Comparative efficacy of volume expansion, inotropes and vasopressors in preterm neonates with probable transitional circulatory instability in the first week of life: a systematic review and network meta-analysis.

BACKGROUND: There exists limited agreement on the recommendations for the treatment of transitional circulatory instability (TCI) in preterm neonates OBJECTIVE: To compare the efficacy of various interventions used to treat TCI METHODS: Medline and Embase were searched from inception to 21st July 2023. Two authors extracted the data independently. A Bayesian random effects network meta-analysis was used. Recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. INTERVENTIONS: Dopamine, dobutamine, epinephrine, hydrocortisone, vasopressin, milrinone, volume and placebo. MAIN OUTCOME MEASURES: Mortality, major brain injury (MBI) (intraventricular haemorrhage > grade 2 or cystic periventricular leukomalacia), necrotising enterocolitis (NEC) ≥stage 2 and treatment response (as defined by the author). RESULTS: 15 Randomized Controlled Trials (RCTs) were included from the 1365 titles and abstracts screened. Clinical benefit or harm could not be ruled out for the critical outcome of mortality. For the outcome of MBI, epinephrine possibly decreased the risk when compared to dobutamine and milrinone (very low certainty). Epinephrine was possibly associated with a lesser risk of NEC when compared with dopamine, dobutamine, hydrocortisone and milrinone (very low certainty). Dopamine was possibly associated with a lesser risk of NEC when compared with dobutamine (very low certainty). Vasopressin possibly decreased the risk of NEC compared with dopamine, dobutamine, hydrocortisone and milrinone (very low certainty). Clinical benefit or harm could not be ruled out for the outcome response to treatment. CONCLUSIONS: Epinephrine may be used as the first-line drug in preterm neonates with TCI, the evidence certainty being very low. We suggest future trials evaluating the management of TCI with an emphasis on objective criteria to define it.

Caring for the hypertensive newborn: a prospective evaluation of risk factors, clinical profile, management, and predictors of outcome of neonatal hypertension.

With the advancement of neonatal care and routine blood pressure monitoring, neonatal hypertension (NHT) has been increasingly recognised over the past few decades. NHT is known to cause target organ damage and risk of renal dysfunction later in life. However, diagnosis and management of NHT remain challenging, and there is a lack of evidence on the persistence of hypertension beyond the neonatal period and factors predicting its severity. This study aimed to identify risk factors, clinical profiles, predictors of the severity of hypertension, and short-term outcomes of NHT. A cohort of neonates diagnosed with hypertension requiring pharmacotherapy from September 2019 to July 2021 was prospectively enrolled. Demographic data, risk factors, the severity of hypertension, target organ damage, and follow-up for the persistence of hypertension at 3, 6, and 12 months of age were recorded. Of 1682 neonates admitted during this period, 34 had hypertension requiring pharmacotherapy, with a hospital incidence rate of 2%. Of these, 19 (55.9%) were preterm, 14 (41.2%) very low birth weight, and 15 (44.1%) were small for gestational age. Malignant hypertension was seen in 29 (85%) cases, moderate hypertension in 5 (15%) cases, and target organ damage (heart, brain, liver) was seen in 10 (29.4%) cases. On univariate and multivariate regression, an increasing total number of postnatal risk factors was an independent predictor of the occurrence of hypertensive crisis (OR = 3.5, p = 0.04; 95% CI 1.06-11.42). A significant positive correlation (p = 0.004) was observed between total number of postnatal risk factors and the duration of hospital stay. Renal causes of hypertension were identified significantly earlier (day 14 vs. 23, p = 0.01, 95% CI 2.5-17) and had shorter hospital stay (24 vs 45 days, p = 0.002, 95% CI 834). At 3 months follow-up, 7 (20.6%) babies were still requiring antihypertensive therapy, and 1 (3%) required antihypertensives at 6 and 12 months of age.  Conclusion: NHT is a clinically important but underrecognised entity. Hypertension was seen in preterm, low birth weight neonates and associated with certain maternal and postnatal risk factors, with majority responding to a single drug. Neonates with multiple comorbid illnesses need careful monitoring for hypertension as they are at a higher risk of developing hypertensive crisis. Most NHT cases were normotensive at the time of discharge and did not require pharmacotherapy beyond the neonatal period. What is Known: • Neonatal hypertension (NHT) is an under-recognised entity, and the spectrum of clinical presentation varies from asymptomatic to severe target organ damage. • Hypertension is commonly seen in preterm, low birth weight neonates and associated with certain maternal and postnatal risk factor. What is New: • NHT is mostly transient, but intrauterine growth retardation, use of antenatal steroids, renal dysfunction due to congenital anomalies, drugs, and chronic lung disease may lead to the persistence of hypertension beyond the neonatal period. • Neonates with multiple comorbid illnesses need careful monitoring for hypertension as they are at a higher risk of developing hypertensive crisis. Three-fourths of hypertensive neonates respond to a single antihypertensive drug, and only one-fourth of patients required an additional drug to control hypertension. Most neonates respond to short duration of treatment, and only a few patients require long-term therapy.

