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.

Maturation of cardioventilatory physiological trajectories in extremely preterm infants.

BACKGROUND: In extremely preterm infants, persistence of cardioventilatory events is associated with long-term morbidity. Therefore, the objective was to characterize physiologic growth curves of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants during the first few months of life. METHODS: The Prematurity-Related Ventilatory Control study included 717 preterm infants <29 weeks gestation. Waveforms were downloaded from bedside monitors with a novel sharing analytics strategy utilized to run software locally, with summary data sent to the Data Coordinating Center for compilation. RESULTS: Apnea, periodic breathing, and intermittent hypoxemia events rose from day 3 of life then fell to near-resolution by 8-12 weeks of age. Apnea/intermittent hypoxemia were inversely correlated with gestational age, peaking at 3-4 weeks of age. Periodic breathing was positively correlated with gestational age peaking at 31-33 weeks postmenstrual age. Females had more periodic breathing but less intermittent hypoxemia/bradycardia. White infants had more apnea/periodic breathing/intermittent hypoxemia. Infants never receiving mechanical ventilation followed similar postnatal trajectories but with less apnea and intermittent hypoxemia, and more periodic breathing. CONCLUSIONS: Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. IMPACT: Physiologic curves of cardiorespiratory events in extremely preterm-born infants offer (1) objective measures to assess individual patient courses and (2) guides for research into control of ventilation, biomarkers and outcomes. Presented are updated maturational trajectories of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in 717 infants born <29 weeks gestation from the multi-site NHLBI-funded Pre-Vent study. Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Different time courses for apnea and periodic breathing suggest different maturational mechanisms.

Quantitative and Qualitative Changes in Peripheral Chemoreceptor Activity in Preterm Infants.

Rationale: Preterm infants are at risk for ventilatory control instability that may be due to aberrant peripheral chemoreceptor activity. Although term infants have increasing peripheral chemoreceptor contribution to overall ventilatory drive with increasing postnatal age, how peripheral chemoreceptor contribution changes in preterm infants with increasing postmenstrual age is not known. Objectives: To evaluate peripheral chemoreceptor activity between 32 and 52 weeks postmenstrual age in preterm infants, using both quantitative and qualitative measures. Methods: Fifty-five infants born between 24 weeks, 0 days gestation and 28 weeks, 6 days gestation underwent hyperoxic testing at one to four time points between 32 and 52 weeks postmenstrual age. Quantitative [Formula: see text] decreases were calculated, and qualitative responses were categorized as apnea, continued breathing with a clear reduction in [Formula: see text], sigh breaths, and no response. Measurements and Main Results: A total of 280 hyperoxic tests were analyzed (2.2 ± 0.3 tests per infant at each time point). Mean peripheral chemoreceptor contribution to ventilatory drive was 85.2 ± 20.0% at 32 weeks and 64.1 ± 22.0% at 52 weeks. Apneic responses were more frequent at earlier postmenstrual ages. Conclusions: Among preterm infants, the peripheral chemoreceptor contribution to ventilatory drive was greater at earlier postmenstrual ages. Apnea was a frequent response to hyperoxic testing at earlier postmenstrual ages, suggesting high peripheral chemoreceptor activity. A clearer description of how peripheral chemoreceptor activity changes over time in preterm infants may help explain how ventilatory control instability contributes to apnea and sleep-disordered breathing later in childhood. Clinical trial registered with www.clinicaltrials.gov (NCT03464396).

Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

Distinct type I collagen alterations cause intrinsic lung and respiratory defects of variable severity in mouse models of osteogenesis imperfecta.

