An Infant with High-Output Heart Failure and Pulmonary Hypertension Resulting from a Giant Cutaneous Hemangioma.

We present the clinical course of an 8-month-old infant with a giant cutaneous hemangioma resulting in high-output heart failure and pulmonary hypertension. The lesion was successfully embolized and excised, with rapid resolution of heart failure and improvement in pulmonary hypertension.

Variability for Age at Successful Extubation in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: The objective of this study was to characterize clinical factors associated with successful extubation in infants with congenital diaphragmatic hernia. STUDY DESIGN: Using the Children's Hospitals Neonatal Database, we identified infants with congenital diaphragmatic hernia from 2017 to 2020 at 32 centers. The main outcome was age in days at the time of successful extubation, defined as the patient remaining extubated for 7 consecutive days. Unadjusted Kaplan-Meier and multivariable Cox proportional hazards ratio equations were used to estimate associations between clinical factors and the main outcome. Observations occurred through 180 days after birth. RESULTS: There were 840 eligible neonates with a median gestational age of 38 weeks and birth weight of 3.0 kg. Among survivors (n = 693), the median age at successful extubation was 15 days (interquartile range [IQR]: 8-29 days, 95th percentile: 71 days). For nonsurvivors (n = 147), the median age at death was 21 days (IQR: 11-39 days, 95th percentile: 110 days). Center (adjusted hazards ratio: 0.22-15, P < .01), low birth weight, intrathoracic liver position, congenital heart disease, lower 5-minute Apgar score, lower pH upon admission to Children's Hospitals Neonatal Database center, and use of extracorporeal support were independently associated with older age at successful extubation. Tracheostomy was associated with multiple failed extubations. CONCLUSION: Our findings suggest that infants who have not successfully extubated by about 3 months of age may be candidates for tracheostomy with chronic mechanical ventilation or palliation. The variability of timing of successful extubation among our centers supports the development of practice guidelines after validating clinical criteria.

Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice.

Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3-/- mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.

The association between pulmonary vascular disease and respiratory improvement in infants with type I severe bronchopulmonary dysplasia.

OBJECTIVE: To describe the association between echocardiographic measures of pulmonary vascular disease and time to respiratory improvement among infants with Type I severe bronchopulmonary dysplasia (sBPD). STUDY DESIGN: We measured the pulmonary artery acceleration time indexed to the right ventricular ejection time (PAAT/RVET) and right ventricular free wall longitudinal strain (RVFWLS) at 34-41 weeks' postmenstrual age. Cox-proportional hazards models were used to estimate the relationship between the PAAT/RVET, RVFWLS, and the outcome: days from 36 weeks' postmenstrual age to room-air or discharge with oxygen (≤0.5 L/min). RESULT: For 102 infants, the mean PAAT/RVET and RVFWLS were 0.27 ± 0.06 and -22.63 ± 4.23%. An abnormal measurement was associated with an increased time to achieve the outcome (PAAT/RVET: 51v24, p < 0.0001; RVFWLS; 62v38, p = 0.0006). A normal PAAT/RVET was independently associated with a shorter time to outcome (aHR = 2.04, 1.11-3.76, p = 0.02). CONCLUSION: The PAAT/RVET may aid in anticipating timing of discharge in patients with type I severe BPD.

Predicting treatment of pulmonary hypertension at discharge in infants with congenital diaphragmatic hernia.

OBJECTIVE: To predict pulmonary hypertension (PH) therapy at discharge in a large multicenter cohort of infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Six-year linked records from Children's Hospitals Neonatal Database and Pediatric Health Information System were used; patients whose diaphragmatic hernia was repaired before admission or referral, who were previously home before admission or referral, and non-survivors were excluded. The primary outcome was the use of PH medications at discharge and the secondary outcome was an inter-center variation of therapies during inpatient utilization. Clinical factors were used to develop a multivariable equation randomly applied to 80% cohort; validated in the remaining 20% infants. RESULTS: A total of 831 infants with CDH from 23 centers were analyzed. Overall, 11.6% of survivors were discharged on PH medication. Center, duration of mechanical ventilation, and duration of inhaled nitric oxide were associated with the use of PH medication at discharge. This model performed well in the validation cohort area under the receiver operating characteristic curve of 0.9, goodness-of-fit χ2, p = 0.17. CONCLUSIONS: Clinical variables can predict the need for long-term PH medication after NICU hospitalization in surviving infants with CDH. This information may be useful to educate families and guide the development of clinical guidelines.

