Surfactant and neonatal hemodynamics during the postnatal transition.

Surfactant replacement therapy (SRT) has revolutionized the management of respiratory distress syndrome (RDS) in premature infants, leading to improved survival rates and decreased morbidity. SRT may, however, be associated with hemodynamic changes, which can have both positive and negative effects on the immature cardiovascular system, during the transitional adaptation from fetal to extrauterine environment. However, there is a relative paucity of evidence in this domain, with most of them derived from small heterogeneous observational studies providing conflicting results. In this review, we will discuss the hemodynamic changes that occur with surfactant administration during this vulnerable period, focusing on available evidence regarding changes in pulmonary and systemic blood flow, cerebral circulation and their clinical implications.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Apnoea-triggered increase in fraction of inspired oxygen in preterm infants: a randomised cross-over study.

OBJECTIVES: To investigate the impact of a pre-emptive apnoea triggered oxygen response on oxygen saturation (SpO2) targeting following central apnoea in preterm infants. DESIGN: Interventional crossover study of a 12-hour period of automated oxygen control with an apnoea response (AR) module, nested within a crossover study of a 24-hour period of automated oxygen control compared with aggregated data from two flanking 12-hour periods of manual control. SETTING: Neonatal intensive care unit PATIENTS: Preterm infants receiving non-invasive respiratory support and supplemental oxygen; median (IQR) birth gestation 27 (26-28) weeks, postnatal age 17 (12-23) days. INTERVENTION: Automated oxygen titration with an automated control algorithm modified to include an AR module. Alterations to inspired oxygen concentration (FiO2) were actuated by a motorised blender. Desired SpO2 range was 90-94%. Apnoea detection was by capsule pneumography. MAIN OUTCOME MEASURES: Duration, magnitude and area under the curve (AUC) of SpO2 deviations following apnoea; frequency and duration of apnoeic events. Comparisons between periods of manual, automated and automated control with AR module. RESULTS: In 60 studies in 35 infants, inclusion of the AR module significantly reduced AUC for SpO2 deviations below baseline compared with both automated and manual control (manual: 87.1%±107.6% s, automated: 84.6%±102.8% s, AR module: 79.4%±102.7% s). However, there was a coincident increase in SpO2 overshoot (AUC (SpO2>SpO2(onset)); manual: 44.3±99.9% s, automated: 54.7%±103.4% s, AR module: 65.7%±126.2% s). CONCLUSION: Automated control with a pre-emptive apnoea-triggered FiO2 boost resulted in a modest reduction in post-apnoea hypoxaemia, but was followed by a greater SpO2 overshoot. TRIAL REGISTRATION NUMBER: ACTRN12616000300471.

The Utility of Serial Echocardiography Parameters in Management of Newborns with Congenital Diaphragmatic Hernia (CDH) and Predictors of Mortality.

Ventricular dysfunction may be found in 40% of newborns with CDH, and is not only a predictor of disease severity, but also mortality and need for ECMO. We conducted this study to assess the utility of serial echocardiography in management of newborns with CDH and their survival outcomes. This is a retrospective study, wherein the demographic, clinical and echocardiographic data from our local CDH registry and hospital clinical database were analyzed to study the correlation of timed echocardiographic findings with mortality and other outcomes. Fourty-two newborns with CDH were admitted during the study period (M/F:19/23), with median gestation of 38 weeks (IQR:36-39) and birth weight of 2.83 kg (IQR 2.45-3.17). Thirty-one were left-sided, seven right, one central, and three bilateral hernias. Twelve infants (28%) died in early infancy. Three infants were excluded from analysis due to either palliation at birth or significant cardiac anomaly. A total of 137 echos from 39 infants were analyzed. Seventy percent of newborns who died and had an echo within the first 72 h, were noted to have suffered from moderate to severe PH. Birth weight < 2.8 kg, RVSP > 45.5 in the first 72 h and postoperative VIS > 23.5 and RSS > 4.3 were good predictors of mortality. Markers of elevated pulmonary pressures and cardiac function were useful in guiding therapy. Serial timed functional echocardiography (f-Echo) monitoring allows targeted therapy of patients with CDH. Birth weight, initial severity of pulmonary hypertension and postoperative RSS and VIS may be useful in predicting mortality.