Type I collagen alterations cause osteogenesis imperfecta (OI), a connective tissue disorder characterized by severe bone fragility. Patients with OI can suffer from significant pulmonary manifestations including severe respiratory distress in the neonatal period and a progressive decline in respiratory function in adulthood. We and others have shown intrinsic lung defects in some mouse models of OI. In this large study, we performed histological, histomorphometric, microcomputed tomography and invasive studies on oim/+, Col1a2+/G610C , CrtapKO and oim/oim mice, mimicking mild to moderate to severe OI, with the overall goal of determining the extent of their pulmonary and respiratory mechanics defects and whether these defects correlate with the skeletal disease severity and affect each sex equally. Although with variable severity, OI lung histology consistently showed alveolar simplification with enlarged acinar airspace and reduced alveolar surface. Numerous respiratory mechanics parameters, including respiratory system resistance and elastance, tissue damping, inspiratory capacity, total lung capacity, and others, were significantly and similarly impacted in CrtapKO and oim/oim but not in oim/+ or Col1a2+/G610C compared to control mice. Our data indicate that the impact of type I collagen alterations and OI on lung morphology and function positively correlate with the severity of the extracellular matrix deficiency. Moreover, the respiratory defects were more pronounced in male compared to female mice. It will be important to determine whether our observations in mice translate to OI patients and to dissect the respective contribution of intrinsic lung defects vs. extrinsic skeletal defects to impaired lung function in OI. KEY POINTS: Different type I collagen alterations in mouse models of osteogenesis imperfecta (OI) cause similar abnormal lung histology, with alveolar simplification and reduced alveolar surface, reminiscent of emphysema. Several respiratory mechanics parameters are altered in mouse models of OI. The impact of type I collagen alterations and OI on lung morphology and function positively correlate with the severity of the extracellular matrix deficiency. Respiratory defects were more pronounced in male compared to female mice. It will be important to determine whether our observations in mice translate to OI patients and to dissect the respective contribution of intrinsic lung defects vs. extrinsic skeletal defects to impaired lung function in OI.

Respiratory defects in the CrtapKO mouse model of osteogenesis imperfecta.

Respiratory disease is a leading cause of mortality in patients with osteogenesis imperfecta (OI), a connective tissue disease that causes severely reduced bone mass and is most commonly caused by dominant mutations in type I collagen genes. Previous studies proposed that impaired respiratory function in OI patients was secondary to skeletal deformities; however, recent evidence suggests the existence of a primary lung defect. Here, we analyzed the lung phenotype of Crtap knockout (KO) mice, a mouse model of recessive OI. While we confirm changes in the lung parenchyma that are reminiscent of emphysema, we show that CrtapKO lung fibroblasts synthesize type I collagen with altered posttranslation modifications consistent with those observed in bone and skin. Unrestrained whole body plethysmography showed a significant decrease in expiratory time, resulting in an increased ratio of inspiratory time over expiratory time and a concomitant increase of the inspiratory duty cycle in CrtapKO compared with WT mice. Closed-chest measurements using the forced oscillation technique showed increased respiratory system elastance, decreased respiratory system compliance, and increased tissue damping and elasticity in CrtapKO mice compared with WT. Pressure-volume curves showed significant differences in lung volumes and in the shape of the curves between CrtapKO mice and WT mice, with and without adjustment for body weight. This is the first evidence that collagen defects in OI cause primary changes in lung parenchyma and several respiratory parameters and thus negatively impact lung function.

Pre-Vent: the prematurity-related ventilatory control study.

BACKGROUND: The increasing incidence of bronchopulmonary dysplasia in premature babies may be due in part to immature ventilatory control, contributing to hypoxemia. The latter responds to ventilation and/or oxygen therapy, treatments associated with adverse sequelae. This is an overview of the Prematurity-Related Ventilatory Control Study which aims to analyze the under-utilized cardiorespiratory continuous waveform monitoring data to delineate mechanisms of immature ventilatory control in preterm infants and identify predictive markers. METHODS: Continuous ECG, heart rate, respiratory, and oxygen saturation data will be collected throughout the NICU stay in 500 infants < 29 wks gestation across 5 centers. Mild permissive hypercapnia, and hyperoxia and/or hypoxia assessments will be conducted in a subcohort of infants along with inpatient questionnaires, urine, serum, and DNA samples. RESULTS: Primary outcomes will be respiratory status at 40 wks and quantitative measures of immature breathing plotted on a standard curve for infants matched at 36-37 wks. Physiologic and/or biologic determinants will be collected to enhance the predictive model linking ventilatory control to outcomes. CONCLUSIONS: By incorporating bedside monitoring variables along with biomarkers that predict respiratory outcomes we aim to elucidate individualized cardiopulmonary phenotypes and mechanisms of ventilatory control contributing to adverse respiratory outcomes in premature infants.

Cardioventilatory Control in Preterm-born Children and the Risk of Obstructive Sleep Apnea.

