Pathological complications of non-survivors of newborn extracorporeal membrane oxygenation

The pathology was reviewed of the early deaths identified from the first 50 neonates treated with extracorporeal membrane oxygenation (ECMO) during its introduction to the UK. Fifteen neonates died during or shortly after ECMO between August 1989 and June 1992. Data on 12 are presented (three did not have a postmortem examination). The clinical diagnoses at referral for ECMO were as follows: persistent pulmonary hypertension of the newborn (six infants), primary congenital pneumonia (one infant), community acquired pneumonia (two infants), birth asphyxia (one infant), respiratory distress syndrome (one infant), and meconium aspiration syndrome (one infant). In our group, at necropsy, five had significant haemorrhage (three intracranial, one pulmonary, one pericardial and intraventricular). Three of five infants with evidence of haemorrhage also had signs of sepsis. Six infants had evidence at necropsy of systemic sepsis, five showed evidence of severe anoxic brain injury, and four infants had cerebellar haemorrhages. Three infants had evidence of myocardial ischaemia. It is difficult to discriminate between the relative influence of the primary diagnosis, the mode of treatment, and the severity of presentation in the genesis of this pathology. It is likely that the extent and severity of some of the findings represent a pathological progression that would have been interrupted by the death of the patient, had ECMO not been instituted.     

Newborn infants supported by extracorporeal membrane oxygenation: survival and clinical outcome]

OBJECTIVES: To assess the prognosis of newborn infants with refractory hypoxemia who required extracorporeal membrane oxygenation (ECMO). METHODS: Eighty-nine newborn infants treated by ECMO during more than 24 hours over a 8-year period (1996-2003) were included in this observational cohort study with a 9-month and 24-month evaluation. RESULTS: Respiratory failure mainly resulted from meconium aspiration syndrome (MAS, 43%), congenital diaphragmatic hernia (CDH, 15%) and sepsis (15%). Overall survival at hospital discharge was 67%. Infants with MAS had the best survival rate (82%) and those with CDH had the worst (46%). Of the remaining 60 survivors, 53% remained oxygen dependent at 28 days and 33% at 45 days. At the age of 2 years, only 1 infant remained oxygen dependent (but did not required oxygen at 3 years) and only 3 infants had significant neurodevelopmental problems. CDH group was associated with a prolonged duration in supplementary oxygen (P<0.001) and a prolonged duration for tube feeding (P=0.01) as compared with other diagnoses. Regarding neurologic outcome, CDH infants had the poorer neurological acquisition rate at 9 months but a very good evolution by the time of the 24-month evaluation. CONCLUSIONS: Morbidity in ECMO survivors is low considering the severity of illness in the newborn period, mainly related to pulmonary and feeding dysfunctions during the first months, in particular for the CDH group. Outcome at the age of 2 years of CDH infants is most often favourable regarding growth and neurodevelopmental evolution.     

Somatostatin treatment of congenital chylothorax may induce transient hypothyroidism in newborns

AIM: To describe a group of neonates with congenital, non-traumatic chylothorax, one of whom developed transient hypothyroidism following treatment with somatostatin. METHODS: The charts of seven infants with congenital chylothorax were reviewed in terms of their clinical presentation, the severity of their disease, the complications they presented and the duration of their hospitalization. Their pituitary-thyroid axis function was monitored in particular. RESULTS: The seven infants, all preterm (32-34 wk), suffered from congenital chylothorax and hydrops fetalis diagnosed during the prenatal period. Four were treated by intrauterine drainage, and four had congenital malformations. Hospitalization lasted from 32 to 120 d. Three of the infants suffered from thrombocytopenia, three had chronic lung disease, and one suffered from Gram-negative sepsis. The infant treated with somatostatin initially had normal thyroid function, but later developed primary transient hypothyroidism and was treated with L-thyroxine. The thyroid screening tests for the infants who were not treated with somatostatin were all normal. CONCLUSIONS: Repeated doses of somatostatin were effective in reducing chylus production. Administering this treatment earlier should be considered in order to minimize known complications. The only potential side effect observed was primary transient hypothyroidism. Therefore, careful monitoring of the pituitary-thyroid axis is advised.     

