The effect of high-flow nasal oxygen flow rate on gas exchange in apnoeic patients: a randomised controlled trial.

High-flow nasal oxygen can be administered at induction of anaesthesia for the purposes of pre-oxygenation and apnoeic oxygenation. This intervention is claimed to enhance carbon dioxide elimination during apnoea, but the extent to which this occurs remains poorly quantified. The optimal nasal oxygen flow rate for gas exchange is also unknown. In this study, 114 patients received pre-oxygenation with high-flow nasal oxygen at 50 l.min-1. At the onset of apnoea, patients were allocated randomly to receive one of three nasal oxygen flow rates: 0 l.min-1; 70 l.min-1; or 120 l.min-1. After 4 minutes of apnoea, all oxygen delivery was ceased, tracheal intubation was performed, and oxygen delivery was recommenced when SpO2 was 92%. Mean (SD) PaCO2 rise during the first minute of apnoea was 1.39 (0.39) kPa, 1.41 (0.29) kPa, and 1.26 (0.38) kPa in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, respectively; p = 0.16. During the second, third and fourth minutes of apnoea, mean (SD) rates of rise in PaCO2 were 0.34 (0.08) kPa.min-1, 0.36 (0.06) kPa.min-1 and 0.37 (0.07) kPa.min-1 in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, respectively; p = 0.17. After 4 minutes of apnoea, median (IQR [range]) arterial oxygen partial pressures in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups were 24.5 (18.6-31.4 [12.3-48.3]) kPa; 36.6 (28.1-43.8 [9.8-56.9]) kPa; and 37.6 (26.5-45.4 [11.0-56.6]) kPa, respectively; p < 0.001. Median (IQR [range]) times to desaturate to 92% after the onset of apnoea in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, were 412 (347-509 [190-796]) s; 533 (467-641 [192-958]) s; and 531 (462-681 [326-1007]) s, respectively; p < 0.001. In conclusion, the rate of carbon dioxide accumulation in arterial blood did not differ significantly between apnoeic patients who received high-flow nasal oxygen and those who did not.

The use of apnea test and brain death determination in patients on extracorporeal membrane oxygenation: A systematic review.

OBJECTIVE: To review practices of brain death (BD) determination in patients on extracorporeal membrane oxygenation (ECMO). METHODS: A systematic search was applied to PubMed and 6 electronic databases from inception to May 22, 2019. Studies reporting methods of BD assessment in adult patients (>18 years old) while on ECMO were included, after which data regarding BD assessment were extracted. RESULTS: Twenty-two studies (n = 177 patients) met the inclusion criteria. Eighty-eight patients (50%) in 19 studies underwent the apnea test (AT); most commonly through decreasing the ECMO sweep flow in 14 studies (n = 42, 48%), followed by providing CO2 through the ventilator in 2 studies (n = 6, 7%), and providing CO2 through the ECMO oxygenator in 1 study (n = 1, 1%). The details of the AT were not reported in 2 studies (n = 39, 44%). In 19 patients (22%), the AT was nonconfirmatory due to hemodynamic instability, hypoxia, insufficient CO2 rise, or unreliability of the AT. A total of 157 ancillary tests were performed, including electroencephalogram (62%), computed tomography angiography (22%), transcranial Doppler ultrasound (6%), cerebral blood flow nuclear study (5%), cerebral angiography (4%), and other (1%). Forty-seven patients (53% of patients with AT) with confirmatory AT still underwent additional ancillary for BD confirmation. Only 21 patients (12% of all patients) were declared brain-dead using confirmatory ATs alone without ancillary testing. CONCLUSIONS: Performing AT for patients with ECMO was associated with high failure rate and hemodynamic complications. Our study highlights the variability in practice in regard to the AT and supports the use of ancillary tests to determine BD in patients on ECMO.

The effects of high altitude ascent on splenic contraction and the diving response during voluntary apnoea.

