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Background: Chronic intermittent hypoxia (CIH) increases the hypoxic ventilation response (HVR). The downstream cytokine IL-1β of the NLRP3 inflammasome regulates respiration by acting on the carotid body (CB) and neurons in the respiratory center, but the effect of the NLRP3 inflammasome on HVR induced by CIH remains unclear., Objective: To investigate the effect of NLRP3 on the increased HVR and spontaneous apnea events and duration induced by CIH, the expression and localization of NLRP3 in the respiratory regulatory center of the rostral ventrolateral medulla (RVLM), and the effect of CIH on the activation of the NLRP3 inflammasome in the RVLM., Methods: Eighteen male, 7-week-old C57BL/6 N mice and eighteen male, 7-week-old C57BL/6 N NLRP3 knockout mice were randomly divided into CON-WT, CON-NLRP3 -/- , CIH-WT and CIH-NLRP3 -/- groups. Respiratory changes in mice were continuously detected using whole-body plethysmography. The expression and localization of the NLRP3 protein and the formation of apoptosis-associated speck-like protein containing CARD (ASC) specks were detected using immunofluorescence staining., Results: NLRP3 knockout reduced the increased HVR and the incidence and duration of spontaneous apnea events associated with CIH. The increase in HVR caused by CIH partially recovered after reoxygenation. After CIH, NLRP3 inflammasome activation in the RVLM, which is related to respiratory regulation after hypoxia, increased, which was consistent with the trend of the ventilation response., Conclusion: The NLRP3 inflammasome may be involved in the increase in the HVR and the incidence and duration of spontaneous apnea induced by CIH. NLRP3 inhibitors may help reduce the increase in the HVR after CIH, which is important for ensuring sleep quality at night in patients with obstructive sleep apnea., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study examined the effect of breath-hold (BH) training on apnoeic performance in novice BH divers (NBH:n = 10) and compared them with data from elite BH divers (EBH:n = 11). Both groups performed 5-maximal BHs (PRE). The NBH group repeated this protocol after two weeks of BH training (POST). The NBH group during BH efforts significantly increased red blood cell concentration (4.56 ± 0.16Mio/μl) by 5.06%, hemoglobin oxygen saturation steady state duration (110.32 ± 29.84 s) by 15.48%, and breath-hold time (BHT:144.19 ± 47.35 s) by 33.77%, primarily due to a 59.70% increase in struggle phase (71.85 ± 30.89 s), in POST. EBH group exhibited longer BHT (283.95 ± 36.93 s) and struggle-phase (150.10 ± 34.69 s) than NBH (POST). Elite divers recorded a higher peak MAP (153.18 ± 12.28 mmHg) compared to novices (PRE:123.70 ± 15.65 mmHg, POST:128.30 ± 19.16 mmHg), suggesting that a higher peak MAP is associated with a better BHT. The concurrent abrupt increase of diaphragmatic activity and MAP, seen only in the EBH group, suggests a potential interaction. Additionally, apnoea training increases red blood cells concentration in repeated apnoea efforts and increases BH stamina., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest with respect to the research, authorship and/or publication of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: DEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions., Methods: Depdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. Electroencephalogram (EEG), cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice., Results: Depdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic-clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non-fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these mice developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole., Interpretation: Depdc5 deletion in excitatory neurons is sufficient to cause DEPDC5-related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5-related epilepsy and SUDEP. ANN NEUROL 2023;94:812-824., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: There is an elevated incidence of hypoxemia during the airway management of the morbidly obese. We aimed to assess whether optimizing body position and ventilation during pre-oxygenation allow a longer safe non-hypoxic apnea period (SNHAP)., Methods: Fifty morbidly obese patients were recruited and randomized for this study. Patients were positioned and preoxygenated for three minutes in the ramp position associated with spontaneous breathing without additional CPAP or PEEP (RP/ZEEP group) or in the reverse Trendelenburg position associated with pressure support ventilation mode with pressure support of 8 cmH 2 O and an additional 10 cmH 2 O of PEEP while breathing spontaneously (RT/PPV group) according to randomization., Results: The SNHAP was significantly longer in the RT/PPV group (258.2 (55.1) vs. 216.7 (42.3) seconds, p = 0.005). The RT/PPV group was also associated to a shorter time to obtain a fractional end-tidal oxygen concentration (FEtO 2 ) of 0.90 (85.1(47.8) vs 145.3(40.8) seconds, p < 0.0001), a higher proportion of patients that reached the satisfactory FEtO 2 of 0.90 (21/24, 88% vs. 13/24, 54%, p = 0.024), a higher FEtO 2 during preoxygenation (0.91(0.05) vs. 0.89(0.01), p = 0.003) and a faster return to 97% oxygen saturation after ventilation resumption (69.8 (24.2) vs. 91.4 (39.2) seconds, p = 0.038)., Conclusion: In the morbidly obese population, RT/PPV, compared to RP/ZEEP, lengthens the SNHAP, decreases the time to obtain optimal preoxygenation conditions, and allows a faster resuming of secure oxygen saturation. The former combination allows a more significant margin of time for endotracheal intubation and minimizes the risk of hypoxemia in this highly vulnerable population., Trial Registration: NCT02590406, 29/10/2015., (© 2023. The Author(s).)

Background: In trigger-free anesthesia a volatile anesthetic concentration of 5 parts per million (ppm) should not be exceeded. According to European Malignant Hyperthermia Group (EMHG) guideline, this may be achieved by removing the vapor, changing the anesthetic breathing circuit and renewing the soda lime canister followed by flushing with O 2 or air for a workstation specific time. Reduction of the fresh gas flow (FGF) or stand-by modes are known to cause rebound effects. In this study, simulated trigger-free pediatric and adult ventilation was carried out on test lungs including ventilation maneuvers commonly used in clinical practice. The goal of this study was to evaluate whether rebounds of sevoflurane develop during trigger-free anesthesia., Methods: A Dräger® Primus® was contaminated with decreasing concentrations of sevoflurane for 120 min. Then, the machine was prepared for trigger-free anesthesia according to EMHG guideline by changing recommended parts and flushing the breathing circuits using 10 or 18 l⋅min - 1 FGF. The machine was neither switched off after preparation nor was FGF reduced. Simulated trigger-free ventilation was performed with volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) including various ventilation maneuvers like pressure support ventilation (PSV), apnea, decreased lung compliance (DLC), recruitment maneuvers, prolonged expiration and manual ventilation (MV). A high-resolution ion mobility spectrometer with gas chromatographic pre-separation was used to measure sevoflurane in the ventilation gas mixture in a 20 s interval., Results: Immediately after start of simulated anesthesia, there was an initial peak of 11-18 ppm sevoflurane in all experiments. The concentration dropped below 5 ppm after 2-3 min during adult and 4-18 min during pediatric ventilation. Other rebounds of sevoflurane > 5 ppm occurred after apnea, DLC and PSV. MV resulted in a decrease of sevoflurane < 5 ppm within 1 min., Conclusion: This study shows that after guideline-compliant preparation for trigger-free ventilation anesthetic machines may develop rebounds of sevoflurane > 5 ppm during typical maneuvers used in clinical practice. The changes in rate and direction of internal gas flow during different ventilation modes and maneuvers are possible explanations. Therefore, manufacturers should provide machine-specific washout protocols or emphasize the use of active charcoal filters (ACF) for trigger-free anesthesia., (© 2023. The Author(s).)

