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Objective: The aim of this study was to compare the effect of targeting arterial oxygen saturation (SpO2) in the high (93–95%) versus the low portion (90–92%) of the recommended range of 90–95% on oxygenation stability in extremely premature infants. Methods: Premature infants of ≤28 weeks of gestational age who received a fraction of inspired oxygen (FiO2) > 0.21 after day 14 were eligible. FiO2 was adjusted by a dedicated investigator to keep SpO2 between 90–92% and 93–95% for 2 h each in random sequence. Episodes of intermittent hypoxemia (IH) were defined as SpO2 <90% for ≥10 s; severe IH episodes were defined as SpO2 <80% for ≥10 s. Hyperoxemia was defined as SpO2 >95% or >98%. Results: Eighteen premature infants were enrolled. Their (mean ± SD) GA was 26 ± 1.5 w. Seven infants were on mechanical ventilation, 4 infants on nasal ventilation, and 7 infants on nasal cannula. They were on a mean FiO2 0.38 ± 0.12 at study entry. Episodes of IH and severe IH were more frequent during the low compared to the high target (36.6 [27.0–41.3] vs. 16.0 [7.8–19.0], p < 0.001; 8.4 ± 9.3 vs. 3.2 ± 4.3, p = 0.002). The proportions of time with SpO2 >95% and >98% were greater with the high target (13.9 ± 11 vs. 34.1 ± 15.4%, p < 0.001; 0.9 [0–5.7] vs. 3.4 [0.5–16.1]%, p = 0.002). Conclusion: In this group of extremely premature infants, targeting SpO2 at the lower portion of the recommended range resulted in more frequent episodes of IH. However, targeting the higher SpO2 range led to more hyperoxemia. This trade-off warrants further investigation. [ABSTRACT FROM AUTHOR]

Apnea of prematurity is a developmental disorder affecting most extremely preterm infants. The consequences of apnea of prematurity on neurodevelopment are not well established, but several reports suggest that apnea and hypoxemia episodes may be associated with worse neurological outcome. Caffeine is the only FDA-approved drug for the prevention and treatment of apnea of prematurity. Besides its clear effectiveness to reduce apnea, the use of caffeine appears to have a wide margin of safety and has been associated with possible beneficial effects on later neurodevelopmental outcome. At the same time, there are also many studies in experimental animals and some in preterm infants suggesting potential serious adverse effects from caffeine administration, especially when using higher doses. Because of these uncertainties, there is a wide variation in caffeine use across institutions. This review summarizes some of the available evidence on caffeine use in this population, its indications and best timing of initiation and discontinuation, appropriate dosing, and some of the possible adverse effects of caffeine administration. Because of the many gaps in knowledge, especially as it relates to efficacy and safety, we encourage further basic and clinical studies to provide stronger evidence, not only on its potential beneficial effects but also its side effects. [ABSTRACT FROM AUTHOR]

Introduction: Positive pressure ventilation (PPV) with T-Piece and self-inflating bag (SIB) during neonatal resuscitation after birth is associated with variability in ventilation. The use of a ventilator with respiratory function monitoring (RFM) for PPV, however, has not been evaluated. Objective: To determine if ventilator + RFM can reduce ventilation variability compared to T-Piece and SIB in a preterm manikin at different combinations of target tidal volume (VT) and lung compliance (CL). Methods: Twenty clinicians provided PPV via mask and endotracheal tube (ETT) using SIB, T-Piece, T-Piece + RFM and Ventilator + RFM to a manikin with adjustable lung CL. Three combinations of CL and target VT: Low CL-Low VT, Low CL-High VT and High CL-Low VT were used in a random order. Results: The use of ventilator + RFM for PPV via ETT during High CL-Low VT period reduced the proportion of breaths with expiratory VT above target when compared to the other 3 devices (56 ± 35%, 85 ± 20%, 90 ± 25%, 92 ± 12% for ventilator + RFM, T-Piece + RFM, T-Piece, SIB, respectively; p < 0.05). During PPV via both mask and ETT, ventilator + RFM maintained the set Ti and rate, whereas SIB and T-Piece use resulted in higher rates, and T-Piece in higher proportion of breaths with prolonged Ti. During PPV via mask, ventilator + RFM reduced gas leakage compared to other devices. Conclusion: In this simulation study, use of a mechanical ventilator with RFM led to an overall improvement in volume targeting at different settings of CL and reduced the gas leak during mask ventilation. The efficacy and safety of using this strategy to neonatal resuscitation in the delivery room needs to be evaluated. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is one of the few diseases in neonatal medicine that has continued to evolve since its first description about 50 years ago. Over these years, advancements in neonatal medicine such as antenatal steroids and exogenous surfactant therapy have significantly reduced neonatal mortality and lowered the limits of viability for preterm infants. Although the incidence of BPD continues to be high, especially in extremely low birth weight infants, the clinical picture has evolved into a milder disease with low mortality or significant morbidities. This new BPD is the result of complex interactions between altered alveolar and vascular development, injury by ante- and postnatal pathogenic factors, and reparative processes in the lung. There has been significant progress in our understanding of risk factors for BPD, but challenges persist in its definition, and in finding effective preventive strategies. There are promising developments with newer preventive interventions such as mesenchymal stem cells, exosomes, immunomodulators, and growth factors, but they are still in preclinical stage. The future challenges include finding ways to define BPD based on the severity of lung pathology, which can better predict long-term outcomes, development of early predictors of lung disease, and finding innovative and evidence-based preventive and management strategies. [ABSTRACT FROM AUTHOR]