NEW FINDINGS: What is the central question of this study? What is the relative contribution of a putative tonic splenic contraction to the haematological acclimatization process during high altitude ascent in native lowlanders? What is the main finding and its importance? Spleen volume decreased by -14.3% (-15.2 ml) per 1000 m ascent, with an attenuated apnoea-induced [Hb] increase, attesting to a tonic splenic contraction during high altitude ascent. The [Hb]-enhancing function of splenic contraction may contribute to restoring oxygen content early in the acclimatization process at high altitude. ABSTRACT: Voluntary apnoea causes splenic contraction and reductions in heart rate (HR; bradycardia), and subsequent transient increases in haemoglobin concentration ([Hb]). Ascent to high altitude (HA) induces systemic hypoxia and reductions in oxygen saturation ( SpO2 ), which may cause tonic splenic contraction, which may contribute to haematological acclimatization associated with HA ascent. We measured resting cardiorespiratory variables (HR, SpO2 , [Hb]) and resting splenic volume (via ultrasound) during incremental ascent from 1400 m (day 0) to 3440 m (day 3), 4240 m (day 7) and 5160 m (day 10) in non-acclimatized native lowlanders during assent to HA in the Nepal Himalaya. In addition, apnoea-induced responses in HR, SpO2 and splenic volume were measured before and after two separate voluntary maximal apnoeas (A1-A2) at 1400, 3440 and 4240 m. Resting spleen volume decreased -14.3% (-15.2 ml) per 1000 m with ascent, from 140 ± 41 ml (1400 m) to 108 ± 28 ml (3440 m; P > 0.99), 94 ± 22 ml (4240 m; P = 0.009) and 84 ± 28 ml (5160 m; P = 0.029), with concomitant increases in [Hb] from 125 ± 18.3 g l-1 (1400 m) to 128 ± 10.4 g l-1 (3440 m), 138.8 ± 12.7 g l-1 (4240 m) and 157.5 ± 8 g l-1 (5160 m; P = 0.021). Apnoea-induced splenic contraction was 50 ± 15 ml (1400 m), 44 ± 17 ml (3440 m; P > 0.99) and 26 ± 8 ml (4240 m; P = 0.002), but was not consistently associated with increases in [Hb]. The apnoea-induced bradycardia was more pronounced at 3440 m (A1: P = 0.04; A2: P = 0.094) and at 4240 m (A1: P = 0.037 A2: P = 0.006) compared to values at 1400 m. We conclude that hypoxia-induced splenic contraction at rest (a) may contribute to restoring arterial oxygen content through its [Hb]-enhancing contractile function and (b) eliminates further apnoea-induced [Hb] increases in hypoxia. We suggest that tonic splenic contraction may contribute to haematological acclimatization early in HA ascent in humans.

Monitorización cardio respiratoria domiciliaria en lactantes / Home respiratory cardio monitoring in infants

Home cardio-respiratory monitoring began over 40 years ago with the aim of preventing sudden infant death. Although it has been shown that monitoring does not meet this objective, its prescription has been maintained in various clinical situations and with very different criteria. Consensus on the subject has not been able to define precisely the type of monitoring or the time required for different diseases. Among the diseases that still consider the indication of cardio-respiratory monitoring at home are: persistent apnea of prematurity, high-risk BRUE (Brief Resolved Unexplained Events), neurological or metabolic diseases with compromise of the respiratory center, convulsive cough, pathologic gastroesophageal reflux and technology-dependent patients (high flow nasal cannula (CNAF), noninvasive ventilation (NIV), invasive mechanical ventilation (IMV) to tracheostomy, and others). A review is presented on the development of cardio-respiratory monitoring at home, highlighting the true usefulness of this technology with a general proposal, which must be evaluated on a case-by-case basis and always taking into account the conditions that must be met to perform adequate monitoring and useful.

La monitorización cardio-respiratoria en domicilio se inició hace más de 40 años con el objetivo de prevenir la muerte súbita del lactante. Aun cuando se ha demostrado que la monitorización no cumple este objetivo, se ha mantenido su prescripción en diversas situaciones clínicas y con criterios muy diversos. Consensos acerca del tema no han llegado a definir con precisión el tipo de monitorización ni el tiempo requerido para distintas enfermedades. Dentro de las enfermedades que todavía consideran la indicación de monitorización cardio-respiratoria en domicilio se encuentran: apnea persistente del prematuro, BRUE (episodio breve resuelto inexplicado) de alto riesgo, enfermedades neurológicas o metabólicas con compromiso del centro respiratorio, tos convulsiva, reflujo gastroesofágico patológico y pacientes dependientes de tecnología (cánula nasal de alto flujo (CNAF), ventilación no invasiva (VNI), ventilación mecánica invasiva (VMI) a traqueostomía, y otros). Se presenta una revisión sobre el desarrollo de la monitorización cardio-respiratoria en domicilio, resaltando la verdadera utilidad que tendría esta tecnología con una propuesta general, que debe evaluarse caso a caso y siempre teniendo en cuenta las condiciones que deben cumplirse para realizar una monitorización adecuada y útil.

