Ruben Alvaro

Small preterm infants (≤1500 g) have only a sustained decrease in ventilation in response to hypoxia

ABSTRACT: The classic “biphasic” ventilatory response to 15% O2 was previously observed in preterm infants who were Large compared with those in the intensive care nursery today. We hypothesized that in the smaller infant (≤1500 g) the response might be closer to that of the fetus, with no initial increase in ventilation. Thus, we studied 14 healthy preterm infants ≤ 1500 g [birth weight 1220 ± 63 g (mean ± SEM); gestationl age 29 ± 0.4 wlq postnatal age 17 ± 3 d] during rapid eye movement and quiet sleep. Ventilation was measured using a nosepiece and a flowthrough system. Sleep states were defined using EEC, electro-oculogram, and body movements. After a control period in 21% O2 (3 min), infants breathed 15% O2, for 5 min. In rapid eye movement sleep, minute ventilation decreased from 0.186 ± 0.020 (control) to 0.178 ± 0.021 (30 s) to 0.171 ± 0.017 (1 min;p = 0.03), to 0.145 ± 0.016 (3 min; p = 0.002), and to 0.129 ± 0.011 1 ± min−1 kg−1 (5 min; p = 0.004). In quiet sleep, it decreased from 0.173 ± 0.019 (control) to 0.164 ± 0.019 (30 s), to 0.166 ± 0.019 (1 ± min−1 to 0.148 ± 0.013 (3 min; p = 0.03) and to 0.146 ± 0.012 1 ± min−1 ± kg−1 (5 min; p =0.04). These changes in ventilation were primarily related to a decrease in frequency in rapid eye movement [38 ± 2 (control) versus 28 ± 3 (5 min); p 0.01 and in quiet sleep [36 ± 5 (control) versus 27 ± 3 (5 min); p = 0.02]. Changes in tidal volume were negligible. These findings suggest that the classic biphas response to hypoxia is not observed in very small preterm infants. These infants show only a sustained decrease in ventilation with low O2. We speculate that the response reflects a more pronounced inhibitory mechanism induced by hypoxia at this gestational age, representing an intermediate profile between that observed in the fetus and that present in larger neonates.

A Randomized Controlled Trial of Theophylline Versus CO2 Inhalation for Treating Apnea of Prematurity

OBJECTIVE To determine whether inhalation of 0.8% CO(2) in preterm infants decreases the duration and rate of apnea as effectively as or better than theophylline with fewer adverse side effects. STUDY DESIGN A prospective, randomized, control study of 42 preterm infants of gestational age 27 to 32 weeks assigned to receive inhaled CO(2) (n = 21) or theophylline (n = 21). The study group had a mean (+/- standard error of the mean) birth weight of 1437 +/- 57 g, gestational age of 29.4 +/- 0.3 weeks, and postnatal age of 43 +/- 4 days. After a control period, 0.8% CO(2) or theophylline was given for 2 hours, followed by a recovery period. RESULTS In the CO(2) group, apneic time and rate decreased significantly, from 9.4 +/- 1.6 seconds/minute and 94 +/- 15 apneic episodes/hour to 3.0 +/- 0.5 seconds/minute and 34 +/- 5 apneic episodes/hour. In the theophylline group, apneic time and rate decreased significantly, from 8 +/- 1 seconds/minute and 80 +/- 8 apneic episodes/hour to 2.5 +/- 0.4 seconds/minute and 28 +/- 3 apneic episodes/hour. Cerebral blood flow velocity (CBFV) decreased only during theophylline administration. CONCLUSIONS Our findings suggest that inhaled low (0.8%) CO(2) concentrations in preterm infants is at least as effective as theophylline in decreasing the duration and number of apneic episodes, has fewer side effects, and causes no changes in CBFV. We speculate that CO(2) may be a better treatment for apnea of prematurity than methylxanthines.

