Noninvasive Respiratory Severity Indices Predict Adverse Outcomes in Bronchopulmonary Dysplasia.

OBJECTIVE: To test the hypothesis that elevated respiratory severity indices will identify patients with severe bronchopulmonary dysplasia (BPD) at the greatest risk for adverse in-hospital outcomes. STUDY DESIGN: This was a retrospective cohort study. A modified respiratory severity score (mean airway pressure × fraction of inspired oxygen) and a modified pulmonary score (respiratory support score × fraction of inspired oxygen + sum of medication scores) were calculated in a consecutive cohort of patients ≥36 weeks of postmenstrual age with severe BPD admitted to a referral center between 2010 and 2018. The association between each score and the primary composite outcome of death/prolonged length of stay (>75th percentile for cohort) was assessed using area under the receiver operator characteristic curve (AUROC) analysis and logistic regression. Death and the composite outcome death/tracheostomy were analyzed as secondary outcomes. RESULTS: In 303 patients, elevated scores were significantly associated with increased adjusted odds of death/prolonged length of stay: aOR 1.5 (95% CI 1.3-1.7) for the modified respiratory severity score and aOR 11.5 (95% CI 5.5-24.1) for the modified pulmonary score. The modified pulmonary score had slightly better discrimination of death/prolonged length of stay when compared with the modified respiratory severity score, AUROC 0.90 (95% CI 0.85-0.94) vs 0.88 (95% CI 0.84-0.93), P = .03. AUROCs for death and death/tracheostomy did not differ significantly when comparing the modified respiratory severity score with the modified pulmonary score. CONCLUSIONS: In our referral center, the modified respiratory severity score or the modified pulmonary score identified patients with established severe BPD at the greatest risk for death/prolonged length of stay, death, and death/tracheostomy.

Established severe BPD: is there a way out? Change of ventilatory paradigms.

Improved survival of extremely preterm newborn infants has increased the number of infants at risk for developing bronchopulmonary dysplasia (BPD). Despite efforts to prevent BPD, many of these infants still develop severe BPD (sBPD) and require long-term invasive mechanical ventilation. The focus of research and clinical management has been on the prevention of BPD, which has had only modest success. On the other hand, research on the management of the established sBPD patient has received minimal attention even though this condition poses large economic and health problems with extensive morbidities and late mortality. Patients with sBPD, however, have been shown to respond to treatments focused not only on ventilatory strategies but also on multidisciplinary approaches where neurodevelopmental support, growth promoting strategies, and aggressive treatment of pulmonary hypertension improve their long-term outcomes. In this review we will try to present a physiology-based ventilatory strategy for established sBPD, emphasizing a possible paradigm shift from acute efforts to wean infants at all costs to a more chronic approach of stabilizing the infant. This chronic approach, herein referred to as chronic phase ventilation, aims at allowing active patient engagement, reducing air trapping, and improving ventilation-perfusion matching, while providing sufficient support to optimize late outcomes. IMPACT: Based on pathophysiological aspects of evolving and established severe BPD in premature infants, this review presents some lung mechanical properties of the most severe phenotype and proposes a chronic phase ventilatory strategy that aims at reducing air trapping, improving ventilation-perfusion matching and optimizing late outcomes.

Factors Associated with Neurodevelopmental Impairment in Bronchopulmonary Dysplasia.

OBJECTIVE: To identify factors associated with neurodevelopmental impairment (NDI) in patients with bronchopulmonary dysplasia (BPD). STUDY DESIGN: We identified 151 patients with moderate to severe BPD from 2010 to 2014 with complete Bayley Scales of Infant Development (BSID) scores at 24 months corrected age. We defined NDI as any diagnosis of cerebral palsy or ≥1 BSID composite scores of <80. RESULTS: The mean corrected age at BSID was 23 ± 1 months; 18% had a cognitive score of <80, 37% had a communication score of <80, and 26% had a motor score of <80. Cerebral palsy was diagnosed in 22 patients (15%); 84 (56%) patients did not have NDI. Patients with NDI had lower birth weight, but there was no difference in gestational age at birth, severe intraventricular hemorrhage (IVH), necrotizing enterocolitis, or patent ductus arteriosus ligation compared with patients with no NDI. Ventilator days were greater in patients with NDI than in patients without NDI. More patients with NDI received furosemide and systemic corticosteroids and the hospital length of stay was longer than in patients with no NDI. Logistic regression modeling demonstrated that for every additional 100 g of birth weight the odds of NDI decreased by 35% and for every additional hospital day the odds of NDI increased by 1.3%. CONCLUSIONS: In our cohort of patients with moderate to severe BPD, the majority had no NDI, and low birth weight and length of hospital stay were associated with increased risk of developing NDI. This finding suggests that there are potentially modifiable factors associated with better neurodevelopmental outcomes in patients with BPD that deserve further study.

