Surfactant therapy using a bronchofiberscope in respiratory distress syndrome.

BACKGROUND: Avoiding endotracheal intubation and using nasal continuous positive airway pressure as the initial treatment is recommended in infants with respiratory distress syndrome (RDS), and modes of lesser invasive surfactant administration have recently been reported. We report a pilot study assessing the feasibility of surfactant therapy using a bronchofiberscope (STUB) in RDS. METHODS: Surfactant was administered to 31 preterm infants (gestational age range of 28 weeks 0 days to 36 weeks 6 days) diagnosed with RDS, through the working channel of the bronchofiberscope or endotracheal tubes. Patient characteristics, outcomes, adverse events, and comorbidities were assessed in the two groups. RESULTS: Twelve infants received STUB. Two of the 12 infants (17%) needed subsequent intubation and additional surfactant administration. Nineteen infants received surfactant through endotracheal tubes. Four of the 19 infants (21%) required additional surfactants. There was no significant difference in the number of infants that needed additional surfactant (p = 1.00). Gestational age, birthweight, length of hospitalization, adverse events, such as desaturations and bradycardias, and comorbidities were similar between the two groups. Days of invasive ventilation were significantly shorter in the STUB group (p = 0.0002). CONCLUSION: STUB was feasible in this small cohort and reduced the need for intubation to 17%, leading to fewer days of invasive ventilation, without increasing comorbidities and adverse events. To the best of our knowledge, this is the first study to administer surfactants using bronchofiberscopes.

Mortality and morbidity of extremely low birth weight infants in Japan, 2015.

BACKGROUND: In Japan, the mortality rate of extremely low birth weight (ELBW) infants is notably low in comparison with other developed countries, but the prevalence of chronic lung disease (CLD) and retinopathy of prematurity (ROP) is relatively high. This study aimed to estimate the mortality and morbidity of ELBW infants born in 2015 who were admitted to neonatal intensive care units (NICUs) in Japan and to examine the factors that affected the short-term outcomes of these infants. We also compared the mortality of ELBW infants born in 2005, 2010, and 2015. METHODS: We analyzed the mortality, morbidity, and factors related to short-term outcomes of ELBW infants, using data from 2782 infants born in 2015 and registered at NICUs in Japan. RESULTS: The mortality rates during NICU stays were 17.0%, 12.0%, and 9.8% for ELBW infants born in 2005, 2010, and 2015, respectively. Among ELBW infants born in 2015, multiple logistic regression analysis showed that short gestational age and low birthweight Z-score contributed to the increased risk of death. Births by cesarean section and antenatal corticosteroid administration were significantly associated with a reduced risk of death. Among infants who survived, CLD was observed in 53.1% and ROP requiring treatment was observed in 30.4%. CONCLUSIONS: Mortality in ELBW infants decreased significantly from 2005 to 2015. As CLD and ROP may affect quality of life and long-term outcomes of infants who survived, prevention strategies and management for these complications are critical issues in neonatal care in Japan.

Study protocol: a multicenter, uncontrolled, open-label study of palivizumab in neonates, infants, and preschool children at high risk of severe respiratory syncytial virus infection.