Lack of influence of mild hypothermia on amplitude integrated-electroencephalography in neonates receiving extracorporeal membrane oxygenation

OBJECTIVE: To observe amplitude integrated electroencephalography (aEEG) in neonates receiving ECMO and to determine whether mild hypothermia influenced the aEEG recording. METHODS: Twenty-six consecutive neonates enrolled in a pilot study of mild hypothermia during ECMO were studied. The first group (N=6) was maintained at 37 degrees C throughout the study period. Subsequent groups were cooled to 36 degrees C (N=4), 35 degrees C (N=5), and finally 34 degrees C (N=6) respectively for 24 h and the final group (N=5) to 34 degrees C for 48 h before being rewarmed to 37 degrees C. The aEEG was recorded continuously during the first 5 days of ECMO. The aEEG was classified as normal, moderately or severely suppressed and examined for the occurrence of seizures. To assess the effect of temperature, the aEEG was compared over 12 h during the final 6 h of cooling and during the first 6 h once infants were rewarmed. RESULTS: No change in aEEG amplitude was noted over the temperature range studied. Of the 26 traces obtained, 16 (62%) were normal throughout, 6 (23%) were intermittently moderately abnormal and 1 (14%) was severely abnormal. Three (11%) traces had periods of frequent seizure activity and these were not associated with clinical manifestations in two neonates. In one infant who suffered a cerebral haemorrhage, the aEEG became abnormal before cranial ultrasound abnormalities were apparent. CONCLUSIONS: Continuous cerebral monitoring with aEEG is feasible during ECMO and may add information to clinical examination. Mild hypothermia to 34 degrees C for up to 48 h does not influence the aEEG suggesting that cerebral monitoring with aEEG is possible during mild hypothermia.     

Neonatal extracorporeal membrane oxygenation: practice patterns and predictors of outcome in the UK

OBJECTIVE: To review the UK neonatal extracorporeal membrane oxygenation (ECMO) service and identify predictors of outcome. DESIGN: Retrospective review of the national cohort. Patients and interventions: 718 neonates received ECMO for respiratory failure between 1993 and 2005. Measurements and results: Diagnoses were: 48.0% meconium aspiration syndrome (97.1% survivors), 15.9% congenital diaphragmatic hernia (CDH; 57.9% survivors), 15.9% sepsis (62.3% survivors), 9.5% persistent pulmonary hypertension (79.4% survivors), 5.6% respiratory distress syndrome (92.5% survivors) and 5.1% congenital lung abnormalities (24.3% survivors). The overall survival rate of 79.7% compared favourably with the worldwide Extracorporeal Life Support Organization (ELSO) Registry. Over the period of review, pre-ECMO use of advanced respiratory therapies increased (p<0.001), but ECMO initiation was not delayed (p = 0.61). The use of veno-venous (VV) ECMO increased (p<0.001) and average run time fell (p = 0.004). Patients treated with VV ECMO had a survival rate of 87.7% compared with 73.4% in the veno-arterial (VA) ECMO group; only 42.4% of those needing conversion from VV to VA ECMO survived. In non-CDH neonates, lower birth weight, lower gestational age, older age at ECMO and higher oxygenation index (OI) were associated with increased risk of death. In CDH neonates, lower birth weight and younger age at ECMO were identified as risk factors for death. CONCLUSION: The UK neonatal ECMO service achieves good outcomes and with overall survival rate reaching 80% compares favourably with international results. Advanced respiratory therapies are used widely in UK ECMO patients. Identification of higher OI and older age at ECMO as risk factors in non-CDH neonates reinforces the importance of timely referral for ECMO.     

