Caffeine and Less Invasive Surfactant Administration for Respiratory Distress Syndrome of the Newborn.

BACKGROUND: Management strategies for preterm neonates with respiratory distress syndrome include early initiation of continuous positive airway pressure (CPAP) and titration of fractional inspired oxygen and may include the use of less invasive surfactant administration (LISA) to avoid the need for endotracheal intubation. This randomized trial investigated whether early administration of caffeine and LISA would decrease the need for endotracheal intubation in the first 72 hours of life (HoL) compared with caffeine and CPAP alone. METHODS: Eligible neonates born at 24 weeks 0 days to 29 weeks 6 days of gestational age were randomly assigned to receive intravenous caffeine in the first 2 HoL followed by surfactant administration via the LISA method (intervention) or caffeine followed by CPAP (control). The primary outcome was the frequency of neonates requiring endotracheal intubation or meeting respiratory failure criteria between groups (caffeine and LISA vs. caffeine and CPAP) within the first 72 HoL. Multivariable logistic regression modeling was used to adjust for gestational age strata in normally distributed primary and secondary outcomes. RESULTS: Enrollment occurred between January 2020 and December 2022. Endotracheal intubation or meeting respiratory failure criteria within the first 72 HoL occurred in 21 (23%) of 92 neonates randomly assigned to receive caffeine and LISA compared with 47 (53%) of 88 neonates in the caffeine and CPAP group (odds ratio, 0.258; 95% confidence interval, 0.136 to 0.490; P<0.001), which remained significant after adjusting for gestational age strata (odds ratio, 0.227; 95% confidence interval, 0.112 to 0.460; P<0.001). Adverse events were similar between groups, except bronchopulmonary dysplasia, which occurred in 26% of the LISA group and 39% of the control group (P=0.049). CONCLUSIONS: In preterm neonates supported with CPAP, early caffeine and LISA resulted in a lower frequency of endotracheal intubation within the first 72 HoL. (Funded by Chiesi USA; ClinicalTrials.gov number, NCT04209946.)

Creating a small baby program: a single center's experience.

Creation of a small baby program requires special resources and multidisciplinary engagement. Such a program has the potential to improve patient care, parent and staff satisfaction, collaboration and communication. We have described benefits, challenges, and practical approaches to creating and maintaining a small baby program that could be a model for the development of special programs for other sub-populations within in the NICU.

Multicentre, randomised trial of preterm infants receiving caffeine and less invasive surfactant administration compared with caffeine and early continuous positive airway pressure (CaLI trial): study protocol.

INTRODUCTION: Respiratory distress syndrome (RDS) or surfactant deficiency occurs primarily in premature infants resulting in composite outcomes of death or bronchopulmonary dysplasia. Initial management strategies for preterm infants with RDS includes early initiation of continuous positive airway pressure (CPAP) and titration of fractional inspired oxygen (FiO2), and may include the use of less invasive surfactant administration (LISA) to avoid the need for mechanical ventilation. In order to optimise success of non-invasive support, the use of early caffeine therapy may be critical to the success of LISA. The objective of our trial is to evaluate whether infants that receive early caffeine, CPAP and surfactant via the LISA method compared with infants that receive caffeine and CPAP alone, have a decreased need for invasive mechanical ventilation in the first 72 hours of life. METHODS AND ANALYSIS: CaLI is an unblinded multicentre, randomised controlled, trial of 180 preterm infants (24+0-29+6 weeks corrected GA). Criteria for intubation/treatment failure will follow guidelines for the management of RDS, including: (1) CPAP level of 6-8 cmH20 and FiO2 >0.40 required to maintain saturations 90%-95% for 2 hours after randomisation; (2) a pH of 7.15 or less or a paCO2 >65 mm Hg on any (2) blood gases (arterial/capillary/or venous) at least 2 hours after randomisation and in the first 72 hours of life; (3) continued apnoea/bradycardia/desaturation events despite nasal intermittent minute ventilation mode of ventilation. Infants will be randomised by 1 hour of life and caffeine/LISA treatments administered by 2 hour of life. Caffeine will be administered prior to surfactant in the LISA arm and before 2 hours of life in the control arm. ETHICS AND DISSEMINATION: Chiesi Farmaceutici, S.p.A is the sponsor of CaLI. Ethical approval has been obtained. Results will be submitted for publication in peer reviewed journals. TRIAL REGISTRATION NUMBER: www.Clinicaltrials.gov: NCT04209946; Pre-results.

Oral dextrose reduced procedural pain without altering cellular ATP metabolism in preterm neonates: a prospective randomized trial.