Background: By continually monitoring end-tidal carbon dioxide concentrations, capnography can detect abnormal ventilation or apnoea early. This randomized, controlled study explored the effect of early intervention with capnography on the incidence of hypoxia in mildly obese patients undergoing sedation for esophagogastroduodenoscopy (EGD) and colonoscopy., Methods: This is a single-center, randomized, single-blind, parallel-assignment, controlled trial. Mildly obese patients (28 kg/m 2  ≤ BMI < 40 kg/m 2 ) undergoing sedation for EGD and colonoscopy were randomly assigned to either the standard or capnography group. Standard cardiopulmonary monitoring equipment was used in both groups, and additional capnography was performed in the capnography group. In the event of inadequate alveolar ventilation during sedation, five interventions were administered in sequence (a-e) : a: increasing oxygen flow (5 L/min); b: a chin lift or jaw thrust maneuver; c: placement of the nasopharyngeal airway and chin lift; d: mask positive-pressure ventilation, and e: ventilator-assisted ventilation with tube insertion. The primary outcome was the incidence of hypoxia (SpO 2  < 90%, ≥ 10 s) in each group. The secondary outcomes included the incidence of severe hypoxia (SpO 2  ≤ 85%), subclinical respiratory depression (90% ≤ SpO 2  < 95%), interventions, minimum SpO 2 during operation, patient satisfaction, endoscopist satisfaction, and other adverse events of anesthesia sedation., Results: 228 patients were included (capnography group = 112; standard group = 113; three patients were excluded) in this study. The incidence of hypoxia was significantly lower in the capnography group than in the standard group (13.4% vs. 30.1%, P = 0.002). Subclinical respiratory depression in the capnography group was higher than that of the standard group (30.4% vs. 17.7%, P = 0.026). There was only a 5.4% incidence of severe hypoxia in the capnography group compared with 14.2% in the standard group (P = 0.026). During sedation, 96 and 34 individuals in the capnography and standard groups, respectively, underwent the intervention. There was a statistically significant difference (P < 0.0001) in the number of the last intraoperative intervention between the two groups ( a:47 vs. 1, b:46 vs. 26, c:2 vs. 5, d:1 vs. 2, e:0 vs. 0 ). No significant differences were found between the two groups in terms of minimum SpO 2 during operation, patient satisfaction, or endoscopist satisfaction rating. There was no statistically significant difference in adverse events of anesthesia sedation between the two groups., Conclusion: Capnography during sedation for EGD and colonoscopy allows for the detection of apnea and altered breathing patterns in mildly obese patients before SpO 2 is reduced. Effective intervention measures are given to patients within this time frame, which reduces the incidence of hypoxia and severe hypoxia in patients., Trial Registration: Ethical approval was granted by the Medical Ethics Committee (Chairperson Professor Tian Hui) of Qilu Hospital, Shandong University ((Ke) Lun Audit 2021 (186)) on 15/07/2021. The study was registered ( https://www.chictr.org.cn ) on 23/10/2021(ChiCTR2100052234). Designed and reported using CONSORT statements., (© 2023. The Author(s).)

Introduction: Sodium oxybate (SXB) was administered for the first time in 1979 in 16 patients with narcolepsy with cataplexy (NT1) that improved up to 20 months., Aims: To evaluate the effect of SXB on daytime sleepiness and sleep architecture by video-polysomnography in a sample of 23 NT1 adult patients (13 men, 10 females) treated up to three years. Additional goal was to study the presence of sleep comorbidities., Patients and Methods: NT1 patients were diagnosed according to International Classification of Sleep Disorders, third edition. We conducted a longitudinal observational study and a video-polysomnography comparing the sleep parameters of patients treated with an initial nocturnal dose of 4.5 g of SXB after six months (FU-1), one year (FU-2) and three years (FU-3) of uninterrupted treatment. Video-polysomnography parameters were analyzed including apnea-hypopnea and periodic leg movements indexes., Results: Patients were HLA-DQB1*06:02 positive except a familial case. Thirteen patients (56%) discontinued SXB treatment over the three-year of the study. The two-nightly doses has been one of the reason for discontinuing treatment as well as insufficient compliance, mild or severe side effects, comorbidities and pregnancy. We found significant differences at FU-2 in sleep structure with an increased in stage N2 (p < 0.03) and a higher periodic leg movements index (p < 0.01). At FU-3 we found significant differences in sleep structure with an increase in stage N1 (p = 0.03) and in comorbidities (periodic leg movements and apnea-hypopnea indexes). There was not significant change on daytime sleepiness during the study., Conclusions: SXB was administered in low-medium doses. Two-nightly doses and sleep fragmentation linked to sleep comorbidities at long-term lead to drug withdrawal.

The irrefutable benefits of physical activity as a tool for the prevention and treatment of several clinical conditions, including cardiovascular diseases, are nowadays widely recognized. However, physical exercise may trigger adverse events in subjects with underlying heart disease, often undiagnosed and asymptomatic. It is fundamental to consider that various sports disciplines have peculiar and specific physiological and metabolic adaptations, and it is essential to consider the individual profile of the subject, including gender. We report the case of an agonistic female swimmer with a history of tachycardia heartbeat when resurfacing from dynamic apnea, in whom a diagnosis of atrioventricular nodal reentrant tachycardia was made. This case report provides practical evidence of the importance of a personalized approach, in both individual sex- and sport-specific terms, to optimize the diagnostic and therapeutic pathways.

Background: Among autonomic seizures apnea still represent a challenge for physicians, and it might constitute the only isolated sign of neurological disorder. The aim of this review is to describe ictal apnea (IA) and its treatment options., Methods: MeSH and keywords were combined: "neonatal seizures", "ictal neonatal apnea", "apneic seizures". All identified papers were screened for neonatal seizures titles and abstracts; case reports describing patients with IA as an isolated manifestation of neonatal seizures were included., Results: Eight studies including a total of 13 patients were identified. Among 13 patients, 9 were full-term and 4 were preterm neonates. All patients developed IA within twenty-one days from birth. Etiologies of seizures included: temporal lobe hemorrhage (3 pt), occipital stroke (1 pt), hypoxic-ischemic encephalopathy (HIE) (1 pt), parasagittal injury (1 pt), 18 trisomy (2 pt). Five patients showed no structural CNS alterations. Ten patients had the ictal focus localized in the temporal lobe; the occipital lobe was the second most involved site. Phenobarbital was administered in 76 % of cases with IA (10 pt), and showed efficacy in 74 % of them; 2 required a second anti-epileptic drug (AED) to reach seizure control. Levetiracetam was given to 11 % (2 pt) successfully. Only one was treated with midazolam and one did not require any anticonvulsant., Conclusions: Not homogeneous data and paucity of isolated IA currently reported in literature limits agreement about definition, management and treatment of entity, however an ever-growing attention is needed, and EEG/aEEG, despite their possible controversies in the diagnosis, should be performed to investigate unexplained forms of apnea., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aim: Oral therapeutic and invasive endoscopy requires deep sedation to reduce patient distress due to prolonged examination and procedures. The usefulness of capnography and bispectral index (BIS) monitoring in the early hypoxia detection in oral therapeutic and invasive endoscopy has yet to be evaluated. This study aimed to investigate the clinical impact of capnography and BIS monitoring on hypoxic events during oral therapeutic and invasive endoscopic procedures., Methods: This is a prospective observational study. Trans-oral non-intubated therapeutic and/or invasive endoscopic procedures were performed with conventional monitoring (pulse oximetry, pulse, and blood pressure) as well as additional monitoring (BIS and end-tidal CO 2 concentration). Hypoxia is defined as oxygen saturation of <90% that lasts >15 s. The clinical impact of capnography and BIS monitoring on hypoxic events during oral therapeutic and invasive endoscopic procedures were investigated with the risk factors for hypoxia in each patient., Results: Patients with hypoxia had significantly more apneas detected using capnography than other patients. The multivariate analysis revealed the detected apnea by capnography as an independent risk factor for hypoxia (odds ratio: 3.48[95% confidence interval: 1.24-9.78], P = 0.02). The BIS was not significantly different as a risk factor for hypoxia; however, per-event analysis revealed significantly decreased BIS values over time in 3 min before hypoxic events., Conclusions: Apnea detected by capnography was an independent predictor of hypoxia. The BIS value was not associated with hypoxia events; however, it showed a significant downward trend before hypoxia events., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: During apnea diving, a patent foramen ovale may function as a pressure relief valve under conditions of high pulmonary pressure, preserving left-ventricular output. Patent foramen ovale prevalence in apneic divers has not been previously reported. We aimed to determine the prevalence of patent foramen ovale in apneic divers compared to non-divers., Design: Cross sectional., Methods: Apnea divers were recruited from a training camp in Cavtat, Croatia and the diving community of Split, Croatia. Controls were recruited from the population of Split, Croatia and Eugene, Oregon, USA. Participants were instrumented with an intravenous catheter and underwent patent foramen ovale screening utilizing transthoracic saline contrast echocardiography. Appearance of microbubbles in the left heart within 3 cardiac cycles indicated the presence of patent foramen ovale. Lung function was measured with spirometry. Comparison of patent foramen ovale prevalence was conducted using chi-square analysis, p < .05., Results: Apnea divers had a significantly higher prevalence of patent foramen ovale (19 of 36, 53%) compared to controls (9 of 36, 25%) (X 2 (1, N = 72) = 5.844, p = .0156)., Conclusions: Why patent foramen ovale prevalence is greater in apnea divers remains unknown, though hyperbaria during an apnea dive results in a translocation of blood volume centrally with a concomitant reduction in lung volume and alveolar hypoxia during ascent results in hypoxic pulmonary vasoconstriction. These conditions increase pulmonary arterial pressure, increasing right-atrial pressure allowing for right-to-left blood flow through a patent foramen ovale which may be beneficial for preserving cardiac output and reducing capillary hydrostatic forces., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Although periodic limb movement during sleep (PLMS) and restless legs syndrome (RLS) are common in children and adolescents, they are relatively overlooked as a target of treatment. PLMS has been evaluated as having a lower clinical significance than RLS. This study examined the relationship of socio-behavioral factors of PLMS in Korean adolescents and checked whether PLMS is associated with excessive daytime sleepiness (EDS), depending on whether restless legs symptoms accompany it. In a cross-sectional study, 25,789 adolescents between 12 and 18 years of age (15.76 ± 1.73 years; female 51.49%) were evaluated using an online survey. Various self-report questionnaires were used to assess PLMS and RLS symptoms, EDS, sleep habits, and various socio-behavioral factors. The prevalence of self-perceived PLMS and restless legs symptoms were 903 (3.50%) and 1311 (5.08%), respectively. Of the 1311 participants, 399 had self-perceived PLMS. The odds ratios (ORs) for self-perceived PLMS in participants with restless legs symptoms were: males (OR = 1.528; 95% CI: 1.145-2.040), usually/always experienced apnea apnea (OR, 3.006; 95% CI, 1.954-4.624), increased proneness to Internet addiction (OR = 1.013; 95% CI: 1.001-1.025), sometimes/often consuming coffee (OR = 1.312; 95% CI: 1.015-1.695), EDS (OR = 0.826; 95% CI: 0.488-1.398), and perceived insufficient sleep (OR = 1.143; 95% CI: 0.835-1.565). The male gender, witness apnea, consuming coffee, and being prone to Internet addiction were identified as factors significantly associated with self-perceived PLMS in participants with restless legs symptoms. However, EDS and insufficient sleep were associated with self-perceived PLMS in the absence of restless legs symptoms.