The role of bedside functional echocardiography in the assessment and management of pulmonary hypertension.

Pulmonary hypertension is an emergency in neonatal intensive care units with high morbidity and mortality. Its timely assessment and management is crucial for intact survival. Over the last couple of decades, there have been significant advances in management and techniques, which have resulted in improved survival. The use of neonatologist-performed echocardiography (NPE) is now increasingly utilized on neonatal intensive care units to understand the pathophysiology of the disease and to direct the treatment to the underlying cause. Its use is now established not only in cases of congenital diaphragmatic hernia and in the newborn with refractory hypoxemia, but also in other conditions such as bronchopulmonary dysplasia and the premature infant with difficulty in oxygenation. The use of NPE, however, requires the availability of trained personnel, equipment, and a close working relationship with pediatric cardiology.

Cardiac structure and function in very preterm-born adolescents compared to term-born controls: A longitudinal cohort study.

BACKGROUND: There is emerging evidence of differences in cardiac structure and function in preterm-born adults and increased risk of heart failure. However, there is a paucity of data in populations who have been exposed to modern intensive care and the impact of perinatal factors is unclear. AIMS: To compare echocardiographic measures of cardiac structure and function in a regional cohort of 17-year-olds born very preterm compared to term-born peers and the influence of perinatal factors. STUDY DESIGN: Observational longitudinal cohort study. SUBJECTS: A regional cohort of ninety-one 17-year-olds born at <32 weeks gestation compared to sixty-two term-born controls. OUTCOME MEASURES: Echocardiographic measures of cardiac structure and function. RESULTS: Left ventricular and right atrial volume and left ventricular mass, indexed to body surface area, were significantly smaller in preterm-born adolescents compared to term-born controls even when adjusted for sex. There were no between group differences in cardiac function. Within those born preterm we found a significant association between gestational age and birthweight z-score and measures of cardiac function at 17 years. Within the preterm group, those with a diagnosis of bronchopulmonary dysplasia had higher left ventricular posterior wall thickness, higher mitral deceleration time and lower left atrial area and tricuspid annular plane of systolic excursion. CONCLUSIONS: Adolescents born very prematurely, who have received modern intensive care, have measurable differences in heart structure compared to their term-born peers but heart function is preserved. For those born preterm, gestational age, birthweight and bronchopulmonary dysplasia are associated with differences in cardiac function.

