J M Di Fiore

Apnea, bradycardia and desaturation in preterm infants before and after feeding

Objective:A common clinical impression is that both gastroesophageal reflux (GER) and cardiorespiratory events increase after feeding in preterm infants. We aimed to measure objectively the effects of feeding on GER, apnea, bradycardia and desaturations.Study Design:We conducted a retrospective review of premature infants with a gestational age of 23 to 37 weeks at birth and a post-conceptional age of 34 to 48 weeks, who were referred for multichannel intraluminal impedance (MII), pH probe and 12-h apnea evaluation. Cardiorespiratory and GER event rates during pre- and post-feeding intervals were compared.Result:Thirty-six infants met the inclusion criteria. More GER events occurred after a feed than before (P=0.012). After feeds, reflux was less acidic and higher in the esophagus (P<0.05). In contrast, the rates of apnea, bradycardia and desaturations were not altered by infant feeding. Apnea of >5 s occurred at a median frequency of 0 (range 0 to 3) events per hour before a feed and 0 (0 to2) events per hour after a feed (P=0.61).Conclusion:The frequency, height and pH of GER are significantly altered by feedings in preterm infants. However, the common clinical impression that apnea, bradycardia and desaturations are more prevalent after feeding is not supported.

Characterization of cardiorespiratory events following gastroesophageal reflux in preterm infants.

Objective:The aim of this study was to characterize cardiorespiratory events in preterm infants after both acid and nonacid gastroesophageal reflux (GER) as detected by pH and multiple intraluminal impedance (MII).Study Design:Twelve hour overnight studies were performed in 71 preterm infants (gestational age 29.4±3.0 weeks, birth weight 1319±496 g). Apnea ⩾10 s in duration, bradycardia ⩽80 b.p.m. and oxygen desaturation ⩽85% that occurred within 30 s after the initiation of GER were classified as associated with GER.Result:A total of 12 957 cardiorespiratory events and 4164 GER episodes were documented. Less than 3% of all cardiorespiratory events were preceded by GER constituting 3.4% of apnea, 2.8% of oxygen desaturation and 2.9% of bradycardia events. GER did not prolong cardiorespiratory event duration or increase severity. In contrast, GER was associated with a shorter duration of oxygen desaturation events (7.8±4.6 vs 6.3±5.6 s, P<0.05).Conclusion:GER is rarely associated with cardiorespiratory events, and has no detrimental effect on cardiorespiratory event duration or severity.

Physiologic Basis for Intermittent Hypoxic Episodes in Preterm Infants

Intermittent hypoxic episodes are typically a consequence of immature respiratory control and remain a troublesome challenge for the neonatologist. Furthermore, their frequency and magnitude are commonly underestimated by clinically employed pulse oximeter settings. In extremely low birth weight infants the incidence of intermittent hypoxia [IH] progressively increases over the first 4 weeks of postnatal life, with a subsequent plateau followed by a slow decline beginning at weeks six to eight. Over this period of unstable respiratory control, increased oxygen-sensitive peripheral chemoreceptor activity has been associated with a higher incidence of apnea of prematurity. In contrast, infants with bronchopulmonary dysplasia [chronic neonatal lung disease] exhibit decreased peripheral chemosensitivity, although the effect on respiratory stability in this population is unclear. Such episodic hypoxia/reoxygenation in early life has the potential to sustain a proinflammatory cascade with resultant multisystem, including respiratory, morbidity. Therapeutic approaches for intermittent hypoxic episodes comprise careful titration of baseline or supplemental inspired oxygen as well as xanthine therapy to prevent apnea of prematurity. Characterization of the pathophysiologic basis for such intermittent hypoxic episodes and their consequences during early life is necessary to provide an evidence-based approach to their management.