OBJECTIVE: To examine the effects of 30% oral dextrose on biochemical markers of pain, adenosine triphosphate (ATP) degradation, and oxidative stress in preterm neonates experiencing a clinically required heel lance. STUDY DESIGN: Utilizing a prospective study design, preterm neonates that met study criteria (n = 169) were randomized to receive either (1) 30% oral dextrose, (2) facilitated tucking, or (3) 30% oral dextrose and facilitated tucking 2 min before heel lance. Plasma markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the premature infant pain profile-revised (PIPP-R). RESULTS: Oral dextrose, administered alone or with facilitated tucking, did not alter plasma markers of ATP utilization and oxidative stress. CONCLUSION: A single dose of 30% oral dextrose, given before a clinically required heel lance, decreased signs of pain without increasing ATP utilization and oxidative stress in premature neonates.

Positive Predictive Value of Administrative Data for Neonatal Abstinence Syndrome.

OBJECTIVES: Neonatal abstinence syndrome (NAS) is a postnatal withdrawal syndrome experienced by some infants with opioid exposure. Hospital administrative data are commonly used for research and surveillance but have not been validated for NAS. Our objectives for this study were to validate the diagnostic codes for NAS and to develop an algorithm to optimize identification. METHODS: Tennessee Medicaid claims from 2009 to 2011 (primary sample) and 2016 (secondary sample; post-International Classification of Diseases, 10th Revision, Clinical Modification [ICD-10-CM]) were obtained. Cases of NAS were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification code (2009-2011) 779.5 and ICD-10-CM code (2016) P96.1. Medical record review cases were then conducted by 2 physicians using a standardized algorithm, and positive predictive value (PPV) was calculated. Algorithms were developed for optimizing the identification of NAS in administrative data. RESULTS: In our primary sample of 112 029 mother-infant dyads, 950 potential NAS cases were identified from Medicaid claims data and reviewed. Among reviewed records, 863 were confirmed as having NAS (including 628 [66.1%] cases identified as NAS requiring pharmacotherapy, 224 [23.5%] as NAS not requiring pharmacotherapy, and 11 [1.2%] as iatrogenic NAS), and 87 (9.2%) did not meet clinical criteria for NAS. The PPV of the International Classification of Diseases, Ninth Revision, Clinical Modification code for NAS in clinically confirmed NAS was 91% (95% confidence interval: 88.8%-92.5%). Similarly, the PPV for the ICD-10-CM code in the secondary sample was 98.2% (95% confidence interval: 95.4%-99.2%). Algorithms using elements from the Medicaid claims and from length of stay improved PPV. CONCLUSIONS: In a large population-based cohort of Medicaid participants, hospital administrative data had a high PPV in identifying cases of clinically diagnosed NAS.

Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection.

BACKGROUND: Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV). In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model. METHODS AND RESULTS: B6.CH-2(bm12) strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice (myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2+ monocytes/macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts. CONCLUSIONS: Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets.

Does duration of donor brain injury affect outcome after orthotopic pediatric heart transplantation?

OBJECTIVE: We tested the hypothesis that duration of donor brain injury and death would have an adverse effect on recipient rejection and mortality in pediatric heart transplantation. METHODS: Ninety-three cardiac transplants were performed at our center from July 1, 1997, through June 30, 2003. The primary study end points were the number of rejection episodes and the time to first rejection. Secondary outcomes were early and late mortality. RESULTS: Among 88 recipients of 93 cardiac allografts, 5 (6%) and 1 (1%) received second and third allografts, respectively. Overall patient mortality (3 early and 2 late) was 6% (5/88), and overall graft loss was 6% (6/93). Median time from donor brain injury to declaration of brain death (brain injury interval), time from brain death to donor cardiectomy (brain death interval), and graft ischemia time were 38, 24, and 3.3 hours, respectively. Cox regression analysis (adjusting for United Network for Organ Sharing status, ventilator dependence, extracorporeal membrane oxygenation and ventricular-assist device status, diagnosis of congenital heart disease, sex and cytomegalovirus mismatches, and type of immunosuppression) demonstrated that recipients of donor hearts with relatively long periods from brain injury to death declaration or from death to organ removal had significantly improved rejection-free survival (hazard ratios 0.3, P = .01, and 0.5, P = .05, for brain injury and brain death times, respectively). Prolonged donor heart ischemia did not impact rejection rate. Increasing brain injury interval, brain death interval, and graft ischemia time had no significant effect on mortality. CONCLUSION: Longer brain injury and death intervals correlated with improved freedom from rejection but had no effect on mortality.

Liberalization of donor criteria in lung transplantation.

