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Background: Apnea is common in preterm infants and can be accompanied with severe hypoxic damage. Early assessment of apnea risk can impact the prognosis of preterm infants. We constructed a prediction model to assess apnea risk in premature infants for identifying high-risk groups., Methods: A total of 162 and 324 preterm infants with and without apnea who were admitted to the neonatal intensive care unit of Xiamen University between January 2018 and December 2021 were selected as the case and control groups, respectively. Demographic characteristics, laboratory indicators, complications of the patients, pregnancy-related factors, and perinatal risk factors of the mother were collected retrospectively. The participants were randomly divided into modeling (n = 388) and validation (n = 98) sets in an 8:2 ratio. Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate logistic regression analyses were used to independently filter variables from the modeling set and build a model. A nomogram was used to visualize models. The calibration and clinical utility of the model was evaluated using consistency index, receiver operating characteristic (ROC) curve, calibration curve, and decision curve, and the model was verified using the validation set., Results: Results of LASSO combined with multivariate logistic regression analysis showed that gestational age at birth, birth length, Apgar score, and neonatal respiratory distress syndrome were predictors of apnea development in preterm infants. The model was presented as a nomogram and the Hosmer-Lemeshow goodness of fit test showed a good model fit (χ 2 =5.192, df=8, P=0.737), with Nagelkerke R 2 of 0.410 and C-index of 0.831. The area under the ROC curve and 95% CI were 0.831 (0.787-0.874) and 0.829 (0.722-0.935), respectively. Delong's test comparing the AUC of the two data sets showed no significant difference (P=0.976). The calibration curve showed good agreement between the predicted and actual observations. The decision curve results showed that the threshold probability range of the model was 0.07-1.00, the net benefit was high, and the constructed clinical prediction model had clinical utility., Conclusions: Our risk prediction model based on gestational age, birth length, Apgar score 10 min post-birth, and neonatal respiratory distress syndrome was validated in many aspects and had good predictive efficacy and clinical utility., (© 2024. The Author(s).)

This study aimed to investigate what factors determine freedivers' maximal static apnea dive time. We correlated some physical/physiological factors with male freedivers' maximum apnea diving duration. Thirty-six experienced male freedivers participated in this study. The divers participated in two days of the experiments. On the first day, apnea diving time, blood oxygen saturation (SpO 2 ), heart rate (HR), blood pressure (BP), stress index, and blood parameters were measured before, during, and after the apnea diving in the pool. On the second day, body composition, lung capacity, resting and maximal oxygen consumption (VO 2 max), and the Wingate anaerobic power were measured in the laboratory. The data were analyzed with Pearson's Correlation using the SPSS 22 program. The correlation coefficient (R) of determination was set at 0.4, and the level of significance was set at p <0.05. There were positive correlations of diving experience, maximum SpO 2 , and lung capacity with the maximum apnea time R>0.4, P<0.05). There were negative correlations of BMI, body fat percentage, body fat mass, minimum SpO 2 , stress index, and total cholesterol with the maximum apnea diving time (R>-0.4, P<0.05). No correlations of age, height, weight, fat-free mass, skeletal muscle mass, HR, BP, blood glucose, beta- hydroxybutyrate, lactate, and hemoglobin levels with the maximum apnea diving time were observed (R<0.4, P>0.05). It is concluded that more experience in freediving, reduced body fat, extended SpO 2 range, and increased lung capacity are the performance predictors and beneficial for freedivers to improve their maximum apnea diving performance., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Background: During stabilisation of preterm infants at birth, a face mask is used to provide respiratory support. However, application of these masks may activate cutaneous stretch receptors of the trigeminal nerve, causing apnoea and bradycardia. This study investigated the amount of force exerted on the face mask during non-invasive ventilation of preterm infants at birth and whether the amount of exerted force is associated with apnoea and bradycardia., Methods: A prospective observational study was performed in preterm infants born <32 weeks of gestation who were stabilised at birth. During the first 10 minutes of respiratory support, we measured breathing and heart rate as well as the amount of force exerted on a face mask using a custom-made pressure sensor placed on top of the face mask., Results: Thirty infants were included (median (IQR) gestational age(GA) 28 +3 (27 +0 -30 +0 ) weeks, birthweight 1104 (878-1275) grams). The median exerted force measured was 297 (198-377) grams, ranging from 0 to 1455 grams. Significantly more force was exerted on the face mask during positive pressure ventilation when compared to CPAP (410 (256-556) vs 286 (190-373) grams, p = 0.009). In a binary logistic regression model, higher forces were associated with an increased risk of apnoea (OR = 1.607 (1.556-1.661), p < 0.001) and bradycardia (OR = 1.140 (1.102-1.180), p < 0.001) during the first 10 minutes of respiratory support at birth., Conclusion: During mask ventilation, the median exerted force on a face mask was 297 grams with a maximum of 1455 grams. Higher exerted forces were associated apnoea and bradycardia during the first 10 minutes of respiratory support at birth., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘K.L.A.M. Kuypers is the recipient of an unrestricted research grant from Fisher & Paykel Healthcare Limited; they had no role or influence in study design nor in the collection, analysis, and interpretation of data, writing of the report and decision to submit the paper for publication.’., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lumbar puncture is a common invasive procedure performed in newborns for diagnostic and therapeutic purposes. Approximately one in two lumbar punctures fail, resulting in both short- and long-term negative consequences for the clinical management of patients. The most common positions used to perform lumbar puncture are the lateral decubitus and sitting position, and each can impact the success rate and safety of the procedure. However, it is uncertain which position best improves patient outcomes., Objectives: To assess the benefits and harms of the lateral decubitus, sitting, and prone positions for lumbar puncture in newborn infants., Search Methods: We used standard, extensive Cochrane search methods. The latest search date was 24 January 2023., Selection Criteria: We included randomized controlled trials (RCTs) and quasi-RCTs involving newborn infants of postmenstrual age up to 46 weeks and 0 days, undergoing lumbar puncture for any indication, comparing different positions (i.e. lateral decubitus, sitting, and prone position) during the procedure., Data Collection and Analysis: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) and standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CI). Our primary outcomes were successful lumbar puncture procedure at the first attempt; total number of lumbar puncture attempts; and episodes of bradycardia. We used GRADE to assess the certainty of evidence for each outcome., Main Results: We included five studies with 1476 participants. Compared to sitting position: lateral decubitus position probably results in little to no difference in successful lumbar puncture procedure at the first attempt (RR 0.99, 95% CI 0.88 to 1.12; RD 0.00, 95% CI -0.06 to 0.05; I 2 = 47% and 46% for RR and RD, respectively; 2 studies, 1249 infants, low-certainty evidence). None of the studies reported the total number of lumbar puncture attempts as specified in this review. Lateral decubitus position likely increases episodes of bradycardia (RR 1.72, 95% CI 1.08 to 2.76; RD 0.03, 95% CI 0.00 to 0.05; number needed to treat for an additional harmful outcome (NNTH) = 33; I 2 = not applicable and 69% for RR and RD, respectively; 3 studies, 1279 infants, moderate-certainty evidence) and oxygen desaturation (RR 2.10, 95% CI 1.42 to 3.08; RD 0.06, 95% CI 0.03 to 0.09; NNTH = 17; I 2 = not applicable and 96% for RR and RD, respectively; 2 studies, 1249 infants, moderate-certainty evidence). Lateral decubitus position results in little to no difference in time to perform the lumbar puncture compared to sitting position (I 2 = not applicable; 2 studies; 1102 infants; high-certainty evidence; in one of the study median and IQR to report time to perform the lumbar puncture were 8 (5-13) and 8 (5-12) in the lateral and sitting position, respectively, I 2 = not applicable; 1 study, 1082 infants; in the other study: mean difference 2.00, 95% CI -4.98 to 8.98; I 2 = not applicable; 1 study, 20 infants). Lateral decubitus position may result in little to no difference in the number of episodes of apnea during the procedure (RR not estimable; RD 0.00, 95% CI -0.03 to 0.03; I 2 = not applicable and 0% for RR and RD, respectively; 2 studies, 197 infants, low-certainty evidence). No studies reported apnea defined as number of infants with one or more episodes during the procedure. Compared to prone position: lateral decubitus position may reduce successful lumbar puncture procedure at first attempt (RR 0.75, 95% CI 0.63 to 0.90; RD -0.21, 95% CI -0.34 to -0.09; number needed to treat for an additional beneficial outcome = 5; I 2 = not applicable; 1 study, 171 infants, low-certainty evidence). None of the studies reported the total number of lumbar puncture attempts or episodes of apnea. Pain intensity during and after the procedure was reported using a non-validated pain scale. None of the studies comparing lateral decubitus versus prone position reported the other critical outcomes of this review., Authors' Conclusions: When compared to sitting position, lateral decubitus position probably results in little to no difference in successful lumbar puncture procedure at first attempt. None of the included studies reported the total number of lumbar puncture attempts as specified in this review. Furthermore, infants in a sitting position likely experience less episodes of bradycardia and oxygen desaturation than in the lateral decubitus, and there may be little to no difference in episodes of apnea. Lateral decubitus position results in little to no difference in time to perform the lumbar puncture compared to sitting position. Pain intensity during and after the procedure was reported using a pain scale that was not included in our prespecified tools for pain assessment due to its high risk of bias. Most study participants were term newborns, thereby limiting the applicability of these results to preterm babies. When compared to prone position, lateral decubitus position may reduce successful lumbar puncture procedure at first attempt. Only one study reported on this comparison and did not evaluate adverse effects. Further research exploring harms and benefits and the effect on patients' pain experience of different positions during lumbar puncture using validated pain scoring tool may increase the level of confidence in our conclusions., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: We investigated the relationship between respiratory events experienced before and after hospital discharge and developmental outcomes at 6 months corrected age (CA)., Study Design: Preterm infants born between 28-32 weeks gestational age (GA) were studied at 32-36 weeks postmenstrual age (PMA), 36-40 weeks PMA, 3- and 6-months CA. Percentage total sleep time (%TST) with respiratory events (isolated apneas, sequential apneas and periodic breathing (PB)) at each study was calculated. Stepwise multiple linear regressions determined significant predictors of developmental outcomes at 6 months., Result: %TST with respiratory events at term were significant predictors of language (R 2  = 0.165, β = -0.416) and motor (R 2  = 0.180, β = -0.485) composite scores of the Bayley Scales of Infant Development at 6 months, independent of GA, birth weight and sex., Conclusions: In clinically stable very preterm infants at term equivalent age, time spent having respiratory events, was related to a reduction in language and motor outcomes at 6 months., (© 2023. The Author(s).)