Efficacy of noninvasive respiratory support modes for primary respiratory support in preterm neonates with respiratory distress syndrome: Systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy of different noninvasive respiratory support (NRS) modes for primary respiratory support of preterm infants with respiratory distress syndrome (RDS). DESIGN: Systematic review and network meta-analysis using the Bayesian random-effects approach. MEDLINE, EMBASE, and CENTRAL were searched. INTERVENTIONS: High flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), bilevel CPAP (BiPAP), noninvasive positive pressure ventilation (NIPPV). MAIN OUTCOME MEASURES: Requirement of invasive mechanical ventilation (MV), any treatment failure. RESULTS: A total of 35 studies including 4078 neonates were included. NIPPV was more effective in decreasing the requirement of MV than CPAP (risk ratios [95% credible interval]: 0.60 [0.44, 0.77]) and HFNC [0.66 (0.43, 0.97)]. Surface under the cumulative ranking curve (SUCRA) for NIPPV, BiPAP, HFNC, and CPAP were 0.95, 0.59, 0.32, and 0.13. For the outcome of treatment failure, both NIPPV and BiPAP were more efficacious compared to CPAP and HFNC (0.56 [0.44, 0.71] {NIPPV vs CPAP}, 0.69 [0.51, 0.93] {BiPAP vs CPAP}, 0.42 [0.30, 0.63] {NIPPV vs HFNC}, 0.53 [0.35, 0.81] {BiPAP vs HFNC}). The SUCRA for NIPPV, BiPAP, CPAP, and HFNC were 0.96, 0.70, 0.32, and 0.01. NIPPV was associated with a reduced risk of air leak compared to BiPAP and CPAP (0.36 [0.16, 0.73]; 0.54 [0.30, 0.87], respectively). NIPPV resulted in lesser incidence of bronchopulmonary dysplasia or mortality when compared to CPAP (0.74 [0.52, 0.98]). Nasal injury was lesser with HFNC compared to CPAP (0.15 [0.01, 0.60]). CONCLUSIONS: Most effective primary mode of NRS in preterm neonates with RDS was NIPPV.

Efficacy of noninvasive respiratory support modes as postextubation respiratory support in preterm neonates: A systematic review and network meta-analysis.

BACKGROUND: Multiple noninvasive respiratory support (NRS) modalities are used for postextubation support in preterm neonates. Seven NRS modalities were compared-constant flow continuous positive airway pressure (CPAP) (CF-CPAP) (bubble CPAP; ventilator CPAP), variable flow CPAP (VF-CPAP), high flow nasal cannula (HFNC), synchronized noninvasive positive pressure ventilation (S-NIPPV), nonsynchronized NIPPV (NS-NIPPV), bilevel CPAP (BiPAP), noninvasive high-frequency oscillation ventilation (nHFOV). DESIGN: Systematic review and network meta-analysis (NMA) using the Bayesian random-effects approach. MEDLINE, EMBASE, CENTRAL, WHO-ICTRP were searched. MAIN OUTCOME MEASURE: Requirement of invasive mechanical ventilation within 7 days of extubation. RESULTS: A total of 33 studies with 4080 preterm neonates were included. S-NIPPV, NS-NIPPV, nHFOV, and VF-CPAP were more efficacious in preventing reintubation than CF-CPAP (risk ratio [RR] [95% credible intervals {CrI}]: 0.22 [0.12, 0.35]; 0.44 [0.27, 0.67]; 0.42 [0.18, 0.81]; 0.73 [0.52, 0.99]). Surface under the cumulative ranking curve (SUCRA) value ranked S-NIPPV to be the best postextubation intervention (SUCRA: 0.98). S-NIPPV was more effective than NS-NIPPV, BiPAP, VF-CPAP, and HFNC (RR [95% CrI]: 0.52 [0.24, 0.97]; 0.32 [0.14, 0.64]; 0.30 [0.16, 0.50]; 0.24 [0.12, 0.41]). NS-NIPPV resulted in lesser reintubation compared to VF-CPAP and HFNC (RR [95% CrI]: 0.61 [0.36, 0.97]; 0.49 [0.27, 0.80]). BiPAP, VF-CPAP, and HFNC had comparable efficacies. The overall quality of evidence was very low to moderate. CONCLUSION: Results of this NMA indicate that S-NIPPV might be the most effective and CF-CPAP the least effective NRS modality for preventing extubation failure.

