Predictors for poor daily weight gain in preterm neonates exposed to different dose regimens of caffeine in ICU- a retrospective cohort study.

BACKGROUND: With a wide therapeutic index, efficacy, ease of use, and other neuroprotective and respiratory benefits, caffeine citrate(CC) is currently the drug of choice for preterm neonates (PTNs). Caffeine-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side-effects (CC-APSEs) result in lower daily-weight gain (WG) in premature neonates. This study aimed to evaluate the risk factors for daily-WG in neonates exposed to different dose regimens of caffeine in ICU. METHOD: This retrospective cohort study included neonates of ≤ 36weeks gestational age (GA) and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I (received; standard-doses = 5 mg/kg/day), group-II (received;>5-7 mg/kg/day), and group-III (received;>7 mg/kg/day). Prenatal and postnatal clinical characteristics, CC-regimen, daily-WG, CC-APSEs, and concomitant risk-factors, including daily-caloric intake, Parenteral-Nutrition duration, steroids, diuretics, and ibuprofen exposure, were analyzed separately for group-II and group-III using group-I as standard. Regression analysis was performed to evaluate the risk factors for daily-WG. RESULTS: Included 314 PTNs. During 15-28 DOL, the mean-daily-WG(MD-WG) was significantly higher in group-I than group-II [19.9 ± 0.70 g/kg/d vs. 17.7 ± 0.52 p = 0.036] and group-III [19.9 ± 0.70 g/kg/d vs. 16.8 ± 0.73 p < 0.001]. During 29-42 DOL the MD-WG of group-I was only significantly higher than group-III [21.7 ± 0.44 g/kg/d vs. 18.3 ± 0.41 g/kg/d p = 0.003] and comparable with group-II. During 15-28 DOL, observed CC-APSEs was significantly higher in group-II and III but during 29-42 DOL it was only significant in group-III. In the adjusted regression analysis for daily-WG during 15-28DOL, with respect to standard-dose, 5-7 mg/kg/day (ß=-1.04; 95%CI:-1.62,-0.93) and > 7-10 mg/kg/day (ß=-1.36; 95%CI:-1.56,-1.02) were associated with a lower daily-WG. However, during 29-42DOL, this association was present only for > 7-10 mg/kg/day (ß=-1.54; 95%CI:-1.66,-1.42). The GA ≤ 27weeks (ß=-1.03 95%CI:-1.24, -0.88) was associated with lower daily-WG only during 15-28DOL. During both periods of therapy, higher cumulative-caffeine dose and presence of culture proven sepsis, tachypnea, hyponatremia, and feeding intolerance were significantly associated with lower daily-WG. Conversely, daily kcal intake was found to be linked with an increase in daily-WG in both periods. CONCLUSION: In this study cohort exposure to higher caffeine daily and cumulative doses is associated with lower postnatal daily-WG in PTNs than standard-daily doses, which may be due to its catabolic effects and CC-APSEs.

Dose-Response Study of Caffeine on Postnatal Weight Gain in Premature Neonates-A Retrospective Cohort Study.

Background: Caffeine citrate (CC)-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side effects (CC-APSEs) result in lower daily weight gain (WG) in premature neonates. This study aimed to assess higher CC-doses' effect on the mean daily-WG (MD-WG) and CC-APSE development, considering 5 mg/kg/day as the standard regimen. Method: This retrospective cohort study included neonates of ≤36 weeks gestational age and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I=(5 mg/kg/day), group-II=(>5-7 mg/kg/day), and group-III=(>7 mg/kg/day). Data was analyzed separately for group-II and group-III using group-I as the standard. Results: The study included 284 neonates. During phase-I, the MD-WG was significantly higher in group-I than group-II (19.9 ± .88 g/kg/d vs 17.5 ± .49, P = .031) and group-III (19.9 ± .88 g/kg/d vs 16.7 ± .71, P < .001). During 29-42 DOL, the MD-WG of group-I was only significantly higher than group-III (21.5 ± .42 g/kg/d vs 18.1 ± .39 g/kg/d, P = .003) and comparable with group-II. During 15-28 DOL, CC-APSEs were significantly higher in group-II and group-III but during 29-42 DOL was significant only in group-III. Conclusion: Exposure to higher caffeine doses in this study cohort is associated with lower postnatal WG in preterm neonates than standard daily doses may be due to its catabolic effects and CC-APSEs.