Qualitative indications for tracheostomy and chronic mechanical ventilation in patients with severe bronchopulmonary dysplasia.

BACKGROUND: The decision to pursue chronic mechanical ventilation involves a complex mix of clinical and social considerations. Understanding the medical indications to pursue tracheostomy would reduce the ambiguity for both providers and families and facilitate focus on appropriate clinical goals. OBJECTIVE: To describe potential indications to pursue tracheostomy and chronic mechanical ventilation in infants with severe BPD (sBPD). STUDY DESIGN: We surveyed centers participating in the Children's Hospitals Neonatal Consortium to describe their approach to proceed with tracheostomy in infants with sBPD. We requested a single representative response per institution. Question types were fixed form and free text responses. RESULTS: The response rate was high (31/34, 91%). Tracheostomy was strongly considered when: airway malacia was present, PCO2 ≥ 76-85 mmHg, FiO2 ≥ 0.60, PEEP ≥ 9-11 cm H2O, respiratory rate ≥ 61-70 breaths/min, PMA ≥ 44 weeks, and weight <10th %ile at 44 weeks PMA. CONCLUSIONS: Understanding the range of indications utilized by high level NICUs around the country to pursue a tracheostomy in an infant with sBPD is one step toward standardizing consensus indications for tracheostomy in the future.

Treatment of pulmonary hypertension during initial hospitalization in a multicenter cohort of infants with congenital diaphragmatic hernia (CDH).

OBJECTIVE: Describe inpatient pulmonary hypertension (PH) treatment and factors associated with therapy at discharge in a multicenter cohort of infants with CDH. METHODS: Six years linked records from Children's Hospitals Neonatal Database and Pediatric Health Information System were used to describe associations between prenatal/perinatal factors, clinical outcomes, echocardiographic findings and PH medications (PHM), during hospitalization and at discharge. RESULTS: Of 1106 CDH infants from 23 centers, 62.8% of infants received PHM, and 11.6% of survivors were discharged on PHM. Survivors discharged on PHM more frequently had intrathoracic liver, small for gestational age, and low 5 min APGARs compared with those discharged without PHM (p < 0.0001). Nearly one-third of infants discharged without PHM had PH on last inpatient echo. CONCLUSIONS: PH medication use is common in CDH. Identification of infants at risk for persistent PH may impact ongoing management. Post-discharge follow-up of all CDH infants with echocardiographic evidence of PH is warranted.

Utility of echocardiography in predicting mortality in infants with severe bronchopulmonary dysplasia.

OBJECTIVE: To determine the relationship between interventricular septal position (SP) and right ventricular systolic pressure (RVSP) and mortality in infants with severe BPD (sBPD). STUDY DESIGN: Infants with sBPD in the Children's Hospitals Neonatal Database who had echocardiograms 34-44 weeks' postmenstrual age (PMA) were included. SP and RVSP were categorized normal, abnormal (flattened/bowed SP or RVSP > 40 mmHg) or missing. RESULTS: Of 1157 infants, 115 infants (10%) died. Abnormal SP or RVSP increased mortality (SP 19% vs. 8% normal/missing, RVSP 20% vs. 9% normal/missing, both p < 0.01) in unadjusted and multivariable models, adjusted for significant covariates (SP OR 1.9, 95% CI 1.2-3.0; RVSP OR 2.2, 95% CI 1.1-4.7). Abnormal parameters had high specificity (SP 82%; RVSP 94%), and negative predictive value (SP 94%, NPV 91%) for mortality. CONCLUSIONS: Abnormal SP or RVSP is independently associated with mortality in sBPD infants. Negative predictive values distinguish infants most likely to survive.

Extracorporeal membrane oxygenation and bloodstream infection in congenital diaphragmatic hernia.

OBJECTIVE: To characterize the risk of bloodstream (BSI) and urinary tract infection (UTI) and describe antibiotic use in infants with congenital diaphragmatic hernia (CDH) requiring extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: The Children's Hospitals Neonatal Database was queried for infants with CDH and ECMO treatment from 2010 to 2016. The outcomes included BSI, UTI, and antimicrobial medication. Member institutions completed a survey on infection practices. RESULT: Eighteen of the 338 patients identified (5.3%) had ≥1 BSI during their ECMO course. The likelihood of BSI increased with time: 1.2/1000 ECMO days; 0.6% (2/315) in the first week and rising to 14.6/1000; 8.6% (5/58) after 21 days (p = 0.002). More than 95% of patients received antibiotics each week on ECMO. CONCLUSIONS: Confirmed BSI is rare in infants with CDH treated with ECMO in the first week, but increases with the duration of ECMO. Use of antibiotics was extensive and did not correspond to infection frequency.