High-Flow Nasal Cannula and Mandibular Advancement Bite Block Decrease Hypoxic Events during Sedative Esophagogastroduodenoscopy: A Randomized Clinical Trial.

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% (AUCDesat). 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.

Clinical characteristics and phenotype-genotype review of 25 Omani children with congenital hyperinsulinism in infancy. A one-decade single-center experience.

OBJECTIVES: To report the genotype-phenotype characteristics, demographic features and clinical outcome of Omani patients with congenital hyperinsulinism (CHI). Methods: We retrospectively analyzed the clinical, biochemical, genotypical, phenotypical characteristics and outcomes of  children with CHI who were presented to the pediatric endocrine team in the Royal Hospital, Muscat, Oman between January 2007 and December 2016. Results: Analysis of 25 patients with CHI genetically revealed homozygous mutation in ABCC8 in 23 (92%) patients and 2 patients (8%) with compound heterozygous mutation in ABCC8. Fifteen (60%) patients underwent subtotal pancreatectomy as medical therapy failed and 2 (8%) patients showed response to medical therapy. Three patients expired during the neonatal period, 2 had cardiomyopathy and sepsis, and one had sepsis and severe metabolic acidosis. Out of the 15 patients who underwent pancreatectomy, 6 developed diabetes mellitus, 6 continued to have hypoglycemia and required medical therapy and one had pancreatic exocrine dysfunction post-pancreatectomy, following up with gastroenterology clinic and was placed on pancreatic enzyme supplements, while 2 patients continued to have hypoglycemia and both had abdominal MRI and 18-F-fluoro-L-DOPA positron emission tomography scan (PET-scan), that showed  persistent of the disease and started on medical therapy. Conclusion:  Mutation in ABCC8 is the most common cause of CHI and reflects the early age of presentation. There is a need for early diagnosis and appropriate therapeutic strategy.

Prolongation of bronchopulmonary C-fiber-mediated apnea by prenatal nicotinic exposure in rat pups: role of 5-HT3 receptors.

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-HT3R) in PCFs, and among the 5-HT3R subunits, 5-HT3B is responsible for shortening the decay time of 5-HT3R-mediated currents. We examined whether PNE would promote pulmonary 5-HT secretion and prolong the apnea mediated by 5-HT3Rs in PCFs via affecting the 5-HT3B 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-HT3R agonist) before and after PCF inactivation, 3) 5-HT3R currents and the stimulus threshold of the action currents of vagal pulmonary C-neurons, and 4) the immunoreactivity (IR) and mRNA expression of 5-HT3A and 5-HT3B in these neurons. Our results showed that PNE up-regulated the pulmonary 5-HT concentration and strengthened the PCF 5-HT3R-mediated apnea. PNE significantly facilitated neural excitability by shortening the decay time of 5-HT3R currents, lowering the stimulus threshold, and increasing 5-HT3B IR. In summary, PNE prolongs the apnea mediated by 5-HT3Rs in PCFs, likely by increasing 5-HT3B subunits to enhance the excitability of 5-HT3 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-HT3 receptors.

Removal of a minimal amount of subdural hematoma is effective and sufficient for term neonates with severe symptomatic spontaneous parenchymal hemorrhage.