Association of Caffeine Daily Dose With Respiratory Outcomes in Preterm Neonates: A Retrospective Cohort Study.

Apnea and poor respiratory drive increase the risk of extubation failure (EF) and prolonged invasive mechanical ventilation (IMV) in preterm neonates (pre-nates) with respiratory distress. Caffeine citrate (CC) is often prescribed for pre-nates in doses of 5-10 mg/kg in 24 h. This study aimed to evaluate the most effective dosage regimen (5 mg/kg/day vs >5-10 mg/kg/day) to prevent apnea and EF with minimal caffeine-associated potential side effects (CC-APSEs) in pre-nates. This one-year retrospective cohort study included all the eligible neonates admitted to NICU and received CC-therapy till 28 days of life (DOL) or discharge. Based on CC-daily dose formed LD-caffeine-group (5 mg/kg/day) and HD-caffeine-group (>5-10 mg/kg/day). Antenatal, prenatal, and postnatal characteristics, CC-regimen, comorbidities, and CC-APSEs were compared between the groups. Predictors of apnea and EF were analyzed through logistic regression. There were 181 and 72 neonates in the LD and HD-caffeine-groups respectively. In HD-caffeine-group daily CC-dose was 7 to 7.5 mg/kg/day in 93% of neonates and >7.5 to 10 mg/kg/day in only 7%. Significantly fewer neonates experienced apnea and EF in the HD-caffeine-group till 28DOL or discharge. This difference was even greater in the subgroup of ≤28 weeks GA (15.6% vs 40.0%; P < .01). In HD-caffeine-group the incidence of severe/moderate-BPD was significantly lower and the frequency of CC-APSEs was higher. Multivariate analysis showed that; the smaller the GA higher the risk of apnea (AOR = 0.510, 95% CI 0.483-0.999) and EF (AOR = 0.787, 95% CI 0.411-0.997). The HD-caffeine was inversely associated with developing apnea (AOR = 0.244, 95% CI 0.053-0.291) and EF (AOR = 0.103, 95% CI 0.098-2.976). IMV-duration before extubation (AOR = 2.229, 95% CI 1.672-2.498) and severe/moderate-BPD (AOR = 2.410, 95%CI 1.104-2.952) had a high risk of EF. Initiating early HD-caffeine may prevent apnea and extubation failure in preterm neonates. Optimization of caffeine initiation time and dosages can be a safe and feasible approach to decrease the burden of neonatal respiratory morbidities.

Detecting central apneas using multichannel signals in premature infants.

Objective. Monitoring of apnea of prematurity, performed in neonatal intensive care units by detecting central apneas (CAs) in the respiratory traces, is characterized by a high number of false alarms. A two-step approach consisting of a threshold-based apneic event detection algorithm followed by a machine learning model was recently presented in literature aiming to improve CA detection. However, since this is characterized by high complexity and low precision, we developed a new direct approach that only consists of a detection model based on machine learning directly working with multichannel signals.Approach. The dataset used in this study consisted of 48 h of ECG, chest impedance and peripheral oxygen saturation extracted from 10 premature infants. CAs were labeled by two clinical experts. 47 features were extracted from time series using 30 s moving windows with an overlap of 5 s and evaluated in sets of 4 consecutive moving windows, in a similar way to what was indicated for the two-step approach. An undersampling method was used to reduce imbalance in the training set while aiming at increasing precision. A detection model using logistic regression with elastic net penalty and leave-one-patient-out cross-validation was then tested on the full dataset.Main results. This detection model returned a mean area under the receiver operating characteristic curve value equal to 0.86 and, after the selection of a FPR equal to 0.1 and the use of smoothing, an increased precision (0.50 versus 0.42) at the expense of a decrease in recall (0.70 versus 0.78) compared to the two-step approach around suspected apneic events.Significance. The new direct approach guaranteed correct detections for more than 81% of CAs with lengthL≥ 20 s, which are considered among the most threatening apneic events for premature infants. These results require additional verifications using more extensive datasets but could lead to promising applications in clinical practice.

