metabolites, i.e., nitrites and nitrates (NOx), and of plasma ET-1 in five infants with PPHN (PPHN group) and in 25 healthy full-term neonates (control group). In both groups, serum NOx concentrations increased over time and plasma ET-1 concentrations decreased with age. The differences in serum NOx concentrations between groups were not significant at <12 h and 24 h of age; however, they were significantly higher in the PPHN group than in the control group at 5 days of age. The differences in plasma ET-1 concentrations between groups were not significant at 5 days of age, but were significantly higher in the PPHN group than in the control group at <12 h and 24 h of age. Conclusion Limited endogenous nitric oxide synthesis and elevated endogenous endothelin-1 production during the first few days of life may contribute to pulmonary hypertension in infants with persistent pulmonary hypertension of the newborn. Received: 2 September 2000 / Accepted: 15 June 2000     

Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil

We present the case of a full term neonate with severe persistent pulmonary hypertension of the newborn (PPHN) after birth asphyxia cared for at the St. Elizabeth Hospital in Curacao, Netherlands Antilles. Although the child was ventilated with high pressures and was given high doses of cardiovascular pressors, the arterial oxygen levels remained low with an alveolar-arterial O₂ gradient of 651 mmHg. As a last resort, sildenafil (1.5 mg/kg) was given via a nasogastric tube. This resulted in an immediate and sustained elevation of arterial oxygenation and subsequent complete recovery. After administration of sildenafil there was a transient hypotension which was corrected by a single bolus of saline. Conclusion:We discuss the current treatment modalities of persistent pulmonary hypertension of the newborn and the potential use of phosphodiesterase 5 inhibitors such as sildenafil in a situation where the standard of practice with inhaled nitric oxide and extracorporeal membrane oxygenation is not available.     

ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn

A newborn with persistent pulmonary hypertension (PH) unresponsive to conventional therapies was found to be homozygous for a mutation in the gene encoding adenosine triphosphate binding cassette protein, member A3 (ABCA3). Most causes of PH respond to lung recruitment, inhaled nitric oxide, and hemodynamic support. When PH is prolonged and does not respond to standard therapies, genetic causes of surfactant abnormalities should be considered in the differential diagnosis.     

高频振荡通气治疗新生儿肺透明膜病文献的Meta分析

目的　综合比较高频振荡通气 (HFOV)与传统机械通气 (CMV)对新生儿肺透明膜病的治疗作用及其潜在危害性。方法　通过数据库检索出符合纳入分析条件的相关文献 12篇 ,采用Meta分析方法进行定性、定量综合分析 ,得出合并OR值及其 95 %可信区间。结果　与CMV相比 ,HFOV能明显改善肺透明膜病患儿的呼吸功能 (P <0 0 0 5 )以及降低慢性肺部疾病的发生率 (P <0 0 1) ,但增加新生儿颅内出血的危险性 (P <0 0 5 ) ;在两种通气方式引起的气漏方面 ,无明显差异 (P >0 0 5 )。结论　应用HFOV治疗新生儿肺透明膜病的效果优于CMV ,并可减少慢性肺部疾病的发生 ,但应注意其它并发症的出现。     

新生儿呼吸衰竭28例高频振荡通气治疗的疗效观察

目的　探讨高频振荡呼吸机在治疗新生儿呼吸衰竭中的应用价值及其安全性。方法　 2 8例新生儿呼吸衰竭患儿经常频呼吸机治疗无效后改用高频振荡呼吸机治疗 ,观察其治疗前后血气指标的变化及临床疗效。结果　 2 8例患儿中治愈 2 0例 ,治愈率 71 4% ,死亡 5例 ,放弃治疗 3例 ;出现颅内出血等并发症 6例 ;治愈患儿中高频振荡通气 (HFOV)治疗后 8～ 12h的PaCO2 迅速下降 [(6 8± 0 4)kPavs(5 5± 0 6 )kPa,P <0 0 5 ],2 4～ 48h的PaO2 明显上升 [(5 8± 1 1)kPavs(9 2± 1 7)kPa ,P <0 0 5 ];同时吸入氧浓度、平均气道压、振荡压力幅度、血氧合指数等均有明显下降 (P均 <0 0 5 )。结论　HFOV用于治疗新生儿呼吸衰竭 ,是一种疗效肯定、安全性好的新型机械通气方法 ,具有常频机械通气 (CMV)难以比拟的优越性。     

体外膜肺氧合技术在新生儿呼吸衰竭中的应用

体外膜肺氧合（extracorporeal membran eoxygenation,ECMO）技术是一种能在较长时间内对心肺功能进行支持的体外生命支持技术。随着一氧化氮吸入、肺表面活性物质及高频通气等治疗手段的出现,需要ECMO支持的呼吸衰竭新生儿越来越少。但临床上仍有部分难治性呼吸衰竭新生儿对以上治疗无效或反应不良,仍需要ECMO支持。本文对国外ECMO技术在新生儿呼吸衰竭的应用情况进行介绍,并与国内的情况进行对比分析,希望有助于下一步我国新生儿ECMO技术的开展。     

Follow-up of 5- to 11-year-old children treated for persistent pulmonary hypertension of the newborn

Aim: Determine the prevalence of sensorineural hearing loss (SNHL) and relate this to cumulative exposure to hypoxia, hypocapnia and hypotension. Describe chronic health problems among 5- to 11-year-old children treated for persistent pulmonary hypertension of the newborn (PPHN).
Methods: The index group consisted of 85 children and a reference group was matched for age, sex and municipality of current residence. Questionnaires were sent to the families. The families in the index group were asked to participate in an examination of their child's hearing.
Results: Seven children (11%) had SNHL. SNHL was not associated with hypoxia, hypocapnia or hypotension during treatment for PPHN. In the index group chronic health problems were reported in 42% compared with 17% in the reference group (chi-square test, p = 0.001). Twenty-one percent in the index group were treated with bronchodilator therapy compared with 8% in the reference group (chi-square test, p = 0.028). In the index group five children had cerebral palsy and two had developmental delay. Nineteen percent in the index group and 5% in the reference group had remedial education (chi-square test, p = 0.008).
Conclusion: Children treated for PPHN are at high risk for SNHL. Exposure to hypoxia, hypocapnia or hypotension did not predict SNHL. The incidence of chronic health problems and use of remedial education was high.     

High frequency ventilation

The 1990s have seen a dramatic resurgence of interest in high frequency ventilation (HFV). The role of HFV in the rescue of infants failing conventional mechanical ventilation (CMV) is now relatively well established. However, the wider role of HFV in the routine management of respiratory failure in the newborn is more contentious. Recent trials in small numbers of infants suggest that HFV may be associated with significantly less chronic lung disease than CMV when used under optimal conditions (i.e. with a 'high-volume' strategy, from early in the disease and continued to the point of weaning). Further, clinical trials are now required to define the role of HFV more clearly.