BACKGROUND: The prophylactic use of anti-respiratory syncytial virus (RSV) antibody (palivizumab) for severe RSV infection is not approved in Japan in specified groups of infants with neuromuscular diseases or other rare diseases associated with reduced ventilation competence or difficulty in expectoration, which increase the risk of exacerbation of severe RSV infection. The objective of this study is to investigate the efficacy, safety, and pharmacokinetics of palivizumab in pediatric patients with those rare diseases for which palivizumab is not indicated at present. METHODS/DESIGN: This study is a multicenter, uncontrolled, open-label study planned to be carried out between July 1, 2019 and June 30, 2022 at 7 medical institutions in Japan. The study population will be recruited from among neonates, infants, or children aged 24 months or younger with a condition falling under any of the following 5 disease groups: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. The planned sample size is 18 subjects, including at least 3 subjects per disease group. Throughout the RSV season, at least 4 continuous doses of palivizumab will be administered intramuscularly at 15 mg/kg at intervals of 30 days. The efficacy and safety of palivizumab will be comprehensively evaluated based on the incidence of RSV-related hospitalization, and serum palivizumab concentration, serum anti-palivizumab antibody concentration, and the occurrence of adverse events/reactions after the start of palivizumab treatment. DISCUSSION: This study will evaluate the efficacy and safety of palivizumab in pediatric patients with rare diseases which place them at high risk of severe RSV infection, but which fall outside the current indications for palivizumab prophylaxis. The generated data will have implications for the regulatory approval of prophylactic palivizumab treatment in this patient group. TRIAL REGISTRATION: This study has been prospectively registered in Japic Clinical Trials Information, which is managed and administered by the Japan Pharmaceutical Information Center (registration number: JapicCTI-194946 , registration date: September 10, 2019).

Pharyngomalacia diagnosed by laryngo-tracheo-bronchoscopy in the neonatal intensive care unit.

BACKGROUND: Flexible fiber-optic laryngo-tracheo-bronchoscopy has become widely performed in infants and neonates since the introduction of thin flexible fiberscopes. Laryngomalacia is the most common airway disease in infants causing stridor. Pharyngomalacia, termed pharyngeal occlusion during inspiration, was the second most common airway disease found in our hospital in patients that underwent laryngo-tracheo-bronchoscopy, but the incidence, patient characteristics, and natural course have not been reported in large numbers in Japan. METHODS: A retrospective review was performed of medical records on patients admitted to our neonatal intensive care unit during the neonatal period diagnosed with pharyngomalacia between April 2009 and November 2018. Patient characteristics, concurrent airway diseases, comorbidities, and treatment were reviewed. RESULTS: Forty-eight patients were diagnosed with pharyngomalacia. The median gestational age was 37.1 weeks, and the median birthweight was 2,552 g. Patients were diagnosed at a median age of 29 days, and cure was achieved at a median age of 4 months. Twenty-eight patients had concurrent airway diseases, laryngomalacia being the most common. Continuous positive airway pressure or high flow nasal cannula was used in 34 patients. CONCLUSIONS: In patients with pharyngomalacia, half were born preterm, and more than half had concurrent airway diseases. The onset and diagnosis were made within the first month of life in more than half of the patients, and resolution was seen mostly within the first 6 months of life. Whenever a patient is suspected of having an airway disease, the pharyngeal space should be carefully observed to diagnose pharyngomalacia.

Videoendoscopic evaluation of swallowing using normal saline in NICU infants.

BACKGROUND: Videoendoscopic evaluation (VE) of swallowing involves inserting a small flexible endoscope transnasally to allow direct observation of pharyngeal and laryngeal structures and swallowing functions. In our neonatal intensive care unit (NICU) VE is performed in infants suspected of severe swallowing dysfunction, using normal saline (NS) with the aim of minimizing the detrimental effect of aspiration on respiration caused by VE. This retrospective study was conducted to evaluate the usefulness of VE using NS in NICU infants. METHODS: We enrolled 28 infants who demonstrated clinical signs of swallowing dysfunction or who were ready to start oral feeding. Swallowing evaluations were completed using flexible fiberoptic laryngobronchoscopy (FLB). While observing the pharyngeal and laryngeal cavity with FLB, NS was gradually increased by 1 mL and injected up to a maximum of 3 mL, and the swallowing reflex, tracheal aspiration, and pharyngeal residue were observed. RESULTS: Median gestational age was 37 weeks 6 days, median birthweight 2,539 g, and median age at first examination was 107.5 days. Abnormalities in VE were observed in 20 cases, most of which were upper airway lesions. Most of these upper airway abnormalities were pharyngeal lesions. In two pharyngeal lesion cases, swallowing function improved using positive airway pressure. CONCLUSIONS: Infants with pharyngeal lesions demonstrated abnormal VE findings. Furthermore, positive airway pressure improved swallowing in some cases, suggesting that narrowing of the pharyngeal cavity may affect swallowing function. In addition, results suggest that VE using NS is a safe and useful method for evaluating swallowing function and determining countermeasures in NICU infants.