Nasal high frequency oscillatory highflow therapy in preterm infants: A randomized crossover trial.

OBJECTIVES: To assess the clinical efficacy, safety, and potential physiological mechanisms of highflow therapy with superimposed high frequency oscillations ("osciflow"). STUDY DESIGN: In this prospective, randomized, single center crossover trial, 30 preterm infants were randomized to receive osciflow or highflow therapy first, each for 180 min. During osciflow, an oscillatory amplitude of 20 mbar and a frequency of 6 Hz were set. The flow rate was 4 L/min during both interventions. Primary outcome was the paired difference in the combined number of desaturations (SpO2 < 80%) and bradycardia (heart rate <80 beats per min) between interventions. Safety outcomes included nasal trauma, pneumothorax and treatment failure, and a pain score was assessed. In 20 infants, electrical impedance tomography (EIT) recordings were performed to evaluate oscillatory (VOsc ) and tidal volumes (VT ) at the lung level. RESULTS: Infants with a mean (SD) postnatal age of 33.1 ± 1.2 weeks were included. The median (IQR) number of episodes of desaturation and bradycardia was 19.5 (6-49) during osciflow and 26 (6-44) during highflow therapy (paired difference -2; IQR -10 to 9; p = .37). There were no differences in safety outcomes and pain scores. During osciflow, EIT recordings showed a signal at 6 Hz, which was not detectable during highflow. Corresponding mean (SD) VOsc /VT ratio was 9% (±5%). CONCLUSIONS: In preterm infants, osciflow did not reduce the number of desaturations and bradycardia compared with highflow therapy. Although VOsc were transmitted to the lung during osciflow, their magnitude was small. Osciflow was safe and well tolerated.

Bradycardia May Decrease Cardiorespiratory Coupling in Preterm Infants.

Bradycardia, frequently observed in preterm infants, presents significant risks due to the immaturity of their autonomic nervous system (ANS) and respiratory systems. These infants may face cardiorespiratory events, leading to severe complications like hypoxemia and neurodevelopmental disorders. Although neonatal care has advanced, the influence of bradycardia on cardiorespiratory coupling (CRC) remains elusive. This exploratory study delves into CRC in preterm infants, emphasizing disparities between events with and without bradycardia. Using the Preterm Infant Cardio-Respiratory Signals (PICS) database, we analyzed interbeat (R-R) and inter-breath intervals (IBI) from 10 preterm infants. The time series were segmented into bradycardic (B) and non-bradycardic (NB) segments. Employing information theory measures, we quantified the irregularity of cardiac and respiratory time series. Notably, B segments had significantly lower entropy values for R-R and IBI than NB segments, while mutual information was higher in NB segments. This could imply a reduction in the complexity of respiratory and cardiac dynamics during bradycardic events, potentially indicating weaker CRC. Building on these insights, this research highlights the distinctive physiological characteristics of preterm infants and underscores the potential of emerging non-invasive diagnostic tools.

Apnea of prematurity induces short and long-term development-related transcriptional changes in the murine cerebellum.