INTRODUCTION: Spontaneous parenchymal hemorrhage of term neonates is usually asymptomatic and does not require surgical intervention. However, there is no consensus on the management of cases with severe life-threatening symptoms, including repeated apnea, respiratory failure with severe cyanosis, severe bradycardia, or uncontrolled seizures. CASES: Our medical records of term neonates with intracranial hemorrhage who underwent surgical intervention were retrospectively reviewed. There were two cases with spontaneous parenchymal hemorrhage. Both cases were delivered vaginally without any use of forceps or vacuum devices. Neither of them showed asphyxia, hypoxic-ischemic encephalopathy, hematological abnormalities, congenital vascular anomalies, infection, or birth trauma. Common symptoms included apnea, cyanosis, bradycardia, and decreased consciousness. The original location of bleeding was the parenchyma of the right temporal lobe. The hemorrhage extended to subdural spaces in both cases. Subdural hematoma (SDH) removal was performed without manipulating the parenchymal hematoma. Only a small amount of SDH (approximately 5 ml) was drained spontaneously with irrigation, which was sufficient to decrease the elevated intracranial pressure. The patients' respiratory conditions improved dramatically after the surgery. CONCLUSION: We propose that removing only a small amount of SDH would be effective and sufficient to relieve severe symptoms of increased intracranial pressure in term neonates with massive spontaneous parenchymal hemorrhage.

Unexpected dislocation following accurate total hip arthroplasty caused by excessive hip joint laxity during myasthenic crisis: a case report.

BACKGROUND: Dislocation following total hip arthroplasty is mainly caused by malposition. However, the coexistence of neuromuscular disorders is also considered a risk for dislocation due to excessive hip joint laxity. To minimize risk of dislocation, preoperative planning using combined anteversion has been widely used. The recommended combined anteversion angle (the total of cup and stem anteversion angles) is 50 ± 10°. CASE PRESENTATION: A 33-year-old Japanese woman underwent elective total hip arthroplasty due to osteonecrosis of the femoral head associated with corticosteroid pulse therapy for myasthenia gravis. Intraoperatively, no tendency of dislocation was found when simulating an evoking position under general anesthesia. In postoperative X-ray and computed tomography scans, cup inclination, cup anteversion, and stem anteversion angles were 37°, 13°, and 35° respectively. The resulting combined anteversion was 48°, which was set as the target along with accurate placement. Her postoperative course was normal and she was discharged without adverse events. Three months postoperatively, due to worsening of myasthenic weakness in her lower extremities while resting, she tended to raise her left limb up using both hands for sitting up. An anterior dislocation occurred when her legs were in a figure-of-four position. She was brought to an emergency department, and reduction of dislocation was performed. It was inferred that myasthenic crisis in the affected limb enabled excessive passive motion due to joint hyperlaxity. At the end of 2016, elective total hip arthroplasty on the contralateral side was performed. Cup anteversion, stem anteversion, and the combined anteversion angles were 27°, 24°, and 51° respectively. We instructed her to exercise care during passive leg movement, which may worsen her myasthenic condition. She returned to a normal life and was able to walk long distances without a cane. No recurrence of dislocation was seen at final follow-up. CONCLUSIONS: Even if accurate component orientation is attained in total hip arthroplasty, patients with neuromuscular disorders such as myasthenia gravis have a potential risk of muscle weakness in the affected limb. Therefore, physicians' instructions and patients' careful attention are required to prevent dislocation due to excessive hip joint laxity under conditions of motor weakness.

Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) vs. facemask breathing pre-oxygenation for rapid sequence induction in adults: a prospective randomised non-blinded clinical trial.

Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) can prolong apnoea time in adults. Therefore, THRIVE used for pre-oxygenation in rapid sequence induction of anaesthesia could extend safe apnoea time during prolonged laryngoscopy and intubation. In this randomised controlled trial, we compared the lowest peripheral oxygen saturation (SpO2 ) during intubation when pre-oxygenating with either traditional facemask or THRIVE. Eighty adult patients, undergoing rapid sequence induction of anaesthesia for emergency surgery, were randomly allocated to pre-oxygenation with 100% oxygen with facemask or with THRIVE. Median (IQR [range]) lowest SpO2 until 1 min after intubation was 99% (97-100 [70-100]%) for the facemask group vs. 99% (99-100 [96-100]%) for the THRIVE group (p = 0.097). Five patients (12.5%) desaturated below 93% when pre-oxygenated with the facemask vs. none in the THRIVE group (p = 0.019). There were no differences in intubation time or apnoea time between the groups. Median intubation time was 51 (34-66 [22-261]) s in the facemask group vs. 48 (38-63 [10-146]) s in the THRIVE group (p = 0.99). Median apnoea time was 109 (86-142 [37-291]) s and 116 (92-146 [63-249]) s when using facemask and THRIVE, respectively (p = 0.49). No signs of regurgitation of gastric content were detected. The data on desaturation indicate potential benefits of oxygenation with THRIVE for rapid sequence induction compared with facemask pre-oxygenation.

KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure.

KEY POINTS: Enhanced carotid body chemoreflex activity contributes to development of disordered breathing patterns, autonomic dysregulation and increases in incidence of arrhythmia in animal models of reduced ejection fraction heart failure. Chronic reductions in carotid artery blood flow are associated with increased carotid body chemoreceptor activity. Krüppel-like Factor 2 (KLF2) is a shear stress-sensitive transcription factor that regulates the expression of enzymes which have previously been shown to play a role in increased chemoreflex sensitivity. We investigated the impact of restoring carotid body KLF2 expression on chemoreflex control of ventilation, sympathetic nerve activity, cardiac sympatho-vagal balance and arrhythmia incidence in an animal model of heart failure. The results indicate that restoring carotid body KLF2 in chronic heart failure reduces sympathetic nerve activity and arrhythmia incidence, and improves cardiac sympatho-vagal balance and breathing stability. Therapeutic approaches that increase KLF2 in the carotid bodies may be efficacious in the treatment of respiratory and autonomic dysfunction in heart failure. ABSTRACT: Oscillatory breathing and increased sympathetic nerve activity (SNA) are associated with increased arrhythmia incidence and contribute to mortality in chronic heart failure (CHF). Increased carotid body chemoreflex (CBC) sensitivity plays a role in this process and can be precipitated by chronic blood flow reduction. We hypothesized that downregulation of a shear stress-sensitive transcription factor, Krüppel-like Factor 2 (KLF2), mediates increased CBC sensitivity in CHF and contributes to associated autonomic, respiratory and cardiac sequelae. Ventilation (Ve), renal SNA (RSNA) and ECG were measured at rest and during CBC activation in sham and CHF rabbits. Oscillatory breathing was quantified as the apnoea-hypopnoea index (AHI) and respiratory rate variability index (RRVI). AHI (control 6 ± 1/h, CHF 25 ± 1/h), RRVI (control 9 ± 3/h, CHF 29 ± 3/h), RSNA (control 22 ± 2% max, CHF 43 ± 5% max) and arrhythmia incidence (control 50 ± 10/h, CHF 300 ± 100/h) were increased in CHF at rest ( FIO2 21%), as were CBC responses (Ve, RSNA) to 10% FIO2 (all P < 0.05 vs. control). In vivo adenoviral transfection of KLF2 to the carotid bodies in CHF rabbits restored KLF2 expression, and reduced AHI (7 ± 2/h), RSNA (18 ± 2% max) and arrhythmia incidence (46 ± 13/h) as well as CBC responses to hypoxia (all P < 0.05 vs. CHF empty virus). Conversely, lentiviral KLF2 siRNA in the carotid body decreased KLF2 expression, increased chemoreflex sensitivity, and increased AHI (6 ± 2/h vs. 14 ± 3/h), RRVI (5 ± 3/h vs. 20 ± 3/h) and RSNA (24 ± 4% max vs. 34 ± 5% max) relative to scrambled-siRNA rabbits. In conclusion, down-regulation of KLF2 in the carotid body increases CBC sensitivity, oscillatory breathing, RSNA and arrhythmia incidence during CHF.

Congenital myasthenic syndrome with episodic apnoea: clinical, neurophysiological and genetic features in the long-term follow-up of 19 patients.

BACKGROUND: Congenital myasthenic syndrome with episodic apnoea (CMS-EA) is a rare but potentially treatable cause of apparent life-threatening events in infancy. The underlying mechanisms for sudden and recurrent episodes of respiratory arrest in these patients are unclear. Whilst CMS-EA is most commonly caused by mutations in CHAT, the list of associated genotypes is expanding. METHODS: We reviewed clinical information from 19 patients with CMS-EA, including patients with mutations in CHAT, SLC5A7 and RAPSN, and patients lacking a genetic diagnosis. RESULTS: Lack of genetic diagnosis was more common in CMS-EA than in CMS without EA (56% n = 18, compared to 7% n = 97). Most patients manifested intermittent apnoea in the first 4 months of life (74%, n = 14). A degree of clinical improvement with medication was observed in most patients (74%, n = 14), but the majority of cases also showed a tendency towards complete remission of apnoeic events with age (mean age of resolution 2 years 5 months). Signs of impaired neuromuscular transmission were detected on neurophysiology studies in 79% (n = 15) of cases, but in six cases, this was only apparent following specific neurophysiological testing protocols (prolonged high-frequency stimulation). CONCLUSIONS: A relatively large proportion of CMS-EA remains genetically undiagnosed, which suggests the existence of novel causative CMS genes which remain uncharacterised. In light of the potential for recurrent life-threatening apnoeas in early life and the positive response to therapy, early diagnostic consideration of CMS-EA is critical, but without specific neurophysiology tests, it may go overlooked.

