Inhaled bronchodilators for the prevention and treatment of chronic lung disease in preterm infants.

BACKGROUND: Chronic lung disease (CLD) occurs frequently in preterm infants and is associated with respiratory morbidity. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increased compliance and tidal volume, and decreased airway resistance, have been documented with the use of bronchodilators in infants with CLD. Therefore, bronchodilators are widely considered to have a role in the prevention and treatment of CLD, but there remains uncertainty as to whether they improve clinical outcomes. This is an update of the 2016 Cochrane review. OBJECTIVES: To determine the effect of inhaled bronchodilators given as prophylaxis or as treatment for chronic lung disease (CLD) on mortality and other complications of preterm birth in infants at risk for or identified as having CLD. SEARCH METHODS: An Information Specialist searched CENTRAL, MEDLINE, Embase, CINAHL and three trials registers from 2016 to May 2023. In addition, the review authors undertook reference checking, citation searching and contact with trial authors to identify additional studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials involving preterm infants less than 32 weeks old that compared bronchodilators to no intervention or placebo. CLD was defined as oxygen dependency at 28 days of life or at 36 weeks' postmenstrual age. Initiation of bronchodilator therapy for the prevention of CLD had to occur within two weeks of birth. Treatment of infants with CLD had to be initiated before discharge from the neonatal unit. The intervention had to include administration of a bronchodilator by nebulisation or metered dose inhaler. The comparator was no intervention or placebo. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Critical outcomes included: mortality within the trial period; CLD (defined as oxygen dependency at 28 days of life or at 36 weeks' postmenstrual age); adverse effects of bronchodilators, including hypokalaemia (low potassium levels in the blood), tachycardia, cardiac arrhythmia, tremor, hypertension and hyperglycaemia (high blood sugar); and pneumothorax. We used the GRADE approach to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included two randomised controlled trials in this review update. Only one trial provided useable outcome data. This trial was conducted in six neonatal intensive care units in France and Portugal, and involved 173 participants with a gestational age of less than 31 weeks. The infants in the intervention group received salbutamol for the prevention of CLD. The evidence suggests that salbutamol may result in little to no difference in mortality (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.50 to 2.31; risk difference (RD) 0.01, 95% CI -0.09 to 0.11; low-certainty evidence) or CLD at 28 days (RR 1.03, 95% CI 0.78 to 1.37; RD 0.02, 95% CI -0.13 to 0.17; low-certainty evidence), when compared to placebo. The evidence is very uncertain about the effect of salbutamol on pneumothorax. The one trial with usable data reported that there were no relevant differences between groups, without providing the number of events (very low-certainty evidence). Investigators in this study did not report if side effects occurred. We found no eligible trials that evaluated the use of bronchodilator therapy for the treatment of infants with CLD. We identified no ongoing studies. AUTHORS' CONCLUSIONS: Low-certainty evidence from one trial showed that inhaled bronchodilator prophylaxis may result in little or no difference in the incidence of mortality or CLD in preterm infants, when compared to placebo. The evidence is very uncertain about the effect of salbutamol on pneumothorax, and neither included study reported on the incidence of serious adverse effects. We identified no trials that studied the use of bronchodilator therapy for the treatment of CLD. Additional clinical trials are necessary to assess the role of bronchodilator agents in the prophylaxis or treatment of CLD. Researchers studying the effects of inhaled bronchodilators in preterm infants should include relevant clinical outcomes in addition to pulmonary mechanical outcomes.

Neonatal Golden Hour: a review of current best practices and available evidence.

