Early nitric oxide is not associated with improved outcomes in congenital diaphragmatic hernia.

BACKGROUND: Inhaled nitric oxide (iNO) is widely used for the management of infants with congenital diaphragmatic hernia (CDH); however, evidence of benefit is limited. METHODS: This is a multicenter cohort study using data from the Congenital Diaphragmatic Hernia Study Group between 2015 and 2020. The impact of early iNO use in the first 3 days of life prior to ECLS use on mortality or ECLS use was explored using multivariate logistic regression models and subgroup analyses. RESULTS: Of the 1777 infants, 863 (48.6%) infants received early iNO treatment. Infants receiving iNO had lower birth weight, larger defect size, more severe pulmonary hypertension, and abnormal ventricular size and function. After controlling for these factors, early iNO use was associated with increased mortality (aOR 2.06, 95% CI 1.05-4.03, P = 0.03) and increased ECLS use (aOR 3.44, 95% CI 2.11-5.60, P < 0.001). Subgroup analyses after stratification by echocardiographic characteristics and defect size revealed no subgroup with a reduction in mortality or ECLS use. CONCLUSIONS: Use of iNO in the first 3 days of life prior to ECLS was not associated with a reduction in mortality or ECLS use in either the regression models or the subgroup analyses. The widespread use of iNO in this vulnerable population requires reconsideration. IMPACT: Evidence to support widespread use of iNO for infants with congenital diaphragmatic hernia is limited. The use of iNO in the first 3 days of life was associated with significantly increased mortality and ECLS use. Stratification by echocardiographic characteristics and defect size did not reveal a subgroup that benefited from iNO. Even the subset of patients with R-to-L shunts at both ductal and atrial levels, a surrogate for elevated pulmonary arterial pressures in the absence of significantly decreased LV compliance, did not benefit from early iNO use. Early iNO therapy was of no benefit in the management of acute pulmonary hypertension in infants with congenital diaphragmatic hernia, supporting reconsideration of its use in this population.

Cerebral oxygen saturation in neonates: a bedside comparison between neonatal and adult NIRS sensors.

BACKGROUND: The majority of neonatal NIRS literature recommends target ranges for cerebral saturation (rScO2) based on data using adult sensors. Neonatal sensors are now commonly used in the neonatal intensive care unit (NICU). However, there is limited clinical data correlating these two measurements of cerebral oxygenation. METHODS: A prospective observational study was conducted in two NICUs between November 2019 and May 2021. An adult sensor was placed on infants undergoing routine cerebral NIRS monitoring with a neonatal sensor. Time-synchronized rScO2 measurements from both sensors, heart rate, and systemic oxygen saturation values were collected over 6 h under varying clinical conditions and compared. RESULTS: Time-series data from 44 infants demonstrated higher rScO2 measurements with neonatal sensors than with adult sensors; however, the magnitude of the difference varied depending on the absolute value of rScO2 (Adult = 0.63 × Neonatal + 18.2). While there was an approximately 10% difference when adult sensors read 85%, readings were similar when adult sensors read 55%. CONCLUSION: rScO2 measured by neonatal sensors is typically higher than measured by adult sensors, but the difference is not fixed and is less at the threshold indicative of cerebral hypoxia. Assuming fixed differences between adult and neonatal sensors may lead to overdiagnosis of cerebral hypoxia. IMPACT: In comparison to adult sensors, neonatal sensors rScO2 readings are consistently higher, but the magnitude of the difference varies depending on the absolute value of rScO2. Marked variability during high and low rScO2 readings was noted, with approximately 10% difference when adult sensors read 85%, but nearly similar (58.8%) readings when adult sensors read 55%. Estimating fixed differences of approximately 10% between adult and neonatal probes may lead to an inaccurate diagnosis of cerebral hypoxia and result in subsequent unnecessary interventions.

POCUS increases successful placement of peripheral arterial lines in neonates by less experienced providers.