Objective: To evaluate the mechanisms leading to intermittent hypoxemia (IH) episodes in spontaneously breathing extremely premature infants at 32 weeks and 36 weeks postmenstrual age (PMA)., Methods: We studied spontaneously breathing premature infants born at 23-28 weeks of gestational age who presented with IH episodes while on noninvasive respiratory support at 32 or 36 weeks PMA. Daytime recordings of arterial oxygen saturation (SpO 2 ), esophageal pressure, respiratory inductive plethysmography of the abdomen, chest wall, and their sum were obtained during 4 hours at 32 weeks and 36 weeks PMA. IH episodes (SpO 2  <90% for ≥5 seconds) and severe IH episodes (SpO 2  < 80% for ≥5 seconds) were classified as resulting from apnea, active exhalation and breath holding, reduced tidal volume (VT), or reduced respiratory rate (RR) during the preceding 60 seconds., Results: Fifty-one infants with a mean gestational age of 25.9 ± 1.5 weeks and a mean birth weight of 846 ± 185 g were included. Of these, 31 and 41 were included in the analysis at 32 weeks and 36 weeks PMA, respectively. At both 32 weeks and 36 weeks PMA, greater proportions of all IH episodes and severe IH episodes were associated with active exhalation and breath holding than with apnea, reduced RR, or reduced VT. The severity and duration of the IH episodes did not differ between mechanisms., Conclusions: In this group of premature infants, the predominant mechanism associated with daytime IH was active exhalation and breath holding. This etiology is more closely associated with behavioral factors than abnormal respiratory control and can have implications for prevention., Competing Interests: Declaration of Competing Interest Supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health of the Prematurity Related Ventilatory Control (Pre-Vent): Role in Respiratory Outcomes Project (Grants U01 HL133689 and U01 HL133708), the Micah Batchelor Foundation, and the University of Miami Project NewBorn. The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Lumbar puncture is a common invasive procedure performed in newborns for diagnostic and therapeutic purposes. Approximately one in two lumbar punctures fail, resulting in both short- and long-term negative consequences for the clinical management of patients. The most common positions used to perform lumbar puncture are the lateral decubitus and sitting position, and each can impact the success rate and safety of the procedure. However, it is uncertain which position best improves patient outcomes., Objectives: To assess the benefits and harms of the lateral decubitus, sitting, and prone positions for lumbar puncture in newborn infants., Search Methods: We used standard, extensive Cochrane search methods. The latest search date was 24 January 2023., Selection Criteria: We included randomized controlled trials (RCTs) and quasi-RCTs involving newborn infants of postmenstrual age up to 46 weeks and 0 days, undergoing lumbar puncture for any indication, comparing different positions (i.e. lateral decubitus, sitting, and prone position) during the procedure., Data Collection and Analysis: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) and standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CI). Our primary outcomes were successful lumbar puncture procedure at the first attempt; total number of lumbar puncture attempts; and episodes of bradycardia. We used GRADE to assess the certainty of evidence for each outcome., Main Results: We included five studies with 1476 participants. Compared to sitting position: lateral decubitus position may result in little to no difference in successful lumbar puncture procedure at the first attempt (RR 0.93, 95% CI 0.85 to 1.02; RD -0.04, 95% CI -0.09 to 0.01; I 2 = 70% and 72% for RR and RD, respectively; 2 studies, 1249 infants, low-certainty evidence). None of the studies reported the total number of lumbar puncture attempts. Lateral decubitus position likely increases episodes of bradycardia (RR 1.72, 95% CI 1.08 to 2.76; RD 0.03, 95% CI 0.00 to 0.05; number needed to treat for an additional harmful outcome (NNTH) = 33; I 2 = not applicable and 69% for RR and RD, respectively; 3 studies, 1279 infants, moderate-certainty evidence) and oxygen desaturation (RR 2.10, 95% CI 1.42 to 3.08; RD 0.06, 95% CI 0.03 to 0.09; NNTH = 17; I 2 = not applicable and 96% for RR and RD, respectively; 2 studies, 1249 infants, moderate-certainty evidence). The evidence is very uncertain regarding the effect of lateral decubitus position on time to perform the lumbar puncture (MD 2.00, 95% CI -4.98 to 8.98; I 2 = not applicable; 1 study, 20 infants, very low-certainty evidence). Lateral decubitus position may result in little to no difference in the number of episodes of apnea during the procedure (RR not estimable; RD 0.00, 95% CI -0.03 to 0.03; I 2 = not applicable and 0% for RR and RD, respectively; 2 studies, 197 infants, low-certainty evidence). No studies reported apnea defined as number of infants with one or more episodes during the procedure. Compared to prone position: lateral decubitus position may reduce successful lumbar puncture procedure at first attempt (RR 0.75, 95% CI 0.63 to 0.90; RD -0.21, 95% CI -0.34 to -0.09; number needed to treat for an additional beneficial outcome = 5; I 2 = not applicable; 1 study, 171 infants, low-certainty evidence). None of the studies reported the total number of lumbar puncture attempts or episodes of apnea. Pain intensity during and after the procedure was reported using a non-validated pain scale. None of the studies comparing lateral decubitus versus prone position reported the other critical outcomes of this review., Authors' Conclusions: When compared to sitting position, lateral decubitus position may result in little to no difference in successful lumbar puncture procedure at first attempt. None of the included studies reported the total number of lumbar puncture attempts. Furthermore, infants in a lateral decubitus position likely experience more episodes of bradycardia and oxygen desaturation, and there may be little to no difference in episodes of apnea. The evidence is very uncertain regarding time to perform lumbar puncture. Pain intensity during and after the procedure was reported using a pain scale that was not included in our prespecified tools for pain assessment due to its high risk of bias. Most study participants were term newborns, thereby limiting the applicability of these results to preterm babies. When compared to prone position, lateral decubitus position may reduce successful lumbar puncture procedure at first attempt. Only one study reported on this comparison and did not evaluate adverse effects. Further research exploring harms and benefits and the effect on patients' pain experience of different positions during lumbar puncture using validated pain scoring tool may increase the level of confidence in our conclusions., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Study Objective: Investigate a low-cost, nasopharyngeal apnoeic oxygenation technique, establish its efficacy, and compare it to preoxygenation only in an obese population. The study's hypothesis was that nasopharyngeal apnoeic oxygenation at 18 l.min -1 would significantly prolong safe apnoea time compared to preoxygenation alone., Design: Randomised controlled study., Setting: Theatre complex of a resource constrained hospital., Patients: 30 adult, obese (BMI ≥ 35 kg.m -2 ) patients presenting for elective surgery. Patients with limiting cardio-respiratory disease, suspected difficult airway, risk of aspiration, and that were pregnant, were excluded. Patients were allocated by block randomisation in a 1:2 ratio to a preoxygenation-only (No-AO) and an intervention group (NPA-O 2 )., Interventions: All patients were preoxygenated to an Et-O2 > 80%, followed by a standardised induction. The intervention group received oxygen at 18 l.min -1 via the nasopharyngeal catheter intervention. The desaturation process was documented until an SpO 2 of 92% or 600 s was reached., Measurements: Baseline demographic and clinical characteristics were collected. The primary outcome was safe apnoea time, defined as the time taken to desaturate to an SpO 2 of 92%. Secondary outcomes were rate of carbon dioxide accumulation and factors affecting the risk of desaturation., Main Results: The study was conducted in a morbidly obese population (NoAO = 41,1 kg.m -2 ; NPA-O 2  = 42,5 kg.m -2 ). The risk of desaturation was signifantly lower in the intervention group (Hazzard Ratio = 0,072, 95% CI[0,019-0,283]) (Log-Rank test, p < 0.001). The median safe apnoea time was significantly longer in the intervention group (NoAO = 262 s [IQR 190-316]; NPA-O 2  = 600 s [IQR 600-600]) (Mann-Whitney-U test, p < 0.001). The mean rate of CO 2 accumalation was significantly slower in the intervention group (NoAO = 0,47 ± 0,14 kPa.min -1 ; NPA-O 2  = 0,3 ± 0,09 kPa.min -1 ) (t-test, p = 0.003). There were no statistically significant risk factors associated with an increased risk of desaturation found., Conclusions: Nasopharyngeal apnoeic oxygenation at 18 l/min prolongs safe apnoea time, compared to preoxygenation alone, and reduces the risk of desaturation in morbidly obese patients., Clinical Trial Registration: PACTR202202665252087; WC/202004/007., Competing Interests: Declaration of Competing Interest There were no conflict of interest of either authors in the production of this wok. The research was conducted for completion of Degree purposes. There was no funding, grants, stock ownership or patent applications made. There are no academic disclosures to mention., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Apnoeic oxygenation is the delivery of oxygen during the apnoeic phase preceding intubation. It is used to prevent respiratory complications of endotracheal intubation that have the potential to lead to significant adverse events including dysrhythmia, haemodynamic decompensation, hypoxic brain injury and death. Oxygen delivered by nasal cannulae during the apnoeic phase of intubation (apnoeic oxygenation) may serve as a non-invasive adjunct to endotracheal intubation to decrease the incidence of hypoxaemia, morbidity and mortality., Objectives: To evaluate the benefits and harms of apnoeic oxygenation before intubation in adults in the prehospital, emergency department, intensive care unit and operating theatre environments compared to no apnoeic oxygenation during intubation., Search Methods: We used standard, extensive Cochrane search methods. The latest search date was 4 November 2022., Selection Criteria: We included randomized controlled trials (RCTs) and quasi-RCTs that compared the use of any form of apnoeic oxygenation including high flow and low flow nasal cannulae versus no apnoeic oxygenation during intubation. We defined quasi-randomization as participant allocation to each arm by means that were not truly random, such as alternation, case record number or date of birth. We excluded comparative prospective cohort and comparative retrospective cohort studies, physiological modelling studies and case reports., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcomes were 1. hospital stay and 2. incidence of severe hypoxaemia. Our secondary outcomes were 3. incidence of hypoxaemia, 4. lowest recorded saturation of pulse oximetry (SpO 2 ), 5. intensive care unit (ICU) stay, 6. first pass success rate, 7. adverse events and 8., Mortality: We used GRADE to assess certainty of evidence., Main Results: We included 23 RCTs (2264 participants) in our analyses. Eight studies (729 participants) investigated the use of low-flow (15 L/minute or less), and 15 studies (1535 participants) investigated the use of high-flow (greater than 15 L/minute) oxygen. Settings were varied and included the emergency department (2 studies, 327 participants), ICU (7 studies, 913 participants) and operating theatre (14 studies, 1024 participants). We considered two studies to be at low risk of bias across all domains. None of the studies reported on hospital length of stay. In predominately critically ill people, there may be little to no difference in the incidence of severe hypoxaemia (SpO 2 less than 80%) when using apnoeic oxygenation at any flow rate from the start of apnoea until successful intubation (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.66 to 1.11; P = 0.25, I² = 0%; 15 studies, 1802 participants; low-certainty evidence). There was insufficient evidence of any effect on the incidence of hypoxaemia (SpO 2 less than 93%) (RR 0.58, 95% CI 0.23 to 1.46; P = 0.25, I² = 36%; 3 studies, 489 participants; low-certainty evidence). There may be an improvement in the lowest recorded oxygen saturation, with a mean increase of 1.9% (95% CI 0.75% to 3.05%; P < 0.001, I² = 86%; 15 studies, 1525 participants; low-certainty evidence). There may be a reduction in the duration of ICU stay with the use of apnoeic oxygenation during intubation (mean difference (MD) ‒1.13 days, 95% CI ‒1.51 to ‒0.74; P < 0.0001, I² = 46%; 5 studies, 815 participants; low-certainty evidence). There may be little to no difference in first pass success rate (RR 1.00, 95% CI 0.93 to 1.08; P = 0.79, I² = 0%; 8 studies, 826 participants; moderate-certainty evidence). There may be little to no difference in incidence of adverse events including oral trauma, arrhythmia, aspiration, hypotension, pneumonia and cardiac arrest when apnoeic oxygenation is used. There was insufficient evidence about any effect on mortality (RR 0.84, 95% CI 0.70 to 1.00; P = 0.06, I² = 0%; 6 studies, 1015 participants; low-certainty evidence)., Authors' Conclusions: There was some evidence that oxygenation during the apnoeic phase of intubation may improve the lowest recorded oxygen saturation. However, the differences in oxygen saturation were unlikely to be clinically significant. This did not translate into any measurable effect on the incidence of hypoxaemia or severe hypoxaemia in a group of predominately critically ill people. We were unable to assess the influence on hospital length of stay; however, there was a reduction in ICU stay in the apnoeic oxygenation group. The mechanism for this is unclear as there was little to no difference in first pass success or adverse event rates., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

