Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Etiology and Mechanism of Intermittent Hypoxemia Episodes in Spontaneously Breathing Extremely Premature Infants.

OBJECTIVE: To evaluate the mechanisms leading to intermittent hypoxemia (IH) episodes in spontaneously breathing extremely premature infants at 32 weeks and 36 weeks postmenstrual age (PMA). METHODS: We studied spontaneously breathing premature infants born at 23-28 weeks of gestational age who presented with IH episodes while on noninvasive respiratory support at 32 or 36 weeks PMA. Daytime recordings of arterial oxygen saturation (SpO2), esophageal pressure, respiratory inductive plethysmography of the abdomen, chest wall, and their sum were obtained during 4 hours at 32 weeks and 36 weeks PMA. IH episodes (SpO2 <90% for ≥5 seconds) and severe IH episodes (SpO2 < 80% for ≥5 seconds) were classified as resulting from apnea, active exhalation and breath holding, reduced tidal volume (VT), or reduced respiratory rate (RR) during the preceding 60 seconds. RESULTS: Fifty-one infants with a mean gestational age of 25.9 ± 1.5 weeks and a mean birth weight of 846 ± 185 g were included. Of these, 31 and 41 were included in the analysis at 32 weeks and 36 weeks PMA, respectively. At both 32 weeks and 36 weeks PMA, greater proportions of all IH episodes and severe IH episodes were associated with active exhalation and breath holding than with apnea, reduced RR, or reduced VT. The severity and duration of the IH episodes did not differ between mechanisms. CONCLUSIONS: In this group of premature infants, the predominant mechanism associated with daytime IH was active exhalation and breath holding. This etiology is more closely associated with behavioral factors than abnormal respiratory control and can have implications for prevention.

Changes in Patent Ductus Arteriosus Treatment Strategy and Respiratory Outcomes in Premature Infants.

OBJECTIVE: To evaluate whether change in patent ductus arteriosus (PDA) management strategies over time had an impact on respiratory outcomes in premature infants. STUDY DESIGN: Prospectively collected data were included from all preterm infants born at 23-30 weeks gestational age with PDA admitted to the Children's Hospital of the University of Miami/Jackson Memorial Medical Center from January 1, 2005 to December 31, 2007 (epoch 1) and January 1, 2011 to December 31, 2015 (epoch 2). The 2 epochs were compared for approach with PDA diagnosis and subsequent management strategies and respiratory outcomes. RESULTS: Significantly fewer infants were treated for PDA in epoch 2 (54%) compared with epoch 1 (90%). Multivariable logistic regression analysis demonstrated that infants in epoch 2, with later PDA diagnosis and less frequent PDA treatment, had greater odds of bronchopulmonary dysplasia (BPD), composite of BPD or death, and more treatment with postnatal steroids than in epoch 1. CONCLUSIONS: The change in approach to diagnosis and management of PDA, from a more proactive and aggressive approach during the earlier epoch 1 to a more expectant approach during the subsequent epoch 2, was associated with worse respiratory outcomes, including increase in BPD and in BPD or death.

Early Caffeine and Weaning from Mechanical Ventilation in Preterm Infants: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: To evaluate in a randomized, double-blind, placebo-controlled trial the effect of early caffeine on the age of first successful extubation in preterm infants. STUDY DESIGN: Preterm infants born at 23-30 weeks of gestation requiring mechanical ventilation in the first 5 postnatal days were randomized to receive a 20 mg/kg loading dose followed by 5 mg/kg/day of caffeine or placebo until considered ready for extubation. The placebo group received a blinded loading dose of caffeine before extubation. RESULTS: Infants were randomized to receive caffeine (n = 41) or placebo (n = 42). Age at first successful extubation did not differ between early caffeine (median, 24 days; IQR, 10-41 days) and control groups (median, 20 days; IQR, 9-43 days; P = .7). An interim analysis at 75% enrollment showed a trend toward higher mortality in 1 of the groups and the data safety and monitoring board recommended stopping the trial. Unblinded analysis revealed mortality did not differ significantly between the early caffeine (9 [22%]) and control groups (5 [12%]; P = .22). CONCLUSIONS: Early initiation of caffeine in this group of premature infants did not reduce the age of first successful extubation. A nonsignificant trend toward higher mortality in the early caffeine group led to a cautious decision to stop the trial. These findings suggest caution with early use of caffeine in mechanically ventilated preterm infants until more efficacy and safety data become available. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01751724.