Background: Tracheal resection and reconstruction are the most effective treatments for tracheal stenosis, but the difficulties are surgery and maintaining ventilation performed on the patient's same airway. High-flow oxygen has begun to be applied to prolong the apnoea time in the tracheal anastomosis period for tracheal resection and reconstruction. This study aims to evaluate the effectiveness of apneic conditions with high-flow oxygen as the sole method of gas exchange during anastomosis construction., Methods: A prospective study was performed on 16 patients with tracheal stenosis, with ages ranging from 19 to 70, who underwent tracheal resection and reconstruction from April 2019 to August 2020 in 108 Military Central Hospital. During the anastomosis phase using high flow oxygen of 35-40 l.min-1 delivered across the open tracheal with an endotracheal tube (ETT) at the glottis in apnoeic conditions., Results: The mean (SD) apnoea time was 20.91 (2.53) mins. Mean (SD) time anastomosis was 22.9 (2.41) mins. The saturation of oxygen was stable during all procedures at 98-100%. Arterial blood gas analysis showed mean (SD) was hypercapnia and acidosis acute respiratory after 10 mins of apnoea and 20 mins apnoea respectively. However, after 15 mins of ventilation, the parameters are ultimately returned to normal. All 16 patients were extubated early and safely at the end of the operation. There were no complications, such as bleeding, hemothorax, pneumothorax, or barotrauma., Conclusion: High-flow oxygen across the open tracheal under apnoeic conditions can provide a satisfactory gas exchange to allow tubeless anesthesia for tracheal resection and reconstruction., (© 2022. The Author(s).)

Background Central apneas (CA) are a frequent comorbidity in patients with heart failure (HF) and are associated with worse prognosis. The clinical and prognostic relevance of CA in each sex is unknown. Methods and Results Consecutive outpatients with HF with either reduced or mildly reduced left ventricular ejection fraction (n=550, age 65±12 years, left ventricular ejection fraction 32%±9%, 21% women) underwent a 24-hour ambulatory polygraphy to evaluate CA burden and were followed up for the composite end point of cardiac death, appropriate implantable cardioverter-defibrillator shock, or first HF hospitalization. Compared with men, women were younger, had higher left ventricular ejection fraction, had lower prevalence of ischemic etiology and of atrial fibrillation, and showed lower apnea-hypopnea index (expressed as median [interquartile range]) at daytime (3 [0-9] versus 10 [3-20] events/hour) and nighttime (10 [3-21] versus 23 [11-36] events/hour) (all P <0.001), despite similar neurohormonal activation and HF therapy. Increased chemoreflex sensitivity to either hypoxia or hypercapnia (evaluated in 356 patients, 65%, by a rebreathing test) was less frequent in women ( P <0.001), but chemoreflex sensitivity to hypercapnia was a predictor of apnea-hypopnea index in both sexes. At adjusted survival analysis, daytime apnea-hypopnea index ≥15 events/hour (hazard ratio [HR], 2.70; 95% CI, 1.06-7.34; P =0.037), nighttime apnea-hypopnea index ≥15 events/hour (HR, 2.84; 95% CI, 1.28-6.32; P =0.010), and nighttime CA index ≥10 events/hour (HR, 5.01; 95% CI, 1.88-13.4; P =0.001) were independent predictors of the primary end point in women but not in men (all P >0.05), also after matching women and men for possible confounders. Conclusions In chronic HF, CA are associated with a greater risk of adverse events in women than in men.

Clinical Rationale for the Study: This study aimed to assess the association between nocturnal hypoxemia and early acute ischaemic stroke (AIS) outcomes in patients without oxygen supplementation., Material and Methods: One hundred and six AIS patients consecutively admitted to the stroke unit were included in this study. Baseline demographic and medical data and arterial blood saturation (SpO2) measurements during night-sleep (from 10pm to 6am) were examined for their association with stroke outcomes, including the National Institutes of Health Stroke Scale (NIHSS) score on the 7th day or differences between the NIHSS score on the 1st day and the 7th day after stroke onset. Measurements of SpO2 were made using a pulse oximeter of the Spacelabs Medical Inc. (USA) monitoring system, and the number of apnoea episodes and their duration were recorded by ECG Holter with respiration monitoring (CardioMem®, Getamed, GE)., Results: The study showed that age (Spearman's r = 0.207, p = 0.033) and parameters attributable to anaemia (RBC r = -0.205, p = 0.035, Hb r = -0.225, p = 0.02 and HCT r = -0.196, p = 0.044), atrial fibrillation and ischaemic changes in both brain hemispheres (p = 0.023 and 0.01, respectively) were correlated with the study outcomes. In terms of saturation parameters, we demonstrated that the 'total desaturation burden' (i.e. [100% minus actual measured SpO2%] x apnoea duration) and multiple apnoeas of longer than 20 seconds were correlated with worse functional outcomes. Measures of shorter desaturation episodes (i.e. SpO2 oxygen desaturation index (ODI) at 3% and 4%, and time-weighted desaturations below the determined thresholds (SpO2 from 95% to 85%) demonstrated non-significant associations with the study outcomes., Conclusions and Clinical Implications: This study demonstrated that long-lasting desaturation episodes during the night, depicted by the 'total desaturation burden', were correlated with worse functional outcomes in AIS, while measures of shorter desaturation episodes were not correlated. In future clinical trials, indications for oxygen supplementation should include the methodology of personalised medicine and introduce individual approaches based on specially formulated, novel multifactorial algorithms.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Human studies and animal models suggest that respiratory arrest is the initiating event leading to death in many cases of SUDEP. It has previously been reported that the onset of apnea can coincide with the spread of seizures to the amygdala, and apnea can be reproduced by electrical stimulation of the amygdala. The aim of the current work was to determine if the amygdala is required for seizure-induced respiratory arrest (S-IRA) in a mouse model of SUDEP. Experiments were performed on DBA/1 mice that have audiogenic seizures with a high incidence of fatal postictal respiratory arrest. Electrolytic lesions of the amygdala significantly reduced the incidence of S-IRA without altering seizures, baseline breathing, or the hypercapnic ventilatory response. These results indicate that the amygdala is a critical node in a pathway to the lower brainstem that is needed for seizures to cause respiratory arrest. SIGNIFICANCE STATEMENT: Sudden unexpected death in epilepsy is the most common cause of mortality in patients with refractory epilepsy, and S-IRA is thought to be important in the pathophysiology in many cases. In a patient with epilepsy, the onset of apnea has been shown to coincide with spread of seizures to the amygdala, and in multiple patients, apnea was induced by stimulation of the amygdala. Here, we show that lesions of the amygdala reduced the incidence of S-IRA and death in a mouse model of SUDEP. These results provide evidence that the amygdala may be a critical node in the pathway by which seizures influence the brainstem respiratory network to cause apnea. This article is part of the Special Issue NEWroscience 2018., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures., Methods: We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele-mutations identified from patients who died from SUDEP-and of seizure-induced death in pentylenetetrazole-treated wild-type mice., Results: The primary cause of seizure-induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea., Interpretation: We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure-induced death in Scn8a mutant mice. ANN NEUROL 2021;89:1023-1035., (© 2021 American Neurological Association.)