Background: In extremely premature infants, arterial hypotension in the first days after birth has been associated with an increased risk for bronchopulmonary dysplasia (BPD). Some infants present with hypotension at a later postnatal age, but the relationship between late onset hypotension (LOH) and BPD has not been evaluated. Objective: To evaluate the association between LOH and BPD and to identify pre- and postnatal factors associated with LOH. Methods: Prospectively collected data from a cohort of 23–28 weeks gestational age (GA) infants born during years 2005–2015 and alive at day 28 were analyzed. LOH was defined as the receipt of vasopressor treatment during days 8–28. BPD was defined as need for oxygen at 36 weeks postmenstrual age. Late mortality was defined as death after day 28. Results: Of 1,058 infants in the cohort, 90 (9%) had LOH during days 8–28. Infants with LOH had a higher incidence of BPD than normotensive infants (55 vs. 21%, p < 0.001). Multivariate logistic regression analysis (LRA) showed that LOH was associated with an increased risk for BPD (OR 1.87, 95% CI 1.10–3.17). LOH was also associated with an increased risk for late mortality. LRA showed the risk for LOH increased with lower GA, sepsis and patent ductus arteriosus during days 8–28. Conclusions: In this cohort of extremely premature infants, LOH was associated with an increased the risk for BPD. This association could be secondary to underlying factors that predispose to LOH and BPD or to the deleterious effects of LOH or its treatments on the lung. Further investigation is needed to assess causality. [ABSTRACT FROM AUTHOR]

Background: Hypoxemia episodes (HE) occur frequently in ventilated preterm infants and hinder the achievement of arterial oxygen saturation (SpO2 ) targets. These episodes may increase the risk for retinopathy of prematurity and neurodevelopmental disability. There are no data on the variation in HE and SpO2 targeting between day and night. Objective: The aim of this study was to evaluate the difference between day and night on the frequency and severity of HE and achievement of SpO2 targets. Methods: Twenty-four mechanically ventilated preterm infants with ≥ 4 episodes of SpO2 <75% over an 8-h period were enrolled. The fraction of inspired oxygen (FiO2 ), SpO2, and ventilator parameters were recorded over 24 h. Data from the day (9 a.m. to 5 p.m.) were compared to the night (9 p.m. to 5 a.m.) for the frequency of HE and proportion of time within and outside the target SpO2 range (90-95%). Results: The frequency of severe HE (SpO2 <75, ≥ 20 s) and prolonged severe HE (SpO2 <75, ≥ 60 s) was lower during the night compared to the day (1.6 ± 1.0 vs. 2.4 ± 1.3 episodes/h, p = 0.008, and 0.53 ± 0.35 vs. 0.90 ± 0.54 episodes/h, p = 0.018). There was no difference in mean episode duration. The frequency and duration of mild HE (SpO2 <85, ≥ 20 s) were lower during the night compared to the day (5.9 ± 2.7 vs. 7.1 ± 2.5 episodes/h, p = 0.003, and 72 ± 15 vs. 87 ± 25 s, p = 0.01, respectively). The proportion of time in severe hypoxemia (SpO2 <75%) was smaller, whereas time in hyperoxemia (SpO2 >95%) was greater, during the night compared to the day. The mean FiO2 did not differ between day and night. Conclusion: In this group of infants with frequent HE, nighttime was associated with fewer episodes when compared to daytime. This is likely due to less handling and sensory stimulation during the night. The increase in time spent with hyperoxemia during the night is likely to be due to more tolerance of high SpO2 with less proactive weaning of FiO2 . [ABSTRACT FROM AUTHOR]