To assess success of peripheral arterial line (PAL) placement after implementing a point-of-care ultrasound (POCUS) program in a neonatal intensive care unit. This was a retrospective chart review of infants who underwent successful PAL placement from January 2019 to March 2021. Outcomes included first-attempt success and the number of attempts with and without the use of POCUS. Among 80 PALs, 36% were POCUS-guided. All POCUS-guided lines were placed by providers with < 5 years neonatology experience. Among infants ≥ 2.5 kg, the use of POCUS was associated with fewer attempts compared to non-POCUS PAL placement (1 vs. 2, p = 0.035).     Conclusions: Use of POCUS for PAL placement was associated with fewer attempts for successful placement in infants ≥ 2.5 kg by providers with less neonatology experience compared with traditional method. What is Known: • Arterial line placement in neonates has been traditionally done by palpation and can be technically challenging. • POCUS is an emerging tool in the NICU with increasing number of less clinically experienced providers in the NICU having access to ultrasound. What is New: • Use of POCUS by less experienced clinicians for arterial line placement resulted in fewer attempts compared to the traditional landmark-based approach in a cohort of neonates.

In-Hospital Morbidities for Neonates with Congenital Diaphragmatic Hernia: The Impact of Defect Size and Laterality.

OBJECTIVE: To determine in-hospital morbidities for neonates with right-sided congenital diaphragmatic hernia (R-CDH) compared with those with left-sided defects (L-CDH) and to examine the differential effect of laterality and defect size on morbidities. STUDY DESIGN: This retrospective, multicenter, cohort study from the international Congenital Diaphragmatic Hernia Study Group registry collected data from neonates with CDH surviving until hospital discharge from 90 neonatal intensive care units between January 1, 2007, and July 31, 2020. Major pulmonary, cardiac, neurologic, and gastrointestinal morbidities were compared between neonates with L-CDH and R-CDH, adjusted for prenatal and postnatal factors using logistic regression. RESULTS: Of 4123 survivors with CDH, those with R-CDH (n = 598 [15%]) compared with those with L-CDH (n = 3525 [85%]) had an increased odds of pulmonary (1.7; 95% CI, 1.4-2.2, P < .0001), cardiac (1.4; 95% CI, 1.1-1.8; P = .01), gastrointestinal (1.3; 95% CI, 1.1-1.6; P = .01), and multiple (1.6; 95% CI, 1.2-2.0; P < .001) in-hospital morbidities, with a greater likelihood of morbidity with increasing defect size. There was no difference in neurologic morbidities between the groups. CONCLUSIONS: Neonates with R-CDH and a larger defect size are at an increased risk for in-hospital morbidities. Counseling and clinical strategies should incorporate knowledge of these risks, and approach to neonatal R-CDH should be distinct from current practices targeted to L-CDH.

Real-Time Ultrasound Guidance for Umbilical Venous Cannulation in Neonates With Congenital Heart Disease.

OBJECTIVES: Umbilical venous cannulation is the favored approach to perinatal central access worldwide but has a failure rate of 25-50% and the insertion technique has not evolved in decades. Improving the success of this procedure would have broad implications, particularly where peripherally inserted central catheters are not easily obtained and in neonates with congenital heart disease, in whom umbilical access facilitates administration of inotropes and blood products while sparing vessels essential for later cardiac interventions. We sought to use real-time, point-of-care ultrasound to achieve central umbilical venous access in patients for whom conventional, blind placement techniques had failed. DESIGN: Multicenter case series, March 2019-May 2021. SETTING: Cardiac and neonatal ICUs at three tertiary care children's hospitals. PATIENTS: We identified 32 neonates with congenital heart disease, who had failed umbilical venous cannulation using traditional, blind techniques. INTERVENTIONS: Real-time ultrasound guidance and liver pressure were used to replace malpositioned catheters and achieve successful placement at the inferior cavoatrial junction. MEASUREMENTS AND MAIN RESULTS: In 32 patients with failed prior umbilical venous catheter placement, real-time ultrasound guidance was used to successfully "rescue" the line and achieve central position in 23 (72%). Twenty of 25 attempts (80%) performed in the first 48 hours of life were successful, and three of seven attempts (43%) performed later. Twenty-four patients (75%) were on prostaglandin infusion at the time of the procedure. We did not identify an association between patient weight or gestational age and successful placement. CONCLUSIONS: Ultrasound guidance has become standard of care for percutaneous central venous access but is a new and emerging technique for umbilical vessel catheterization. In this early experience, we report that point-of-care ultrasound, together with liver pressure, can be used to markedly improve success of placement. This represents a significant advance in this core neonatal procedure.