Apnea of prematurity (AOP) affects more than 50% of preterm infants and leads to perinatal intermittent hypoxia (IH) which is a major cause of morbimortality worldwide. At birth, the human cerebellar cortex is still immature, making it vulnerable to perinatal events. Additionally, studies have shown a correlation between cerebellar functions and the deficits observed in children who have experienced AOP. Yet, the cerebellar alterations underpinning this link remain poorly understood. To gain insight into the involvement of the cerebellum in perinatal hypoxia-related consequences, we developed a mouse model of AOP. Our previous research has revealed that IH induces oxidative stress in the developing cerebellum, as evidenced by the over-expression of genes involved in reactive oxygen species production and the under-expression of genes encoding antioxidant enzymes. These changes suggest a failure of the defense system against oxidative stress and could be responsible for neuronal death in the cerebellum. Building upon these findings, we conducted a transcriptomic study of the genes involved in the processes that occur during cerebellar development. Using real-time PCR, we analyzed the expression of these genes at different developmental stages and in various cell types. This enabled us to pinpoint a timeframe of vulnerability at P8, which represents the age with the highest number of downregulated genes in the cerebellum. Furthermore, we discovered that our IH protocol affects several molecular pathways, including proliferation, migration, and differentiation. This indicates that IH can impact the development of different cell types, potentially contributing to the histological and behavioral deficits observed in this model. Overall, our data strongly suggest that the cerebellum is highly sensitive to IH, and provide valuable insights into the cellular and molecular mechanisms underlying AOP. In the long term, these findings may contribute to the identification of novel therapeutic targets for improving the clinical management of this prevalent pathology.

Evaluation of NAVA-PAP in premature neonates with apnea of prematurity: minimal backup ventilation and clinically significant events.

Background: Neonates with apnea of prematurity (AOP) clinically deteriorate because continuous positive airway pressure (CPAP) provides inadequate support during apnea. Neurally adjusted ventilatory assist (NAVA) provides proportional ventilator support from the electrical activity of the diaphragm. When the NAVA level is 0 cmH2O/mcV (NAVA-PAP), patients receive CPAP when breathing and backup ventilation when apneic. This study evaluates NAVA-PAP and time spent in backup ventilation. Methods: This was a prospective, two-center, observational study of preterm neonates on NAVA-PAP for AOP. Ventilator data were downloaded after 24 h. The number of clinically significant events (CSEs) was collected. A paired t-test was used to perform statistical analysis. Results: The study was conducted on 28 patients with a gestational age of 25 ± 1.8 weeks and a study age of 28 ± 23 days. The number of CSEs was 4 ± 4.39/24 h. The patients were on NAVA-PAP for approximately 90%/min, switched to backup mode 2.5 ± 1.1 times/min, and spent 10.6 ± 7.2% in backup. Conclusion: Preterm neonates on NAVA-PAP had few CSEs with minimal time in backup ventilation.

A consequence of immature breathing induces persistent changes in hippocampal synaptic plasticity and behavior: a role of prooxidant state and NMDA receptor imbalance.

Underdeveloped breathing results from premature birth and causes intermittent hypoxia during the early neonatal period. Neonatal intermittent hypoxia (nIH) is a condition linked to the increased risk of neurocognitive deficit later in life. However, the mechanistic basis of nIH-induced changes to neurophysiology remains poorly resolved. We investigated the impact of nIH on hippocampal synaptic plasticity and NMDA receptor (NMDAr) expression in neonatal mice. Our findings indicate that nIH induces a prooxidant state that leads to an imbalance in NMDAr subunit composition favoring GluN2B over GluN2A expression and impairs synaptic plasticity. These consequences persist in adulthood and coincide with deficits in spatial memory. Treatment with an antioxidant, manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin (MnTMPyP), during nIH effectively mitigated both immediate and long-term effects of nIH. However, MnTMPyP treatment post-nIH did not prevent long-lasting changes in either synaptic plasticity or behavior. In addition to demonstrating that the prooxidant state has a central role in nIH-mediated neurophysiological and behavioral deficits, our results also indicate that targeting the prooxidant state during a discrete therapeutic window may provide a potential avenue for mitigating long-term neurophysiological and behavioral outcomes that result from unstable breathing during early postnatal life.

Effect of prophylactic caffeine in the treatment of apnea in very low birth weight infants: a meta-analysis.