Neonatal maternal separation opposes the facilitatory effect of castration on the respiratory response to hypercapnia of the adult male rat: Evidence for the involvement of the medial amygdala.

Respiratory manifestations of panic disorder (PD) include a greater respiratory instability and enhanced responsiveness to CO2 compared to normal individuals. Although the prevalence of PD is approximately three times greater in women compared to men, the origins of this sexual dimorphism remain poorly understood. Similar to PD patients, adult female rats previously subjected to neonatal maternal separation (NMS) show an increase in their ventilatory response to CO2 . Because this effect of NMS is not observed in males, we hypothesised that testosterone prevents NMS-induced hyper-responsiveness to CO2 . Pups subjected to NMS were placed in an incubator for 3 h d-1 from postnatal days 3-12. Control pups remained undisturbed. At adulthood (8-10 weeks of age), rats were then subjected either to sham surgery or castration. Fourteen days later, breathing was measured at rest (room air) and during acute exposure to hypercapnia (5 and 10% CO2 for 10 minutes each) using plethysmography. To gain insight into the mechanisms involved, c-fos expression was used as an indicator of neuronal activation. Brains were collected following air or CO2 exposure for quantification of c-fos positive cells by immunohistochemistry in selected regions, including the paraventricular nucleus of the hypothalamus, the dorsomedial hypothalamus and the amygdalar complex. Castration produced a 100% increase of hyperventilatory response to 10% CO2 in control rats. Unexpectedly, castration had no effect on the hyperventilatory response of NMS rats. The intensity of the hypercapnic response was inversely correlated with c-fos expression in the medial amygdala. We conclude that testosterone prevents the hyper-responsiveness to CO2 , whereas NMS attenuates sensitivity to hormone withdrawal. We propose that an inhibitory influence from the medial amygdala contributes to this effect.

Apnoeic oxygenation with high-flow nasal oxygen for laryngeal surgery: a case series.

Surgery under apnoeic conditions with the use of high-flow nasal oxygen is novel. Between November 2016 and May 2017, 28 patients underwent tubeless laryngeal or tracheal surgery under apnoeic conditions with high-flow nasal oxygen as the sole method of gas exchange. Patients received total intravenous anaesthesia and neuromuscular blocking agents for the duration of their surgery. The median (IQR [range]) apnoea time was 19 (15-24 [9-37]) min. Four patients experienced an episode of oxygen desaturation to a value between 85% and 90%, lasting less than 2 min in each case. Median (IQR [range]) end-tidal carbon dioxide (ETCO2 ) level following apnoea was 8.2 (7.2-9.4 [5.8-11.8]) kPa. The mean (SD) rate of ETCO2 increase was 0.17 (0.07) kPa.min-1 from an approximated baseline value of 5.00 kPa. Venous blood sampling from 19 patients demonstrated a mean (SD) partial pressure of carbon dioxide (PV CO2 ) of 6.29 (0.71) kPa at baseline and 9.44 (1.12) kPa after 15 min of apnoea. This equates to a mean (SD) PV CO2 rise of 0.21 (0.08) kPa.min-1 during this period. Mean (SD) pH was 7.40 (0.03) at baseline and 7.23 (0.04) after 15 min of apnoea. Mean (SD) standard bicarbonate was 26.7 (1.8) mmol.l-1 at baseline and 25.4 (1.8) mmol.l-1 at 15 min. We conclude that high-flow nasal oxygen under apnoeic conditions can provide satisfactory gas exchange in order to allow tubeless anaesthesia for laryngeal surgery.