Background: Inflammatory injury, particularly the production of active interleukin (IL)-1β plays a major role in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. The release of active IL-1β is controlled by posttranscriptional modifications of its proform (pro-IL-1β) through the inflammasome. Rac1 is a member of the Rho family of GTPases that regulate the inflammatory process. Objective: This study tested the hypothesis that Rac1 signaling increases inflammasome activation that results in damaging inflammation, and that the inhibition of Rac1 signaling prevents lung injury, by inhibiting inflammasome activation in a newborn rat model of BPD induced by hyperoxia. Methods: Newborn rat pups were exposed to room air or hyperoxia (85% O2) and received daily intraperitoneal injections of placebo (normal saline) or NSC23766, a specific Rac1 inhibitor, for 10 days. The effects on lung inflammation, alveolarization, vascular development, vascular remodeling, right ventricular systolic pressure, and right ventricular hypertrophy (RVH) were then assessed. Results: Hyperoxia exposure upregulated Rac1 and increased the production of active IL- 1β, which was accompanied by increasing expression of the inflammasome. In addition, hyperoxia induced the pathological hallmarks of BPD. However, treatment with NSC23766 significantly decreased inflammasome activation and macrophage infiltration, improved alveolar and vascular development, and reduced pulmonary vascular remodeling and RVH. Conclusion: These results indicate that Rac1 signaling regulates the expression of the inflammasome and plays a pivotal role in the pathogenesis of hyperoxia-induced neonatal lung injury. Therefore, targeting Rac1 signaling may provide a novel strategy to prevent and treat BPD in preterm infants. [ABSTRACT FROM AUTHOR]

Background: Preterm infants on mechanical ventilation have spontaneous hypoxemia episodes (HE) triggered by decreases in lung volume and tidal volume (V T ). Volume guarantee (VG) is a mode where the ventilator peak pressure is adjusted to keep the exhaled V T at a target level. The effect of VG on HE under routine clinical conditions has not been fully evaluated. Objective: To evaluate the effect of VG on HE in preterm infants in comparison to pressure control (PC) ventilation under routine clinical conditions. Methods: Twenty-four mechanically ventilated preterm infants with ≥ 4 HE of arterial oxygen saturation (SpO2) <75% over 8 h were enrolled. They were studied over 2 consecutive 24-hour periods of VG and PC, in random order. Results: While the frequency of HE (SpO2 <85% for ≥ 20 s) did not differ, their duration was reduced during VG. The frequency or duration of severe HE (SpO2 <75% for ≥ 20 s) did not differ between PC and VG. The proportion of time in severe hypoxemia (SpO2 <75%) during VG did not differ from PC [median: 4.4 (IQR 2.9-5.0) vs. 5.0% (IQR 3.9-6.9), p = 0.44]. The fraction of inspired oxygen (FiO2) was lower during VG compared to PC. Conclusion: The use of VG during routine clinical conditions resulted in a modest reduction in the duration of HE (SpO2 <85%) and FiO2 compared to PC. The use of VG did not reduce the more severe HE. [ABSTRACT FROM AUTHOR]

The article focuses on the diagnostic criteria of extremely low birth weight infants, and includes development of pulmonary hypertension during hospital course of infants; mortality rates of the same; and development of algorithms for screening of the same and followed up after discharge.