High frequency oscillatory ventilation and extracorporeal membrane oxygenation in severe persistent pulmonary hypertension of the newborn

We report on 50 term and near-term neonates (birth weight > 1800 g, gestational age > 33 weeks) with severe persistent pulmonary hypertension of the newborn (PPHN), referred to us from January 1987 to July 1991 after failure of maximum conventional treatment. All infants had paO₂<45 mm Hg when ventilated with peak inspiratory pressure >38 cm H₂O and FiO₂=1.0, hence meeting entry criteria for extracorporeal membrane oxygenation (ECMO). High frequency oscillatory ventilation (HFOV) was tried in all patients. If sufficient oxygenation could not be achieved (paO₂<40 mm Hg for at least 2 h), ECMO therapy was begun, which was the case in 25 children. Neonates responding to HFOV (n=25) were of a slightly younger gestational age (37.0 weeks vs 38.8 weeks,P<0.05), had higher Apgar scores and were less hypoxaemic before HFOV (paO₂ 36.6 mm Hg vs 28.8 mm Hg,P<0.01); during HFOV there was a significant rise in paO₂ (> 150 mm Hg;P<0.001) and a fall in pCO₂ to 21.6 mm Hg (P<0.001). Due to air leaks, which was the main complication of HFOV (52%), ECMO therapy had to be begun in two additional infants after an initial positive effect. HFOV tended to be successful in cases of primary PPHN, meconium aspiration and sepsis, but not in infants with lung hypoplasia as a result of diaphragmatic hernia or other reasons. Success or failure of HFOV could not be reliably predicted by any parameter. Mean duration of HFOV was 37.8 h vs 84.9 h of ECMO. PPHN could be overcome in 88% of the HFOV-treated and in 76% of the ECMO-treated infants; overall survival rate was 74% (predicted probability of survival using maximum conventional treatment <10%). There were no significant differences between HFOV/ECMO groups with regard to duration of ventilation following HFOV/ECMO, total time in hospital, rate of bronchopulmonary dysplasia and neurological complications (intracranial haemorrhage, brain infarction). Among the survivors, the rate of mentally handicapped children was equal in both groups (overall 18.9%). Our analysis shows that about 50% of neonates with PPHN who fail to respond to conventional ventilatory support and maximum treatment can be treated successfully with HFOV, thus avoiding ECMO. By applying both forms of therapy, the survival rate of infants with severe PPHN can be increased from an estimated rate of <10% up to 80%.     

Bacterial infection in preterm infants during xanthine therapy for idiopathic apnoea of prematurity

Three preterm infants who acquired systemic bacterial infection during xanthine derivative therapy for idiopathic apnoea of prematurity are described. Apnoea, despite therapeutic serum levels of theophylline, was the presenting symptom of infection in two of the infants. Apnoea did not develop in the third infant, despite co-existent hyponatraemia and intraventricular haemorrhage, though sepsis was diagnosed from other signs. All three infants, including one with Pseudomonas aeruginosa meningitis, responded rapidly to antimicrobial therapy and survived. An increase in the frequency and/or severity of apnoea in a preterm infant being treated with xanthines should alert the physician to symptomatic apnoea such as that associated with bacterial infection. Conversely, the development of symptomatic apnoea may be suppressed by concurrent xanthine derivative therapy for idiopathic apnoea of prematurity.     

Assisted ventilation in infants with meconium aspiration syndrome.

In a retrospective analysis of infants born with meconium staining over an 18-month period at Cook County Hospital, 32 infants met two of the three criteria for the diagnosis of meconium aspiration syndrome: (1) history of meconium in the oropharynx or trachea; (2) clinical evidence of respiratory distress; and (3) x-ray evidence of aspiration pneumonia. Seventeen infants developed respiratory failure; nine of these infants died. One infant without respiratory failure died of sepsis. Analysis of sequential arterial blood pH and gas tension showed that nonsurviving infants had persistently high PCO2 and A-a gradient in spite of initiation of assisted ventilation. These changes seem to be related to severe right-to-left shunting and ventilation perfusion abnormalities. The data further suggest that asphyxia and acidosis occur well before the infant is born and that intrapartum monitoring to recognize fetal asphyxia may help in improving morbidity and mortality from meconium aspiration syndrome.     