RATIONALE: The contribution of ventilatory control to the pathogenesis of obstructive sleep apnea (OSA) in preterm-born children is unknown. OBJECTIVES: To characterize phenotypes of ventilatory control that are associated with the presence of OSA in preterm-born children during early childhood. METHODS: Preterm- and term-born children without comorbid conditions were enrolled. They were categorized into an OSA group and a non-OSA group on the basis of polysomnography. MEASUREMENTS AND MAIN RESULTS: Loop gain, controller gain, and plant gain, reflecting ventilatory instability, chemoreceptor sensitivity, and blood gas response to a change in ventilation, respectively, were estimated from spontaneous sighs identified during polysomnography. Cardiorespiratory coupling, a measure of brainstem maturation, was estimated by measuring the interval between inspiration and the preceding electrocardiogram R-wave. Cluster analysis was performed to develop phenotypes based on controller gain, plant gain, cardiorespiratory coupling, and gestational age. The study included 92 children, 63 of whom were born preterm (41% OSA) and 29 of whom were born at term (48% OSA). Three phenotypes of ventilatory control were derived with risks for OSA being 8%, 47%, and 77% in clusters 1, 2, and 3, respectively. There was a stepwise decrease in controller gain and an increase in plant gain from clusters 1 to 3. Children in cluster 1 had significantly higher cardiorespiratory coupling and gestational age than clusters 2 and 3. No difference in loop gain was found between clusters. CONCLUSIONS: The risk for OSA could be stratified according to controller gain, plant gain, cardiorespiratory coupling, and gestational age. These findings could guide personalized care for children at risk for OSA.

Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H.

OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. RESULTS: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. SIGNIFICANCE: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches.

An Official American Thoracic Society Clinical Practice Guideline: Pediatric Chronic Home Invasive Ventilation.

BACKGROUND: Children with chronic invasive ventilator dependence living at home are a diverse group of children with special health care needs. Medical oversight, equipment management, and community resources vary widely. There are no clinical practice guidelines available to health care professionals for the safe hospital discharge and home management of these complex children. PURPOSE: To develop evidence-based clinical practice guidelines for the hospital discharge and home/community management of children requiring chronic invasive ventilation. METHODS: The Pediatric Assembly of the American Thoracic Society assembled an interdisciplinary workgroup with expertise in the care of children requiring chronic invasive ventilation. The experts developed four questions of clinical importance and used an evidence-based strategy to identify relevant medical evidence. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to formulate and grade recommendations. RESULTS: Clinical practice recommendations for the management of children with chronic ventilator dependence at home are provided, and the evidence supporting each recommendation is discussed. CONCLUSIONS: Collaborative generalist and subspecialist comanagement is the Medical Home model most likely to be successful for the care of children requiring chronic invasive ventilation. Standardized hospital discharge criteria are suggested. An awake, trained caregiver should be present at all times, and at least two family caregivers should be trained specifically for the child's care. Standardized equipment for monitoring, emergency preparedness, and airway clearance are outlined. The recommendations presented are based on the current evidence and expert opinion and will require an update as new evidence and/or technologies become available.

Possible Role of TRP Channels in Rat Glomus Cells.

Carotid body (CB) glomus cells depolarize in response to hypoxia, causing a [Ca(2+)](i) increase, at least in part, through activation of voltage-dependent channels. Recently, Turner et al. (2013) showed that mouse glomus cells with knockout of TASK1/3(-/-) channels have near-normal [Ca(2+)](i) response to hypoxia. Thus, we postulated that TRP channels may provide an alternate calcium influx pathway which may be blocked by the TRP channel antagonist, 2-APB (2-aminoethoxydiphenylborane). We confirmed that 2-APB inhibited the afferent nerve response to hypoxia, as previously reported (Lahiri S, Patel G, Baby S, Roy A (2009) 2-APB mediated effects on hypoxic calcium influx in rat carotid body glomus cells. FASEB 2009, Abstract, LB157; Kumar P, Pearson S, Gu Y (2006) A role for TRP channels in carotid body chemotransduction? FASEB J 20:A12-29). To examine the mechanism for this inhibition, we examined dissociated rat CB glomus cells for [Ca(2+)](i) responses to hypoxia, anoxia (with sodium dithionite), 20 mM K(+), NaSH, NaCN, and FCCP in absence/presence of 2-APB (100 µM). Also the effect of 2-APB on hypoxia and/or anoxia were investigated on NADH and mitochondria (MT) membrane potential. Our findings are as follows: (1) 2-APB significantly blocked the [Ca(2+)](i) increase in response to hypoxia and anoxia, but not the responses to 20 mM K(+). (2) The [Ca(2+)](i) responses NaSH, NaCN, and FCCP were significantly blocked by 2-APB. (3) Hypoxia-induced increases in NADH/NAD(+) and MT membrane depolarization were not effected by 2-APB. Thus TRP channels may provide an important pathway for calcium influx in glomus cells in response to hypoxia.