PURPOSE OF REVIEW: Recommendations made by several scientific bodies advocate for adoption of evidence-based interventions during the first 60 min of postnatal life, also known as the 'Golden Hour', to better support the fetal-to-neonatal transition. Implementation of a Golden Hour protocol leads to improved short-term and long-term outcomes, especially in extremely premature and extreme low-birth-weight (ELBW) neonates. Unfortunately, several recent surveys have highlighted persistent variability in the care provided to this vulnerable population in the first hour of life. RECENT FINDINGS: Since its first adoption in the neonatal ICU (NICU) in 2009, published literature shows a consistent benefit in establishing a Golden Hour protocol. Improved short-term outcomes are reported, including reductions in hypothermia and hypoglycemia, efficiency in establishing intravenous access, and timely initiation of fluids and medications. Additionally, long-term outcomes report decreased risk for bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) and retinopathy of prematurity (ROP). SUMMARY: Critical to the success and sustainability of any Golden Hour initiative is recognition of the continuous educational process involving multidisciplinary team collaboration to ensure coordination between providers in the delivery room and beyond. Standardization of practices in the care of extremely premature neonates during the first hour of life leads to improved outcomes. VIDEO ABSTRACT: http://links.lww.com/MOP/A68 .

History of Neonatal Resuscitation: From Uncivilized to Evidence-based Practices.

Neonatal resuscitation, an early and critical intervention in human life, has dramatically evolved. This procedure has gone through phases from uncivilized practices that were sometimes based on myths to the current evidence-based approaches. In this review, we will shed light on the evolution of neonatal resuscitation from early centuries to the current day. Our goal is to highlight the value of clinical research and its role in invalidating hazardous practices and establishing evidence-based guidelines.

Ventilation Strategies During Extracorporeal Membrane Oxygenation for Neonatal Respiratory Failure: Current Approaches Among Level IV Neonatal ICUs.

To describe ventilation strategies used during extracorporeal membrane oxygenation (ECMO) for neonatal respiratory failure among level IV neonatal ICUs (NICUs). DESIGN: Cross-sectional electronic survey. SETTING: Email-based Research Electronic Data Capture survey. PATIENTS: Neonates undergoing ECMO for respiratory failure at level IV NICUs. INTERVENTIONS: A 40-question survey was sent to site sponsors of regional referral neonatal ECMO centers participating in the Children's Hospitals Neonatal Consortium. Reminder emails were sent at 2- and 4-week intervals. MEASUREMENTS AND MAIN RESULTS: Twenty ECMO centers responded to the survey. Most primarily use venoarterial ECMO (65%); this percentage is higher (90%) for congenital diaphragmatic hernia. Sixty-five percent reported following protocol-based guidelines, with neonatologists primarily responsible for ventilator management (80%). The primary mode of ventilation was pressure control (90%), with synchronized intermittent mechanical ventilation (SIMV) comprising 80%. Common settings included peak inspiratory pressure (PIP) of 16-20 cm H2O (55%), positive end-expiratory pressure (PEEP) of 9-10 cm H2O (40%), I-time 0.5 seconds (55%), rate of 10-15 (60%), and Fio2 22-30% (65%). A minority of sites use high-frequency ventilation (HFV) as the primary mode (5%). During ECMO, 55% of sites target some degree of lung aeration to avoid complete atelectasis. Fifty-five percent discontinue inhaled nitric oxide (iNO) during ECMO, while 60% use iNO when trialing off ECMO. Nonventilator practices to facilitate decannulation include bronchoscopy (50%), exogenous surfactant (25%), and noninhaled pulmonary vasodilators (50%). Common ventilator thresholds for decannulation include PEEP of 6-7 (45%), PIP of 21-25 (55%), and tidal volume 5-5.9 mL/kg (50%). CONCLUSIONS: The majority of level IV NICUs follow internal protocols for ventilator management during neonatal respiratory ECMO, and neonatologists primarily direct management in the NICU. While most centers use pressure-controlled SIMV, there is considerable variability in the range of settings used, with few centers using HFV primarily. Future studies should focus on identifying respiratory management practices that improve outcomes for neonatal ECMO patients.

Targeted Mutations in the Fusion Peptide Region of La Crosse Virus Attenuate Neuroinvasion and Confer Protection against Encephalitis.