OBJECTIVE: The purpose of this meta-analysis is to investigate the effect of prophylactic caffeine use in the treatment of apnea and other clinical outcomes in very low birth weight infants. METHODS: We searched PubMed, Embase, Web of Science, Scopus, EBSCO, CNKI, and Cochrane databases for all relevant studies up to May 20, 2022. The meta-analysis was carried out using Stata16.0 and RevMan5.4 software. RESULTS: Eleven randomized controlled trials were evaluated, including a total of 4375 very low birth weight infants. The results demonstrated that prophylactic caffeine use was linked with a significantly lower probability of AOP (OR 0.31, 95% CI: 0.19-0.49, p < .001), duration of mechanical ventilation and oxygen therapy when compared to the control group. It also reduced the incidence of BPD (OR 0.62, 95% CI: 0.54-0.71, p < .001), PDA (OR 0.49, 95% CI: 0.30-0.80, p = .005) and ROP (OR 0.76, 95% CI: 0.65-0.90, p = .001), without raising the risk of NEC, IVH and death before hospital discharge (p > .05). CONCLUSION: This meta-analysis confirmed the beneficial effects of prophylactic caffeine in preventing apnea of prematurity and improving clinical outcomes.

Significance of Intermittent Hypoxic Episodes in Premature Infants Prior to Discharge.

Objective The aim of this study was to determine the rate and severity of intermittent hypoxic episodes in premature infants who underwent overnight pulse oximetry prior to discharge. Methods Preterm infants with a birth weight of 1500 grams or less and who underwent overnight pulse oximetry prior to discharge were included. Maternal and neonatal demographic data and complications of prematurity were recorded. All infants underwent overnight pulse oximetry prior to discharge and the McGill score was used to categorize the degree of desaturations (categories 1-4; normal, mildly, moderately, and severely abnormal). Results Fifty infants underwent the overnight pulse oximetry The McGill score showed that 2% had no hypoxia, 50% had mild hypoxia, 20% had moderate hypoxia, and 28% had severe hypoxia. The frequency of desaturations (62.5%) was found more in infants with a birth weight of 1000 grams or less. The results showed that the O2 requirement at discharge was significant (p = 0.0341), and increased values of O2 at discharge were associated with more severe hypoxia. As a result of these findings, 40% of infants were discharged home on oxygen and 26% were discharged on caffeine. Fifty-two percent of infants were initially diagnosed to have stages 1 & 2 retinopathy of prematurity (ROP), 14% had stage 3, and 2% had stage 4 ROP. Eight percent of infants required surgical intervention for ROP. Conclusions Clinically inapparent significant episodes of intermittent hypoxia (IH) are frequent in preterm infants in the early postnatal age, and they may persist post-discharge. Knowledge of the association between IH and morbidity among all neonatal intensive care unit (NICU) caregivers would be of great benefit. Indications for screening preterm infants at risk of severe IH should be reconsidered.

Incidence of Intermittent Hypoxemia Increases during Clinical Care and Parental Touch in Extremely Preterm Infants.

OBJECTIVES: An increased frequency of intermittent hypoxemia (IH) is associated with a higher risk for poor developmental outcomes, disability, or death in extremely preterm infants. The objective of the prFesent study is to quantify the effect of hands-on medical and parental interventions on the incidence of IH in extremely preterm infants. METHODS: An observational design with intraindividual comparisons was used. Blood oxygen saturation levels (SpO2) and time-lapse video were recorded. Frequency, duration, and time to occurrence of IH (SpO2 <80% for ≥10 s) were compared between nursing and medical care (NMC), health care by parents, skin-to-skin contact (SSC), touch in incubator, physiotherapy, and rest. Each infant was observed for six consecutive 24-h periods. Inclusion criteria were as follows: gestational age ≤28 weeks, birth weight <1500 g, postnatal age 0-6 weeks, gavage feeding, no severe illnesses or invasive procedures, no mechanical ventilation. RESULTS: The highest proportion of time with IH occurred during NMC (2.49%) and incubator touch (1.32%), the lowest during SSC (0.74%) and health care by parents (0.67%). IH frequency per hour was highest during NMC (2.95, IQR 1.19-4.01) and lowest during SSC (0.88, IQR 0.37-2.32, p < 0.001). While an increase in IH during NMC was expected, the high incidence during incubator touch was surprising. Parental touch in the incubator is intended to be soothing, not stressful. CONCLUSIONS: Future studies need to clarify how preterm infants process touch, which attributes of touch are fundamental trigger mechanisms of IH, and which handling strategies are most effective in lowering the incidence of IH during hands-on medical care.