Evaluation of respiratory center function in congenital central hypoventilation syndrome by monitoring electrical activity of the diaphragm.

BACKGROUND: A definitive diagnosis of congenital central hypoventilation syndrome (CCHS) is made by genetic testing. However, there are only a few examinations that warrant genetic testing. Electrical activity of the diaphragm (Edi) reflects neural respiratory drive from respiratory center to diaphragm. We evaluated the function of the respiratory center in CCHS by Edi monitoring. METHODS: Monitoring of Edi was performed in six CCHS cases without mechanical ventilation. The monitoring time was 30 consecutive minutes from wakefulness to sleep. The TcPCO2 or EtCO2 and SpO2 were recorded simultaneously. RESULTS: The Edi peak during wakefulness was 14.0 (10.3-21.0) µV and the Edi peak during sleep was 6.7 (3.8-8.0) µV. The Edi peak during sleep was significantly lower than the Edi peak during wakefulness, and patients were in a state of hypoventilation. Although TcPCO2 or EtCO2 increased due to hypoventilation, an increase in the Edi peak that reflects central respiratory drive was not observed. ΔEdi/ΔCO2 was -0.06µV/mmHg. Maximum EtCO2 or TcPco2 was 51 mmHg, and the average SpO2 was 91.5% during monitoring. CONCLUSIONS: We confirmed that Edi monitoring could evaluate the function of the respiratory center and reproduce the hypoventilation of CCHS. The present study suggested that Edi monitoring is a useful examination in deciding whether to perform genetic testing or not and it may lead to an early diagnosis of CCHS.

Is the neonatal creatine phosphokinase level a reliable marker for fetal hypoxia?

AIM: The creatine phosphokinase (CPK) level is believed to increase in neonatal peripheral blood after tissue damage, including damage from perinatal hypoxia. However, it is not clear whether it is truly a reliable marker for fetal hypoxia. We investigated the chronological changes in neonatal CPK and the reliability of CPK as a marker for fetal hypoxia. METHODS: Sixty term neonates admitted to the neonatal intensive care unit at Tokyo Women's Medical University Medical Center East from April 2009 to April 2010 were enrolled in this study. We evaluated whether asphyxia and fetal heart rate (FHR) abnormality could predict the neonatal CPK level by using receiver-operator curve analysis. We also compared umbilical cord blood pH levels with neonatal CPK levels. In addition, we investigated factors that influence neonatal CPK in non-asphyxia cases. RESULTS: The median value of CPK peaked on day 1. There were no significant differences in CPK levels regardless of the presence of asphyxia or FHR abnormality. Non-asphyxiated neonates with older gestational ages and amniotic fluid abnormalities had significantly higher levels of CPK. CONCLUSION: Our results indicate that the neonatal CPK level is not an appropriate marker for retrospectively predicting either asphyxia or FHR abnormality. There are influencing factors other than asphyxia that increase neonatal CPK. Therefore, one should be careful when making a diagnosis of perinatal hypoxia based solely on increased levels of neonatal CPK after birth.

Genotype-phenotype relationship in Japanese patients with congenital central hypoventilation syndrome.