Automated versus Manual Oxygen Control with Different Saturation Targets and Modes of Respiratory Support in Preterm Infants.

OBJECTIVE: To determine the efficacy and safety of automated adjustment of the fraction of inspired oxygen (FiO2) in maintaining arterial oxygen saturation (SpO2) within a higher (91%-95%) and a lower (89%-93%) target range in preterm infants. STUDY DESIGN: Eighty preterm infants (gestational age [median]: 26 weeks, age [median] 18 days) on noninvasive (n = 50) and invasive (n = 30) respiratory support with supplemental oxygen, were first randomized to one of the SpO2 target ranges and then treated with automated FiO2 (A-FiO2) and manual FiO2 (M-FiO2) oxygen control for 24 hours each, in random sequence. RESULTS: The percent time within the target range was higher during A-FiO2 compared with M-FiO2 control. This effect was more pronounced in the lower SpO2 target range (62 ± 17% vs 54 ± 16%, P < .001) than in the higher SpO2 target range (62 ± 17% vs 58 ± 15%, P < .001). The percent time spent below the target or in hypoxemia (SpO2 <80%) was consistently reduced during A-FiO2, independent of the target range. The time spent above the target range or at extreme hyperoxemia (SpO2 >98%) was only reduced during A-FiO2 when targeting the lower SpO2 range (89%-93%). These outcomes did not differ between infants on noninvasive and invasive respiratory support. Manual adjustments were significantly reduced during A-FiO2 control. CONCLUSIONS: A-FiO2 control improved SpO2 targeting across different SpO2 ranges and reduced hypoxemia in preterm infants on noninvasive and invasive respiratory support. TRIAL REGISTRATION: ISRCTN 56626482.

A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants.

OBJECTIVE: To compare extubation failure rate with two ranges of nasal continuous positive airway pressure (NCPAP) in oxygen dependent preterm infants. STUDY DESIGN: Preterm infants of birth weight 500-1000 g and gestational age 23-30 weeks, extubated for the first time during the first 6 weeks while requiring fraction of inspired oxygen ≥ 0.25, were randomly assigned to a NCPAP range of 4-6 (low NCPAP) or 7-9 (high NCPAP) cmH2O. RESULTS: Infants were randomized to low (n = 47) or high NCPAP (n = 46) at day 16.3 ± 14.7 and 15.5 ± 12.4, respectively. Rates of extubation failure per criteria (24% vs 43%, P = .04, OR and 95% CI: 0.39 [0.16-0.96]) and re-intubation (17% vs 38%, P = .023, 0.33 [0.016-0.85]) within 96 hours were significantly lower in the high- compared with the low NCPAP group. This was mainly due to a strikingly lower failure rate in the 500-750 g birth weight strata. Duration of ventilation, bronchopulmonary dysplasia, or severe bronchopulmonary dysplasia did not differ significantly. No infant developed pneumothorax during 96 hours post-extubation. CONCLUSIONS: Extubation failure in preterm infants with residual lung disease was lower with NCPAP range of 7-9 compared with 4-6 cmH2O. These findings suggest the need for higher distending pressure post-extubation in the more immature infants who are still oxygen dependent.

Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial.

OBJECTIVE: To determine whether "early" ibuprofen treatment, at the onset of subtle patent ductus arteriosus (PDA) symptoms, would improve respiratory outcome in premature infants compared with "expectant" management, with ibuprofen treatment only when the PDA becomes hemodynamically significant (HS). STUDY DESIGN: We conducted a randomized double-blind controlled trial of infants with gestational ages 23 to 32 weeks and birth weights 500 to 1250 g who had echocardiography for subtle PDA symptoms (metabolic acidosis, murmur, bounding pulses). Infants were then randomized to "early" treatment (blinded ibuprofen; n = 54) or "expectant management" (blinded placebo, n = 51). If the PDA became HS (pulmonary hemorrhage, hypotension, respiratory deterioration), infants received open label ibuprofen. Infants with HS PDA at enrollment were excluded from the study. Respiratory outcomes and mortality and major morbidities were determined. RESULTS: "Early" treatment infants received ibuprofen at median age of 3 days; infants in the "expectant group" in whom HS symptoms developed (20%) received ibuprofen at median of 11 days. A total of 49% of "expectant" infants never required ibuprofen or ligation. No significant differences were found in the primary outcome (days on oxygen [O(2)] during the first 28 days), death, O(2) at 36 weeks, death or O(2) at 36 weeks, intestinal perforation, surgical necrotizing enterocolitis, grades III and IV intracranial hemorrhage, periventricular leukomalacia, sepsis or retinopathy of prematurity. CONCLUSION: Infants with mild signs of PDA do not benefit from early PDA treatment compared with delayed treatment.