Gastrointestinal hemodynamic changes during therapeutic hypothermia and after rewarming in neonatal hypoxic-Ischemic encephalopathy.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is associated with disturbances in visceral blood flow velocities. Therapeutic Hypothermia (TH) is a standard of care; however, its impact on gastrointestinal blood flow in infants with HIE is unknown. The objective of this study was to assess gastrointestinal (GI) blood flow and left ventricle output (LVO) in infants with hypoxic-ischemic encephalopathy during whole body TH and after rewarming. METHODS: Serial echocardiography and Doppler evaluation of intestinal blood flow (celiac (CA) and superior mesenteric (SMA) arteries) were prospectively performed in a cohort of 20 newborn infants with HIE at 4 time points during hypothermia and after rewarming. Demographic, clinical and biochemical data were collected and analyzed for their relevance. RESULTS: Median gestational age and birth weight was 40 weeks (37-41) and 3410 g (2190-4950) respectively. Celiac and mesenteric artery flow remained low during hypothermia and rose significantly after rewarming [peak systolic velocity in CA (0.63 m/s to 0.77 m/s, p = 0.004) and SMA (0.43 m/s to 0.55 m/s, p = 0.001)]. This increase was temporally associated with increased left ventricular output (106 ml/kg/min to 149 ml/kg/min, p < 0.0001). Median age to reach 25% of the feeds was 5 days (1-7 days). All patients survived. CONCLUSIONS: CA and SMA blood flow velocity and LVO did not vary during hypothermia but rose after rewarming. This may suggest protective effect of therapeutic hypothermia on gastrointestinal system. The association of these physiological changes with neonatal outcome needs further assessment.

Factors affecting N-terminal pro-B-type natriuretic peptide levels in preterm infants and use in determination of haemodynamic significance of patent ductus arteriosus.

This study aimed to investigate factors affecting N-terminal pro-B-type natriuretic peptide (NTproBNP) in preterm infants and the ability of NTproBNP to predict haemodynamically significant patent ductus arteriosus (HsPDA). Prospective cohort study of 51 infants < 30 weeks gestation. Blood NTproBNP and heart ultrasound were performed on day of life 3, 10, 28 and 36 weeks corrected age. NTproBNP levels analysed for prediction of HsPDA. The effect of gestational age, ventilation, hypoxia, bronchopulmonary dysplasia (BPD), creatinine and haemoglobin levels on NTproBNP levels were investigated. Infants with HsPDA had higher mean (SD) day 3 NTproBNP (1840 pmol/L (1058) versus 178 pmol/L (140) p < 0.001). Receiver operator curves of day 3 NTproBNP for prediction of day 3 and day 10 HsPDA had an area under the curve of 0.98 and 0.94, respectively. A chosen day 3 NTproBNP value of ≥ 287 pmol/L for the prediction of day 3 HsPDA correctly classified 92% (sensitivity 92%, specificity 92%). NTproBNP demonstrated only modest ability to predict severe BPD. Chronological but not gestational age affected NTproBNP. Ventilation, hypoxia and haemoglobin levels did not influence NTproBNP but creatinine level was positively correlated. CONCLUSION: Day 3 NTproBNP is a useful biomarker to predict HsPDA and may be a valuable tool in future trial design. What is Known: • NTproBNP is a cardiac hormone used to diagnose and monitor cardiac dysfunction in adults and has been shown to be higher in premature infants with haemodynamically significant ductus arteriosus (HsPDA). What is new: • NTproBNP is highly predictive of ultrasound-defined HsPDA and may be a useful tool for further triage • Early NTproBNP higher in infants who develop severe BPD and with renal impairment but not affected by gestational age, recent exposure to hypoxia or haemoglobin levels while late levels unexpectedly higher in those without BPD or HsPDA.