Predictors and outcome of low initial forced expiratory volume in 1 second measurement in children with cystic fibrosis.

OBJECTIVE: To identify the characteristics of children with cystic fibrosis with low initial forced expiratory volume in 1 second (FEV1) % predicted and to investigate their outcome. STUDY DESIGN: Patients were categorized into low or high initial FEV1 groups using cluster analysis. Comparisons of the demographic and clinical data were performed between the 2 groups. RESULTS: From 122 children, 21 clustered into the low and 101 into the high FEV1 group. The mean FEV1 was 69% ± 12% predicted for the low and 95% ± 12% predicted for the high FEV1 group (P < .001). The low FEV1 group had lower body mass index percentiles (P = .003), were hospitalized more frequently (P = .001), and had been on dornase alfa longer (P = .006). Low FEV1 group had more patients with positive cultures for Pseudomonas aeruginosa (P = .002) and Stenotrophomonas maltophilia (P < .001) and had more total number of cultures positive for mucoid P. aeruginosa (P = .009) and methicillin resistant Staphylococcus aureus + P. aeruginosa (P = .005). The low FEV1 group continued to have low FEV1 measurements, their FEV1 declined slower, required more hospitalizations per year (P = .01), and had more cultures for mucoid (P = .003) and nonmucoid P. aeruginosa (P = .02) ± methicillin resistant S. aureus (P = .002) in comparison with the high FEV1 group. Poor adherence was associated with lower initial FEV1 values in females, and early, rapid decline of FEV1 in males. CONCLUSIONS: Some children with cystic fibrosis may present with poor lung function early in life and continue to have subnormal lung function associated with reduced body mass index, more frequent hospitalization, and higher rates of infection. Such children may benefit from careful evaluation and close follow-up.

Highly comparative time series analysis of oxygen saturation and heart rate to predict respiratory outcomes in extremely preterm infants.

Objective.Highly comparative time series analysis (HCTSA) is a novel approach involving massive feature extraction using publicly available code from many disciplines. The Prematurity-Related Ventilatory Control (Pre-Vent) observational multicenter prospective study collected bedside monitor data from>700extremely preterm infants to identify physiologic features that predict respiratory outcomes.Approach. We calculated a subset of 33 HCTSA features on>7 M 10 min windows of oxygen saturation (SPO2) and heart rate (HR) from the Pre-Vent cohort to quantify predictive performance. This subset included representatives previously identified using unsupervised clustering on>3500HCTSA algorithms. We hypothesized that the best HCTSA algorithms would compare favorably to optimal PreVent physiologic predictor IH90_DPE (duration per event of intermittent hypoxemia events below 90%).Main Results.The top HCTSA features were from a cluster of algorithms associated with the autocorrelation of SPO2 time series and identified low frequency patterns of desaturation as high risk. These features had comparable performance to and were highly correlated with IH90_DPE but perhaps measure the physiologic status of an infant in a more robust way that warrants further investigation. The top HR HCTSA features were symbolic transformation measures that had previously been identified as strong predictors of neonatal mortality. HR metrics were only important predictors at early days of life which was likely due to the larger proportion of infants whose outcome was death by any cause. A simple HCTSA model using 3 top features outperformed IH90_DPE at day of life 7 (.778 versus .729) but was essentially equivalent at day of life 28 (.849 versus .850).Significance. These results validated the utility of a representative HCTSA approach but also provides additional evidence supporting IH90_DPE as an optimal predictor of respiratory outcomes.

Highly comparative time series analysis of oxygen saturation and heart rate to predict respiratory outcomes in extremely preterm infants.