La Crosse virus (LACV) is a major cause of pediatric encephalitis and aseptic meningitis in the Midwestern, Mid-Atlantic, and Southern United States, where it is an emerging pathogen. The LACV Gc glycoprotein plays a critical role in the neuropathogenesis of LACV encephalitis as the putative virus attachment protein. Previously, we identified and experimentally confirmed the location of the LACV fusion peptide within Gc and generated a panel of recombinant LACVs (rLACVs) containing mutations in the fusion peptide as well as the wild-type sequence. These rLACVs retained their ability to cause neuronal death in a primary embryonic rat neuronal culture system, despite decreased replication and fusion phenotypes. To test the role of the fusion peptide in vivo, we tested rLACVs in an age-dependent murine model of LACV encephalitis. When inoculated directly into the CNS of young adult mice (P28), the rLACV fusion peptide mutants were as neurovirulent as the rLACV engineered with a wild-type sequence, confirming the results obtained in tissue culture. In contrast, the fusion peptide mutant rLACVs were less neuroinvasive when suckling (P3) or weanling (P21) mice were inoculated peripherally, demonstrating that the LACV fusion peptide is a determinant of neuroinvasion, but not of neurovirulence. In a challenge experiment, we found that peripheral challenge of weanling (P21) mice with fusion peptide mutant rLACVs protected from a subsequent WT-LACV challenge, suggesting that mutations in the fusion peptide are an attractive target for generating live-attenuated virus vaccines. Importantly, the high degree of conservation of the fusion peptide amongst the Bunyavirales and, structurally, other arboviruses suggests that these findings are broadly applicable to viruses that use a class II fusion mechanism and cause neurologic disease.

Incidence of Nerve Transection in Upper Extremity Gunshot Wounds.

INTRODUCTION: Reported rates of nerve injury after upper extremity (UE) gunshot wound (GSW) range from 15% to 45%. Many surgeons prefer initial observation; however, this may delay diagnosis of neurotmesis and surgical treatment. We aimed to determine the incidence of nerve transection in adults after upper extremity GSWs. METHODS: This was a retrospective chart review approved by the institutional review board. Operative records of five orthopedic surgeons between 2014 to 2019 were filtered for ICD-10 and CPT codes cross-referenced to include both UE GSW assault and nerve injuries. Inclusion criteria consisted of age greater than 18 at time of injury, neurologic deficit on presentation, and surgical exploration nerve procedure. Records were reviewed for degree of nerve injury, procedure performed, and complications. Postoperative outcomes included nerve recovery, complications, and reoperation rate. RESULTS: Of the 17 patients that fit the inclusion criteria, the incidence of complete nerve transection was 64.7% and the incidence of a complete or partial nerve transection was 70.6%. The most common location of GSWs was the hand (70.5%). Average time from date of injury to surgery was 26.1 days. There were 14 identifiable nerve injuries-complete transection in 11, partial transection in one, and contusion in two patients. Of patients with nerve transection, 72.7% sustained a fracture. Postoperative complications included stiffness, chronic pain, and wound infection. The re-operation rate was 29.4%. The average postoperative follow-up was 4.4 months. There was longer follow-up among nerve transection patients (5.3 months) compared to neuropraxia patients (2.68 months). CONCLUSION: This study demonstrates a higher incidence of nerve transection in upper extremity GSW patients than previously reported. Predictors of nerve transection are GSWs to the hand and associated fracture.

Chronic lung disease in full-term infants: Characteristics and neonatal intensive care outcomes in infants referred to children's hospitals.

OBJECTIVE: To describe characteristics, outcomes, and risk factors for death or tracheostomy with home mechanical ventilation in full-term infants with chronic lung disease (CLD) admitted to regional neonatal intensive care units. STUDY DESIGN: This was a multicenter, retrospective cohort study of infants born ≥37 weeks of gestation in the Children's Hospitals Neonatal Consortium. RESULTS: Out of 67,367 full-term infants admitted in 2010-2016, 4886 (7%) had CLD based on receiving respiratory support at either 28 days of life or discharge. 3286 (67%) were still hospitalized at 28 days receiving respiratory support, with higher mortality risk than those without CLD (10% vs. 2%, p < 0.001). A higher proportion received tracheostomy (13% vs. 0.3% vs. 0.4%, p < 0.001) and gastrostomy (30% vs. 1.7% vs. 3.7%, p < 0.001) compared to infants with CLD discharged home before 28 days and infants without CLD, respectively. The diagnoses and surgical procedures differed significantly between the two CLD subgroups. Small for gestational age, congenital pulmonary, airway, and cardiac anomalies and bloodstream infections were more common among infants with CLD who died or required tracheostomy with home ventilation (p < 0.001). Invasive ventilation at 28 days was independently associated with death or tracheostomy and home mechanical ventilation (odds ratio 7.6, 95% confidence interval 5.9-9.6, p < 0.0001). CONCLUSION: Full-term infants with CLD are at increased risk for morbidity and mortality. We propose a severity-based classification for CLD in full-term infants. Future work to validate this classification and its association with early childhood outcomes is necessary.