Background: During induction of general anaesthesia, patients frequently experience apnoea, which can lead to dangerous hypoxaemia. An obstructed upper airway can impede attempts to provide ventilation. Although unrelieved apnoea is rare, it continues to cause deaths. Clinical investigation of management strategies for such scenarios is effectively impossible because of ethical and practical considerations., Methods: A population-representative cohort of 100 virtual (in silico) subjects was configured using a high-fidelity computational model of the pulmonary and cardiovascular systems. Each subject breathed 100% oxygen for 3 min and then became apnoeic, with an obstructed upper airway, during induction of general anaesthesia. Apnoea continued throughout the protocol. When arterial oxygen saturation (Sao 2 ) reached 20%, 40%, or 60%, airway obstruction was relieved. We examined the effect of varying supraglottic oxygen fraction (Fo 2 ) on the degree of passive re-oxygenation occurring without tidal ventilation., Results: Relief of airway obstruction during apnoea produced a single, passive inhalation (caused by intrathoracic hypobaric pressure) in all cases. The degree of re-oxygenation after airway opening was markedly influenced by the supraglottic Fo 2 , with a supraglottic Fo 2 of 100% providing significant and sustained re-oxygenation (post-rescue Pao 2 42.3 [4.4] kPa, when the airway rescue occurred after desaturation to Sao 2 60%)., Conclusions: Supraglottic oxygen supplementation before relieving upper airway obstruction improves the effectiveness of simulated airway rescue. Management strategies should be implemented to assure a substantially increased pharyngeal Fo 2 during difficult airway management., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Child abuse was suspected in a case of out-of-hospital arrest with minor brain injuries. Confronted with continued disputes on pathophysiologic correlates even after autopsy, to assist the differentiation of potential causes of sudden cardiopulmonary arrest in children, we tried to identify the mechanism of cardiopulmonary arrest in brain injuries from different causes. Systematic review was carried out in two stages. First, major external causes of cardiopulmonary arrest among children and infants were identified from Pubmed and Google Scholar search, and then the exact sequence of cardiopulmonary arrest, and their pathophysiologic features were identified based on articles of animal models of brain injury. From the review, we have identified four major groups of external circumstances for rather sudden cardiopulmonary arrest from brain damage in children, after excluding congenital and other unrelated diseases; 1) impact brain apnea, 2) anoxic insults, 3) drug or other substance induced central nervous system depression, and 4) traumatic brain damage. Each group has different features in the course of cardiac and respiratory arrests. Based on this review of pathophysiologic features of cardio-respiratory responses from external causes, we have presented a suspected, but unlikely, child abuse case of respiratory arrest from brain injury. The social consequences of both unknowingly missing, and falsely incriminating the abuse can be grave, and the identification of the mechanisms of cardiopulmonary arrest from brain injury can be important for the differentiation of various potential causes., (Copyright © 2020 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Background: The factors influencing the severity of apnea-related hypoxemia and bradycardia are incompletely characterized, especially in infants receiving noninvasive respiratory support., Objectives: To identify the frequency and predictors of physiological instability (hypoxemia-oxygen saturation (SpO 2 ) <80%, or bradycardia-heart rate (HR) < 100 bpm) following respiratory pauses in infants receiving noninvasive respiratory support., Methods: Respiratory pause duration, derived from capsule pneumography, was measured in 30 preterm infants of gestation 30 (24-32) weeks [median (interquartile range)] receiving noninvasive respiratory support and supplemental oxygen. For identified pauses of 5 to 29 seconds duration, we measured the magnitude and duration of SpO 2 and HR reductions over a period starting at the pause onset and ending 60 seconds after resumption of breathing. Temporally clustered pauses (<60 seconds separation) were analyzed separately. The relative contribution of respiratory pauses to overall physiological instability was determined, and predictors of instability were sought in regression analysis, including demographic, clinical and situational variables as inputs., Results: In total, 17 105 isolated and 9180 clustered pauses were identified. Hypoxemia and bradycardia were more likely after longer duration and temporally-clustered pauses. However, the majority of such episodes occurred after 5 to 9 second pauses given their numerical preponderance, and short-lived pauses made a substantial contribution to physiological instability overall. Birth gestation, hemoglobin concentration, form of respiratory support, caffeine treatment, respiratory pause duration and temporal clustering were identified as predictors of instability., Conclusions: Brief respiratory pauses, especially when clustered, contribute substantially to hypoxemia and bradycardia in preterm infants., (© 2019 Wiley Periodicals, Inc.)

Objective: To determine the relationship between serum serotonin (5-HT) levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA) in epileptic seizures., Methods: We prospectively evaluated video EEG, plethysmography, capillary oxygen saturation (SpO 2 ), and ECG for 49 patients (49 seizures) enrolled in a multicenter study of sudden unexpected death in epilepsy (SUDEP). Postictal and interictal venous blood samples were collected after a clinical seizure for measurement of serum 5-HT levels. Seizures were classified according to the International League Against Epilepsy 2017 seizure classification. We analyzed seizures with and without ICA (n = 49) and generalized convulsive seizures (GCS) with and without PCCA (n = 27)., Results: Postictal serum 5-HT levels were increased over interictal levels for seizures without ICA ( p = 0.01), compared to seizures with ICA ( p = 0.21). In patients with GCS without PCCA, serum 5-HT levels were increased postictally compared to interictal levels ( p < 0.001), but not in patients with seizures with PCCA ( p = 0.22). Postictal minus interictal 5-HT levels also differed between the 2 groups with and without PCCA ( p = 0.03). Increased heart rate was accompanied by increased serum 5-HT levels (postictal minus interictal) after seizures without PCCA ( p = 0.03) compared to those with PCCA ( p = 0.42)., Conclusions: The data suggest that significant seizure-related increases in serum 5-HT levels are associated with a lower incidence of seizure-related breathing dysfunction, and may reflect physiologic changes that confer a protective effect against deleterious phenomena leading to SUDEP. These results need to be confirmed with a larger sample size study., (© 2019 American Academy of Neurology.)