宫内感染与新生儿肺疾病

宫内感染和新生儿肺疾病如脓毒症/肺炎、呼吸窘迫综合征、支气管肺发育不良存在一定关系.宫内感染增加新生儿感染风险,可能发生脓毒症/肺炎;也增加了支气管肺发育不良发生率,但可能降低呼吸窘迫综合征发生率和严重性.近年来,各种动物实验研究有助于解释产前炎症对胎儿肺成熟、肺发育的影响.宫内感染可导致新生儿肺不良结局,但远期影响有待进一步观察.     

Neurodevelopmental outcome of periventricular haemorrhage and leukomalacia in infants 1250 g or less at birth

The brains of 50 consecutively admitted infants weighing 1250 g or less at birth were serially examined beyond the neonatal period for periventricular haemorrhage and for periventricular leukomalacia with real-time ultrasound. There was significant correlation between the presence or absence and the severity of haemorrhage with survival. A prospective neurodevelopmental assessment was completed at 2 years of age, corrected for prematurity, on all survivors. None of the 20 survivors with normal scans or germinal layer haemorrhages had evidence of major disability and all four survivors with intracerebral haemorrhage or periventricular leukomalacia had major disability. The mental performance on the Bayley scales of infant development was also significantly worse in the latter group. Six of the eight survivors with intraventricular haemorrhage had no major disability, including three who had post-haemorrhagic hydrocephalus. Our results showed that cerebral ultrasound detection of brain pathology is a good predictor of neurodevelopmental outcome in such extremely low birthweight infants. However, as the maximum extent of periventricular haemorrhage may develop beyond one week of age and cystic periventricular leukomalacia commonly develops after the neonatal period, serial scanning is mandatory to ensure diagnostic accuracy for both periventricular haemorrhage and leukomalacia.     

中国住院新生儿流行病学调查

目的：通过全国范围内城市医院住院新生儿的调查,以了解我国目前住院新生儿的疾病谱及转归。方法：抽取全国22个省和自治区的47个城市中的80所医院,回顾性调查了2005年1月1日至同年12月31日期间出院的住院新生儿 43 289名。结果：①男女性别比为1.73∶1。②早产儿占住院新生儿的26.2%,其中晚期早产儿占住院新生儿的 16.4%,住院早产儿所占比例较2002年（19.7%）有明显增高。③发生率最高的前3位的疾病依次为黄疸、肺炎和缺氧缺血性脑病。④足月儿肺炎、胎粪吸入综合征和胆红素脑病等疾病的发生率高于早产儿;而早产儿窒息、呼吸窘迫综合征和肺出血等疾病的发生率高于足月儿。⑤妊娠高血压综合征母亲所生的新生儿中窒息、小于胎龄儿（SGA）和湿肺等疾病所占比率均高于无妊娠高血压综合征母亲。⑥转归：治愈占63.9%,好转占27.3%,自动出院占7.6%,死亡占1.2%。新生儿死亡发生在入院后24 h内占46.4%。结论：①住院新生儿中早产儿所占比例有增加趋势。②住院新生儿死亡主要发生在入院后24 h内,应加强入院后24 h内的监护工作。［中国当代儿科杂志,2009,11（1）：15-20］     

High frequency oscillatory ventilation: Initial experience in 22 patients

Objectives: To report the outcome of a consecutive cohort of neonates treated with high frequency oscillatory ventilation (HFOV).
Methodology Prospective cohort study of 22 neonates failing conventional mechanical ventilation (CMV) between October 1992 and August 1993. Outcomes evaluated were in-hospital survival rate, comorbidities including patent ductus arteriosus (PDA), cerebroventricular haemorrhages (CVH), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP), and acute changes in respiratory status.
Results Eighteen of 22 (81.8%) survived. Of the four children who died, one did not respond to HFOV and died within 24 h of treatment. Two died of respiratory failure complicated by pulmonary haemorrhage. The remaining infant responded to HFOV but later developed severe NEC while on minimal CMV and died at 2 weeks of age.
Three subjects were ≥34 weeks' gestation; each responded well to HFOV with no substantial comorbidity. Of the remaining 19 infants <34 weeks' gestation, six (31.6%) had a PDA, and seven (36.8%) had a CVH. One infant developed cystic periventricular leucomalacia. Three infants (15.8%) had NEC. Respiratory failure in the 15 survivors with gestational ages <34 weeks improved dramatically with HFOV. Ten (66.7%) survivors <34 weeks developed BPD and 10 (66.7%) ROP.
Conclusion High frequency oscillatory ventilation was associated with a survival rate of 81.8%, but with significant comorbidity.     