Electrocardiogram for heart rate evaluation during preterm resuscitation at birth: a randomized trial.

BACKGROUND: Although electrocardiogram (ECG) can detect heart rate (HR) faster compared to pulse oximetry, it remains unknown if routine use of ECG for delivery room (DR) resuscitation reduces the time to stabilization in preterm infants. METHODS: Neonates <31 weeks' gestation were randomized to either an ECG-displayed or an ECG-blinded HR assessment in the DR. HR, oxygen saturation, resuscitation interventions, and clinical outcomes were compared. RESULTS: During the study period, 51 neonates were enrolled. The mean gestational age in both groups was 28 ± 2 weeks. The time to stabilization, defined as the time from birth to achieve HR ≥100 b.p.m., as well as oxygen saturation within goal range, was not different between the ECG-displayed and the ECG-blinded groups [360 (269, 435) vs 345 (240, 475) s, p = 1.00]. There was also no difference in the time to HR ≥100 b.p.m. [100 (75, 228) vs 138 (88, 220) s, p = 0.40] or duration of positive pressure ventilation (PPV) [345 (120, 558) vs 196 (150, 273) s, p = 0.36]. Clinical outcomes were also similar between groups. CONCLUSIONS: Although feasible and safe, the use of ECG in the DR during preterm resuscitation did not reduce time to stabilization. IMPACT: Although feasible and apparently safe, routine use of the ECG in the DR did not decrease time to HR >100 b.p.m., time to stabilization, or use of resuscitation interventions such as PPV for preterm infants <31 weeks' gestational age. This article adds to the limited randomized controlled trial evidence regarding the impact of routine use of ECG during preterm resuscitation on DR clinical outcomes. Such evidence is important when considering recommendations for routine use of the ECG in the DR worldwide as such a recommendation comes with a significant cost burden.

A comparison of newer classifications of bronchopulmonary dysplasia: findings from the Children's Hospitals Neonatal Consortium Severe BPD Group.

OBJECTIVE: To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. STUDY DESIGN: Data from the Children's Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. RESULTS: Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (<1%), but Grade 2 infants had aOR 7-21-fold higher for death and 23-56-fold higher for tracheostomy. CONCLUSIONS: Definitions with 3 BPD grades had better discrimination and Grade 3 2019 NRN had the strongest association with outcomes. No/Grade 1 infants rarely had severe outcomes, but Grade 2 infants were at risk. These data may be useful for counseling families and determining therapies for infants with BPD.

A study protocol for a Pilot Masked, Randomized Controlled Trial Evaluating Locally-applied Gentamicin versus Saline in Open Tibia Fractures (pGO-Tibia) in Dar es Salaam, Tanzania.

BACKGROUND: Open tibia fractures are a major source of disability in low- and middle-income countries (LMICs) due to the high incidence of complications, particularly infection and chronic osteomyelitis. One proposed adjunctive measure to reduce infection is prophylactic local antibiotic delivery, which can achieve much higher concentrations at the surgical site than can safely be achieved with systemic administration. Animal studies and retrospective clinical studies support the use of gentamicin for this purpose, but no high-quality clinical trials have been conducted to date in high- or low-income settings. METHODS: We describe a protocol for a pilot study conducted in Dar es Salaam, Tanzania, to assess the feasibility of a single-center masked randomized controlled trial to compare the efficacy of locally applied gentamicin to placebo for the prevention of fracture-related infection in open tibial shaft fractures. DISCUSSION: The results of this study will inform the design and feasibility of a definitive trial to address the use of local gentamicin in open tibial fractures. If proven effective, local gentamicin would be a low-cost strategy to reduce complications and disability from open tibial fractures that could impact care in both high- and low-income countries. TRIAL REGISTRATION: ClinicalTrials.gov, Registration # NCT03559400 ; Registered June 18, 2018.