Examine the genotype-phenotype relationship in Japanese congenital central hypoventilation syndrome (CCHS) patients and estimate the incidence of CCHS in Japan. Subjects were 92 Japanese patients with PHOX2B mutations; 19 cases carried 25 polyalanine repeat expansion mutations (PARMs); 67 cases carried 26 or more PARMs; and 6 had non-PARMs (NPARMs). We collected clinical data in all patients and estimated the development or intelligent quotients only in the patients carrying 25 PARM. The estimated incidence of CCHS was greater than one case per 148 000 births. Polyhydramnios was observed in three cases. Twelve infants exhibited depressed respiration at birth. In 19 cases carrying 25 PARM, the male-to-female ratio was ~3, no cases had Hirschsprung disease; 7 cases (37%) developed hypoventilation after the neonatal period, and 8 cases (42%) had mental retardation. In other 73 cases carrying 26 or more PARMs or NPARMs, male-to-female ratio was equal; patients frequently complicated with Hirschsprung disease and constipation, and all patients presented with hypoventilation in the neonatal period. Clinical symptoms were severe in most patients carrying long PARMs and NPARMs. In 25 PARM, additional genetic and/or epigenetic factors were required for CCHS development and male sex is likely a predisposing factor. The patients carrying 25 PARM frequently had mental retardation likely because they were not able to receive appropriate ventilation support following a definitive diagnosis owing to subtle and or irregular hypoventilation. Molecular diagnosis provides a definitive diagnosis and enables to receive appropriate ventilator support.

Decreased granulomatous reaction by polyurethane-coated stent in the trachea.

BACKGROUND: Reducing granulomatous reaction for stent implantation is important for the treatment of tracheobronchomalacia because formation of granuloma leads to refractory complication causing further respiratory distress. The purpose of this study was to clarify granulomatous reaction of newly innovated coated stents compared to non-coated metal stents. METHODS: Materials and animal experiments were performed using the newly invented metallic stent (laser-cut stainless steel with a coating of polyurethane). In the materials experiment, the correlation between the holding force and deformity was tested by a compressor. In the animal examination, coated stents were orally implanted into the trachea in five rabbits, while non-coated stents were implanted in another five rabbits. After 3 weeks' observation, the inner diameter was measured by 3-D computed tomography, and the number of granulation tissues was counted by bronchofiberscope. Histological investigation followed in both groups. RESULTS: In the materials experiment, new stents demonstrated a holding force similar to stainless steel stents. In the animal experiment, no difference was found in the inner diameter of the coated and non-coated stent groups (5.70 ± 0.17 vs 5.60 ± 0.27, P = 0.07). However, the number of granulation tissues was higher in non-coated stents than in coated stents (1.60 ± 0.55 vs 0.40 ± 0.55, P < 0.01). Histological investigation showed direct attachment of metal to the tracheal wall around the non-coated stents where epithelial structure was destroyed, while tracheal epithelia were preserved in the group of coated stents. CONCLUSIONS: The new polyurethane-coated metallic stent maintains enough holding force, and reduces histobiological reaction to foreign bodies in this experiment.

Breathing intolerance index in healthy infants.

BACKGROUND: The breathing intolerance index (BITI) is used to justify ventilator use in adult patients with pulmonary or chest wall disease. BITI in ventilated patients is mostly ≥0.15. The mean BITI of healthy adults in the upright sitting position and the supine position is 0.050 ± 0.009 and 0.057 ± 0.016, respectively. The aim of this study was to establish a normal BITI in infants. METHODS: Thirty healthy infants were examined in the supine position. BITI was defined as BITI = (Ti/Ttot) × (TV/VC), where Ti is inspiratory time, Ttot is total breath cycle duration, TV is tidal volume, and VC is vital capacity. TV and Ti/Ttot were obtained from tidal breathing at rest and VC was obtained spirometrically. BITI was calculated using customized software. RESULTS: The mean ± SD BITI of 30 healthy infants in the supine position was 0.120 ± 0.013. The BITI of infants was significantly higher than that of adults. CONCLUSIONS: BITI was measured in healthy infants. Further evaluation is needed to determine the significance and usefulness of BITI.

Efficacy of bronchial fiberscope in esophageal fistula caused by necrotizing bronchitis.

Neonatal necrotizing bronchitis is a disease that occurs in premature and low-birthweight infants who are subject to artificial respiratory management, and which has a poor prognosis, because it progresses suddenly and can result in death. There have been no reports of survival to date in cases of tracheo-esophageal fistula caused by necrotizing bronchitis, and no swift and effective management method has yet been reported. This report describes a case in which the use of a bronchial fiberscope in making an early diagnosis facilitated appropriate management and survival. The proactive use of a bronchial fiberscope in regard to this disease, which has a high fatality rate, may save lives.