Background: Among the most common autonomic signs visible in preterm neonates, apnea can represent the first sign of several neurologic and non-neurologic disorders, and seizure is a relatively infrequent cause. Herein authors present a case of neonatal autonomic apnea, discussing the polygraphic video-EEG features of this pathological entity and the differential diagnosis with central apnea and autonomic apnea., Case Report: A female preterm Caucasian infant (29 + 4 weeks' gestational age (GA)), first twin of a twin pregnancy, at birth was intubated and surfactant administration was performed. She was ventilated via invasive ventilation for three days, with subsequent weaning with non-invasive ventilation for other two days, when she stopped requiring any ventilator support. After one week the ventilation weaning, the child presented episodes of cyanosis associated with sudden oxygen desaturation, skin pallor, apnea, and bradycardia. Therefore, the child underwent a continuous video-eeg recording with polygraphic study. The exam showed the presence of apneic episodes with an abrupt and clear start, associated with oxygen desaturation at 70%, with minimal thoracic effort at onset, and then evolving into central apnea. Central apnea lasted about 16 s and presented clear start- and end-points. These episodes were also associated with suppression of the EEG trace in frequency and amplitude, and after about 10 s of central apnea an abrupt decrease of the child's heart rate (more than 50% variation, from 160 bpm to 65 bpm) was recorded. In the suspect of epileptic apneas of autonomic origin, a therapy with oral Levetiracetam, at a starting dose of 10 mg/Kg/day, then increased up to 40 mg/Kg/day, was initiated, and after about 48 h the first administration of the anticonvulsant therapy, no new episodes of cyanosis or electrical apneas were recorded., Hypothesis: Herein the authors suggest to consider the diagnosis of autonomic seizures in those neonates with apneic events associated with EEG suppression. Considering that apnea events are not only present in preterm infants but also in term neonates, it is mandatory to diagnose in this context neonatal seizures for a correct diagnosis and a proper therapeutic choice., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Obstructive sleep apnea (OSA) is associated with sympathetic overactivity. Intermittent hypoxemia and repetitive arousals are the proposed mechanisms; however, the main contributing factor for sympathetic overactivity remains to be determined. We therefore investigated the independent effect of apnea or arousal on sympathetic activity in a large cohort of OSA patients using heart rate variability analysis., Methods: Frequency domain heart rate variability parameters were measured and compared between 782 patients with OSA (198 mild, 259 moderate, 325 severe) and 119 non-OSA controls. Univariate analysis was performed to identify associations between clinical and polysomnographic variables and heart rate variability measurements. Multivariate analysis was further performed to determine the potential contributing factors for sympathetic overactivity., Results: Patients with OSA exhibited overall alterations in heart rate variability measures indicating sympathetic overactivity compared to controls, and this tendency was more pronounced in those with severe OSA. Univariate analysis showed that both apnea-hypopnea and arousal indices correlated with increased sympathetic activity and decreased parasympathetic activity. In multivariate analysis, arousal index was found to be more closely associated with sympathetic overactivity than apnea-hypopnea index., Conclusion: The present study showed that arousal may be a more potent contributing factor than apnea for sympathetic overactivity in OSA patients. Our results suggest that arousal index, rather than apnea-hypopnea index, could be considered as a surrogate marker for sympathetic overactivity in OSA. Further longitudinal studies should elucidate causal relationship between arousals and sympathetic overactivity in patients with OSA., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Study Objectives: The aim was to investigate how the severity of apneas, hypopneas, and related desaturations is associated with obstructive sleep apnea (OSA)-related daytime sleepiness., Methods: Multiple Sleep Latency Tests and polysomnographic recordings of 362 patients with OSA were retrospectively analyzed and novel diagnostic parameters (eg, obstruction severity and desaturation severity), incorporating severity of apneas, hypopneas, and desaturations, were computed. Conventional statistical analysis and multivariate analyses were utilized to investigate connection of apnea-hypopnea index (AHI), oxygen desaturation index (ODI), conventional hypoxemia parameters, and novel diagnostic parameters with mean daytime sleep latency (MSL)., Results: In the whole population, 10% increase in values of desaturation severity (risk ratio = 2.01, P < .001), obstruction severity (risk ratio = 2.18, P < .001) and time below 90% saturation (t 90% ) (risk ratio = 2.05, P < .001) induced significantly higher risk of having mean daytime sleep latency ≤ 5 minutes compared to 10% increase in AHI (risk ratio = 1.63, P < .05). In severe OSA, desaturation severity had significantly (P < .02) stronger negative correlation (ρ = -.489, P < .001) with mean daytime sleep latency compared to AHI (ρ = -.402, P < 0.001) and ODI (ρ = -.393, P < .001). Based on general regression model, desaturation severity and male sex were the most significant factors predicting daytime sleep latency., Conclusions: Severity of sleep-related breathing cessations and desaturations is a stronger contributor to daytime sleepiness than AHI or ODI and therefore should be included in the diagnostics and severity assessment of OSA., Citation: Kainulainen S, Töyräs J, Oksenberg A, Korkalainen H, Sefa S, Kulkas A, Leppänen T. Severity of desaturations reflects OSA-related daytime sleepiness better than AHI. J Clin Sleep Med. 2019;15(8):1135-1142., (© 2019 American Academy of Sleep Medicine.)

Background: Respiratory adverse events are not uncommon in the post-anesthesia care unit (PACU) following general anesthesia. In this regard, hyperventilation leading to apnea and desaturation is a rare entity. Here we have reported a case of a 15-year-old girl who, following an uneventful general anesthesia, developed severe hyperventilation leading to apnea and desaturation in the PACU., Case Presentation: The 15-year-old girl underwent cortical mastoidectomy under general anesthesia. After a smooth anesthesia and an uneventful early recovery, she developed hyperventilation after about 15 min in the PACU. The symptom was severe enough to lead to apnea, desaturation and severe respiratory alkalosis. She required bag and mask ventilation and the symptoms resolved only transiently with propofol sedation. Finally, she responded to intravenous haloperidol and did not have any further episode after receiving haloperidol., Conclusion: Hyperventilation after a smooth recovery from anesthesia is not a common presentation. In this article we have tried to discuss the possible cause of such symptom in our patient and how we successfully managed this case. We have also proposed an algorithmic approach to diagnose and manage such cases in the PACU.

The possible relationship between lung cancer and nocturnal intermittent hypoxia, apnea and daytime sleepiness, especially the possible relationship between the occurrence and progression of lung cancer and obstructive sleep apnea syndrome (OSAS) was explored. Forty-five cases of primary lung cancer suitable for surgical resection at the Third Affiliated Hospital of Kunming Medical University between January 2017 and December 2017 were recruited (lung cancer group), and there were 45 patients in the control group who had no significant differences in age, sex and other general data from lung cancer group. The analyzed covariates included general situation, snore score, the Epworth Sleeping Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), apnea and hypopneas index (AHI), oxygen desaturation index 4 (ODI 4 ), lowest arterial oxygen saturation [LSpO 2 (%)], oxygen below 90% of the time [T90% (min)], the percentage of the total recorded time spend below 90% oxygen saturation (TS90%), to explore the possible relationship between lung cancer and above indicators. The participants were followed up for one year. The results showed that: (1) There was significant difference in body mass index (BMI), ESS, AHI, T90% (min), TS90%, ODI 4 , snore score and LSpO 2 (%) between lung cancer group and control group (P<0.05). There was no statistically significant difference in age, gender, PSQI score, incidence of concurrent hypertension, diabetes and coronary heart disease (CHD), and smoking history between the two groups (P>0.05); (2) Patients in the lung cancer group were divided into OSAS subgroup and non-OSAS subgroup according to the international standard for the diagnosis of OSAS. There was significant difference in BMI, age, staging, incidence of concurrent hypertension and concurrent CHD, snore score, ESS score, T90% (min), TS90%, ODI 4 and LSpO 2 (%) between OSAS subgroup and non-OSAS subgroup (P<0.05). There was no statistically significant difference in gender, PSQI score, incidence of concurrent diabetes, smoking history and lung cancer type between the two groups (P>0.05); (3) AHI was strongly negatively correlated with the LSpO 2 (%) and positively with ESS, staging, snoring score, T90% (min), TS90%, ODI 4 and BMI (P<0.05); (4) There were 3 deaths, 5 cases of recurrence, and 4 cases of metastasis in OSAS subgroup; and there was 1 death, 4 cases of recurrence and 2 cases of metastasis in non-OSAS subgroup during the follow-up period of one year, respectively. There was no significant difference in mortality, recurrence rate and metastasis rate between the two subgroups, and the total rate of deterioration in OSAS subgroup was significantly increased compared to the non-OSAS subgroup (P<0.05). It was concluded that the patients with lung cancer are prone to nocturnal hypoxemia, apnea, snoring and daytime sleepiness compared to control group. The incidence of OSAS in patients with lung cancer was higher, and the difference in the hypoxemia-related indicators was statistically significant. The mortality, recurrence rate, and metastasis rate increases in lung cancer patients with OSAS during the one-year follow-up period, suggesting that OSAS may be a contributing factor to the occurrence and progression of lung cancer.

Background The autonomic nervous system response to apnea and its mechanistic connection to atrial fibrillation (AF) are unclear. We hypothesize that sensory neurons within the ganglionated plexi (GP) play a role. We aimed to delineate the autonomic response to apnea and to test the effects of ablation of cardiac sensory neurons with resiniferatoxin (RTX), a neurotoxic TRPV1 (transient receptor potential vanilloid 1) agonist. Methods Sixteen dogs were anesthetized and ventilated. Apnea was induced by stopping ventilation until oxygen saturations decreased to 80%. Nerve recordings from bilateral vagal nerves, left stellate ganglion, and anterior right GP were obtained before and during apnea, before and after RTX injection in the anterior right GP (protocol 1, n=7). Atrial effective refractory period and AF inducibility on single extrastimulation were assessed before and during apnea, and before and after intrapericardial RTX administration (protocol 2, n=9). GPs underwent immunohistochemical staining for TRPV1. Results Apnea increased anterior right GP activity, followed by clustered crescendo vagal bursts synchronized with heart rate and blood pressure oscillations. On further oxygen desaturation, a tonic increase in stellate ganglion activity and blood pressure ensued. Apnea-induced effective refractory period shortening from 110.20±31.3 ms to 90.6±29.1 ms ( P<0.001), and AF induction in 9/9 dogs versus 0/9 at baseline. After RTX administration, increases in GP and stellate ganglion activity and blood pressure during apnea were abolished, effective refractory period increased to 126.7±26.9 ms ( P=0.0001), and AF was not induced. Vagal bursts remained unchanged. GP cells showed cytoplasmic microvacuolization and apoptosis. Conclusions Apnea increases GP activity, followed by vagal bursts and tonic stellate ganglion firing. RTX decreases sympathetic and GP nerve activity, abolishes apnea's electrophysiological response, and AF inducibility. Sensory neurons play a role in apnea-induced AF.