Donor shortage remains a major obstacle to widespread application of lung transplantation. In region 5, including California, Nevada, New Mexico, Utah, and Arizona, the United Network of Organ Sharing (UNOS) database median waiting time for lung transplant candidates in 2000-2001 exceeded 17 months. The purpose of this study was to determine the impact of liberalization of donor criteria on median waiting time and short-term outcome of lung transplantation. From September 1999 to October 2002, 42 patients underwent lung transplantation from nonstandard donors. The donors were classified as nonstandard due to (1) infiltrate on chest radiograph (n = 33), (2) PaO2 < 300 on FiO2 1.0 and PEEP 5 (n = 3), (3) PaO2 < 100 on FiO2 0.4 and PEEP 5 (n = 3), (4) purulent sputum on bronchoscopy (n = 22), and (5) smoking history greater than 50 pack-years (n = 1). Perioperative characteristics and short-term outcome of this group was analyzed. The median waiting time for this cohort was 114 days (range, 10-1267), as compared with the national UNOS database median waiting time of 24 months between 1996 and 2001. The incidence of ischemia reperfusion injury was 2.3 per cent. None of the recipients developed pneumonia. The median ventilator support time was 2 days (range, 1-95). The median ICU stay and hospital stay were 4 days (range, 2-103) and 14 days (range, 5-194), respectively. The 3-month survival was 97.6 per cent. Selective liberalization of donor lung criteria can decrease the waiting time and is associated with favorable short-term outcome. Utilization of nonstandard lungs can expand the donor pool.

Cardiac surgery in children with end-stage liver disease awaiting liver transplantation.

BACKGROUND: Cardiac repair for congenital heart disease in children awaiting liver transplantation presents unique therapeutic challenges and dilemmas. We tested the hypothesis that operations in these children requiring cardiopulmonary bypass (CPB) were not associated with prohibitive morbidity and mortality. METHODS: Over the last 10 years (1994-2004), five infants were identified in our database with end-stage liver disease and awaiting liver transplantation that required cardiac surgery. Primary end point for the study was mortality. Secondary end points included morbidity and time to liver transplantation. The new pediatric end-stage liver disease (PELD) model was used to score liver disease severity. RESULTS: Three boys and two girls with mean age of 8.6 months (range, 1.5-21 months) and mean PELD of 18.0 (range, 10-29) required CPB for repair. The only early mortality in the series occurred after cardiac arrest during creation of a central shunt. The child expired two days later despite extracorporeal membrane oxygenation support. The patient had important myocardial hypertrophy. All other patients survived and underwent successful liver transplantation. CONCLUSIONS: Children with significant congenital heart disease awaiting liver transplantation can undergo safe cardiac repair with judicious perioperative support thereby reducing the risks of subsequent liver transplantation.

Chemokine monokine induced by IFN-gamma/CXC chemokine ligand 9 stimulates T lymphocyte proliferation and effector cytokine production.

Monokine induced by IFN-gamma (MIG; CXC chemokine ligand (CXCL)9) is important in T lymphocyte recruitment in organ transplantation. However, it is not known whether this chemokine, in addition to its chemotactic properties, exerts any effect on T lymphocyte effector functions. For in vivo studies, we used a previously characterized murine model of chronic rejection. The recipient mice were treated with anti-MIG/CXCL9 Ab; graft-infiltrating cells were analyzed for IFN-gamma production. For in vitro studies, exogenous CXCR3 ligands were added to CD4 lymphocytes in MLRs, and the proliferative responses were measured. Separate experiments quantitated the number of IFN-gamma-producing cells in MLRs by ELISPOT. Neutralization of MIG/CXCL9, in the in vivo model, resulted in significant reduction in the percentage of IFN-gamma-producing graft-infiltrating T lymphocytes. In vitro experiments demonstrated that 1) exogenous MIG/CXCL9 stimulated CD4 lymphocyte proliferation in a MHC class II-mismatched MLR, 2) MIG/CXCL9 also increased the number of IFN-gamma-producing CD4 lymphocytes in ELISPOT, 3) neutralization of MIG/CXCL9 in MLR reduced T lymphocyte proliferation, 4) IFN-gamma-inducible protein 10/CXCL10 and IFN-inducible T cell alpha chemoattractant/CXCL11 had similar effects on T lymphocyte proliferation, 5) MIG/CXCL9 stimulated T lymphocyte proliferation in MHC class I- and total MHC-mismatched MLRs, 6) neutralization of CXCR3 reduced MIG/CXCL9-induced T lymphocyte proliferation and the number of IFN-gamma-positive spots on ELISPOT, and 7) the proliferative effects of MIG/CXCL9 were mediated via an IL-2-independent pathway and were controlled by IFN-gamma. This study demonstrates that MIG/CXCL9 stimulates T lymphocyte proliferation and effector cytokine production, in addition to its chemotactic effects. This novel observation expands our current understanding of MIG/CXCL9 biology beyond that of mediating T cell trafficking.