Method establishment and clinical practice for concentration determination of caffeine and its metabolites in urine / 中国药房

OBJECTIVE To establish a method for concentration determination of caffeine and its three metabolites， theophylline， paraxanthine and theobromine in urine， and apply it in clinical practice. METHODS Using caffeine-13C3-d3 as internal standard （IS）， and the urine samples were protein precipitated with acetonitrile； HPLC-MS/MS method was adopted to determine the concentrations of caffeine and its three metabolites. The determination was performed on Waters ACQUITY UPLC® BEH HILIC column with mobile phase consisting of 60 mmol/L ammonium acetate （A）-acetonitrile （B） （gradient elution） at the flow rate of 0.5 mL/min. The column temperature was set at 38 ℃ ， and the sample size was 2 μL. The electrospray ionization detection was operated in a positive mode by multiple reaction monitoring. The detection ions for quantitative analysis were m/z 195.1→110.0 for caffeine， m/z 181.1→124.0 for theophylline， m/z 181.1→124.0 for paraxanthine， m/z 181.1→138.0 for theobromine， and m/z 198.1→ 140.1 for IS. The above method was used to determine the concentrations of caffeine and its three metabolites in the urine of 19 infants with apnea of prematurity （AOP）. RESULTS The linear ranges of mass concentration of caffeine， theophylline， paraxanthin and theobromine were 0.200-200， 0.050-50.0，0.050 0-50.0， and 0.100-100 μg/mL， respectively. The lower limits of quantification were 0.200， 0.050， 0.050 and 0.100 μg/mL （r＞0.990）， respectively. RSDs of intra-day and intra- day precision were not above 10.37%， and matrix factors were 85.68%-109.90%； extraction recoveries were 93.53%-109.40% （RSD≤15%）， and RSDs of stability tests were all lower than 15%. The concentrations of caffeine and its three metabolites in the urine of 19 cases were （27.346±7.951）， （0.351±0.223）， （0.428±0.395） and （0.472±0.374） μg/mL， respectively. CONCLUSIONS The established HPLC-MS/MS method is simple， sensitive and can be used for the determination of caffeine and its three metabolites in urine samples of AOP.

Precision caffeine therapy for apnea of prematurity and circadian rhythms: New possibilities open up.

Caffeine is the globally consumed psychoactive substance and the drug of choice for the treatment of apnea of prematurity (AOP), but its therapeutic effects are highly variable among preterm infants. Many of the molecular underpinnings of the marked individual response have remained elusive yet. Interestingly, the significant association between Clock gene polymorphisms and the response to caffeine therapy offers an opportunity to advance our understanding of potential mechanistic pathways. In this review, we delineate the functions and mechanisms of human circadian rhythms. An up-to-date advance of the formation and ontogeny of human circadian rhythms during the perinatal period are concisely discussed. Specially, we summarize and discuss the characteristics of circadian rhythms in preterm infants. Second, we discuss the role of caffeine consumption on the circadian rhythms in animal models and human, especially in neonates and preterm infants. Finally, we postulate how circadian-based therapeutic initiatives could open new possibilities to promote precision caffeine therapy for the AOP management in preterm infants.

A Novel Agnostic Respiratory Stimulant as a Treatment for Apnea of Prematurity: A Proof-of-Concept Study.