This meta-analysis aimed at investigating the efficacy of high-flow nasal oxygenation (HFNO) against hypoxemia in patients with obesity compared with conventional oxygenation therapy and non-invasive ventilation. Databases were searched from inception to August 2021. Studies involving peri- or post-procedural use of HFNO were included. The primary outcome was risk of hypoxemia, while the secondary outcomes included status of oxygenation and carbon dioxide elimination. Ten randomized controlled trials (RCTs) were included. We found that HFNO prolonged the safe apnea time at induction compared to control group [mean difference (MD) = 73.88 s, p = 0.0004; 2 RCTs] with no difference in risk of peri-procedural hypoxemia [relative risk (RR) = 0.91, p = 0.64; 4 RCTs], minimum SpO2 (MD = 0.09%, p = 0.95; 4 RCTs), PaO2 (MD = - 8.13 mmHg, p = 0.86; 3 RCTs), PaCO2 (MD = - 6.71%, p = 0.2; 2 RCTs), EtCO2 (MD = - 0.28 mmHg, p = 0.8; 4 RCTs) between the two groups. HFNO also did not improve postprocedural PaO2/FiO2 ratio (MD = 41.76, p = 0.58; 2 RCTs) and PaCO2 (MD = - 2.68 mmHg, p = 0.07; 2 RCTs). This meta-analysis demonstrated that the use of HFNO may be associated with a longer safe apnea time without beneficial impact on the risk of hypoxemia, oxygenation, and CO2 elimination in patients with obesity. The limited number of trials warranted further large-scale studies to support our findings., (© 2022. The Author(s).)