Preliminary study of automated oxygen titration at birth for preterm infants.

OBJECTIVE: To study the feasibility of automated titration of oxygen therapy in the delivery room for preterm infants. DESIGN: Prospective non-randomised study of oxygenation in sequential preterm cohorts in which FiO2 was adjusted manually or by an automated control algorithm during the first 10 min of life. SETTING: Delivery rooms of a tertiary level hospital. PARTICIPANTS: Preterm infants <32 weeks gestation (n=20 per group). INTERVENTION: Automated oxygen control using a purpose-built device, with SpO2 readings input to a proportional-integral-derivative algorithm, and FiO2 alterations actuated by a motorised blender. The algorithm was developed via in silico simulation using abstracted oxygenation data from the manual control group. For both groups, the SpO2 target was the 25th-75th centile of the Dawson nomogram. MAIN OUTCOME MEASURES: Proportion of time in the SpO2 target range (25th-75th centile, or above if in room air) and other SpO2 ranges; FiO2 adjustment frequency; oxygen exposure. RESULTS: Time in the SpO2 target range was similar between groups (manual control: median 60% (IQR 48%-72%); automated control: 70 (60-84)%; p=0.31), whereas time with SpO2 >75th centile when receiving oxygen differed (manual: 17 (7.6-26)%; automated: 10 (4.4-13)%; p=0.048). Algorithm-directed FiO2 adjustments were frequent during automated control, but no manual adjustments were required in any infant once valid SpO2 values were available. Oxygen exposure was greater during automated control, but final FiO2 was equivalent. CONCLUSION: Automated oxygen titration using a purpose-built algorithm is feasible for delivery room management of preterm infants, and warrants further evaluation.

Automated control of oxygen titration in preterm infants on non-invasive respiratory support.

OBJECTIVE: To evaluate the performance of a rapidly responsive adaptive algorithm (VDL1.1) for automated oxygen control in preterm infants with respiratory insufficiency. DESIGN: Interventional cross-over study of a 24-hour period of automated oxygen control compared with aggregated data from two flanking periods of manual control (12 hours each). SETTING: Neonatal intensive care unit. PARTICIPANTS: Preterm infants receiving non-invasive respiratory support and supplemental oxygen; median birth gestation 27 weeks (IQR 26-28) and postnatal age 17 (12-23) days. INTERVENTION: Automated oxygen titration with the VDL1.1 algorithm, with the incoming SpO2 signal derived from a standard oximetry probe, and the computed inspired oxygen concentration (FiO2) adjustments actuated by a motorised blender. The desired SpO2 range was 90%-94%, with bedside clinicians able to make corrective manual FiO2 adjustments at all times. MAIN OUTCOME MEASURES: Target range (TR) time (SpO2 90%-94% or 90%-100% if in air), periods of SpO2 deviation, number of manual FiO2 adjustments and oxygen requirement were compared between automated and manual control periods. RESULTS: In 60 cross-over studies in 35 infants, automated oxygen titration resulted in greater TR time (manual 58 (51-64)% vs automated 81 (72-85)%, p<0.001), less time at both extremes of oxygenation and considerably fewer prolonged hypoxaemic and hyperoxaemic episodes. The algorithm functioned effectively in every infant. Manual FiO2 adjustments were infrequent during automated control (0.11 adjustments/hour), and oxygen requirements were similar (manual 28 (25-32)% and automated 26 (24-32)%, p=0.13). CONCLUSION: The VDL1.1 algorithm was safe and effective in SpO2 targeting in preterm infants on non-invasive respiratory support. TRIAL REGISTRATION NUMBER: ACTRN12616000300471.

Effect of Optimizing Oxygen Saturation Targets on the Incidence of Retinopathy of Prematurity in a Quaternary NICU.