The apnea test is an essential examination for the determination of brain death; however, hypotension, hypoxemia, and other complications during the apnea test can affect the stability of brain-dead patients, as well as organ function for recipients. Therefore, it is necessary to establish standard guidelines for apnea testing.The modified apnea test (MAT) comprises delivery of 100% oxygen through the endotracheal tube connected to manual resuscitator (Ambu bag) with the positive end-expiratory pressure (PEEP) valve after disconnection of the mechanical ventilator for maintenance of PEEP. Forty-nine instances of the conventional apnea test (CAT) were performed in 25 brain-dead patients; 77 instances of the MAT were performed in 39 brain-dead patients.The mean duration of the apnea test was 3.5 ± 1.4 minutes in the CAT group and 3.0 ± 1.2 minutes in the MAT group. There were no significant changes in PaCO2, PaO2, or pH between the CAT and MAT groups (P = .341, .593, and .503, respectively). In overweight patients (body mass index ≥ 23 kg/m), MAT prevented dramatic reductions in PaO2 and SaO2 (P < .05 for both). In the patients who had hypoxic brain injury due to hanging, differences in PaO2 and SaO2 in the MAT group were significantly smaller than in the CAT group (P < .05).Although MAT, which was invented to maintain PEEP, was not efficient for all brain-dead patients, it could be helpful in selected patient groups, such as overweight patients or those who had hypoxic injury due to hanging. And clinicians should consider short-term apnea test to avoid unnecessarily prolonged hypoxemia.

Pseudocholinesterase deficiency is a rare genetic as well as an acquired disorder that affects the body's ability to metabolize choline esters such as succinylcholine and mivacurium. It can be inherited as an autosomal recessive trait, occurring in approximately 1 in 3,200 to 1 in 5,000 people. In most cases of pseudocholinesterase deficiency, no signs or symptoms of the condition exist. It is first suspected after a prolonged recovery from paralysis following general anesthesia in which succinylcholine or mivacurium are administered. We emphasize the importance of obtaining a detailed history prior to any endoscopic intervention or surgery requiring monitored anesthesia care or general anesthesia. In addition, a family history of anesthesia complications may help identify patients at risk. This article examines a case of a patient who underwent a successful endoscopic pneumatic dilation under general anesthesia for the treatment of achalasia, but was subsequently admitted to the intensive care unit, requiring mechanical ventilator support, for 18 hours. The patient made a complete recovery and was discharged home with no further complications. This case stimulated a review of this entity and we provide recommendations relevant to all proceduralist and anesthesia staff, as well as all personnel involved in procedures., (Copyright © 2018. Published by Elsevier Inc.)

Background: Placebo-controlled trials have shown that caffeine is highly effective in treating apnoea of prematurity and reduces the risk of bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI)., Objective: To identify, appraise and summarise studies investigating the modulating effect of different caffeine dosages., Methods: A systematic review identified all randomised controlled trials (RCTs) comparing a high versus a standard caffeine treatment regimen in infants with a gestational age <32 weeks, by searching the main electronic databases and abstracts of the Pediatric Academic Societies. Studies comparing caffeine to placebo or theophylline only were excluded. Primary outcomes were BPD and mortality at 36 weeks postmenstrual age. Secondary key-outcome was neurodevelopmental outcome at 12 and 24 months corrected age. Meta-analysis was performed using RevMan 5.3., Results: Six RCTs including 620 infants were identified. Meta-analysis showed a significant decrease in BPD, the combined outcome BPD or mortality, and failure to extubate in infants allocated to a higher caffeine dose. No differences were found in mortality alone and NDI. The quality of the outcome measures were deemed low to very low according to the Grading of Recommendations Assessment, Development and Evaluation guidelines., Conclusions: Although this review suggests that administering a higher dose of caffeine might enhance its beneficial effect on death or BPD, firm recommendations on the optimal caffeine dose cannot be given due to the low level of evidence. A large RCT is urgently needed to confirm or refute these findings and determine the optimal dose of caffeine., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The following review explores the effect that intermittent or sustained hypercapnia coupled to intermittent hypoxia has on respiratory plasticity. The review explores published work which suggests that intermittent hypercapnia leads to long-term depression of respiration when administered in isolation and prevents the initiation of long-term facilitation when administered in combination with intermittent hypoxia. The review also explores the impact that sustained hypercapnia alone and in combination with intermittent hypoxia has on the magnitude of long-term facilitation. After exploring the outcomes linked to intermittent hypoxia/hypercapnia and intermittent hypoxia/sustained hypercapnia the translational relevance of the outcomes as it relates to breathing stability during sleep is addressed. The likelihood that naturally induced cycles of intermittent hypoxia, coupled to oscillations in carbon dioxide that range between hypocapnia and hypercapnia, do not initiate long-term facilitation is addressed. Moreover, the conditions under which intermittent hypoxia/sustained hypercapnia could serve to improve breathing stability and mitigate co-morbidities associated with sleep apnea are considered., (Published by Elsevier B.V.)

Background: Cardiorespiratory (CR) events (apnea, bradycardia, oxygen desaturation) and gastroesophageal reflux (GER) symptoms often coexist in infants admitted to Neonatal Intensive Care Unit, leading to over-prescription of drugs and delayed discharge. We aimed to evaluate the relationships between CR and GER events., Methods: The temporal associations between CR and GER events were analyzed in symptomatic infants who underwent synchronized CR and pH-impedance monitoring. The symptom association probability (SAP) index was used to identify infants with a significant number of temporal associations. Gastroesophageal reflux characteristics and the chronological sequence of CR and GER events occurring within 30 seconds of each other were evaluated according to SAP index., Key Results: Of the 66 infants enrolled, aged 29 (18-45) days, 58 had CR events during monitoring. From these 58 patients, a total of 1331 CR events and 5239 GER (24% acidic) were detected. The SAP index was positive in seven (12%) infants. These infants had greater GER frequency, duration, and proximal extent (P < .05). The number of temporal associations was 10 times greater in the positive SAP group. Gastroesophageal reflux events preceded CR events in 83% of these associations. These GER events had a higher proximal extent (P = .004), but showed no differences in pH values., Conclusions & Inferences: The simultaneous evaluation of CR and GER events could be useful to identify infants with severe GER and significant temporal associations between these events. Treatment of GER could be indicated in these infants, but as the GER events involved are mainly non-acidic, empirical treatment with antacids is, often, inappropriate., (© 2017 John Wiley & Sons Ltd.)