Predicting Risk of Infection in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: To predict incident bloodstream infection and urinary tract infection (UTI) in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: We conducted a retrospective analysis using the Children's Hospital Neonatal Database during 2010-2016. Infants with CDH admitted at 22 participating regional neonatal intensive care units were included; patients repaired or discharged to home prior to admission/referral were excluded. The primary outcome was death or the occurrence of bloodstream infection or UTI prior to discharge. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants. RESULTS: Median gestation and postnatal age at referral in this cohort (n = 1085) were 38 weeks and 3.1 hours, respectively. The primary outcome occurred in 395 patients (36%); and was associated with low birth weight, low Apgar, low admission pH, renal and associated anomalies, patch repair, and extracorporeal membrane oxygenation (P < .001 for all; area under receiver operating curve = 0.824; goodness of fit χ2 = 0.52). After omitting death from the outcome measure, admission pH, patch repair of CDH, and duration of central line placement were significantly associated with incident bloodstream infection or UTI. CONCLUSIONS: Infants with CDH are at high risk of infection which was predicted by clinical factors. Early identification and low threshold for sepsis evaluations in high-risk infants may attenuate acquisition and the consequences of these infections.

The Impact of Pulmonary Hypertension in Preterm Infants with Severe Bronchopulmonary Dysplasia through 1 Year.

OBJECTIVES: To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. STUDY DESIGN: This was a multicenter, retrospective cohort study of 1677 infants born <32 weeks of gestation with severe bronchopulmonary dysplasia enrolled in the Children's Hospital Neonatal Consortium with records linked to the Pediatric Health Information System. RESULTS: Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR 3.15, 95% CI 2.10-4.73, P < .001), ventilator support at 36 weeks of postmenstrual age (60% vs 40%, P < .001), duration of ventilation (72 IQR 30-124 vs 41 IQR 17-74 days, P < .001), and higher respiratory severity score (3.6 IQR 0.4-7.0 vs 0.8 IQR 0.3-3.3, P < .001). At discharge, pulmonary hypertension was associated with tracheostomy (27% vs 9%, P < .001), supplemental oxygen use (84% vs 61%, P < .001), and tube feeds (80% vs 46%, P < .001). Through 1 year of corrected age, pulmonary hypertension was associated with increased frequency of readmission (incidence rate ratio [IRR] = 1.38, 95% CI 1.18-1.63, P < .001). CONCLUSIONS: Infants with severe bronchopulmonary dysplasia-associated pulmonary hypertension have increased morbidity and mortality through 1 year of corrected age. This highlights the need for improved diagnostic practices and prospective studies evaluating treatments for this high-risk population.

Survival of melanopsin expressing retinal ganglion cells long term after optic nerve trauma in mice.

In this study we have compared the response to optic nerve crush (ONC) and to optic nerve transection (ONT) of the general population of retinal ganglion cells in charge of the image-forming visual functions that express Brn3a (Brn3a+RGCs) with that of the sub-population of non-image forming RGCs that express melanopsin (m+RGCs). Intact animals were used as control. ONT and ONC were performed at 0.5 mm from the optic disk, and retinas dissected 3, 5, 7, 14, 30, 45 or 90 days later (n = 5/injury/time point). In all the retinas, Brn3a+RGCs and m+RGCs were identified and their survival analyzed quantitatively and topographically. There were no differences in the course of RGC loss between lesions. The decrease of RGCs was significant at short time points (3 or 5 days for Brn3a+ or m+ RGCs, respectively) and, up to 14 days, the course of loss of both RGC populations was similar, surviving at this time point between 20 and 22% of their original population. However, while the loss of Brn3a+RGCs continues steadily up to 90 days when only 5-6% of them still remain, the loss of m+RGCs stops at 14 days, and the proportion of surviving m+RGCs remains constant up to 90 days (26-30%). In conclusion, m+RGC do not respond to axotomy in the same way than the rest of RGCs, and so whilst image-forming RGCs die in two exponential phases a quick one and a slow protracted one, non-image forming RGCs die only during the first quick phase.

Nerve fibre layer degeneration and retinal ganglion cell loss long term after optic nerve crush or transection in adult mice.