Introduction: Retinopathy of prematurity (ROP) is a multifactorial disease and a preventable cause of blindness in childhood. Hyperoxia and hypoxia can cause retinal neovascularization resulting in retinal detachment and blindness if left untreated. Besides oxygen treatment, other reasons for ROP development are well known. We prospectively adopt various strategies to keep oxygen saturation (SpO2) within targets, between 91 and 95% for those on supplemental oxygen. By adapting this, we postulated that the incidence of severe ROP might be reduced. Methods: 2018-2019 provided pre-intervention and 2020 post-intervention data for the project. For all babies (≤32 weeks, ≤1,500 g with FiO2 >0.21), target SpO2 between 91 and 95% was measured as a percentage of time spent within and outside target SpO2 during 1-4 weeks of life. Results: 112 and 60 preterm neonates were screened for ROP during the pre- and post-intervention phase. Twenty neonates (18.3%) during pre-intervention and 16 (26.7%) in the post-intervention phase developed severe ROP requiring treatment. Despite a statistically significant increase of 10 percent points in time spent within target SpO2 (91-95%) in the post-intervention phase (p < 0.05), the incidence of severe ROP did not decline. Using a multivariate model, odds of ROP development decreased with gestational age (25%) while increasing with PDA requiring treatment (4.33 times) and glucose ≥10 mg/dL (4.15 times), considering one variable at a time, keeping others constant. Conclusion: Our QI project showed successful attainment of maximum time; the SpO2 remained within targets during supplemental oxygen; however, the incidence of severe ROP had not declined. Factors other than SpO2 might be responsible for a high incidence of ROP in our neonatal intensive care unit.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

"Current concepts in assisted mechanical ventilation in the neonate" - Part 2: Understanding various modes of mechanical ventilation and recommendations for individualized disease-based approach in neonates.

Mechanical ventilation is a lifesaving intervention in critically ill preterm and term neonates. However, it has the potential to cause significant damage to the lungs resulting in long-term complications. Understanding the pathophysiological process and having a good grasp of the basic concepts of conventional and high-frequency ventilation is essential for any medical or allied healthcare practitioner involved in the neonates' respiratory management. This review aims to describe the various types and modes of ventilation usually available in neonatal units. It also describes recommendations of an individualized disease-based approach to mechanical ventilation strategies implemented in the authors' institutions.

"Current concepts of mechanical ventilation in neonates" - Part 1: Basics.

Mechanical ventilation is potentially live saving in neonatal patients with respiratory failure. The main purpose of mechanical ventilation is to ensure adequate gas exchange, including delivery of adequate oxygenation and enough ventilation for excretion of CO2. The possibility to measure and deliver small flows and tidal volumes have allowed to develop very sophisticated modes of assisted mechanical ventilation for the most immature neonates, such as volume targeted ventilation, which is used more and more by many clinicians. Use of mechanical ventilation requires a basic understanding of respiratory physiology and pathophysiology of the disease leading to respiratory failure. Understanding pulmonary mechanics, elastic and resistive forces (compliance and resistance), and its influence on the inspiratory and expiratory time constant, and the mechanisms of gas exchange are necessary to choose the best mode of ventilation and adequate ventilator settings to minimize lung injury. Considering the pathophysiology of the disease allows a physiology-based approach and application of these concepts in daily practice for decision making regarding the use of modes and settings of mechanical ventilation, with the ultimate aim of providing adequate gas exchange and minimising lung injury.

Physiological instability after respiratory pauses in preterm infants.

BACKGROUND: The factors influencing the severity of apnea-related hypoxemia and bradycardia are incompletely characterized, especially in infants receiving noninvasive respiratory support. OBJECTIVES: To identify the frequency and predictors of physiological instability (hypoxemia-oxygen saturation (SpO2 ) <80%, or bradycardia-heart rate (HR) < 100 bpm) following respiratory pauses in infants receiving noninvasive respiratory support. METHODS: Respiratory pause duration, derived from capsule pneumography, was measured in 30 preterm infants of gestation 30 (24-32) weeks [median (interquartile range)] receiving noninvasive respiratory support and supplemental oxygen. For identified pauses of 5 to 29 seconds duration, we measured the magnitude and duration of SpO2 and HR reductions over a period starting at the pause onset and ending 60 seconds after resumption of breathing. Temporally clustered pauses (<60 seconds separation) were analyzed separately. The relative contribution of respiratory pauses to overall physiological instability was determined, and predictors of instability were sought in regression analysis, including demographic, clinical and situational variables as inputs. RESULTS: In total, 17 105 isolated and 9180 clustered pauses were identified. Hypoxemia and bradycardia were more likely after longer duration and temporally-clustered pauses. However, the majority of such episodes occurred after 5 to 9 second pauses given their numerical preponderance, and short-lived pauses made a substantial contribution to physiological instability overall. Birth gestation, hemoglobin concentration, form of respiratory support, caffeine treatment, respiratory pause duration and temporal clustering were identified as predictors of instability. CONCLUSIONS: Brief respiratory pauses, especially when clustered, contribute substantially to hypoxemia and bradycardia in preterm infants.