Synergistic effects of sepsis and prematurity on neonatal postoperative mortality.

INTRODUCTION: Compared with term neonates, preterm babies are more likely to die from sepsis. However, the combined effects of sepsis and prematurity on neonatal postoperative mortality are largely unknown. Our objective was to quantify the proportion of neonatal postoperative mortality that is attributable to the synergistic effects of preoperative sepsis and prematurity. METHODS: We performed a multicentre, propensity-score-weighted, retrospective, cohort study of neonates who underwent inpatient surgery across hospitals participating in the United States National Surgical Quality Improvement Program-Pediatric (2012-2017). We assessed the proportion of the observed hazard ratio of mortality and complications that is attributable to the synergistic effect of prematurity and sepsis by estimating the attributable proportion (AP) and its 95% confidence interval (CI). RESULTS: We identified 19 312 neonates who realised a total of 321 321 person-days of postsurgical observations, during which 683 died (mortality rate: 2.1 per 1000 person-days). The proportion of mortality risk that is attributable to the synergistic effect of prematurity and sepsis was 50.5% (AP=50.5%; 95% CI, 28.8-72.3%; P < 0.001). About half of mortality events among preterm neonates with sepsis occurred within 24 h after surgery. Just over 45% of postoperative complications were attributable to the synergistic effect of prematurity and sepsis when both conditions were present (AP=45.8; 95% CI, 13.4-78.1%; P<0.001). CONCLUSION: Approximately half of postsurgical mortality and complications were attributable to the combined effect of sepsis and prematurity among neonates with both exposures. These neonates typically died within a few days after surgery, indicating a very narrow window of opportunity to predict and prevent mortality. CLINICAL TRIAL NUMBER AND REGISTRY: Not applicable.

Clinical phenotypes and management concepts for severe, established bronchopulmonary dysplasia.

With advances in care, the bronchopulmonary dysplasia phenotypes have evolved, so that infants who would have died in previous eras are now surviving with significant pulmonary and neurologic morbidities. The spectrum of bronchopulmonary dysplasia phenotypes is broad, however, ranging from very mild to very severe disease, and management strategies used in previous eras of care may not be appropriate for the most severe phenotypes. The pathophysiology depends largely on the gestational age at birth, but disease progression and long-term outcome depends on the net sum of antenatal, perinatal and postnatal exposures. There is no single management strategy for the wide spectrum of clinical presentations of BPD; care must be individualized. Regardless of the phenotype, the support apparatus should match the disease physiology. Here we describe an interdisciplinary approach to management in terms of achieving clinical stability and progress along a continuum, from diagnosis at 36 weeks of corrected gestational age to convalescence. The clinical trajectory depends on the balance of factors related to support of respiration, healing of the lungs, and return of organ growth and development. The overall treatment strategy should optimize positive influences that lead to a pro-growth state, while minimizing exposures that interfere with lung growth and development. This is best achieved by use of a multi-disciplinary team, with feedback loops that inform clinical decision-making regarding respiratory stability, tolerance for cares and activities, the clinical response to changes in the care plan, and progress in growth and development.

MAPK phosphatases--regulating the immune response.

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are protein phosphatases that dephosphorylate both the phosphothreonine and phosphotyrosine residues on activated MAPKs. Removal of the phosphates renders MAPKs inactive, effectively halting their cellular function. In recent years, evidence has emerged that, similar to MAPKs, MKPs are pivotal in the regulation of immune responses. By deactivating MAPKs, MKPs can modulate both innate and adaptive immunity. A number of immunomodulatory agents have been found to influence the expression of MKP1 in particular, highlighting the central role of this phosphatase in immune regulation. This Review discusses the properties, function and regulation of MKPs during immune responses.

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

IMPORTANCE: Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. OBJECTIVE: To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. INTERVENTIONS: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). MAIN OUTCOMES AND MEASURES: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. RESULTS: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. CONCLUSIONS AND RELEVANCE: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

Skin Rounds: A Quality Improvement Approach to Enhance Skin Care in the Neonatal Intensive Care Unit.