Predictors of respiratory instability in neonates undergoing patient ductus arteriosus ligation after the introduction of targeted milrinone treatment.

INTRODUCTION: The postoperative course of preterm babies undergoing surgical closure of a patent ductus arteriosus (PDA) is often complicated by postligation cardiac syndrome (PLCS). Despite targeted milrinone prophylaxis, some infants continue to experience postoperative respiratory deterioration. Our objective is to describe the immediate postoperative course and identify risk factors for respiratory instability when preterm infants undergoing PDA ligation are managed with targeted milrinone treatment. METHODS: A retrospective review of a cohort of infants undergoing PDA ligation between January, 2010 and August, 2013 was conducted. All infants had a targeted neonatal echocardiogram performed 1 hour after surgery. Infants received prophylactic milrinone treatment if the left ventricular output was <200 mL/kg/min. The primary outcome measure was the development of respiratory instability within 24 hours of surgery. Multivariable logistic regression was performed to identify predictors of respiratory instability. RESULTS: Eighty-six infants with a median gestational age of 25 weeks (interquartile range [IQR], 24-26) and a birth weight of 740 g (IQR, 640-853) were included in this study. Forty-nine (57.0%) received milrinone prophylaxis. There were 44 (51.2%) infants who developed oxygenation or ventilation failure, and 7 (8.1%) neonates developed PLCS. Infants with longer isovolumic relaxation time (IVRT ≥30 milliseconds) were more likely to develop either oxygenation or ventilation failure. CONCLUSIONS: Although the incidence of PLCS has declined after the introduction of targeted milrinone prophylaxis, many preterm infants continue to develop respiratory instability after surgical ligation. In this population, diastolic dysfunction manifested by prolonged IVRT could be associated with an adverse postoperative respiratory course.

Minimally invasive surfactant administration in preterm infants: a meta-narrative review.

IMPORTANCE: Surfactant administration by minimally invasive methods that allow for spontaneous breathing might be safer and more effective than administration with endotracheal intubation and mechanical ventilation; however, the efficacy and safety of minimally invasive methods have not been reviewed. OBJECTIVE: To conduct a meta-narrative review of the efficacy and safety of minimally invasive surfactant administration using a thin catheter, aerosolization, a laryngeal mask airway, and pharyngeal administration in preterm infants with or at risk for respiratory distress syndrome. DATA SOURCES: We searched the PubMed, EMBASE, Cochrane, and CINAHL databases, published journals, and conference proceedings from inception to June 30, 2013. STUDY SELECTION: Randomized clinical trials or observational studies of preterm infants who were given surfactant for respiratory distress syndrome by minimally invasive methods. DATA EXTRACTION AND SYNTHESIS: An overall meta-narrative review was conducted encompassing the evolution of noninvasive surfactant therapy. Risk ratios and 95% confidence intervals are reported when appropriate. MAIN OUTCOMES AND MEASURES: Chronic lung disease diagnosed by the need for oxygen therapy at a postmenstrual age of 36 weeks, need for mechanical ventilation within the first 72 hours of birth, need for mechanical ventilation any time during the hospital stay, and adverse events associated with administration of surfactant by various methods. RESULTS: We included 10 studies (6 randomized and 4 observational) of 3081 neonates. Thin catheter administration was evaluated in 6 studies (2 randomized and 4 observational); aerosolization, in 2 randomized studies; and laryngeal mask and pharyngeal administration, in 1 observational study each. The meta-narrative review confirmed the slow evolution and challenges of the different modes of administration, with thin catheter administration being the most studied intervention. Two randomized studies of surfactant administration using a thin catheter revealed no significant difference in the outcome of bronchopulmonary dysplasia but a potential reduction in the need for mechanical ventilation within 72 hours of birth when compared with standard care. CONCLUSIONS AND RELEVANCE: Surfactant administration via a thin catheter may be an efficacious and potentially safe method; however, further studies are needed. Further studies are also needed for other methods of minimally invasive surfactant administration.