Effect of Postnatal Intermittent Hypoxia on Growth and Cardiovascular Regulation of Rat Pups

Background: Intermittent hypoxic episodes are common among preterm infants, although longer term consequences on growth pattern and cardiovascular regulation are unclear. Furthermore, the effects of intermittent hypoxia (IH) may depend on the pattern of hypoxia-reoxygenation. Objectives: We tested the hypothesis that a clustered versus dispersed pattern of repetitive IH during early postnatal life would induce differential long-term alteration in growth and cardiovascular regulation. Methods: Sprague-Dawley rat pups were exposed to room air or to one of two patterns of IH (clustered vs. dispersed) from 1 to 7 days of life. Body weight was measured daily for the first 8 days and weekly from weeks 2 to 8. Blood pressure (BP) and heart rate were measured weekly from weeks 4 to 8 using a noninvasive tail-cuff method for awake, nonanesthetized animals. Results: Exposure to both patterns of repetitive IH induced early growth restriction followed by later catch-up of growth to controls 3 weeks after completion of IH exposures. IH-exposed rats exhibited a sustained decrease in heart rate regardless of the hypoxic exposure paradigm employed. In contrast, a differential response was seen for arterial pressure; the clustered paradigm was associated with a significantly lower BP versus controls, while the pups exposed to the dispersed paradigm showed no effect on BP. Conclusion: We speculate that repetitive IH during a critical developmental window and regardless of IH exposure paradigm contributes to prolonged changes in sympathovagal balance of cardiovascular regulation.

Implementation and analysis of a pilot in-hospital newborn screening program for glucose-6-phosphate dehydrogenase deficiency in the United States

Objective:The purpose of this study was to analyze a targeted screening program for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDdef) and clinical outcomes of G6PD-deficient vs G6PD normal newborns.Study Design:Retrospective chart review for 1578 male newborns was performed. The study group was those screened for G6PDdef. Comparisons between G6PD-deficient and normal infants were made with χ 2-test and unpaired t-test.Result:A total of 1095 male newborns were screened, 11.1% had G6PDdef. 97.8% of screen results were reported by 48 h. Total bilirubin (TB) levels in deficient infants were significantly higher than in normal infants throughout birth hospitalization and they were more likely to receive phototherapy. Nineteen screened newborns were rehospitalized for hyperbilirubinemia, 47% had G6PDdef.Conclusion:In-hospital newborn screening for G6PDdef with rapid turnaround time is possible. G6PDdef is a risk factor for hyperbilirubinemia in American newborns. US centers with large at-risk populations can identify newborns at risk for severe hyperbilirubinemia with similar screening.

Cardiorespiratory events in preterm infants: interventions and consequences

Stabilization of respiration and oxygenation continues to be one of the main challenges in clinical care of the neonate. Despite aggressive respiratory support including mechanical ventilation, continuous positive airway pressure, oxygen and caffeine therapy to reduce apnea and accompanying intermittent hypoxemia, the incidence of intermittent hypoxemia events continues to increase during the first few months of life. Even with improvements in clinical care, standards for oxygen saturation targeting and modes of respiratory support have yet to be identified in this vulnerable infant cohort. In addition, we are only beginning to explore the association between the incidence and pattern of cardiorespiratory events during early postnatal life and both short- and long-term morbidity including retinopathy of prematurity, growth, sleep-disordered breathing and neurodevelopmental impairment. Part 1 of this review included a summary of lung development and diagnostic methods of cardiorespiratory monitoring. In Part 2 we focus on clinical interventions and the short- and long-term consequences of cardiorespiratory events in preterm infants.

Vulnerability of neonatal respiratory neural control to sustained hypoxia during a uniquely sensitive window of development

The first postnatal weeks represent a period of development in the rat during which the respiratory neural control system may be vulnerable to aberrant environmental stressors. In the present study, we investigated whether sustained hypoxia (SH; 11% O2) exposure starting at different postnatal ages differentially modifies the acute hypoxic (HVR) and hypercapnic ventilatory response (HCVR). Three different groups of rat pups were exposed to 5 days of SH, starting at either postnatal age 1 (SH1-5), 11 (SH11-15), or 21 (SH21-25) days. Whole body plethysmography was used to assess the HVR and HCVR the day after SH exposure ended. The primary results indicated that 1) the HVR and HCVR of SH11-15 rats were absent or attenuated (respectively) compared with age-matched rats raised in normoxia; 2) there was a profoundly high (∼84% of pups) incidence of unexplained mortality in the SH11-15 rats; and 3) these phenomena were unique to the SH11-15 group with no comparable effect of the SH exposure on the HVR, HCVR, or mortality in the younger (SH1-5) or older (SH21-25) rats. These results share several commonalities with the risk factors thought to underlie the etiology of sudden infant death syndrome, including 1) a vulnerable neonate; 2) a critical period of development; and 3) an environmental stressor.