We have investigated the long term effects of two different models of unilateral optic nerve (ON) lesion on retinal ganglion cells (RGCs) and their axons, in the injured and contralateral retinas of adult albino mice. Intact animals were used as controls. The left ON was intraorbitally crushed or transected at 0.5 mm from the optic disk and both retinas were analyzed at 2, 3, 5, 7, 14, 30, 45 or 90 days after injury. RGCs were immunoidentified with anti-Brn3a, and their axons with anti-highly phosphorylated axonal neurofilament subunit H (pNFH). After both lesions, RGC death in the injured retinas is first significant at day 3, and progresses quickly up to 7 days slowing down till 90 days. In the same retinas, the anatomical loss of RGC axons is not evident until day 30. However, by two days after both lesions there are changes in the expression pattern of pNFH: axonal beads, axonal club- or bulb-like formations, and pNFH+RGC somas. The number of pNFH+RGC somata peak at day 5 after either lesion and is significantly higher than in intact retinas at all time points. pNFH+RGC somata are distributed across the retina, in accordance with the pattern of RGC death which is diffuse and homogenous. In the contralateral retinas there is no RGC loss, but there are few pNFH+RGCs from day 2 to day 90. In conclusion, in albino mice, axotomy-induced RGC death precedes the loss of their intraretinal axons and occurs in two phases, a rapid and a slower, but steady, one. Injured retinas show similar changes in the pattern of pNFH expression and a comparable course of RGC loss.

Palliative care approaches to neonates with chronic respiratory failure.

Neonates with chronic respiratory failure have uncertain prognosis and can face significant treatment burden. As the trajectory of the illness becomes more concerning, consultation with a pediatric palliative service should be considered, especially as therapeutic options shift from standard to "innovative." Benefits include as follows: supporting emotionally conflicted providers and parents, maintaining transparency in determination of goals, and balancing medical progress with each individual patient's and family's best interests.

Retino-retinal projection in juvenile and young adult rats and mice.

Identification of retino-retinal projecting RGCs (ret-ret RGCs) has been accomplished by tracing RGCs in one retina after intravitreal injection of different tracers in the other eye. In mammals, rabbit and rat, ret-ret RGCs are scarce and more abundant in newborn than in adult animals. To our knowledge, ret-ret RGCs have not been studied in mice. Here we purpose to revisit the presence of ret-ret RGCs in juvenile and young adult rats and mice by using retrograde tracers applied to the contralateral optic nerve instead of intravitreally. In P20 (juvenile) and P60 (young adult) animals, the left optic nerve was intraorbitally transected and Fluorogold (rats) or its analogue OHSt (mice) were applied onto its distal stump. P20 animals were sacrificed 3 (mice) or 5 (rats) days later and adult animals at 5 (mice) or 7 (rats) days. Right retinas were dissected as flat-mounts and double immunodetected for Brn3a and melanopsin. Ret-ret RGCs were those with tracer accumulation in their somas. Out of them some expressed Brn3a and/or melanopsin, while other were negative for both markers. In young adult rats, we found 2 ret-ret RGCs displaced to the inner nuclear layer. In both species, ret-ret RGCs are quite scarce and found predominantly in the nasal retina. In juvenile animals there are significantly more ret-ret RGCs (9 ± 3, rats, 13 ± 3 mice) than in young adult ones (5 ± 6 rats, 7 ± 3 mice). Finally, juvenile and young adult mice have more ret-ret RGCs than rats.

Number and spatial distribution of intrinsically photosensitive retinal ganglion cells in the adult albino rat.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) respond directly to light and are responsible of the synchronization of the circadian rhythm with the photic stimulus and for the pupillary light reflex. To quantify the total population of rat-ipRGCs and to assess their spatial distribution we have developed an automated routine and used neighbour maps. Moreover, in all analysed retinas we have studied the general population of RGCs - identified by their Brn3a expression - and the population of ipRGCs - identified by melanopsin immunodetection - thus allowing the co-analysis of their topography. Our results show that the total mean number ± standard deviation of ipRGCs in the albino rat is 2047 ± 309. Their distribution in the retina seems to be complementary to that of Brn3a(+)RGCs, being denser in the periphery, especially in the superior retina where their highest densities are found in the temporal quadrant, above the visual streak. In addition, by tracing the retinas from both superior colliculi, we have also determined that 90.62% of the ipRGC project to these central targets.