Impact of Delivery Room Resuscitation on Outcomes up to 18 Months in Very Low Birth Weight Infants

OBJECTIVE To examine the relationships between intensity of delivery room resuscitation and short- and long-term outcomes of very low birth weight infants enrolled in the Caffeine for Apnea of Prematurity (CAP) Trial. STUDY DESIGN The CAP Trial enrolled 2006 infants with birthweights between 500 and 1250 g who were eligible for caffeine therapy. All levels of delivery room resuscitation were recorded in study participants. We divided infants in 4 groups of increasing intensity of resuscitation: minimal, n = 343; bag-mask ventilation, n = 372; endotracheal intubation, n = 1205; and cardiopulmonary resuscitation (chest compressions/epinephrine), n = 86. We used multivariable logistic regression models to compare outcomes across the 4 groups. RESULTS The observed rates of death or disability, death, cerebral palsy, cognitive deficit, and hearing loss at 18 months increased with higher levels of resuscitation. Risk of bronchopulmonary dysplasia, severe retinopathy of prematurity, and brain injury also increased with higher levels of resuscitation. Adjustment for prognostic variables reduced the differences between the groups for most outcomes. Only the adjusted rates of bronchopulmonary dysplasia and severe retinopathy remained significantly higher after more intense resuscitation. CONCLUSIONS In CAP Trial participants, the risk of death or neurodevelopmental disability at 18 months did not increase substantially with increasing intensity of delivery room resuscitation.

Adverse Impact of Maternal Cigarette Smoking on Preterm Infants: A Population-Based Cohort Study.

OBJECTIVE The aim of the study is to examine the impact of exposure to maternal cigarette smoking on neonatal outcomes of very preterm infants. STUDY DESIGN A retrospective cohort study examined preterm infants (<33 weeks gestational age) admitted to the Canadian Neonatal Network centers between 2003 and 2011. Mortality and major morbidities (bronchopulmonary dysplasia, severe intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy) were compared between infants exposed and unexposed to maternal smoking during pregnancy after adjusting for confounders. RESULTS Among 29,051 study infants, 4,053 (14%) were exposed to maternal smoking during pregnancy. Multivariable analysis revealed higher odds of grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia (adjusted odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.04-1.41) and bronchopulmonary dysplasia (adjusted OR: 1.16, 95% CI: 1.02-1.33) in the smoking group, while mortality, severe retinopathy, and necrotizing enterocolitis were not significantly different. CONCLUSION Maternal smoking during pregnancy is associated with severe neurological injury and bronchopulmonary dysplasia in preterm infants.

Short apneas and their relationship to body movements and sighs in preterm infants.

To test the hypothesis that there is an association among short apneas (3-10 s), body movements, and sighs, we studied 11 preterm infants (body weight 1,500 +/- 200 g, mean +/- SE; gestational age 30 +/- 1 weeks, postnatal age 28 +/- 5 days) using a flow-through system. A total of 1,166 apneas, 1,024 movements, and 473 sighs were recorded. Of the 1,166 apneas, 460 (39%) were associated with movements, 91 (8%) with sighs, and 226 (19%) with both movements and sighs. The rate of apneas associated with movements and sighs was significantly greater than expected if only a random association had occurred. These differences remained in quiet, rapid eye movement, and indeterminate sleep. The frequency of each of the three events was similar in a given sleep state. Of the 460 movements associated with apnea, 26% preceded, 23% followed, and 51% occurred during apnea. Similarly, of the 315 sighs associated with apnea, 44% preceded and 56% followed apnea. Apneas preceded by movements were longer than those without movements (5.6 +/- 0.2 vs. 4.9 +/- 0.1 s; p = 0.01). Oxygen saturation before apnea with movement (94 +/- 0.1%) was lower than before apnea alone (96 +/- 0.6%; p = 0.02) and also lower than before movement alone (96 +/- 0.1%; p = 0.001). These findings suggest: (1) there is a strong association among short apneas, movements, and sighs in these infants; (2) sighs appear not to be an isolated event and are likely to be part of a more general motor discharge, and (3) these events are accompanied by mild desaturations and bradycardias.(ABSTRACT TRUNCATED AT 250 WORDS)

Survey of noninvasive respiratory support practices in Canadian neonatal intensive care units

To evaluate practice variation with respect to noninvasive respiratory support (NRS) use across Canadian neonatal intensive care units (NICUs).