BACKGROUND: Skin injuries are common among neonatal intensive care unit (NICU) patients and may lead to significant complications. Standardized methods of preventing, detecting, and treating skin injuries are needed. PURPOSE: The aim of this project was to standardize the assessment, documentation, and tracking of skin injuries among hospitalized neonatal patients and to determine the incidence of pressure ulcers in this patient population. METHODS: (1) Creation of an interdisciplinary skin team to identify skin injuries through weekly skin rounds. (2) Assessment of all patients at least twice daily for the presence of skin injuries. Interventions were implemented upon identification of a skin injury. Pressure ulcers of Stage II or more were further assessed by wound/ostomy nurses. FINDINGS: A total of 2299 NICU patients were hospitalized and assessed between July 2011 and December 2015. After the initiation of skin rounds, the baseline incidence of pressure ulcers increased from 0.49 per 1000 patient days to 4.6 per 1000 patient days, reflecting an improvement in detection and reporting. The most common skin injuries detected included erythema, skin tears, and ecchymosis; the most common cause of injuries was medical devices. IMPLICATIONS FOR PRACTICE: A dedicated skin team can improve the detection and reporting of skin injuries among NICU patients. Determination of the incidence of pressure ulcers in this population is critical to develop targeted interventions. IMPLICATIONS FOR RESEARCH: Further research is needed to determine the most effective interventions to prevent and treat skin injuries among hospitalized neonates.

Significant Reduction of Central-Line Associated Bloodstream Infections in a Network of Diverse Neonatal Nurseries.

OBJECTIVE: To describe a quality improvement (QI) initiative that was associated with a dramatic reduction in neonatal central-line associated bloodstream infection (CLABSI) rate in a diverse group of 8 intensive care nurseries (Neonatal Services). STUDY DESIGN: A quasi-experimental time series QI initiative using the model for improvement and evidenced-based interventions. RESULTS: The aggregate CLABSI rate for Nationwide Children's Hospital-associated Neonatal Services decreased from 6.0 CLABSI per 1000 catheter days to 1.43 CLABSI per 1000 catheter days in less than 2 years and has remained in control at 0.68 per 1000 catheter days for over 5 years. Each of 8 nurseries has had a 1 year or more CLABSI-free period, including the neonatal intensive care unit with the largest patient volume, acuity, and central line usage. Aggregate Neonatal Services has experienced 3 CLABSI-free quarters since 2007. Key success factors included: (1) engagement of senior executive leadership; (2) bedside "huddles" among clinical and epidemiology staffs conducted within 72 hours after a positive blood culture; (3) implementation of chlorhexidine antisepsis and the use of chlorhexidine-impregnated catheter site discs; and (4) and establishment of a dedicated team for percutaneously inserted central catheter insertion to serve units in which central lines are placed less frequently. CONCLUSIONS: Using the model for improvement and evidenced-based interventions, this QI project has been associated with reduction in the CLABSI rate by 89%, and over 430 CLABSIs likely have been avoided.

Apgar Score at 5 Minutes Is Associated with Mortality in Extremely Preterm Infants Even after Transfer to an All Referral NICU.

OBJECTIVE: The Apgar score has been shown to have utility in predicting mortality in the extremely preterm infant in delivery hospital populations, where most mortality occurs within 12 hours of birth. We tested the hypothesis that the 5 minute Apgar score would remain associated with mortality in extremely preterm infants after transfer from the delivery hospital to an all referral neonatal intensive care unit at an average age of 10 days. STUDY DESIGN: A retrospective analysis of 454 infants born at < 27 weeks gestation. RESULTS: The median Apgar score was 3 at 1 minute (interquartile range [IQR] 2-6) and 6 at 5 minutes (IQR 4-7). The Apgar score increased from 1 to 5 minutes by 2.0 ± 1.7 (p < 0.001). In logistic regression modeling, an Apgar score of < 5 at 5 minutes was associated with an increased mortality (odds ratio 1.76 [95% confidence interval 1.06-2.94], p < 0.05), but not morbidities. CONCLUSION: Infants born at < 27 weeks gestation admitted to an all referral children's hospital at a mean age of 10 days with a 5 minute Apgar < 5 are at an increased risk of mortality. Our findings continue to support the importance of the Apgar score given at delivery even in the extremely preterm infant referred to a nondelivery children's hospital.

Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial.

IMPORTANCE: Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models. OBJECTIVE: To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: A randomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013. INTERVENTIONS: Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours. MAIN OUTCOMES AND MEASURES: The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes). RESULTS: The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%. CONCLUSIONS AND RELEVANCE: Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

If mothers had their say: research-informed intervention design for empowering mothers to establish smoke-free homes.