Background: Left to right (L-R) shunting through a patent ductus arteriosus (PDA) can reduce systemic and cerebral blood flow in preterm infants. To minimize this, the positive end-expiratory pressure (PEEP) is often raised to increase pulmonary vascular resistance and reduce L-R shunting. The effects of this maneuver on systemic and cerebral hemodynamics and oxygenation are not well documented. Objective: To compare the effects of different PEEP on the left ventricular output (LVO), superior vena cava (SVC) flow, LVO/SVC flow ratio, cerebral oxygenation (CrSO2) and gas exchange in mechanically ventilated preterm infants with PDA. Methods: Sixteen mechanically ventilated infants of 23-30 weeks' gestational age with L-R shunting through the PDA were studied. Ultrasound measurements of LVO and SVC flow, CrSO2, arterial oxygen saturation and transcutaneous CO2 tension (TcPCO2) obtained at PEEP of 2 and 8 cm H2O were compared with baseline values at 5 cm H2O. Results: There was a small but significant reduction in LVO and the LVO/SVC flow ratio at PEEP of 8 compared to 5 cm H2O. SVC flow and CrSO2 did not differ significantly. Conclusions: Increasing PEEP to 8 cm H2O in ventilated preterm infants with a PDA produced a modest decrease in L-R ductal shunting as indicated by a lower LVO/SVC flow ratio. The higher PEEP did not have a significant effect on cerebral perfusion or oxygenation. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: A single dose of NONOate attenuates pulmonary hypertension (PH) induced by group B Streptococcus (GBS) infusion and this is accompanied by a decrease in systemic vascular resistance (SVR). Objective: The objective of the study was to determine whether two doses of the NONOate sustain the attenuation in GBS-induced PH without further systemic compromise. Methods: 15 anesthetized newborn piglets were randomized to receive placebo (n = 8) or two doses of nebulized DPTA/NO (n = 7) at 15 and 75 min after GBS-induced PH. Pulmonary artery (Ppa) and systemic (Psa) pressures, cardiac output (CO) and arterial blood gases were obtained at baseline and every 15 min until 180 min during GBS infusion. Results: Ppa and pulmonary vascular resistance (PVR) decreased significantly after the first dose of nebulized DPTA/NO and this effect was maintained after the second dose. Psa and SVR decreased after the first dose of DPTA/NO to values close to baseline and no further changes in systemic circulation were observed with repeated treatment. PVR/SVR increased with GBS infusion, but decreased after the first dose of DPTA/NO and remained significantly lower for 180 min. CO was significantly higher in the DPTA/NO group. Changes in Ppa, PVR, Psa, SVR, and CO with GBS infusion were not modified by placebo infusion. PaCO2, base deficit, and pH did not differ between groups. PaO2 was significantly lower in the DPTA/NO group after the second dose. Conclusion: These data demonstrated that GBS-induced PH is attenuated with two doses of DPTA/NO without significant systemic effect. The vasodilatory effect is more pronounced in the pulmonary than in the systemic vasculature, as suggested by lower PVR/SVR in the DPTA/NO group. We speculate that NONOates may have a clinical application in the management of PH in neonates. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractMechanical ventilatory support is required by a large number of neonates in respiratory failure. However, its use in preterm infants is frequently associated with acute complications and long-term respiratory sequelae. Therefore, it is recommended to avoid or limit the exposure to ventilatory support. This is a review of existing practices and novel strategies to achieve weaning of ventilatory support in this population.Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Preterm infants often present with recurrent episodes of hypoxemia after mechanical ventilation. Objective: To evaluate the role of abdominal muscle activity and central apnea on the frequency and severity of hypoxemia episodes (HEs) in preterm infants with a history of mechanical ventilation. Methods: Continuous recordings of arterial oxygen saturation (SpO2), gastric pressure, respiratory inductance plethysmography and abdominal surface electromyography were obtained during 4 h from spontaneously breathing preterm infants who had recently been extubated and presented with frequent HEs. Results: Ten infants (gestational age 26.4 ± 1.1 weeks, body weight 816 ± 128 g, age 44 ± 21 days, FiO2 0.31 ± 0.09, mechanically ventilated for 33 ± 37 days) were studied 12 ± 7 (mean ± SD) days after extubation. These infants presented with 10.2 ± 9.3 HEs/h (SpO2 <88%, ≥10 s). Of these, 8.2 ± 6.2 HEs/h were associated with abdominal muscle contraction while only 2.0 ± 4.5 HEs/h were associated with ≥10 s apnea (p < 0.05). Of the more severe HEs (SpO2 <75%, ≥10 s), 2.7 ± 3.1 HEs/h were associated with abdominal contraction and only 0.7 ± 2.1 HEs/h with apnea (p < 0.05). Resting lung volume decreased by 69 ± 16% of tidal volume in HEs associated with abdominal contraction. Conclusions: In this group of premature infants who presented with frequent HEs after mechanical ventilation, most HEs were associated with abdominal muscles contraction and a loss in lung volume. These findings provide an alternate mechanism to explain these episodes in spontaneously breathing preterm infants with a history of mechanical ventilation. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractBackground:Episodes of hypoxemia are often observed in ventilated preterm infants. The factors that determine their duration, severity and the failure of the mechanical breaths to maintain ventilation have not been fully defined. Objective:To determine the relation between activity of the abdominal muscles and the duration and severity of hypoxemia episodes in ventilated preterm infants. Methods:Clinically stable ventilated preterm infants weighing between 500 and 1,000 g at birth, who presented with frequent episodes of hypoxemia, were studied. Recordings of arterial oxygen saturation (SpO2), tidal volume and abdominal surface electromyography were obtained during 4 h to assess the temporal relationship between activation of abdominal musculature with the onset, duration and severity of hypoxemia episodes. Results:In 15 infants, GA (mean ± SD) 25 ± 1.5 weeks, BW 697 ± 141 g, age 37 ± 14 days, synchronized intermittent mandatory ventilation rate 17 ± 6 breaths/min, peak inspiratory pressure 18 ± 1.9 cm H2O, positive end-expiratory pressure 4.8 ± 0.6 cm H2O, and fraction of inspired oxygen (FiO2) 0.4 ± 0.1 were studied. These infants presented with 7.2 ± 4.4 episodes of hypoxemia (SpO2<88) per hour. The number of abdominal muscle contractions per episode correlated with the duration and severity of the episodes of hypoxemia. The episode duration increased by 14 ± 18 s per abdominal muscle contraction. The lowest SpO2reached during an episode of hypoxemia decreased by 1.7 ± 1.4 for every abdominal muscle contraction. Conclusions:These data document a relationship between abdominal muscles contraction and the duration and severity of hypoxemia episodes in ventilated preterm infants. These findings can explain the failure of mechanical ventilation to prevent their occurrence or decrease their severity.Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]