AIM/OBJECTIVE: ENA-001 is a novel selective antagonist of large-conductance BK (big potassium) channels located in the carotid bodies, where they act as chemoreceptors that sense low arterial oxygen levels and establish a feedback loop to brainstem nuclei responsible for initiating spontaneous breathing and maintaining adequate oxygen to tissues. ENA-001 attenuates respiratory depression induced by a variety of chemical agents, essentially "agnostic" to the precipitating drug (e.g., opioid(s), benzodiazepine, alcohol, or propofol). But it had not been tested against respiratory depression resulting from a physiological cause, such as apnea of prematurity (AOP). This proof-of-principle study used a well-described animal model (premature lamb) to test the effectiveness of ENA-001 in the setting of an under-developed respiratory control system, similar to that in human AOP. MATERIALS AND METHODS: A set of twin lambs was delivered prematurely via caesarian section at 135 ± 2 d gestational age (GA). An arterial catheter was connected to a transducer for pressure monitoring and a venous catheter was connected to a pump for continuous infusion of 5% dextrose in water (D5W). Lambs were to receive four mechanical breaths for lung recruitment and then started on continuous positive airway pressure (CPAP). After a stabilization period of 15 minutes, the protocol called for the first lamb to be started on continuous infusion of ENA-001, with ascending dose hourly (0.4, 1.1, 2.0, 12.0 mg/kg/hr), while the second lamb was to serve as a sham (D5W) control. At least 10 representative breaths free of artifact from motion or atypical breaths were recorded using a pulmonary function system designed for neonatal research. To maintain a stable plane of anesthesia, repeat doses of fentanyl (1 µg IM) were given as needed based on blood pressure response to stimulation. RESULTS: Two male lambs were delivered. Unexpectedly, neither lamb exhibited a drive for spontaneous breathing. Each required manual ventilation, with a complete absence of spontaneous effort. Despite the poor prognosis owing to the absence of ventilatory effort, continuous infusion of the first dose of ENA-001 was started 20 minutes after birth. The test animal continued to require manual ventilation, which was continued for an additional 10 minutes. An intravenous (IV) bolus of ENA-001 was given. Nearly instantaneously following the delivery of the IV bolus, the lamb began breathing spontaneously and did not require manual intervention for the remainder of the study. The sham animal was delivered approximately an hour following the test animal. As with the test animal, the sham animal lacked spontaneous breathing efforts. A decision was made to manually ventilate for 30 minutes to match the course for the test animal. At the 30-minute time point, an IV bolus infusion of ENA-001 was delivered. Nearly instantaneously following the delivery of the IV bolus, the lamb began breathing spontaneously. After several minutes, the spontaneous breathing efforts abated, and manual ventilation was resumed. The animal was then sacrificed for tissue harvest. CONCLUSION: These results suggest that ENA-001 might be an effective therapy, alone or as a co-medication, for the treatment of AOP. They further suggest that ENA-001 might have broader applications in situations of neurological ventilatory insufficiency.

Central apnea detection in premature infants using machine learning.

BACKGROUND AND OBJECTIVE: Apnea of prematurity is one of the most common diagnosis in neonatal intensive care units. Apneas can be classified as central, obstructive or mixed. According to the current international standards, minimal fluctuations or absence of fluctuations in the chest impedance (CI) suggest a central apnea (CA). However, automatic detection of reduced CI fluctuations leads to a high number of central apnea-suspected events (CASEs), the majority being false alarms. We aim to improve automatic detection of CAs by using machine learning to optimize detection of CAs among CASEs. METHODS: Using an optimized algorithm for automated detection, all CASEs were detected in a population of 10 premature infants developing late-onset sepsis and 10 age-matched control patients. CASEs were inspected by two clinical experts and annotated as CAs or rejections in two rounds of annotations. A total of 47 features were extracted from the ECG, CI and oxygen saturation signals considering four 30 s-long moving windows, from 30 s before to 15 s after the onset of each CASE, using a moving step size of 5 s. Consecutively, new CA detection models were developed based on logistic regression with elastic net penalty, random forest and support vector machines. Performance was evaluated using both leave-one-patient-out and 10-fold cross-validation considering the mean area under the receiver-operating-characteristic curve (AUROC). RESULTS: The CA detection model based on logistic regression with elastic net penalty returned the highest mean AUROC when features extracted from all four time windows were included, both using leave-one-patient-out and 10-fold cross-validation (mean AUROC of 0.88 and 0.90, respectively). Feature relevance was found to be the highest for features derived from the CI. A threshold for the false positive rate in the mean receiver-operating-characteristic curve equal to 0.3 led to a high percentage of correct detections for all CAs (78.2%) and even higher for CAs followed by a bradycardia (93.4%) and CAs followed by both a bradycardia and a desaturation (95.2%), which are more critical for the well-being of premature infants. CONCLUSIONS: Models based on machine learning can lead to improved CA detection with fewer false alarms.