The Empowering Mothers to Establish Smoke-free Homes (EMESH) project developed in response to an interdisciplinary health team seeking effective interventions for reducing/eliminating the environmental tobacco smoke exposure of infants with compromised respiratory status. Two study phases that informed the EMESH intervention design are described. Phase I involved semi-structured interviews with 20 caretakers of infants diagnosed with Bronchopulmonary Dysplasia (BPD). In Phase II, 75 randomly selected medical records of infants with BPD were reviewed to explore the family demographics and staff behavior regarding environmental tobacco smoke (ETS) interventions. Interview results suggest that families are open to partnering with social workers and interdisciplinary team members in addressing infants' ETS exposure, families' unique circumstances indicate a need for tailored interventions, and the use of self-efficacy and decisional balance tools are feasible options. Results from the medical records review indicate that many families are economically vulnerable and reside in regions where smoking is common. There is a paucity of staff documentation regarding ETS conversations and interventions, indicating that these conversations may not take place. Together these results suggest a two-pronged approach in the next phases of EMESH: staff training in hosting and documenting ETS conversations and a tailored, parent-driven set of intervention options.

Managing established bronchopulmonary dysplasia without using routine blood gas measurements.

OBJECTIVE: Routine blood gas measurements are common in infants with severe bronchopulmonary dysplasia (sBPD) and are a noxious stimulus. We developed a guideline-driven approach to evaluate the care of infants with sBPD without routine blood gas sampling in the chronic phase of NICU care (after diagnosis at 36 weeks PMA). STUDY DESIGN: We examined blood gas utilization and outcomes in our sBPD inpatient care unit using data collected between 2014 and 2020. RESULTS: 485 sBPD infants met inclusion criteria, and 303 (62%) never had a blood gas obtained after 36 weeks PMA. In infants who had blood gas measurements, the median number of total blood gases per patient was only 4 (IQR 1-10). We did not identify adverse effects on hospital outcomes in patients without routine blood gas measurements. CONCLUSIONS: We found that patients with established BPD could be managed without routine blood gas analyses after 36 weeks PMA.

Multidisciplinary bronchopulmonary dysplasia care.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease in neonates and infants, which often presents with multisystem organ involvement, co-morbidities, and prolonged hospital stays. Therefore, a multidisciplinary chronic care approach is needed in the severest forms of BPD to optimize outcomes. However, this approach can be challenging to implement. The objective of this article is to review and synthesize the available literature regarding multidisciplinary care in infants and children with established BPD, and to provide a framework that can guide clinical practice and future research. AREAS COVERED: A literature search was conducted using Ovid MEDLINE, CINAHL, and Embase and several components of multidisciplinary management of BPD were identified and reviewed, including chronic care, team development, team members, discharge planning, and outpatient care. EXPERT OPINION: Establishing a core multidisciplinary group familiar with the chronicity of established BPD is recommended as best practice for this population. Acknowledging this is not feasible for all individual centers, it is important for clinical practice and future research to focus on the development and incorporation of national consulting services, telemedicine, and educational resources.

Respiratory management of established severe bronchopulmonary dysplasia.

Respiratory management of infants with established severe BPD is difficult and there is little evidence upon which to base decisions. Nonetheless, the physiology of severe BPD is well described with a predominantly obstructive pattern. This pulmonary dysfunction results in prolonged exhalatory time constants and thus ventilator management must be focused on maintaining adequate oxygenation and ventilation through achieving full exhalation. This approach is often difficult to maintain in acute care settings and a culture of chronic care focused on slow change and steady progress is imperative. Once respiratory stability is achieved, the focus should shift to growth and development and avoidance of care practices and medications that impair neurodevelopment.

Tracheostomy in Severe Bronchopulmonary Dysplasia-How to Decide in the Absence of Evidence.

Infants with the most severe forms of bronchopulmonary dysplasia (BPD) may require long-term invasive positive pressure ventilation for survival, therefore necessitating tracheostomy. Although life-saving, tracheostomy has also been associated with high mortality, postoperative complications, high readmission rates, neurodevelopmental impairment, and significant caregiver burden, making it a highly complex and challenging decision. However, for some infants tracheostomy may be necessary for survival and the only way to facilitate a timely and safe transition home. The specific indications for tracheostomy and the timing of the procedure in infants with severe BPD are currently unknown. Hence, centers and clinicians display broad variations in practice with regard to tracheostomy, which presents barriers to designing evidence-generating studies and establishing a consensus approach. As the incidence of severe BPD continues to rise, the question remains, how do we decide on tracheostomy to provide optimal outcomes for these patients?