Objectives: This study sought to characterize trends in the diagnosis of apnea, associated comorbidities and complications, and 30-day readmission rates in preterm singleton infants., Subjects and Methods: The study design was a retrospective, longitudinal, observational study. 2003-2014 New York State Statewide Planning and Research Cooperative System and New York City Vital Statistics databases were merged identifying preterm live singleton births. Hospitalizations of preterm newborns with and without apnea were compared; multivariable logistic regression and log-linear Poisson regression models applied., Results: Of 1,384,013 singleton births, 7.5% were identified as preterm. While relative risk of preterm birth rates declined (RR = 0.987, 95% CI = 0.982-0.991), the diagnosis of apnea increased significantly (RR = 1.069, 95% CI = 1.049-1.089). Multivariable analysis identified two apnea predictors, gastric reflux (OR = 3.19, 95% CI = 2.80-3.63) and early gestational age (OR = 0.83 for 1 week GA increase, 95% CI = 0.82-0.84). Preterm newborns with apnea were more likely to be readmitted within the first 30 days and total charges were 5.4 times higher., Conclusions: While the preterm birth rate has declined the rate of diagnosis of apnea with associated comorbidities and complications has increased. Given the additional findings of higher 30-day readmission rates and charges, more multidisciplinary research appears warranted to identify ways to optimize the quality of high risk newborn care., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To assess the impact of short time hypnosis for retro-bulbar anesthesia on ventilation in patients undergoing ophthalmic surgery of the anterior eye chamber. In all patients, a combined continuous transcutaneous carbon dioxide tension (PtcCO 2 ) and partial oxygen saturation (SpO 2 ) measurement was applied in addition to routine monitoring. To enable unconscious application of retro-bulbar anesthesia, intravenous thiopental was given in one to multiple bolus doses. Transient breathing support included chin lift, Esmarch maneuver and manual hand-bag ventilation via face mask. Main endpoints were apnea time, recovery time according to the Richmond Agitation Sedation Scale, as well as SpO 2 and PtcCO 2 readings at predefined time points. Fifty-two patients with a mean age of 68 ± 13 years were included. Average thiopental dose was 2.7 ± 0.6 mg/kg. In seven (13.5%) patients repeated doses of thiopental were necessary to a total of 3.3 ± 1.1 mg/kg. Except one patient, no severe, significant or clinical relevant hypercapnia or desaturation periods were observed, and the occurring elevation of PtcCO 2 values did not correlate with the application of repeated doses of thiopental or the need for the Esmarch maneuver. Higher PtcCO 2 values were associated with the presence of hypertension and smoking. Apnea (p < 0.001) and recovery (p = 0.003) time were significantly prolonged in the patients needing the Esmarch maneuver. Short term anesthesia with thiopental in ophthalmic surgery is associated with a mild but not clinically relevant hypercapnia.

Peripheral chemoreflex mediated increases in both parasympathetic and sympathetic drive under chronic hypoxia may evoke bradyarrhythmias during apneic periods. We determined whether 1) voluntary apnea unmasks arrhythmia at low (344 m) and high (5,050 m) altitude, 2) high-altitude natives (Nepalese Sherpa) exhibit similar cardiovagal responses at altitude, and 3) bradyarrhythmias at altitude are partially chemoreflex mediated. Participants were grouped as Lowlanders ( n = 14; age = 27 ± 6 yr) and Nepalese Sherpa ( n = 8; age = 32 ± 11 yr). Lowlanders were assessed at 344 and 5,050 m, whereas Sherpa were assessed at 5,050 m. Heart rate (HR) and rhythm (lead II ECG) were recorded during rest and voluntary end-expiratory apnea. Peripheral chemoreflex contributions were assessed in Lowlanders ( n = 7) at altitude after 100% oxygen. Lowlanders had higher resting HR at altitude (70 ± 15 vs. 61 ± 15 beats/min; P < 0.01) that was similar to Sherpa (71 ± 5 beats/min; P = 0.94). High-altitude apnea caused arrhythmias in 11 of 14 Lowlanders [junctional rhythm ( n = 4), 3° atrioventricular block ( n = 3), sinus pause ( n = 4)] not present at low altitude and larger marked bradycardia (nadir -39 ± 18 beats/min; P < 0.001). Sherpa exhibited a reduced bradycardia response during apnea compared with Lowlanders ( P < 0.001) and did not develop arrhythmias. Hyperoxia blunted bradycardia (nadir -10 ± 14 beats/min; P < 0.001 compared with hypoxic state) and reduced arrhythmia incidence (3 of 7 Lowlanders). Degree of bradycardia was significantly related to hypoxic ventilatory response (HVR) at altitude and predictive of arrhythmias ( P < 0.05). Our data demonstrate apnea-induced bradyarrhythmias in Lowlanders at altitude but not in Sherpa (potentially through cardioprotective phenotypes). The chemoreflex is an important mechanism in genesis of bradyarrhythmias, and the HVR may be predictive for identifying individual susceptibility to events at altitude. NEW & NOTEWORTHY The peripheral chemoreflex increases both parasympathetic and sympathetic drive under chronic hypoxia. We found that this evoked bradyarrhythmias when combined with apneic periods in Lowlanders at altitude, which become relieved through supplemental oxygen. In contrast, high-altitude residents (Nepalese Sherpa) do not exhibit bradyarrhythmias during apnea at altitude through potential cardioprotective adaptations. The degree of bradycardia and bradyarrhythmias was related to the hypoxic ventilatory response, demonstrating that the chemoreflex plays an important role in these findings.

Objective: Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1 -/- mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1 -/- mice, thereby increasing risk of respiratory failure and sudden death (SD)., Methods: Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1 +/+ , Kcna1 +/- , and Kcna1 -/- littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1 -/- mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46, and P48-56, respectively. Saturated arterial O 2 (SaO 2 ) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh., Results: Kcna1 -/- mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume, and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1 -/- mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1 -/- mice approached SD. MCh-induced seizures experienced by a subset of younger Kcna1 -/- mice triggered death. Respiratory parameters of these younger Kcna1 -/- mice resembled older near-SD Kcna1 -/- mice. Kcna1 gene and protein were not expressed in Kcna1 +/+ and Kcna1 +/- lungs, and MCh-mediated airway smooth muscle contractions exhibited similar half-maximal effective concentration( EC 50 ) in isolated Kcna1 +/+ and Kcna1 -/- trachea., Significance: The Kcna1 -/- model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Background: Gastro-oesophageal reflux (GOR) and apnoea are common in infants; whether there is a causal relationship is controversial., Objectives: To determine whether there was a temporal relationship between GOR and apnoea, in particular, the frequency of obstructive apnoeas and if the frequency of GOR episodes correlated with apnoea frequency when maturity at testing was taken into account., Methods: Polysomnography and pH/multichannel intraluminal impedance (MII) studies were performed. Apnoeas were classified as central, obstructive, or mixed. MII events were classified as acidic (pH <4) or weakly acidic (4 < pH < 7). Apnoea frequency in the 5-min period after a reflux event was compared to that in the 5-min period preceding the event and that in a 5-min reflux-free period (control period)., Results: Forty infants (median gestational age 29 [range 24-42] weeks) were assessed at a post-conceptional age of 37 (30-54) weeks. Obstructive (n = 580), central (n = 900), and mixed (n = 452) apnoeas were identified; 381 acid reflux events were detected by MII and 153 by the pH probe only. Apnoeas were not more frequent following GOR than during control periods. Both the frequency of apnoeas (p = 0.002) and GOR episodes (p = 0.01) were inversely related to post-conceptional age at testing, but were not significantly correlated with each other when controlled for post-conceptional age., Conclusions: These results suggest that GOR does not cause apnoea., (© 2017 S. Karger AG, Basel.)

Sudden unexpected death in epilepsy (SUDEP) is one of the most frequent causes of death among patients with epilepsy. Most SUDEP or near-SUDEP are unwitnessed and not observed or recorded during video-EEG recording in epilepsy monitoring units. This report describes a young woman with post ictal apnea and generalized EEG suppression (PGES) after a secondary generalized tonic-clonic seizure (sGTCS). This was accompanied by bradycardia and then ventricular tachycardia (VT). But at the end of VT, the patient's breath recovered without any intervention, such as cardio-respiratory resuscitation. This case report with continuous EEG, EKG, EMG during near SUDEP may provide insights into the mechanism of action., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Home cardiorespiratory monitoring has changed significantly since it was first introduced in the 1970s. It has improved from a simple alarm system to a sophisticated piece of equipment capable of monitoring the patient's electrocardiogram, respiratory effort, and oxygen saturations. In addition, the indications for using a monitor have also changed. The home monitor was initially used to reduce the incidence of sudden infant death syndrome (SIDS). Although there were several studies demonstrating the reduction of SIDS rates in communities where apnea programs existed, none was a prospective, double-blinded study or had adequate numbers to be clinically significant. Therefore, the American Academy of Pediatrics took the stance that monitors were not an effective way to reduce SIDS. However, when used appropriately, as part of a complete program (ie, the monitor is just one of many clinically based modalities), by a clinician with expertise in interpreting download tracings, home cardiorespiratory monitoring can be a useful, lifesaving, and economical tool to observe infants who are at increased risk of sudden death or increased morbidity secondary to intermittent hypoxia. [Pediatr Ann. 2017;46(8):e303-e308.]., (Copyright 2017, SLACK Incorporated.)