Objective: Highly comparative time series analysis (HCTSA) is a novel approach involving massive feature extraction using publicly available code from many disciplines. The Prematurity-Related Ventilatory Control (Pre-Vent) observational multicenter prospective study collected bedside monitor data from > 700 extremely preterm infants to identify physiologic features that predict respiratory outcomes. We calculated a subset of 33 HCTSA features on > 7M 10-minute windows of oxygen saturation (SPO2) and heart rate (HR) from the Pre-Vent cohort to quantify predictive performance. This subset included representatives previously identified using unsupervised clustering on > 3500 HCTSA algorithms. Performance of each feature was measured by individual area under the receiver operating curve (AUC) at various days of life and binary respiratory outcomes. These were compared to optimal PreVent physiologic predictor IH90 DPE, the duration per event of intermittent hypoxemia events with threshold of 90%. Main Results: The top HCTSA features were from a cluster of algorithms associated with the autocorrelation of SPO2 time series and identified low frequency patterns of desaturation as high risk. These features had comparable performance to and were highly correlated with IH90_DPE but perhaps measure the physiologic status of an infant in a more robust way that warrants further investigation. The top HR HCTSA features were symbolic transformation measures that had previously been identified as strong predictors of neonatal mortality. HR metrics were only important predictors at early days of life which was likely due to the larger proportion of infants whose outcome was death by any cause. A simple HCTSA model using 3 top features outperformed IH90_DPE at day of life 7 (.778 versus .729) but was essentially equivalent at day of life 28 (.849 versus .850). These results validated the utility of a representative HCTSA approach but also provides additional evidence supporting IH90_DPE as an optimal predictor of respiratory outcomes.

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

Objectives: Detection of changes in cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, may facilitate earlier detection of sepsis. Our objective was to examine the association of cardiorespiratory events with late-onset sepsis for extremely preterm infants (<29 weeks' gestational age (GA)) on versus off invasive mechanical ventilation. Study Design: Retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in five level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean GA 26.4w, 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 >72h after birth and ≥5d 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 IH80 events 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 predicted sepsis with an AUC 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.

Postnatal hyperoxia impairs acute oxygen sensing of rat glomus cells by reduced membrane depolarization.

Previous work demonstrated that hyperoxia (30-60% O(2)) exposure in the post-natal period reduces the ventilatory response to acute hypoxia and this impairment may continue considerably beyond the period of hyperoxia exposure. Previous work from our laboratory demonstrated that 1-2 weeks of hyperoxia (60% O(2)) starting between P1 and P14: reduced the single chemoreceptor unit response to hypoxia, reduced the rise in glomus cell calcium caused by acute hypoxia and reduced hypoxia-induced catecholamine release (Donnelly 05, Donnelly 09). The present study asked whether the impairment extended to hypoxia-induced membrane depolarization, an earlier step in the transduction cascade. Perforated patch, whole-cell recordings were obtained from rat glomus cells exposed to hyperoxia from P0-P8 or P8-P15 and age-matched control groups. In both cases, hypoxia-induced membrane depolarization was significantly less in the hyperoxia treated groups compared to controls, while depolarization to 20 mM K(+) was not significantly affected. Resting membrane potential and input resistance were also not different in the hyperoxia treated groups. Whole carotid body quantitative real time PCR showed that TASK-1, TASK-3 and L-type Ca(2+) channel expression was significantly down-regulated at Hyper 8-15 compared to controls. We conclude that 1 week of postnatal hyperoxia during the early and late stage of CB maturation impairs organ function by affecting the coupling between hypoxia and glomus cell depolarization. This may be caused by altered expression of TASK1, TASK3 or L-type Ca(2+) channel gene expression. We speculate that an identification of cellular changes caused by hyperoxia may yield unique insights to the mechanism of oxygen sensing by the carotid bodies.

Purinergic modulation of carotid body glomus cell hypoxia response during postnatal maturation in rats.