The Effect of Red Blood Cell Transfusion on Intermittent Hypoxemia in ELBW Infants

Objective:To test the hypothesis that the effect of red blood cell (RBC) transfusion on intermittent hypoxemia (IH) in extremely low birth weight (ELBW) infants is dependent on postnatal age.Study Design:Oxygen saturation of 130 ELBW infants, who required transfusion, was monitored continuously for the first 8 weeks of life. We compared the characteristics of IH (SpO2⩽80% for ⩾4 s and ⩽3 min), 24 h before and both 24 h and 24 to 48 h after each RBC transfusion at three distinct time periods: Epoch 1, 1 to 7 days; Epoch 2, 8 to 28 days; and Epoch 3, >28 days.Result:In Epoch 1, the frequency and severity of IH events were not significantly different before and after transfusion. In both Epochs 2 and 3 there was a decrease in IH frequency and severity 24 h after RBC transfusion that persisted for 48 h. In addition, there was a decrease in the overall time spent with SpO2 ⩽80% which persisted for 24 h after transfusion in Epochs 1 and 3, and for 48 h in Epoch 3.Conclusion:The benefit of RBC transfusion on IH is age dependent as improvement in the frequency and severity of IH after transfusion only occurs beyond the first week of life. These observations will aid clinician’s decision making by clarifying the benefit of RBC transfusions on patterns of oxygenation in preterm infants.

Impaired hypoxic ventilatory response following neonatal sustained and subsequent chronic intermittent hypoxia in rats

Neonatal chronic intermittent hypoxia (CIH) enhances the ventilatory sensitivity to acute hypoxia (acute hypoxic ventilatory response, HVR), whereas sustained hypoxia (SH) can have the opposite effect. Therefore, we investigated whether neonatal rats pre-treated with SH prior to CIH exhibit a modified HVR. Rat pups were exposed to CIH (5% O2/5min, 8h/day) between 6 and 15 days of postnatal age (P6-15) after pre-treatment with either normoxia or SH (11% O2; P1-5). Using whole-body plethysmography, the acute (5min, 10% O2) HVR at P16 (1 day post-CIH) was unchanged following CIH (67.9±6.7% above baseline) and also SH (58.8±10.5%) compared to age-matched normoxic rats (54.7±6.3%). In contrast, the HVR was attenuated (16.5±6.0%) in CIH exposed rats pre-treated with SH. These data suggest that while neonatal SH and CIH alone have little effect on the magnitude of the acute HVR, their combined effects impose a synergistic disturbance to postnatal development of the HVR. These data could provide important insight into the consequences of not maintaining adequate levels of oxygen saturation during the early neonatal period, especially in vulnerable preterm infants susceptible to frequent bouts of hypoxemic events (CIH) that are commonly associated with apnea of prematurity.

Cardiorespiratory events in preterm infants: etiology and monitoring technologies.

Every year, an estimated 15 million infants are born prematurely (<37 weeks gestation) with premature birth rates ranging from 5 to 18% across 184 countries. Although there are a multitude of reasons for this high rate of preterm birth, once birth occurs, a major challenge of infant care includes the stabilization of respiration and oxygenation. Clinical care of this vulnerable infant population continues to improve, yet there are major areas that have yet to be resolved including the identification of optimal respiratory support modalities and oxygen saturation targets, and reduction of associated short- and long-term morbidities. As intermittent hypoxemia is a consequence of immature respiratory control and resultant apnea superimposed upon an immature lung, improvements in clinical care must include a thorough knowledge of premature lung development and pathophysiology that is unique to premature birth. In Part 1 of a two-part review, we summarize early lung development and diagnostic methods for cardiorespiratory monitoring.