A multicenter study of primary graft failure after infant heart transplantation: Impact of extracorporeal membrane oxygenation on outcomes

Primary graft failure is the major cause of mortality in infant HTx. The aim of this study was to characterize the indication and outcomes of infants requiring ECMO support due to primary graft failure after HTx. We performed a retrospective review of all infants (<1 yr) who underwent Htx from three institutions. From 1999 to 2008, 92 infants (<1 yr) received Htx. Sixteen children (17%) required ECMO after Htx due to low cardiac output syndrome. Eleven (69%) infants were successfully weaned off ECMO, and 9 (56%) infants were discharged with a mean follow‐up of 2.3 ± 2.5 yr. Mean duration of ECMO in survivors was 5.4 days (2–7 days) compared with eight days (2–10 days) in non‐survivors (p = NS). The five‐yr survival rate for all patients was 75%; however, the five‐yr survival rate was 40% in the ECMO cohort vs. 80% in the non‐ECMO cohort (p = 0.0001). Graft function within one month post‐Htx was similar and normal between ECMO and non‐ECMO groups (shortening fraction = 42 ± 3 vs. 40 ± 2, p = NS). For infants, ECMO support for primary graft failure had a lower short‐term and long‐term survival rate vs. non‐ECMO patients. Duration of ECMO did not adversely impact graft function and is an acceptable therapy for infants after HTx for low cardiac output syndrome.     

Plasma guanosine 3',5'-cyclic monophosphate and severity of peri/intraventricular haemorrhage in the preterm newborn

A poorly controlled cerebral circulation, caused by excessive production of nitric oxide, has been suggested as predisposing to peri/intraventricular haemorrhage (PIVH) in the immature neonate. It is hypothesized that a relation exists between plasma cyclic GMP (cGMP) as an effector of endogenous vasodilatory nitric oxide production and severity of PIVH. In 83 consecutively admitted preterm neonates, nitric oxide production was assessed by measuring plasma cGMP at 0, 24, 48, 72 and 168 h of age. Simultaneously, cranial ultrasound investigations were performed and haemodynamic parameters registered. The investigations showed that 60 neonates (72%) had no PIVH; 18 neonates (22%) had mild to moderate PIVH; and 5 neonates (6%) had severe PIVH. At 48 and 72 h of age, cGMP levels of infants with severe PIVH were significantly higher than those of infants with no or only mild PIVH, whereas at 72 and at 168 h, infants with moderate PIVHs had significantly higher cyclic cGMP levels than infants without PIVH. Finally, at 168 h of age infants with mild PIVH also had higher cyclic cGMP values than those of infants without PIVH. Maximal cGMP values preceded the final extension of PIVH in moderate and severe PIVHs. Blood pressure support was necessary significantly more often in infants with moderate and severe PIVH. A logistic regression model revealed that cGMP was significantly associated with PIVH, irrespective of gestational age, mean arterial pressure or severity of infant respiratory distress syndrome. Conclusion: Increased cGMP levels are associated with the development of PIVH. It is suggested that vasodilatory nitric oxide-induced impairment of cerebral autoregulation plays a role here.     

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.     

Pulmonary involvement with cytomegalovirus infections in children.