Although the amygdala plays an important part in the pathogenesis of anxiety and generation of exteroceptive fear, recent discoveries have challenged the directionality of this brain-behavior relationship with respect to interoceptive fear. Here we highlight several paradoxical findings including: (1) amygdala lesion patients who experience excessive fear and panic following inhalation of carbon dioxide (CO 2 ), (2) clinically anxious patients who have significantly smaller (rather than larger) amygdalae and a pronounced hypersensitivity toward CO 2 , and (3) epilepsy patients who exhibit apnea immediately following stimulation of their amygdala yet have no awareness that their breathing has stopped. The above findings elucidate an entirely novel role for the amygdala in the induction of apnea and inhibition of CO 2 -induced fear. Such a role is plausible given the strong inhibitory connections linking the central nucleus of the amygdala with respiratory and chemoreceptive centers in the brainstem. Based on this anatomical arrangement, we propose a model of Apnea-induced Anxiety (AiA) which predicts that recurring episodes of apnea are being unconsciously elicited by amygdala activation, resulting in transient spikes in CO 2 that provoke fear and anxiety, and lead to characteristic patterns of escape and avoidance behavior in patients spanning the spectrum of anxiety. If this new conception of AiA proves to be true, and activation of the amygdala can repeatedly trigger states of apnea outside of one's awareness, then it remains possible that the chronicity of anxiety disorders is being interoceptively driven by a chemoreceptive system struggling to maintain homeostasis in the midst of these breathless states., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: AUTHOR DISCLOSURE:Drs Ness, King, Kukreja, and Sundgren have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

Background: Hypoxaemia occurs frequently in infants during anaesthetic induction., Objective: We evaluated the effect of positive end-expiratory pressure during anaesthesia induction on nonhypoxic apnoea time in infants., Design: Randomised controlled trial., Setting: Tertiary care children's hospital, single centre, from November 2018 to October 2019., Patients: We included patients under 1 year of age receiving general anaesthesia., Intervention: We assigned infants to a 7 cmH2O or 0 cmH2O positive end-expiratory pressure group. Anaesthesia was induced with 0.02 mg kg-1 atropine, 5 mg kg-1 thiopental sodium and 3 to 5% sevoflurane, and neuromuscular blockade with 0.6 mg kg-1 rocuronium. Thereafter, 100% oxygen was provided via face mask with volume-controlled ventilation of 6 ml kg-1 tidal volume, and either 7 cmH2O or no positive end-expiratory pressure. After 3 min of ventilation, the infants' trachea was intubated but disconnected from the breathing circuit, and ventilation resumed when pulse oximetry reached 95%., Main Outcome Measure: The primary outcome was nonhypoxic apnoea time defined as the time from cessation of ventilation to a pulse oximeter reading of 95%, whereas the secondary outcome was the incidence of significant atelectasis (consolidation score ≥2) assessed by lung ultrasound., Results: Sixty patients were included in the final analysis. Apnoea time in the 7 cmH2O positive end-expiratory pressure group (105.2 s) increased compared with that in the control group (92.1 s) (P = 0.011, mean difference 13.0 s, 95% CI, 3.1 to 22.9 s). Significant atelectasis was observed in all patients without positive end-expiratory pressure and 66.7% of those with 7 cmH2O positive end-expiratory pressure (P = 0.019, 95% CI, 1.7 to 563.1, odds ratio 31.2)., Conclusion: Positive end-expiratory pressure during anaesthesia induction with face mask ventilation increased nonhypoxic apnoea time in infants., Clinical Trial Registration: www.clinicaltrials.gov, NCT03540940., (Copyright © 2020 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