Carotid body (CB) glomus cells respond to hypoxia by releasing neurotransmitters, such as ATP, which are believed to stimulate excitatory receptors on apposed nerve endings of the carotid sinus nerves as well as bind to autoreceptors on the glomus cell membrane to modulate response magnitude. The CB response to hypoxia is small at birth and increases during postnatal maturation in mammals. As ATP has been shown to inhibit the glomus cell response to hypoxia via an autoreceptor mechanism, we hypothesized that ATP-mediated inhibition may vary with age and play a role in postnatal development of the hypoxia response magnitude. The effects of ATP on CB glomus cell intracellular calcium ([Ca(2+)](i)) responses to hypoxia were studied at two ages, P0-1 and P14-18. The inhibitory effect of ATP or a stable ATP analog on the glomus cell response to hypoxia was greater in newborn rats compared to the more mature age group. Use of selective P2Y receptor agonists and antagonists suggests that the inhibitory effect of ATP on the glomus cell [Ca(2+)](i) response to hypoxia may be mediated by a P2Y12 receptor. Thus, developmental changes in ATP-mediated glomus cell inhibition may play a role in carotid chemoreceptor postnatal maturation.

Haploinsufficiency of Col5a1 causes intrinsic lung and respiratory changes in a mouse model of classical Ehlers-Danlos syndrome.

The Ehlers-Danlos syndromes (EDS) are inherited connective tissue diseases with primary manifestations that affect the skin and the musculoskeletal system. However, the effects of EDS on the respiratory system are not well understood and are described in the literature as sporadic case reports. We performed histological, histomorphometric, and the first in-depth characterization of respiratory system function in a mouse model of classical EDS (cEDS) with haploinsufficiency of type V collagen (Col5a1+/-). In young adult male and female mice, lung histology showed reduced alveolar density, reminiscent of emphysematous-like changes. Respiratory mechanics showed a consistent increase in respiratory system compliance accompanied by increased lung volumes in Col5a1+/- compared to control mice. Flow-volume curves, generated to mimic human spirometry measurements, demonstrated larger volumes throughout the expiratory limb of the flow volume curves in Col5a1+/- compared to controls. Some parameters showed a sexual dimorphism with significant changes in male but not female mice. Our study identified a clear respiratory phenotype in the Col5a1+/- mouse model of EDS and indicated that intrinsic respiratory and lung changes may exist in cEDS patients. Their potential impact on the respiratory function during lung infections, other respiratory disease processes, or insults may be significant and justify further clinical evaluation.

Infant inclined sleep product safety: A model for using biomechanics to explore safe infant product design.

Over 450 adverse incidents have been reported in infant inclined sleep products over the past 17 years, with many infants found dead in both the supine and prone positions. The unique design of inclined sleep products may present unexplored suffocation risks related to how these products impact an infant's ability to move. The purpose of this study was to assess body movement and muscle activity of healthy infants when they lie supine and prone on different inclined sleep products. Fifteen healthy full-term infants (age: 17.7 ±â€¯4.9 weeks) were recruited for this IRB-approved study. Three inclined sleep products with unique features, representative of different sleeper designs, were included. Surface electromyography (EMG) was recorded from infants' cervical paraspinal, abdominal, and lumbar erector spinae muscles for 60 s during supine and prone positioning. Neck and trunk sagittal plane movements were evaluated for each testing condition. Paired t-tests and Wilcoxon signed-rank tests were performed to compare each inclined sleeper to a flat crib mattress (0° baseline condition). During prone positioning, abdominal muscle activity significantly nearly doubled for all inclined sleep products compared to the flat crib mattress, while erector spinae muscle activity decreased by up to 48%. Trunk movement significantly increased compared to the flat crib mattress during prone lying. During prone lying, inclined sleep products resulted in significantly higher muscle activity of the trunk core muscles (abdominals) and trunk movement, which has the potential to exacerbate fatigue and contribute to suffocation if an infant cannot self-correct to the supine position.

Development of ventilatory control in infants.

Most abnormalities of ventilatory control in infants are due to immaturity or abnormal development of ventilatory control. This includes a broad range, from rare disorders like congenital central hypoventilation syndrome to common problems such as apnoea of prematurity. Development of the ventilatory control system, including central respiratory rhythmogenesis and central and peripheral chemoreception, begins early in gestation and continues for weeks or months after birth. Development of the neural components of central rhythmogenesis and their highly complex interconnectivity results from complex, timing-sensitive interactions between patterning and other genes, transcription factors and neurotrophic factors. At birth, nearly all aspects of ventilatory control remain immature, especially in preterm infants; and postnatal maturation can be altered by hypoxia, toxins and other stressors. Clinical care may be greatly enhanced by increased awareness of ventilatory control maturation and related disorders.