Implementation of a Bedside Point-of-Care Ultrasound Program in a Large Academic Neonatal Intensive Care Unit.

OBJECTIVE: In the adult and pediatric critical care population, point-of-care ultrasound (POCUS) can aid in diagnosis, patient management, and procedural accuracy. For neonatal providers, training in ultrasound and the use of ultrasound for diagnosis and management is increasing, but use in the neonatal intensive care unit (NICU) is still uncommon compared with other critical care fields. Our objective was to describe the process of implementing a POCUS program in a large academic NICU and evaluate the role of ultrasound in neonatal care during early adaption of this program. STUDY DESIGN: A POCUS program established in December 2018 included regular bedside scanning, educational sessions, and quality assurance, in collaboration with members of the cardiology, radiology, and pediatric critical care divisions. Core applications were determined, and protocols outlined guidelines for image acquisition. An online database included images and descriptive logs for each ultrasound. RESULTS: A total of 508 bedside ultrasounds (76.8% diagnostic and 23.2% procedural) were performed by 23 providers from December 2018 to December 2020 in five core diagnostic applications: umbilical line visualization, cardiac, lung, abdomen (including bladder), and cranial as well as procedural applications. POCUS guided therapy and influenced clinical management in all applications: umbilical line assessment (26%), cardiac (33%), lung (14%), abdomen (53%), and cranial (43%). With regard to procedural ultrasound, 74% of ultrasound-guided arterial access and 89% of ultrasound-guided lumbar punctures were successful. CONCLUSIONS: Implementation of a POCUS program is feasible in a large academic NICU and can benefit from a team approach. Establishing a program in any NICU requires didactic opportunities, a defined scope of practice, and imaging review with quality assurance. Bedside clinician performed ultrasound findings can provide valuable information in the NICU and impact clinical management. KEY POINTS: · Use of point-of-care ultrasound is increasing in neonatology and has been shown to improve patient care.. · Implementation of a point-of-care ultrasound program requires the definition of scope of practice and can benefit from the support of other critical care and imaging departments and providers.. · Opportunities for point-of-care ultrasound didactics, imaging review, and quality assurance can enhance the utilization of bedside ultrasound..