This narrative review provides a broad perspective on immature control of breathing, which is universal in infants born premature. The degree of immaturity and severity of clinical symptoms are inversely correlated with gestational age. This immaturity presents as prolonged apneas with associated bradycardia or desaturation, or brief respiratory pauses, periodic breathing, and intermittent hypoxia. These manifestations are encompassed within the clinical diagnosis of apnea of prematurity, but there is no consensus on minimum criteria required for diagnosis. Common treatment strategies include caffeine and noninvasive respiratory support, but other therapies have also been advocated with varying effectiveness. There is considerable variability in when and how to initiate and discontinue treatment. There are significant knowledge gaps regarding effective strategies to quantify the severity of clinical manifestations of immature breathing, which prevent us from better understanding the long-term potential adverse outcomes, including neurodevelopment and sudden unexpected infant death., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: Application of a face mask may induce apnoea and bradycardia, possibly via the trigeminocardiac reflex (TCR). We aimed to describe rates of apnoea and bradycardia in term and late-preterm infants following facemask application during neonatal stabilisation and compare the effects of first facemask application with subsequent applications., Design: Subgroup analysis of a prospective, randomised trial comparing two face masks., Setting: Single-centre study in the delivery room PATIENTS: Infants>34 weeks gestational age at birth METHODS: Resuscitations were video recorded. Airway flow and pressure were measured using a flow sensor. The effect of first and subsequent facemask applications on spontaneously breathing infants were noted. When available, flow waveforms as well as heart rate (HR) were assessed 20 s before and 30 s after each facemask application., Results: In total, 128 facemask applications were evaluated. In eleven percent of facemask applications infants stopped breathing. The first application was associated with a higher rate of apnoea than subsequent applications (29% vs 8%, OR (95% CI)=4.76 (1.41-16.67), p=0.012). On aggregate, there was no change in median HR over time. In the interventions associated with apnoea, HR dropped by 38bpm [median (IQR) at time of facemask application: 134bpm (134-150) vs 96bpm (94-102) 20 s after application; p=0.25] and recovered within 30 s., Conclusions: Facemask applications in term and late-preterm infants during neonatal stabilisation are associated with apnoea and this effect is more pronounced after the first compared with subsequent applications. Healthcare providers should be aware of the TCR and vigilant when applying a face mask to newborn infants., Trial Registration Number: ACTRN12616000768493., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Caffeine is an antagonist of the adenosine pathway, which is involved in regulation of breathing. Extracellular concentrations of adenosine are increased in the immediate aftermath of a seizure. Seizure-related overstimulation of adenosine receptors might promote peri-ictal apnea. However, the relation between caffeine consumption and risk of seizure-related respiratory dysfunction in patients with drug-resistant focal epilepsy remains unknown., Methods: We performed a cross-sectional analysis of data collected in patients included in the SAVE study in Lyon's epilepsy monitoring unit at the Adult Epilepsy Department of the Lyon University Hospital between February 2016 and October 2018. The video-electroencephalographic recordings of 156 patients with drug-resistant focal epilepsy included in the study were reviewed to identify those with ≥1 focal seizure (FS), valid pulse oximetry (SpO 2 ) measurement, and information about usual coffee consumption. This latter was collected at inclusion using a standardized self-questionnaire and further classified into four groups: none, rare (≤3 cups/week), moderate (4 cups/week to 3 cups/day), and high (≥4 cups/day). Peri-ictal hypoxemia (PIH) was defined as SpO 2 < 90% for at least 5 s occurring during the ictal period, the post-ictal period, or both., Results: Ninety patients fulfilled inclusion criteria, and 323 seizures were analyzed. Both the level of usual coffee consumption (p = .033) and the level of antiepileptic drug withdrawal (p = .004) were independent risk factors for occurrence of PIH. In comparison with FS in patients with no coffee consumption, risk of PIH was four times lower in FS in patients with moderate consumption (odds ratio [OR] = .25, 95% confidence interval [CI] = .07-.91, p = .036) and six times lower in FS in patients with high coffee consumption (OR = .16, 95% CI = .04-.66, p = .011). However, when PIH occurred, its duration was longer in patients with moderate or high consumption than in those with no coffee consumption (p = .042)., Significance: Coffee consumption may be a protective factor for seizure-related respiratory dysfunction, with a dose-dependent effect., (© 2021 International League Against Epilepsy.)

Chronic opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired opioid effect. Intake of high-dose or potent opioids may cause life-threatening respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic-pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid-naïve subjects to quantify tolerance to respiratory depression. Fourteen opioid-naïve individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid-naïve subjects: 75-350 µg/70 kg; chronic users: 250-700 µg/70 kg). Isohypercapnic ventilation was measured and the fentanyl plasma concentration-ventilation data were analyzed using nonlinear mixed-effects modeling. Apneic events occurred in opioid-naïve subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n = 3) and 475 µg (n = 6), and in 7 chronic opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 µg (n = 3). The time course of fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (E max ) model. Differences in tolerance between populations were successfully modeled. The effect-site concentration causing 50% ventilatory depression, was 0.42 ± 0.07 ng/mL in opioid-naïve subjects and 1.82 ± 0.39 ng/mL in chronic opioid users, indicative of a 4.3-fold sensitivity difference. Despite higher tolerance to fentanyl-induced respiratory depression, apnea still occurred in the opioid-tolerant population indicative of the potential danger of high-dose opioids in causing life-threatening respiratory depression in all individuals, opioid-naïve and opioid-tolerant., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Perioperative pulse oximetry hemoglobin saturation (Spo2) measurement is associated with fewer desaturation and hypoxia episodes. However, the sigmoidal nature of oxygen-hemoglobin dissociation limits the accuracy of estimation of the partial pressure of oxygen (Pao2) >80 mm Hg and correspondingly limits the ability to identify when Pao2 >80 mm Hg but falling. We hypothesized that a proxy measurement for oxygen saturation (Oxygen Reserve Index [ORI]) derived from multiwavelength pulse oximetry may allow additional warning time before critical desaturation or hypoxia. To test our hypothesis, we used a Masimo multiwavelength pulse oximeter to compare ORI and Spo2 warning times during apnea in high-risk surgical patients undergoing cardiac surgery., Methods: This institutional review board-approved prospective study (NCT03021473) enrolled American Society of Anesthesiologists physical status III or IV patients scheduled for elective surgery with planned preinduction arterial catheter placement. In addition to standard monitors, an ORI sensor was placed and patients were monitored with a pulse oximeter displaying the ORI, a nondimensional parameter that ranges from 0 to 1. Patients were then preoxygenated until ORI plateaued. Following induction of anesthesia, mask ventilation with 100% oxygen was performed until neuromuscular blockade was established. Endotracheal intubation was accomplished using videolaryngoscopy to confirm placement. The endotracheal tube was not connected to the breathing circuit, and patients were allowed to be apneic. Ventilation was resumed when Spo2 reached 94%. We defined ORI warning time as the time from when the ORI alarm registered (based on the absolute value and the rate of change) until the Spo2 decreased to 94%. We defined the Spo2 warning time as the time for Spo2 to decrease from 97% to 94%. The added warning time provided by ORI was defined as the difference between ORI warning time and Spo2 warning time., Results: Forty subjects were enrolled. Complete data for analysis were available from 37 patients. The ORI alarm registered before Spo2 decreasing to 97% in all patients. Median (interquartile range [IQR]) ORI warning time was 80.4 seconds (59.7-105.9 seconds). Median (IQR) Spo2 warning time was 29.0 seconds (20.5-41.0 seconds). The added warning time provided by ORI was 48.4 seconds (95% confidence interval [CI], 40.4-62.0 seconds; P < .0001)., Conclusions: In adult high-risk surgical patients, ORI provided clinically relevant added warning time of impending desaturation compared to Spo2. This additional time may allow modification of airway management, earlier calls for help, or assistance from other providers. The potential patient safety impact of such monitoring requires further study., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2020 International Anesthesia Research Society.)

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO 2 and/or O 2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal-ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non-cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non-cell autonomous maldevelopment of key brainstem respiratory neurons., (© 2020 International Society of Neuropathology.)