Among 40 hospitalized infants and children with cytomegalovirus infection, 14 (35%) had interstitial pneumonitis, 4 (10%) had wheezing or tachypnoea but without x-ray evidence of classical interstitial pneumonia, the remaining 22 (55%) were free of pulmonary involvement. Most patients had tachypnoea and nonproductive cough of varying durations: those with underlying pulmonary pathology tended to have persistent and prolonged respiratory symptoms. Mortality and severity of the lung disease were related to the underlying immunodeficiency or concomitant pulmonary process.     

Adrenal hemorrhage in infants undergoing ECMO: Prevalence and clinical significance

Objective: To determine the prevalence and clinical significance of adrenal hemorrhage in infants undergoing ECMO therapy.Methods: Prospective US evaluation of the adrenal glands was performed in 50 consecutive infants undergoing ECMO. The infants were examined at least every other day while on bypass. Adrenal hemorrhage was diagnosed at US examination when a suprarenal mass or adrenal gland enlargement was identified.Results: Adrenal hemorrhage was identified in two infants (4%); one infant with septicemia, and one with primary pulmonary hypertension. Both hemorrhages were unilateral; one was right-sided, and one left-sided. One hemorrhage occurred on the first day following the onset of ECMO and the other on the third day. The adrenal hemorrhage was not associated with an acute drop in hematocrit nor with adrenal insufficiency in either infant.Conclusion: Adrenal hemorrhage is uncommon in infants undergoing ECMO. When hemorrhage did occur in this series, it did not result in clinical complications.     

Changing populations being treated with ECMO in the neonatal period – who are the others?

Extracorporeal life support via extracorporeal membrane oxygenation (ECMO) has served the sickest of neonates for almost 50 years. Naturally, the characteristics of neonates receiving ECMO have changed. Advances in care have averted the need for ECMO for some, while complex cases with uncertain outcomes, previously not eligible for ECMO, are now considered. Characterizing the disease states and outcomes for neonates on ECMO is challenging as many infants do not fall into classic categories, i.e. meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), or congenital diaphragmatic hernia (CDH). Since 2017, over one third of neonatal respiratory ECMO runs reported to the Extracorporeal Life Support Organization Registry are grouped as Other, a catch-all that encompasses those with a diagnosis not included in the classic categories. This review summarizes the historical neonatal ECMO population, reviews advances in therapy and technology impacting neonatal care, and addresses the unknowns in the ever-growing category of Other.     

Computed Tomographic Angiography of Infants with Congenital Heart Disease Receiving Extracorporeal Membrane Oxygenation

Patients with respiratory and/or cardiac failure occasionally require the use of extracorporeal membrane oxygenation (ECMO), which presents an obstacle for standard imaging modalities. Computed tomographic angiography (CTA) can be used in patients with congenital heart disease, usually to define extra-cardiac anatomy in the chest. We describe the use of CTA to evaluate two infants with congenital heart disease while on ECMO. The first infant had totally anomalous pulmonary venous connection, and the second had a pulmonary sling that resulted in tracheal stenosis. The studies achieved high diagnostic quality with minimal radiation exposure. Subsequently, both infants had successful surgical repairs.     

Preferential distribution of lobar emphysema and atelectasis in bronchopulmonary dysplasia.

The chest roentgenograms of 142 neonates who survived mechanical ventilation for respiratory distress syndrome (N = 99) and prolonged apnea (N = 43) were reviewed. Thirty-seven infants had bronchopulmonary dysplasia (BPD) and 17 of these developed lobar hyperinflation of the right lower lobe and collapse of the right upper lobe. Regional lung function was measured with a xenon 133 technique in three of these infants and in five other patients who either died or were lost to follow-up. All had BPD with right lower lobe overinflation. Ventilation was less in the lower regions than the upper regions bilaterally (P less than .001), indicating that the hyperinflation of the lower lobes was not compensatory for upper lobe collapse but was due to emphysema. Mean regional perfusion was equal in the upper and lower regions of the chest. This preferential distribution of lobaremphysema and ipsilateral atelectasis in BPD tended to present and regress simultaneously, but in many infants it lasted as long as eight weeks. Only one infant with persistent atelectasis developed pneumonia. The best mode of therapy appears to be supportive.