Automated adjustment of inspired oxygen in preterm infants with frequent fluctuations in oxygenation: a pilot clinical trial.

OBJECTIVE: To assess the efficacy of a system for automated fraction of inspired oxygen (FiO(2)) adjustment in maintaining oxygen saturation (SpO(2)) within an intended range in preterm infants with spontaneous fluctuations in SpO(2). STUDY DESIGN: Sixteen infants (gestational age, 24.9 +/- 1.4 weeks; birth weight, 678 +/- 144 g; age, 33 +/- 15 days) with frequent hypoxemia episodes underwent two 4-hour periods of FiO(2) adjustment by clinical personnel (routine) and the automated system (automated). RESULTS: Compared with the routine period, the percent time within intended SpO(2) range (88%-95%) increased during the automated period (58% +/- 10% versus 42% +/- 9%; P < .001), whereas the percent time with SpO(2) higher than the intended range and >or=98% were reduced (9% +/- 10% versus 31% +/- 8% [P < .001] and 3% +/- 5% versus 16% +/- 9% [P < .001], respectively). Percent time with SpO(2) < 88% increased during the automated period (33% +/- 7% versus 27% +/- 9%; P = .003) because of more frequent episodes, whereas the time with SpO(2) < 75% did not differ. The 4-hour median FiO(2) was lower during the automated period (29% +/- 4% versus 34% +/- 5%; P < .001). CONCLUSION: Automated FiO(2) adjustment improved maintenance of SpO(2) within the intended range and reduced hyperoxemia and FiO(2). These findings should be examined in longer periods with standard clinical conditions and, eventually, in the context of randomized trials powered to detect clinically important effects on outcome.

Elimination of ventilator dead space during synchronized ventilation in premature infants.

BACKGROUND: Mainstream airflow sensors used in neonatal ventilators to synchronize mechanical breaths with spontaneous inspiration and measure ventilation increase dead space and may impair carbon dioxide (CO(2)) elimination. OBJECTIVE: To evaluate a technique consisting of a continuous gas leakage at the endotracheal tube (ETT) adapter to wash out the airflow sensor for synchronization and ventilation monitoring without CO(2) rebreathing in preterm infants. DESIGN: Minute ventilation (V'(E)) by respiratory inductance plethysmography, end-inspiratory and end-expiratory CO(2) by side-stream microcapnography, and transcutaneous CO(2) tension (TcPCO(2)) were measured in 10 infants (body weight, 835+/-244 g; gestational age, 26+/-2 weeks; age, 19+/-9 days; weight, 856+/-206 g; ventilator rate, 21+/-6 beats/min; PIP, 16+/-1 centimeters of water (cmH(2)O); PEEP, 4.2+/-0.4 cmH(2)O; fraction of inspired oxygen (FIo(2)), 0.26+/-0.6). The measurements were made during four 30-minute periods in random order: IMV (without airflow sensor), IMV+Sensor, SIMV (with airflow sensor), and SIMV+Leak (ETT adapter continuous leakage). RESULTS: Airflow sensor presence during SIMV and IMV+Sensor periods resulted in higher end-inspiratory and end-expiratory CO(2), Tcpco(2), and spontaneous V'(E) compared with IMV. These effects were not observed during SIMV+Leak. CONCLUSIONS: The significant physiologic effects of airflow sensor dead space during synchronized ventilation in preterm infants can be effectively prevented by the ETT adapter continuous leakage technique.