Impact of Minimally Invasive Surfactant Therapy in Preterm Infants at 29-32 Weeks Gestation.

BACKGROUND: Most preterm infants born at 29-32 weeks gestation now avoid intubation in early life, and thus lack the usual conduit through which exogenous surfactant is given if needed. OBJECTIVE: The aim of this work was to examine whether a technique of minimally invasive surfactant therapy used selectively at 29-32 weeks gestation would improve outcomes. METHODS: We studied the impact of selective administration of surfactant (poractant alfa 100-200 mg/kg) by thin catheter in infants with respiratory distress syndrome on continuous positive airway pressure (CPAP). The threshold for consideration of treatment was CPAP ≥7 cm H2O and FiO2 ≥0.35 prior to 24 h of life. In-hospital outcomes were compared before and after introducing minimally invasive surfactant therapy (epochs 1 and 2, respectively). RESULTS: During epoch 2, of 266 infants commencing CPAP, 51 (19%) reached the treatment threshold. Thirty-seven infants received surfactant via thin catheter, and CPAP failure was avoided in 34 of these (92%). For the overall cohort of infants at 29-32 weeks gestation, after the introduction of minimally invasive surfactant therapy, there were reductions in CPAP failure (epoch 1: 14%, epoch 2: 7.2%) and average days of intubation, with equivalent surfactant use and days of respiratory support (intubation + CPAP). Pneumothorax was substantially reduced (from 8.0 to 2.4%). These findings were mirrored within the subgroups reaching the severity threshold in each epoch. The incidence of bronchopulmonary dysplasia was low in both epochs. CONCLUSIONS: Selective use of minimally invasive surfactant therapy at 29-32 weeks gestation permits a primary CPAP strategy to be pursued with a high rate of success, and a low risk of pneumothorax.

Clinical evaluation of a novel adaptive algorithm for automated control of oxygen therapy in preterm infants on non-invasive respiratory support.

OBJECTIVE: To evaluate the performance of a novel rapidly responsive proportional-integral-derivative (PID) algorithm for automated oxygen control in preterm infants with respiratory insufficiency. DESIGN: Interventional study of a 4-hour period of automated oxygen control compared with combined data from two flanking periods of manual control (4 hours each). SETTING: Neonatal intensive care unit. PARTICIPANTS: Preterm infants (n=20) on non-invasive respiratory support and supplemental oxygen, with oxygen saturation (SpO2) target range 90%-94% (manual control) and 91%-95% (automated control). Median gestation at birth 27.5 weeks (IQR 26-30 weeks), postnatal age 8.0 (1.8-34) days. INTERVENTION: Automated oxygen control using a standalone device, receiving SpO2 input from a standard oximeter and computing alterations to oxygen concentration that were actuated with a modified blender. The PID algorithm was enhanced to avoid iatrogenic hyperoxaemia and adapt to the severity of lung dysfunction. MAIN OUTCOME MEASURE: Proportion of time in the SpO2 target range, or above target range when in air. RESULTS: Automated oxygen control resulted in more time in the target range or above in air (manual 56 (48-63)% vs automated 81 (76-90)%, p<0.001) and less time at both extremes of oxygenation. Prolonged episodes of hypoxaemia and hyperoxaemia were virtually eliminated. The control algorithm showed benefit in every infant. Manual changes to oxygen therapy were infrequent during automated control (0.24/hour vs 2.3/hour during manual control), and oxygen requirements were unchanged (automated control period 27%, manual 27% and 26%, p>0.05). CONCLUSIONS: The novel PID algorithm was very effective for automated oxygen control in preterm infants, and deserves further investigation.