Intermittent hypoxia in a mouse model of apnea of prematurity leads to a retardation of cerebellar development and long-term functional deficits.

BACKGROUND: Apnea of prematurity (AOP) is caused by respiratory control immaturity and affects nearly 50% of premature newborns. This pathology induces perinatal intermittent hypoxia (IH), which leads to neurodevelopmental disorders. The impact on the brain has been well investigated. However, despite its functional importance and immaturity at birth, the involvement of the cerebellum remains poorly understood. Therefore, this study aims to identify the effects of IH on cerebellar development using a mouse model of AOP consisting of repeated 2-min cycles of hypoxia and reoxygenation over 6 h and for 10 days starting on postnatal day 2 (P2). RESULTS: At P12, IH-mice cerebella present higher oxidative stress associated with delayed maturation of the cerebellar cortex and decreased dendritic arborization of Purkinje cells. Moreover, mice present with growth retardation and motor disorders. In response to hypoxia, the developing cerebellum triggers compensatory mechanisms resulting in the unaltered organization of the cortical layers from P21 onwards. Nevertheless, some abnormalities remain in adult Purkinje cells, such as the dendritic densification, the increase in afferent innervation, and axon hypomyelination. Moreover, this compensation seems insufficient to allow locomotor recovery because adult mice still show motor impairment and significant disorders in spatial learning. CONCLUSIONS: All these findings indicate that the cerebellum is a target of intermittent hypoxia through alterations of developmental mechanisms leading to long-term functional deficits. Thus, the cerebellum could contribute, like others brain structures, to explaining the pathophysiology of AOP.

Population pharmacokinetic modeling of caffeine in preterm infants with apnea of prematurity: New findings from concomitant erythromycin and AHR genetic polymorphisms.

Current standard-dose caffeine therapy results in significant intersubject variability. The aims of this study were to develop and evaluate population pharmacokinetic (PPK) models of caffeine in preterm infants through comprehensive screening of covariates and then to propose model-informed precision dosing of caffeine for this population. A total of 129 caffeine concentrations from 96 premature neonates were incorporated into this study. Comprehensive medical record and genotype data of these neonates were collected for analysis. PPK modeling was performed by a nonlinear mixed effects modeling program (NONMEM). Final models based on the current weight (CW) or body surface area (BSA) were evaluated via multiple graphic and statistical methods. The model-informed dosing regimen was performed through Monte Carlo simulations. In addition to CW or BSA, postnatal age, coadministration with erythromycin (ERY), and aryl hydrocarbon receptor coding gene (AHR) variant (rs2158041) were incorporated into the final PPK models. Multiple evaluation results showed satisfactory prediction performance and stability of the CW- and BSA-based models. Monte Carlo simulations demonstrated that trough concentrations of caffeine in preterm infants would be affected by concomitant ERY therapy and rs2158041 under varying dose regimens. For the first time, ERY and rs2158041 were found to be associated with the clearance of caffeine in premature infants. Similar predictive performance and stability were obtained for both CW- and BSA-based PPK models. These findings provide novel insights into caffeine precision therapy for preterm infants.

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Apnea of prematurity (AOP) is one of the common diseases in preterm infants. The main cause of AOP is immature development of the respiratory control center. If AOP is not treated timely and effectively, it will lead to respiratory failure, hypoxic brain injury, and even death in severe cases. Caffeine is the first choice for the treatment of AOP, but its effectiveness varies in preterm infants. With the deepening of AOP research, more and more genetic factors have been confirmed to play important roles in the pathogenesis and treatment of AOP; in particular, the influence of single nucleotide polymorphism on the efficacy of caffeine has become a research hotspot in recent years. This article reviews the gene polymorphisms that affect the efficacy of caffeine, in order to provide a reference for individualized caffeine therapy. Citation.