Airway diseases in very low birth weight infants.

OBJECTIVE: To identify the incidence and characteristics of airway diseases in very low birth weight infants (VLBWIs). METHODS: A retrospective study of 214 inborn VLBWIs admitted to our NICU between April 2009 and March 2022 (approval no: 2023-0008). Neonatologists ourselves performed bronchoscopy to diagnose airway diseases. RESULTS: Symptomatic airway diseases were present in 36/214 (16.8%) of VLBWIs. Common airway diseases were tracheobronchomalacia (TBM) and pharyngomalacia. Infants with airway diseases had shorter gestational age, lower birth weight, more boys, and more moderate/severe bronchopulmonary dysplasia (BPD). Regarding treatment, more infants with airway diseases required intubation were intubated longer, used more dexamethasone, were on ventilators and oxygen longer, and were hospitalized longer. CONCLUSION: We found that VLBWIs were more frequently complicated with airway diseases, especially TBM. We also observed many pharyngeal lesions, which have not been previously reported. Intensity of prematurity, BPD, and the need for stronger respiratory management were risks for airway diseases. In VLBWIs, bronchoscopy should be actively performed because airway diseases are important complications.

Examination of changes in the breathing intolerance index to determine the respiratory support needs of very low birth weight infants.

BACKGROUND: The breathing intolerance index (BITI) is used to evaluate respiratory muscle tolerance. The higher the ratio of the inspiratory time to the total breathing time and the ratio of the tidal volume to the vital capacity, the more easily the respiratory muscles become fatigued. The BITI is high with chronic respiratory failure, and values of 0.15 or more indicate the need for assisted ventilation. OBJECTIVE: This study aimed to examine the changes in the BITI of very low birth weight infants (VLBWIs) and determine whether it is possible to use the BITI as an objective indicator of the timing of noninvasive respiratory support (NRS) withdrawal. METHODS: VLBWIs admitted to our neonatal intensive care unit between July 2020 and July 2022 under NRS at 36 weeks' postmenstrual age (PMA). If the BITI was less than 0.15, then we attempted to determine whether NRS could be withdrawn. RESULTS: Sixteen infants with a median gestational age and birth weight of 30.9 weeks and 1249 g, respectively, were eligible. The median PMA at the time of the first examination was 36.6 weeks. The BITI of two VLBWIs was less than 0.15. For 11 of the other VLBWIs, the BITI decreased over time to less than 0.15 at 39 weeks' PMA. After confirming that the BITI was less than 0.15, weaning from NRS was attempted. Weaning from NRS was possible except one VLBWI. CONCLUSION: The BITI can help evaluate respiratory tolerance and could be an objective indicator of the timing of NRS withdrawal.

Safety, efficacy and pharmacokinetics of palivizumab in off-label neonates, infants, and young children at risk for serious respiratory syncytial virus infection: a multicenter phase II clinical trial.

Background: Pediatric patients with certain rare diseases are at increased risk of severe respiratory syncytial virus (RSV) infection. However, the prophylactic use of anti-RSV antibody (palivizumab) in these patients is not indicated at present in Japan. Methods: This first-in-the-world multicenter, uncontrolled, open-label, phase II clinical trial was carried out between 28 July 2019 and 24 September 2021 at seven medical institutions in Japan to investigate the efficacy, safety, and pharmacokinetics of palivizumab in 23 subjects recruited from among neonates, infants, or children aged 24 months or younger who had any of the following conditions: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. At least four continuous doses of palivizumab were administered intramuscularly at 15 mg/kg at intervals of 30 days. Findings: Twenty-three enrolled subjects completed the study. No subject required hospitalization for RSV. Adverse events (AE) did not notably differ from the event terms described in the latest interview form. Five severe AEs required unplanned hospitalization, but resolved without RSV infection. Therapeutically effective concentrations of palivizumab were maintained throughout the study period. Interpretation: Palivizumab might be well tolerated and effective in preventing serious respiratory symptoms and hospitalization due to severe RSV infection, indicating the prophylactic use in the pediatric patients included in this study. Funding: Japan Agency for Medical Research and Development (AMED), grant numbers 19lk0201097h0001 (to MM), 20lk0201097h0002 (to MM), 21lk0201097h0003 (to MM), and 22lk0201097h0004 (to MM). AMED did not have any role in the execution of this study, analysis and interpretation of the data, or the decision to submit the results.