Background: Transnasal Humidified Rapid-Insufflation Ventilatory Exchange has been shown to safely prolong the safe apnea time in well children post induction of anesthesia and is rapidly becoming a new standard for apneic oxygenation in adults. The same oxygenation technique is described as nasal high flow and can be used in infants and children at risk of apnea during anesthesia., Aim: We investigated the use of nasal high flow oxygen delivery during anesthesia in children with abnormal airways requiring tubeless airway assessment or surgery., Methods: Data and outcomes of pediatric patients receiving nasal high flow for upper airway procedures were analyzed. Four categories were defined: (i) tubeless airway surgery, (ii) flexible bronchoscopy, (iii) expected difficult airway, and (iv) comorbidity related risk of apnea. Anesthesia was induced intravenously or with sevoflurane (4-8%) and then converted to total intravenous anesthesia aiming for spontaneous ventilation. Age appropriate nasal high flow cannulae were secured with 100% oxygen delivery at weight-related flow rates. Topicalization of the airway was achieved with lignocaine. Complication rates of desaturation requiring interruption of procedure for rescue oxygenation were recorded., Results: Twenty children were analyzed with age range of 5 days to 11 years, ASA 1-4, and weight range 3-57 kg. Fifteen were induced with sevoflurane and 100% oxygen, five received total intravenous anesthesia only. All children received Optiflow™ nasal high flow and intravenous anesthesia during their procedure. Average SpO 2 recorded was 96% with lowest SpO 2 77%. One required rescue oxygenation. Median length of procedure was 32 min, (range 3-61). Most common indication was tubeless airway surgery but seven children had more than one indication., Conclusion: Nasal high flow can be used in spontaneously breathing children with abnormal airways for maintenance of oxygenation during anesthesia for tubeless airway procedures., (© 2017 John Wiley & Sons Ltd.)

Importance: Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years., Objective: To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later., Design, Setting, and Participants: A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English- or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome., Interventions: Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed., Main Outcomes and Measures: Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of ≤5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score ≥2 SD above the mean on the Child Behavior Checklist)., Results: Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P = .009)., Conclusions and Relevance: Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age., Trial Registration: clinicaltrials.gov Identifier: NCT00182312; isrctn.org Identifier: ISRCTN44364365.

Objectives: Respiratory symptoms are a possible atypical clinical picture of gastro-esophageal reflux disease (GERD). However, a significant number of patients with GERD-related respiratory symptoms do not report improvement despite aggressive acid-suppressive therapy. Some of these refractory cases may be due to the recently appreciated entity of non-acid or weakly acidic reflux. The aim of our study is to assess the pH-impedance features of GER inducing airway symptoms, compared with GER inducing typical gastro-intestinal (GI) symptoms., Methods: We prospectively enrolled infants and children with GERD-related respiratory symptoms from January 2015 to December 2015. Age- and sex-matched patients with GERD-related GI symptoms were enrolled as comparison group. The overall number, the acidity pattern, and the height of reflux episodes were compared between the two groups., Results: Forty patients (M/F: 20/20; mean age: 58.3 months) were enrolled in the study group and 40 in the comparison group. The mean acid exposure index was 7.9% within the study group and 15.9% within the comparison group (p:0.026). Children with respiratory symptoms versus children with GI symptoms had a mean of 40.8 acid reflux episodes versus 62.4 (p:0.001), a mean of 2.2 weakly acid reflux episodes versus 20.1 (p:0.002), and a mean of 22.1 weakly alkaline reflux episodes versus 10.2 (P < 0.001). Separate analysis of both infants and children was performed., Conclusions: The main finding of this prospective, controlled study is that children >1 year with GERD-related respiratory symptoms showed a significantly higher number of weakly alkaline refluxes than children with GERD-related GI symptoms. This supports the hypothesis that respiratory symptoms are less related to acidity than GI symptoms. Pediatr Pulmonol. 2017;52:669-674. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background.: Mask ventilation and tracheal intubation are basic techniques for airway management and mutually inclusive rescue measures to restore ventilation. The aim of this study was to compare the effectiveness of mask ventilation between two commonly used techniques of two-handed mask ventilation in obese unconscious apnoeic adults., Methods.: Eighty-one obese adults received mask ventilation after induction using C-E clamp and modified V-E clamp techniques in a randomized crossover manner. Mechanical ventilation was provided using a pressure-control mode, at a rate of 10 bpm, with an inspiratory-to-expiratory time ratio of 1:2 and a pre-set plateau airway pressure of 20 cm H 2 O. The primary outcome was expired tidal volume., Results.: The BMI for the subjects was 37 ( sd 4.9) kg m -2 . The failure rates for mask ventilation (tidal volume≤anatomical dead space) were 44% for the C-E technique and 0% for the V-E technique ( P <0.001). Tidal volume was significantly lower for the C-E than the V-E technique [371 ( sd 345) vs 720 (244) ml, P <0.001]. The peak airway pressures were 21 ( sd 1.5) cm H 2 O for the C-E technique and 21 (1.3) cm H 2 O for the V-E technique., Conclusions.: Mask ventilation using the modified V-E technique is more effective than with the C-E technique in unconscious obese apnoeic adults. Subjects who fail ventilation with the C-E technique can be ventilated effectively with the V-E technique., Clinical Trial Registration.: NCT02580526., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: Hemoglobin vesicles (HbV) are hemoglobin-based oxygen carriers manufactured by liposome encapsulation of hemoglobin molecules. We hypothesised that the infusion of oxygenated HbV could prolong the time to circulatory collapse during apnea in rats., Methods: Twenty-four Sprague-Dawley rats were randomly divided into four groups (Air, Oxy, NS and HbV). The rats were anaesthetized with isoflurane and the trachea was intubated using 14-gauge intravenous catheters. Rats in the Air group were mechanically ventilated with 1.5% isoflurane in room air, and those in other groups received 1.5% isoflurane in 100% oxygen. Mechanical ventilation was withdrawn 1 min after the administration of rocuronium bromide to induce apnea. After 30 s, 6 mL saline and HbV boluses were infused at a rate of 0.1 mL/s in the NS and HbV groups, respectively. Circulatory collapse was defined as a pulse pressure < 20 mmHg and the time to reach this point (PP 20 ) was compared between the groups. The results were analysed via a one-way analysis of variance and post-hoc Holm-Sidak test., Results: PP 20 times were 30.4 ± 4.2 s, 67.5 ± 9.7 s, 95 ± 17.3 s and 135 ± 38.2 s for the Air (ventilated in room air with no fluid bolus), Oxy (ventilated with 100% oxygen with no fluid bolus), NS (ventilated with 100% oxygen with a normal saline bolus), and HbV (ventilated in 100% oxygen with an HbV bolus) groups, respectively, and differed significantly between the four groups (P = 0.0001). The PP 20 times in the HbV group were significantly greater than in the Air (P = 0.0001), Oxy (P = 0.007) and NS (P = 0.04) groups., Conclusion: Infusion of oxygenated HbV prolongs the time to circulatory collapse during apnea in rats.

Objective: To assess the incidence and impact of persistent apnea on heart rate (HR), oxygen saturation (SpO 2 ), and brain tissue oxygenation index (TOI) over the first 6 months after term equivalent age in ex-preterm infants., Study Design: Twenty-four preterm infants born between 27 and 36 weeks of gestational age were studied with daytime polysomnography at 2-4 weeks, 2-3 months, and 5-6 months post-term corrected age. Apneas lasting ≥3 seconds were included and maximal percentage changes (nadir) in HR, SpO 2, and tissue oxygenation index (TOI, NIRO-200 Hamamatsu) from baseline were analyzed., Results: A total of 253 apneas were recorded at 2-4 weeks, 203 at 2-3 months, and 148 at 5-6 months. There was no effect of gestational age at birth, sleep state, or sleep position on apnea duration, nadir HR, SpO 2 , or TOI. At 2-4 weeks, the nadirs in HR (-11.1 ± 1.2 bpm) and TOI (-4.4 ± 1.0%) were significantly less than at 2-3 months (HR: -13.5 ± 1.2 bpm, P < .05; TOI: -7.5 ± 1.1 %, P < .05) and at 5-6 months (HR: -13.2 ± 1.3 bpm, P < .01; TOI: -9.3 ± 1.2%, P < .01)., Conclusions: In ex-preterm infants, apneas were frequent and associated with decreases in heart rate and cerebral oxygenation, which were more marked at 2-3 months and 5-6 months than at 2-4 weeks. Although events were short, they may contribute to the adverse neurocognitive outcomes that are common in ex-preterm children., (Copyright © 2016. Published by Elsevier Inc.)