Relationship between donor-derived cell-free DNA and tissue-based rejection-related transcripts in heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB)-based traditional microscopy remains the gold standard for the detection of cardiac allograft rejection, despite its limitation of inherent subjectivity leading to inter-reader variability. Alternative techniques now exist to surveil for allograft injury and classify rejection. Donor-derived cell-free DNA (dd-cfDNA) testing is now a validated blood-based assay used to surveil for allograft injury. The molecular microscope diagnostic system (MMDx) utilizes intragraft rejection-associated transcripts (RATs) to classify allograft rejection and identify injury. The use of dd-cfDNA and MMDx together provides objective molecular insight into allograft injury and rejection. The aim of this study was to measure the diagnostic agreement between dd-cfDNA and MMDx and assess the relationship between dd-cfDNA and MMDx-derived RATs, which may provide further insight into the pathophysiology of allograft rejection and injury. METHODS: This is a retrospective observational study of 156 EMB evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood before EMB (up to 9 days). Diagnostic agreement between traditional histopathology, MMDx, and dd-cfDNA (threshold of 0.20%) was compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated. RESULTS: MMDx characterized allograft tissue as no rejection (62.8%), antibody-mediated rejection (ABMR) (26.9%), T-cell-mediated rejection (TCMR) (5.8%), and mixed ABMR/TCMR (4.5%). For the diagnosis of any type of rejection (TCMR, ABMR, and mixed rejection), there was substantial agreement between MMDx and dd-cfDNA (76.3% agreement). All transcript clusters (group of gene sets designated by MMDx) and individual transcripts considered abnormal from MMDx had significantly elevated dd-cfDNA. In addition, a positive correlation between dd-cfDNA levels and certain MMDx-derived RATs was observed. Tissue transcript clusters were correlated with dd-cfDNA scores, including DSAST, GRIT, HT1, QCMAT, and S4. For individual transcripts, tissue ROBO4 was significantly correlated with dd-cfDNA in both nonrejection and rejection as assessed by MMDx. CONCLUSIONS: Collectively, we have shown substantial diagnostic agreement between dd-cfDNA and MMDx. Furthermore, based on the findings presented, we postulate a common pathway between the release of dd-cfDNA and expression of ROBO4 (a vascular endothelial-specific gene that stabilizes the vasculature) in the setting of antibody-mediated rejection, which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to acute cellular rejection.

Newer indications for neuromonitoring in critically ill neonates.

Continuous neuromonitoring in the neonatal intensive care unit allows for bedside assessment of brain oxygenation and perfusion as well as cerebral function and seizure identification. Near-infrared spectroscopy (NIRS) reflects the balance between oxygen delivery and consumption, and use of multisite monitoring of regional oxygenation provides organ-specific assessment of perfusion. With understanding of the underlying principles of NIRS as well as the physiologic factors which impact oxygenation and perfusion of the brain, kidneys and bowel, changes in neonatal physiology can be more easily recognized by bedside providers, allowing for appropriate, targeted interventions. Amplitude-integrated electroencephalography (aEEG) allows continuous bedside evaluation of cerebral background activity patterns indicative of the level of cerebral function as well as identification of seizure activity. Normal background patterns are reassuring while abnormal background patterns indicate abnormal brain function. Combining brain monitoring information together with continuous vital sign monitoring (blood pressure, pulse oximetry, heart rate and temperature) at the bedside may be described as multi-modality monitoring and facilitates understanding of physiology. We describe 10 cases in critically ill neonates that demonstrate how comprehensive multimodal monitoring provided greater recognition of the hemodynamic status and its impact on cerebral oxygenation and cerebral function thereby informing treatment decisions. We anticipate that there are numerous other uses of NIRS as well as NIRS in conjunction with aEEG which are yet to be reported.

Image-based prenatal predictors of postnatal survival, extracorporeal life support, and defect size in right congenital diaphragmatic hernia.

OBJECTIVE: To determine the association between prenatal ultrasound (US) and magnetic resonance imaging (MRI) characteristics in right congenital diaphragmatic hernia (RCDH) with postnatal outcome. STUDY DESIGN: CDH Study Group data were reviewed for all RCDH infants (n = 156) born between 2015 and 2019. Prenatal US and MRI lung size measurements were correlated with survival, extracorporeal life support (ECLS), and defect size. RESULT: Overall survival was 64.1%. ECLS was required in 40.4%. US and MRI-based prenatal assessment of pulmonary hypoplasia does not predict survival. Prenatal measurement of lung size using either US or MRI correlates with ECLS use. Only MRI-based measures of lung size are associated with defect size. CONCLUSION: Image-based prenatal predictors of survival, ECLS, and defect size are of limited value in RCDH. Extrapolation of prenatal survival and morbidity indicators from left to right-sided CDH is not appropriate. There is an urgent need to develop RCDH prenatal prediction models.