Epidemiologic survey of patients with congenital central hypoventilation syndrome in Japan.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare disease characterized by hypoventilation during sleep. This study discusses the first epidemiologic survey of patients with CCHS in Japan. METHODS: The first survey was conducted between September and December 2006 and involved 507 registered institutes for pediatric training in Japan. The second survey was conducted between January and April 2007 and involved only those institutes that confirmed diagnosis of CCHS in the first survey or reported on CCHS at a conference during the preceding decade. RESULTS: Thirty-seven patients with CCHS were reported from 23 hospitals. Patient characteristics were as follows: 18 were male, 19 were female; and age range 4 months to 34 years. Diagnosis was based on clinical symptoms in 37/37 patients; blood gas analysis in 25/37; ventilatory response to inhaled CO(2) in 14/37; and genetic analysis (paired-like homeobox gene 2B) in 11/37. Complications included Hirschsprung's disease in 13/37 and central nervous system disorders in 15/37. Prognoses were as follows: 3/37 died in hospital, 1/37 remained in hospital, 33/37 were on home mechanical ventilation (died 4/33, survived 29/33), and 0/37 were cured. Ventilation methods included tracheostomy (21/37), use of a nasal mask (9/37), use of a facemask (5/37), and diaphragmatic pacing (1/37). CONCLUSIONS: There is currently no consensus on the most appropriate methods for diagnosing and treating patients with CCHS in Japan. More CCHS-related data need to be collected in the near future in order to enable appropriate diagnosis and management of patients with CCHS.

A neonatal case of an elongated soft palate.

The development of stridor and periodic desaturation in a 2-day-old neonate born at term lead to the suspicion of upper airway obstruction. The patient underwent flexible fiberoptic laryngo-tracheo-bronchoscopy and was diagnosed as having an elongated soft palate and secondary mild pharyngomalacia. Early intervention with high PEEP therapy using nasal CPAP led to improvement in the patient condition.

Ventilatory response to CO2 with Read's rebreathing method in normal infants.

BACKGROUND: Methods of evaluating the ventilatory response to CO2 (VRCO2 ) of the respiratory center include the steady-state and the rebreathing method. Although the rebreathing method can evaluate the ventilatory response continuously to gradually increasing CO2 , the rebreathing method has been rarely performed in infants. The aim of this study was to investigate whether we could perform the VRCO2 with the rebreathing method in normal infants. METHODS: The subjects were 80 normal infants. The gestational age was 39.9 (39.3-40.3) weeks, and the birth body weight was 3142 (2851-3451) grams. We performed the VRCO2 with Read's rebreathing method, measuring the increase in minute volume (MV) in response to the increase in EtCO2 by rebreathing a closed circuit. The value of VRCO2 was calculated as follow: VRCO2 (ml/min/mmHg/kg) = ΔMV/ΔEtCO2 /body weight. RESULTS: We performed the examination without adverse events. The age in days at examination was 3 (2-4), and the examination time was 150 ± 38 s. The maximum EtCO2 was 51.1 (50.5-51.9) mmHg. The value of VRCO2 was 34.6 (29.3-42.8). The intraclass correlation coefficient of the VRCO2 of cases with multiple measurements was 0.79. CONCLUSION: This study suggests that the rebreathing method can evaluate the ventilatory response to high blood CO2 in a short examination time. We conclude that the rebreathing method is useful even in infants. In the future, we plan to measure the VRCO2 of preterm infants, and evaluate the respiratory center of infants in more detail.