Neonatal Toxic Shock Syndrome-Like Exanthematous Disease in North America.

Neonatal toxic shock syndrome (TSS)-like exanthematous disease (NTED) is a syndrome first reported in Japan. Neonates develop systemic exanthema, thrombocytopenia, and fever usually during the first week of life. The disease is distinguished from frank TSS because affected infants are not severely ill and do not meet TSS criteria. Most infants are confirmed to be colonized with TSST-1 producing strains of S. aureus. Suggested diagnostic criteria for NTED include a skin rash with generalized macular erythema and one of the following symptoms: fever >38.0°C, thrombocytopenia <150 x103uL, or low positive C-reactive protein (1-5 mg/dL) in the absence of another known disease process. NTED is common in Japanese NICUs, but outside Japan, only one case has been reported in France. We describe the first case of NTED reported in North America.

Discontinuing Nasal Continuous Positive Airway Pressure in Infants ≤32 Weeks of Gestational Age: A Randomized Control Trial.

OBJECTIVES: To compare immediate cessation of nasal continuous positive airway pressure (NCPAP) vs a stepwise decrease in pressure on the duration of NCPAP therapy in infants born prematurely. STUDY DESIGN: A single center study in infants 230-326 weeks of gestational age. NCPAP was stopped either at 5 cm H2O (control) or 3 cm H2O after a stepwise pressure wean (wean) using defined stability and failure criteria. Primary outcome is total NCPAP days. RESULTS: We enrolled 226 infants; 116 were randomly assigned to control and 110 to the wean group. There was no difference in the total NCPAP days between groups (median [25th, 75th percentiles] 16 [5, 36] vs 14 [7, 33] respectively). There were no differences between groups in secondary outcomes, including duration of hospital stay, critical care days, and oxygen supplementation. A higher proportion of control infants failed the initial attempt to discontinue NCPAP (43% vs 27%, respectively; P < .01) and required ≥2 attempts (20% vs 5%, respectively; P < .01). In addition, infants 23-27 weeks of gestational age in the wean group were 2.4-times more likely to successfully stop NCPAP at the first attempt (P = .02) vs controls. CONCLUSIONS: Discontinuation of NCPAP after a gradual pressure wean to 3 cm H2O did not decrease the duration of NCPAP therapy compared with stopping from 5 cm H2O in infants ≤32 weeks of gestational age. However, weaning decreased failed initial attempts to stop NCPAP, particularly among infants <28 weeks of gestational age. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02064712.

Analysis and Review of Automated Risk Calculators Used to Predict Postoperative Complications After Orthopedic Surgery.

PURPOSE OF REVIEW: To discuss the automated risk calculators that have been developed and evaluated in orthopedic surgery. RECENT FINDINGS: Identifying predictors of adverse outcomes following orthopedic surgery is vital in the decision-making process for surgeons and patients. Recently, automated risk calculators have been developed to quantify patient-specific preoperative risk associated with certain orthopedic procedures. Automated risk calculators may provide the orthopedic surgeon with a valuable tool for clinical decision-making, informed consent, and the shared decision-making process with the patient. Understanding how an automated risk calculator was developed is arguably as important as the performance of the calculator. Additionally, conveying and interpreting the results of these risk calculators with the patient and its influence on surgical decision-making are paramount. The most abundant research on automated risk calculators has been conducted in the spine, total hip and knee arthroplasty, and trauma literature. Currently, many risk calculators show promise, but much research is still needed to improve them. We recommend they be used only as adjuncts to clinical decision-making. Understanding how a calculator was developed, and accurate communication of results to the patient, is paramount.