Objectives: To determine the prevalence of adverse events during apnea testing for determination of death by neurologic criteria using continuous positive airway pressure in children., Design: Single-center retrospective descriptive study., Setting: Academic children's hospital., Patients: Children evaluated for death by neurologic criteria in the PICU from 2013 to 2018., Interventions: None., Measurements and Main Results: For each patient evaluated for death by neurologic criteria, we abstracted the number of apnea tests performed, vital signs and arterial blood gases during apnea testing, and outcome from the medical record. Adverse events were defined as oxygen-hemoglobin desaturation (arterial oxygen saturation < 85%), hypotension, or other significant event (e.g. arrhythmia, cardiac arrest) based on documentation in the medical record. We determined which adverse events resulted in early termination of the apnea test. We used oxygenation index, ventilator variables, and presence of vasopressors to determine preapnea test cardiopulmonary dysfunction. Seventy-two patients (age 7 yr [2.7-13.2 yr]; 48% male) underwent 121 apnea tests. Nine patients (12%) had 13 potential apnea tests deferred due to concern for cardiopulmonary instability as determined by the attending physician. Patients who underwent apnea testing had an oxygenation index of 3.5 (2.5-4.8) and were receiving vasopressors at the time of 108 apnea tests (89%). Hypotension was reported during seven apnea tests (6%) and resulted in the early termination of one apnea test (<1%). No other adverse events were reported. One hundred and twenty apnea tests (99%) were consistent with death by neurologic criteria., Conclusions: Apnea testing following a protocol that uses continuous positive airway pressure for apneic oxygenation has a low rate of adverse events in children meeting prerequisite criteria and determined by a pediatric intensivist to be physiologically appropriate for testing.

Pitt-Hopkins syndrome is a rare genetic disease, characterised by severe intellectual disability, distinctive dysmorphic features, epilepsy and distinctive breathing abnormalities during wakefulness. Here, we describe the case of a 22-year-old woman with Pitt-Hopkins syndrome who presented with intractable generalised tonic seizures from the age of 11 years, which increased in frequency with age and onset of menstruation despite usage of some anticonvulsant drugs. From the age of 16 years, polysomnography and video-EEG led to the detection of frequent epileptic apnoea during sleep. Although the frequency of generalised tonic seizure clusters was reduced by treatment with phenobarbital and potassium bromide, epileptic apnoea persisted. Furthermore, frequent epileptic apnoea observed in our patient was regarded as a factor for aspiration and deterioration of respiratory function. This study indicates that patients with Pitt-Hopkins syndrome require close monitoring for epileptic apnoea. Moreover, long-term EEG and respiratory monitoring are necessary to distinguish epileptic apnoea from other respiratory disorders in patients with Pitt-Hopkins syndrome.

Background: Evidence is accruing to suggest that microbiota-gut-brain signalling plays a regulatory role in cardiorespiratory physiology. Chronic intermittent hypoxia (CIH), modelling human sleep apnoea, affects gut microbiota composition and elicits cardiorespiratory morbidity. We investigated if treatment with prebiotics ameliorates cardiorespiratory dysfunction in CIH-exposed rats., Methods: Adult male rats were exposed to CIH (96 cycles/day, 6.0% O 2 at nadir) for 14 consecutive days with and without prebiotic supplementation (fructo- and galacto-oligosaccharides) beginning two weeks prior to gas exposures., Findings: CIH increased apnoea index and caused hypertension. CIH exposure had modest effects on the gut microbiota, decreasing the relative abundance of Lactobacilli species, but had no effect on microbial functional characteristics. Faecal short-chain fatty acid (SCFA) concentrations, plasma and brainstem pro-inflammatory cytokine concentrations and brainstem neurochemistry were unaffected by exposure to CIH. Prebiotic administration modulated gut microbiota composition and diversity, altering gut-metabolic (GMMs) and gut-brain (GBMs) modules and increased faecal acetic and propionic acid concentrations, but did not prevent adverse CIH-induced cardiorespiratory phenotypes., Interpretation: CIH-induced cardiorespiratory dysfunction is not dependant upon changes in microbial functional characteristics and decreased faecal SCFA concentrations. Prebiotic-related modulation of microbial function and resultant increases in faecal SCFAs were not sufficient to prevent CIH-induced apnoea and hypertension in our model. Our results do not exclude the potential for microbiota-gut-brain axis involvement in OSA-related cardiorespiratory morbidity, but they demonstrate that in a relatively mild model of CIH, sufficient to evoke classic cardiorespiratory dysfunction, such changes are not obligatory for the development of morbidity, but may become relevant in the elaboration and maintenance of cardiorespiratory morbidity with progressive disease., Funding: Department of Physiology and APC Microbiome Ireland, University College Cork, Ireland. APC Microbiome Ireland is funded by Science Foundation Ireland, through the Government's National Development Plan., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Data regarding coronavirus disease 2019 (COVID-19) cases and outcomes in infants are sparse compared to older pediatric and adult populations., Case Presentation: We present a three-week-old full-term male with a history of mild hypoxic ischemic encephalopathy (HIE) who was admitted as an inpatient twice for episodes of apnea and perioral cyanosis. The patient tested positive for COVID-19 and negative for other common respiratory viruses at both admissions., Conclusions: To our knowledge, this is the first report of apnea and perioral cyanosis associated with COVID-19 in an infant. This case highlights a previously undocumented COVID-19 presentation and suggests that even mildly symptomatic infants warrant viral diagnostic testing in an effort to prevent further spread of the disease.

Background: Currently, car seat tolerance screens (CSTSs) are recommended for all infants born prematurely in the United States. Although many late-preterm infants are cared for exclusively in newborn nurseries (NBNs), data on implementation of CSTS in nurseries are limited. Our objective for this study was to determine management strategies and potential variation in practice of CSTS in NBNs across the nation., Methods: We surveyed NBNs across 35 states using the Better Outcomes through Research for Newborns (BORN) network to determine what percentage perform CSTSs, inclusion and failure criteria, performance characteristics, follow-up of failed CSTSs including use of car beds, and provider attitudes toward CSTS., Results: Of the 84 NBNs surveyed, 90.5% performed predischarge CSTSs. The most common failure criteria were saturation <90%, bradycardia <80 beats per minute, and apnea >20 seconds. More than 55% noted hypotonia as an additional inclusion criterion for testing, and >34% tested any infant who had ever required supplemental oxygen. After an initial failed CSTS, >93% of NBNs retested in a car seat at a future time point, whereas only ∼1% automatically discharged infants in a car bed. When asked which infants should undergo predischarge CSTS, the most common recommendations by survey respondents included infants with hypotonia (83%), airway malformations (78%), hemodynamically significant congenital heart disease (63%), and prematurity (61%)., Conclusions: There is a large degree of variability in implementation of CSTS in NBNs across the United States. Further guidance on screening practices and failure criteria is needed to inform future practice and policy., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

A causal relationship between gastro-esophageal reflux (GER) and apnea in preterm infants has been frequently hypothesized and is currently debated. The present study aims at reviewing the currently available scientific evidence, in order to clarify the role of GER on the occurrence of apnea and to help improving the clinical management of apneic preterm neonates. We performed a systematic literature search to identify all the clinical studies on preterm neonates that properly assessed the relationship between apnea and GER. Two-hundred and fifty-two papers, including 32 reviews and meta-analysis, were screened. Out of them, only 7 were included in the final analysis according to the selected criteria. Among them, 3 studies reported an increased frequency of apnea after reflux compared to reflux-free period and 4 denied a significant temporal relation. In conclusion, a minority of apneic events occurs soon after GER episodes. Whether this happens by chance or because of a causal relationship is still impossible to define. Based on the available data, empirical treatment with acid inhibitors is not recommended in neonates with apnea unless a proven temporal relation is shown by simultaneous esophageal pH-impedance and polysomnography or cardiorespiratory monitoring and in the absence of a clear clinical benefit., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

This case series aimed to characterize the clinical features, management, and outcomes of apnea in infants with trisomy 18. Participants in this study were infants with trisomy 18 who were born alive and admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2018. Retrospective analysis was performed on clinical data recorded in our department. Twenty-seven infants with trisomy 18 were admitted to our hospital during the study period, of which 25 (nine males, 16 females) were enrolled as eligible participants in this study. Among them, 14 started presenting with apnea from median 3.5 days of age (range 0-47d). In these infants with apnea, eight received respiratory support of positive pressure ventilation (PPV). The 1-year survival rate of infants in the PPV group was higher than that of non-PPV-supported infants (5 out of 8 vs 0 out of 6 infants). Five PPV-supported infants received a diagnosis of epilepsy, which was controlled by antiepileptic drugs. Postnatal respiratory intervention provides better prognosis in infants with trisomy 18. Improved survival leads to accurate diagnosis and treatment of apneic events in association with epilepsy. WHAT THIS PAPER ADDS: Respiratory support is effective against apnea in infants with trisomy 18. Intervention with ventilation provides a higher chance of prolonged survival. Improved survival leads to the accurate diagnosis and treatment of epilepsy-associated apnea., (© 2019 Mac Keith Press.)

BACKGROUNDSeizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown.METHODSWe studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine-learning algorithm was used to delineate brain regions that inhibit respiration.RESULTSIn 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 subjects (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine-learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons.CONCLUSIONSA focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target.FUNDINGNational Institute of Neurological Disorders and Stroke - Congress of Neurological Surgeons, National Institute of General Medical Sciences, Roy J. Carver Charitable Trust.

Introduction: Apnea is commonly encountered in children with bronchiolitis. Despite the lack of recommendations regarding bronchiolitis-related apnea (BRA) management, some pediatric intensive care unit (PICU) practitioners use caffeine treatment based on extrapolation from the recommendations for prematurity-related apnea management. The objectives of this study were to describe the management of BRA in our PICU, evaluate the caffeine prescription rate for this indication, and explore its potential effects on clinical outcomes., Methods: This was a retrospective study in a university hospital PICU between January 1st, 2009 and December 31st, 2016. All children under 1 year of age admitted to the PICU with a diagnosis of BRA were included. Patients were allocated to a control group or a caffeine group depending on the administration of caffeine., Results: In total, 54 infants were included and caffeine treatment was administered to 49 (91%) of them. Patient characteristics were similar between the two groups. Ventilatory support was initiated for 50 patients (93%). Supportive care and length of PICU stay were similar between the two groups. Caffeine was not associated with adverse events., Conclusion: Caffeine treatment in BRA could be considered as a local standard practice. This retrospective study was underpowered to show any benefit of caffeine treatment on clinical outcomes. This treatment was not associated with significant adverse effects. We raised the question of the appropriate caffeine dosing regimen for BRA in this postterm population. Further studies on this topic are warranted., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Obese patients have a propensity to desaturate during induction of general anesthesia secondary to their reduced functional residual capacity and increased oxygen consumption. Apneic oxygenation can provide supplemental oxygen to the alveoli, even in the absence of ventilation, during attempts to secure the airway. In this study, we hypothesized that oxygen administration through a nasopharyngeal airway and standard nasal cannula during a simulated prolonged laryngoscopy would significantly prolong the safe apneic duration in obese patients., Methods: One hundred thirty-five obese patients undergoing non-emergent surgery requiring general anesthesia were randomized to either the control group or to receive apneic oxygenation with air versus oxygen. All patients underwent a standard intravenous induction. For patients randomized to receive apneic oxygenation, a nasopharyngeal airway and standard nasal cannula were inserted. A simulated prolonged laryngoscopy was performed to determine the duration of the safe apneic period, defined as the beginning of laryngoscopy until the peripheral oxygen saturation (SpO 2 ) reached 95%., Results: The oxygen group had a median safe apneic duration that was 103 s longer than the control group. The lowest mean SpO 2 value during the induction period was 3.8% higher in the oxygen group compared to the control group. Following intubation, patients in the oxygen group had a mean end tidal carbon dioxide (ETCO 2 ) level that was 3.0 mmHg higher than patients in the control group., Conclusions: In obese patients, oxygen insufflation at 15 L/min through a nasopharyngeal airway and standard nasal cannula can significantly increase the safe apneic duration during induction of anesthesia.

Objective: To evaluate the clinical presentation and management strategies for neonatal retropharyngeal abscess (RPA)., Methods: Retrospective chart review was performed, and literature reviewed., Results: We report two cases of neonatal RPA, with one complicated by cervical osteomyelitis, and the other presenting with apparent life-threatening events (ALTEs). A 6-week-old female underwent transoral drainage of an RPA, which grew methicillin sensitive Staphylococcus aureus. She had a prolonged recovery course and was found to have developed osteomyelitis of the dens and atlas. She was treated with 14 weeks of IV antibiotics and rigid collar fixation for spinal cord instability. A 2-month-old female was admitted after multiple ALTEs with episodes of apnea and pallor. Direct laryngoscopy revealed a bulging RPA, which was drained transorally. This grew multiple organisms including methicillin resistant Staphylococcus aureus, Streptococcal oralis and Prevotella species., Conclusions: Uncommon in neonates, RPA can present in this age group without fever, and are is likely to have airway complications than in older children. In cases with prolonged recovery, additional diagnostic intervention is recommended to rule out rare complications such as osteomyelitis. Emphasis in such complex cases is placed on a multidisciplinary approach to patient care, coordinating neonatologists, infectious disease specialists, neurosurgeons, and otolaryngologists., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The deletion of Mecp2 , the gene encoding methyl-CpG-binding protein 2, causes severe breathing defects and developmental anomalies in mammals. In Mecp2 -null mice, impaired GABAergic neurotransmission is demonstrated at the early stage of life. GABAergic dysfunction in neurons in the rostral ventrolateral medulla (RVLM) is considered as a primary cause of breathing abnormality in Mecp2 -null mice, but its molecular mechanism is unclear. Here, we report that mRNA expression levels of Gad1 , which encodes glutamate decarboxylase 67 (GAD67), in the RVLM of Mecp2 -null ( Mecp2 -/y , B6.129P2(C)- Mecp2 tm1.1Bird mRNA expression in the RVLM and reduced apnea counts in Gad1 through epigenetic mechanisms. The administration of VPA (300 mg/kg/day) together with L-carnitine (30 mg/kg/day) from day 8 to day 14 after birth increased Gad1 mRNA expression in the RVLM and reduced apnea counts in Mecp2 -/y mice on postnatal day 15. Cytosine methylation levels in the Gad1 promoter were higher in the RVLM of Mecp2 -/y mice compared to wild-type mice born to C57BL/6J females, while VPA treatment decreased the methylation levels in Mecp2 -/y mice. Chromatin immunoprecipitation assay revealed that the VPA treatment reduced the binding of methyl-CpG binding domain protein 1 (MBD1) to the Gad1 promoter in Mecp2 -/y mice. These results suggest that VPA improves breathing of Mecp2 -/y mice by reducing the Gad1 promoter methylation, which potentially leads to the enhancement of GABAergic neurotransmission in the RVLM., Competing Interests: The authors declare no conflict of interest.