Control of Breathing in Newborns

There are at least three important considerations regarding the study of the control of breathing during the neonatal period. First, the neonates are noncooperative subjects. This means that we must study their respiratory control without their being aware and try to compare the measurements with those of the adult under similar conditions. This is difficult to do. Second, measurements in the neonate are usually made, by necessity, in the decubitus position, whereas those in the adult subject are usually made in the sitting or standing position [1, 2]. Third, babies are usually studied with a nosepiece because they are nose breathers; adults are usually studied using a mouthpiece. These methodological differences have made comparison of breathing in newborns with that in adult subjects difficult to interpret. There is currently a major need for studies to be done using similar methodology. Unless there is some consistency in the methodology, it is hard to define what is actually distinct or unique about the control of breathing in the neonate. In recent years, we have experienced tremendous advances in the field of respiratory control, and we are now witnessing the initial discovery of several of the genes that control the development and maturation of multiple neurally controlled respiratory functions

Effects of a Prolonged Infusion of a Placental Extract on Breathing and Electrocortical Activity in the Fetal Sheep. • 1783

We have previously found that brief infusion (2 minutes) of a placental extract into the carotid artery inhibited spontaneous fetal breathing in sheep; in 50% of the infusions, the electrocortical activity (ECoG) switched from low voltage (LV) to high voltage (HV). The action was primarily found in the 1-10 kD subfraction and was tissue specific. In the present study we determined the effects of a more prolonged infusion of the 1-10 kD subfraction(over 3 hr) to see if the inhibition of breathing was independent of changes in ECoG and whether it persisted throughout the infusion. Infusion of the 1-10 kD subfraction (40 cc/hr) into the carotid artery of the fetal sheep (139± 2 days of gestation), induced a decrease in the incidence of breathing from 58% (baseline) to 43%, 27%, and 7% during the first, second, and third hour of infusion respectively (p<0.001); during the first hr post-infusion, breathing increased to 51%. There was also a decrease in the time spent in LV-ECoG from 57% (baseline) to 50%, 38%, and 18% during the 3 hr of infusion (p<0.005); this increased to 58% during the first hr post-infusion. The decrease in breathing was independent of the changes in ECoG, since there was a simultaneous decrease in breathing during LV-ECoG from 92% (baseline) to 65%, 56%, and to 17% during the infusion (p<0.001); this breathing activity in LV-ECoG recovered to 78% during the first hr post infusion. Krebs solution (control) had no effect on breathing or ECoG. No significant changes were observed in blood gases and pH during the infusions. The findings suggest that a) the inhibitory action of the placental factor is independent of changes in electrocortical activity; and b) continuous infusion of a placental factor is capable of inhibiting fetal breathing for prolonged periods and may be responsible for the inhibition of breathing observed in fetal life. Supported by the Childrens Hospital of Winnipeg Research Foundation.

Periodic Breathing (BP) in Small Infants (≤1500g): Ventilatory Correlates and Significance. 1450

Periodic Breathing (BP) in Small Infants (≤1500g): Ventilatory Correlates and Significance. 1450

Admission Systolic Blood Pressure and Outcomes in Preterm Infants of ≤ 26 Weeks' Gestation

Objective To examine the relationship between admission systolic blood pressure (SBP) and adverse neonatal outcomes. Specifically, we aimed to identify the optimal SBP that is associated with the lowest rates of adverse outcomes in extremely preterm infants of ≤ 26 weeks’ gestation. Methods In this retrospective study, inborn neonates born at ≤ 26 weeks’ gestational age and admitted to tertiary neonatal units participating in the Canadian Neonatal Network between 2003 and 2009 were included. The primary outcome was early mortality (≤ 7 days). Secondary outcomes included severe brain injury, late mortality, and a composite outcome defined as early mortality or severe brain injury. Nonlinear multivariable logistic regression models examined the relationship between admission SBP and outcomes. Results Admission SBP demonstrated a U‐shaped relationship with early mortality, severe brain injury, and composite outcome after adjustment for confounders (p < 0.01). The lowest risks of early mortality, severe brain injury, and composite outcome occurred at admission SBPs of 51, 55, and 54 mm Hg, respectively. Conclusion In extremely preterm infants of ≤ 26 weeks’ gestational age, the relationship between admission SBP, and early mortality and severe brain injury was “ U‐shaped.” The optimal admission SBP associated with lowest rates of adverse outcome was between 51 and 55 mm Hg.