Outcomes and Quality of Life Improvement After Multilevel Spinal Fusion in Elderly Patients.

STUDY DESIGN: Retrospective case series. OBJECTIVES: Both the rate and complexity of spine surgeries in elderly patients has increased. This study reports the outcomes of multilevel spine fusion in elderly patients and provides evidence on the appropriateness of complex surgery in elderly patients. METHODS: We identified 101 patients older than70 years who had ≥5 levels of fusion. Demographic, medical, and surgical data, and change between preoperative and >500 days postoperative health survey scores were collected. Health surveys were visual analogue scale (VAS), EuroQoL 5 Dimensions (EQ-5D), Oswestry Disability Index (ODI), Scoliosis Research Society questionnaire (SRS-30), and Short Form health survey (SF-12) (physical composite score [PCS] and mental composite score [MCS]). Minimal clinically important differences (MCIDs) were defined for each survey. RESULTS: Complications included dural tears (19%), intensive care unit admission (48%), revision surgery within 2 to 5 years (24%), and death within 2 to 5 years (16%). The percentage of patients who reported an improvement in health-related quality of life (HRQOL) of at least an MCID was: VAS Back 69%; EQ-5D 41%; ODI 58%; SRS-30 45%; SF-12 PCS 44%; and SF-12 MCS 48%. Improvement after a primary surgery, as compared with a revision, was on average 13 points higher in ODI (P = .007). Patients who developed a surgical complication averaged an improvement 11 points lower on ODI (P = .042). Patients were more likely to find improvement in their health if they had a lower American Society of Anesthesiologists or Charlson Comorbidity Index score or a higher metabolic equivalent score. CONCLUSIONS: In multilevel surgery in patients older than 70 years, complications are common, and on average 77% of patients attain some improvement, with 51% reaching an MCID. Physiological status is a stronger predictor of outcomes than chronological age.

Practice Patterns for Management of Pediatric Femur Fractures in Low- and Middle-Income Countries.

BACKGROUND: Femoral shaft fractures in children are common in low and middle income countries. In high-income countries, patient age, fracture pattern, associated injuries, child/family socioeconomic status, and surgeon preference dictate fracture management. There is limited literature on treatment patterns for pediatric femur fractures in resource-limited settings. This study surveys surgeons from low (LIC), lower-middle (LMIC), and upper-middle income (UMIC) countries regarding treatment patterns for pediatric femur fractures. METHODS: Surgeons completed an electronic survey reporting surgeon demographics and treatment preference for pediatric femur fractures. Treatment preferences and indications for treatment were separated into 4 groups: infant (0 to 6 mo); toddler (7 mo to 4 y); child (5 to 12 y); adolescent (12 to 17 y). The survey was available in English, Spanish, and French. Analysis was completed with t test and χ test for continuous and categorical variables, respectively, and weighted Pearson correlation (P<0.05). RESULTS: Survey respondents consisted of 413 surgeons from 83 countries (20 LIC, 33 LMIC, 30 UMIC). The majority of respondents were fellowship trained (83%) most commonly in pediatrics (26%) and trauma (43%). Most treated >10 pediatric femur fractures per year (68%). Respondents reported treating infant femur fractures nonoperatively using Pavlik harness (19%), spica cast (60%), or traction with delayed spica cast (14%). Decreasing socioeconomic status was associated with higher nonoperative treatment rate in toddlers, children, and adolescents. Respondents commonly utilize bed rest and traction for child femur fractures in LICs (63%) and LMICs (65%) compared with UMICs (35%) (UMIC vs. LMIC P<0.001; UMIC vs. LIC P<0.001). Surgeries in children more commonly involve open reduction with internal fixation (UMIC 19%, LMIC 33%, LIC 40%; P<0.05 between UMIC-LMIC and UMIC-LIC). CONCLUSION: This is one of the largest surveys describing treatment patterns for pediatric femur fractures in low and middle income countries. Differences are evident including lower operative treatment rate in younger children and lower intramedullary fixation rates in older children. Future studies should investigate the value of treatment options in resource-limited settings. LEVEL OF EVIDENCE: Level II-prospective comparative study.