Objectives: To describe temporal trends in car seat tolerance screening (CSTS) failure within a large hospital system (2014-2018)., Methods: We conducted a retrospective cohort study using electronic medical record data for infants who underwent a CSTS. Our primary outcome measure was the CSTS failure rate. Covariates included year, CSTS location (well nursery or NICU), gestational age (GA), race, sex, birth weight, CSTS date, and age at CSTS. Associations of covariates with CSTS failure were examined by using χ 2 tests, t tests, analysis of variance, and Wilcoxon rank tests. Multivariable logistic regression was used to determine the adjusted odds of CSTS failure., Results: Of 4849 infants tested, the failure rate was 8.1% ( n = 394). Most CSTS occurred in the well nursery (79.5%) and involved late preterm (55.2%) or term infants (23.7%). In bivariate analyses, year, unit location, higher birth weight, younger chronological age at testing, and higher GA were positively associated with CSTS failure ( P < .05). After stratification by CSTS location, the CSTS failure rate rose in the well nursery but remained stable in the NICU, and use of screening rose among term infants. In the adjusted model, year, GA, and corrected gestational age at CSTS were associated with failure. Each subsequent year was associated with a 19% increase in odds of CSTS failure ( P < .001)., Conclusions: We found a higher rate of CSTS failure in the well nursery compared with the NICU, and the difference in failure rates increased over time. Improved understanding of infants at the highest risk of CSTS failure could impact routine screening guidelines., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Prenatal nicotinic exposure (PNE) reportedly sensitizes bronchopulmonary C-fibers (PCFs) and prolongs PCF-mediated apnea in rat pups, contributing to the pathogenesis of sudden infant death syndrome. Serotonin, or 5-hydroxytryptamine (5-HT), induces apnea via acting on 5-HT receptor 3 (5-HT 3 R) in PCFs, and among the 5-HT 3 R subunits, 5-HT 3B is responsible for shortening the decay time of 5-HT 3 R-mediated currents. We examined whether PNE would promote pulmonary 5-HT secretion and prolong the apnea mediated by 5-HT 3 Rs in PCFs via affecting the 5-HT 3B subunit. To this end, the following variables were compared between the control and PNE rat pups: 1 ) the 5-HT content in bronchoalveolar lavage fluid, 2 ) the apneic response to the right atrial bolus injection of phenylbiguanide (a 5-HT 3 R agonist) before and after PCF inactivation, 3 ) 5-HT 3 R currents and the stimulus threshold of the action currents of vagal pulmonary C-neurons, and 4 ) the immunoreactivity (IR) and mRNA expression of 5-HT 3A and 5-HT 3B in these neurons. Our results showed that PNE up-regulated the pulmonary 5-HT concentration and strengthened the PCF 5-HT 3 R-mediated apnea. PNE significantly facilitated neural excitability by shortening the decay time of 5-HT 3 R currents, lowering the stimulus threshold, and increasing 5-HT 3B IR. In summary, PNE prolongs the apnea mediated by 5-HT 3 Rs in PCFs, likely by increasing 5-HT 3B subunits to enhance the excitability of 5-HT 3 channels.-Zhao, L., Gao, X., Zhuang, J., Wallen, M., Leng, S., Xu, F. Prolongation of bronchopulmonary C-fiber-mediated apnea by prenatal nicotinic exposure in rat pups: role of 5-HT 3 receptors.

During sedated endoscopic examinations, upper airway obstruction occurs. Nasal breathing often shifts to oral breathing during open mouth esophagogastroduodenoscopy (EGD). High-flow nasal cannula (HFNC) which delivers humidified 100% oxygen at 30 L min -1 may prevent hypoxemia. A mandibular advancement (MA) bite block with oxygen inlet directed to both mouth and nose may prevent airway obstruction during sedated EGD. The purpose of this study was to evaluate the efficacy of these airway devices versus standard management. One hundred and eighty-nine patients were assessed for eligibility. One hundred and fifty-three were enrolled. This study randomly assigned eligible patients to three arms: the standard bite block and standard nasal cannula, HFNC, and MA bite block groups. EGD was performed after anaesthetic induction. The primary endpoint was the oxygen desaturation area under curve at 90% (AUC Desat ). The secondary endpoints were percentage of patients with hypoxic, upper airway obstruction, and apnoeic and rescue events. One hundred and fifty-three patients were enrolled. AUCdesat was significantly lower for HFNC and MA bite blocks versus the standard management (p= 0.019). The HFNC reduced hypoxic events by 18% despite similar airway obstruction and apnoeic events as standard group. The MA bite block reduced hypoxic events by 12% and airway obstructions by 32%. The HFNC and MA groups both showed a 16% and 14% reduction in the number of patients who received rescue intervention, respectively, compared to the standard group. The HFNC and MA bite block may both reduce degree and duration of hypoxemia. HFNC may decrease hypoxemic events while maintaining nasal patency is crucial during sedative EGD. The MA bite block may prevent airway obstruction and decrease the need for rescue intervention., Competing Interests: The authors declare no conflicts of interest.

Importance: Apnea is a rare, life-threatening complication of bronchiolitis, the leading cause of infant hospitalization in the United States. Currently, no objective method exists for identifying which infants will become apneic., Objective: To investigate whether serum albumin levels are associated with apnea in infants with severe bronchiolitis., Design, Setting, and Participants: A secondary data analysis of the 35th Multicenter Airway Research Collaboration, an ongoing multicenter cohort study of infants hospitalized for bronchiolitis, was conducted from December 11, 2018, to May 30, 2019. Seventeen hospitals across the United States enrolled infants (n = 1016) during 3 consecutive bronchiolitis seasons (November 1 to April 30) between 2011 and 2014. Infants with heart-lung disease or a gestational age less than 32 weeks were excluded., Exposures: Serum albumin level was categorized as low (<3.8 g/dL) or normal (≥3.8 g/dL)., Main Outcomes and Measures: Apnea during the hospitalization., Results: Of the 1016 infants hospitalized for bronchiolitis, the median (interquartile range [IQR]) age was 3 (2-6) months, 610 (60.0%) were male, and 186 (18.3%) were born preterm (32-37 weeks' gestation). Among the 25 infants (2.5%) with apnea while hospitalized, the median (IQR) serum albumin level was 3.5 (3.1-3.6) g/dL, and 22 (88.0%) had low serum albumin levels. The prevalence of apnea was 5.7% among all infants with low albumin levels, compared with 0.5% prevalence in infants with normal serum albumin levels. In unadjusted analyses, apnea was associated with younger age, preterm birth, weight-for-age z score, and low albumin (odds ratio [OR], 12.69; 95% CI, 3.23-49.82). After adjustment for age, preterm birth, and weight-for-age z score, low serum albumin levels remained statistically significantly associated with apnea (OR, 4.42; 95% CI, 1.21-16.18)., Conclusions and Relevance: Low serum albumin levels appeared to be associated with increased risk of apnea after adjustment for known apnea risk factors. This finding provides a path to potentially identifying apnea, a life-threatening complication of bronchiolitis.

Objective: To compare the differential effects of the retinopathy of prematurity (ROP) examination on the physiology of premature infants with and without oxygen support., Study Design: We collected data from 42 premature infants (room air = 19, oxygen support = 23) and compared physiological metrics including heart rate (HR), systemic peripheral saturation (SpO 2 ), mesenteric tissue oxygen saturation (StO 2 ) and clinical events (oxygen desaturation episodes, bradycardia events, and gastric residuals)., Results: We found significant differences between groups in HR during and briefly after the exam, and in mesenteric StO 2, during eye drop administration, eye exam, and up to 8 min after the exam. SpO 2 was significantly different between the groups at all time points. Gastric residuals were higher after the exam in infants on oxygen support, compared to baseline., Conclusion: Premature infants on oxygen support may be at a higher risk of adverse physiologic effects in response to the ROP exam.