Intermittent apnea elicits inactivity-induced phrenic motor facilitation via a retinoic acid- and protein synthesis-dependent pathway.

Respiratory motoneuron pools must provide rhythmic inspiratory drive that is robust and reliable, yet dynamic enough to respond to respiratory challenges. One form of plasticity that is hypothesized to contribute to motor output stability by sensing and responding to inadequate respiratory neural activity is inactivity-induced phrenic motor facilitation (iPMF), an increase in inspiratory output triggered by a reduction in phrenic synaptic inputs. Evidence suggests that mechanisms giving rise to iPMF differ depending on the pattern of reduced respiratory neural activity (i.e., neural apnea). A prolonged neural apnea elicits iPMF via a spinal TNF-α-induced increase in atypical PKC activity, but little is known regarding mechanisms that elicit iPMF following intermittent neural apnea. We tested the hypothesis that iPMF triggered by intermittent neural apnea requires retinoic acid and protein synthesis. Phrenic nerve activity was recorded in urethane-anesthetized and -ventilated rats treated intrathecally with an inhibitor of retinoic acid synthesis (4-diethlyaminobenzaldehyde, DEAB), a protein synthesis inhibitor (emetine), or vehicle (artificial cerebrospinal fluid) before intermittent (5 episodes, ~1.25 min each) or prolonged (30 min) neural apnea. Both DEAB and emetine abolished iPMF elicited by intermittent neural apnea but had no effect on iPMF elicited by a prolonged neural apnea. Thus different patterns of reduced respiratory neural activity elicit phenotypically similar iPMF via distinct spinal mechanisms. Understanding mechanisms that allow respiratory motoneurons to dynamically tune their output may have important implications in the context of respiratory control disorders that involve varied patterns of reduced respiratory neural activity, such as central sleep apnea and spinal cord injury.NEW & NOTEWORTHY We identify spinal retinoic acid and protein synthesis as critical components in the cellular cascade whereby repetitive reductions in respiratory neural activity elicit rebound increases in phrenic inspiratory activity.

High levels of IGF-1 predict difficult intubation of patients with acromegaly.

PURPOSE: To investigate the characteristics of difficult intubation and identify novel efficient predictors in patients with acromegaly. METHODS: Patients with either untreated acromegaly or non-functional pituitary adenomas were enrolled. Patients with acromegaly underwent hormone assays, upper airway computed tomography and magnetic resonance imaging examinations and preoperative overnight polysomnography. The modified Mallampati classification, mouth opening, neck circumference, and neck extension were assessed, and the Cormack-Lehane grades and the time of tracheal intubation were recorded. RESULTS: Patients with acromegaly had a higher incidence of difficult intubation (62.5%). The time of tracheal intubation was prolonged, the neck circumference was enlarged, and the neck extension was confined. In patients with acromegaly and difficult intubation, the insulin-like growth factor 1 levels and apnea/hypoxia index were significantly higher compared to patients without difficult intubation (1115.40 ± 253.73 vs. 791.67 ± 206.62 ng/ml, P = 0.020; 22.17 ± 23.25 vs. 2.47 ± 2.84, P = 0.026, respectively). The bilateral regression analysis revealed that high levels of insulin-like growth factor 1 were an independent risk factor for developing difficult intubation (p = 0.042, Exp B = 1.006). The modified Mallampati classification was positively correlated with apnea/hypoxia index and could be calculated using the following logarithmic equation: MMC = 0.2982 * ln (AHI) + 2.1836. CONCLUSIONS: In patients with acromegaly, neck movement is confined, the time of tracheal intubation is prolonged, and the neck circumference is enlarged, and these patients suffer from an increased incidence of difficult intubation (62.5%) during anesthesia induction. The apnea/hypoxia index and insulin-like growth factor 1 levels are both increased in acromegalic patients with difficult intubation, and elevated insulin-like growth factor 1 levels are an independent risk factor of difficult intubation in acromegalic patients.

Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis.

BACKGROUND: Ghrelin is the only orexigenic hormone known to stimulate food intake and promote obesity and insulin resistance. We recently showed that plasma ghrelin is controlled by butyrylcholinesterase (BChE), which has a strong impact on feeding and weight gain. BChE knockout (KO) mice are prone to obesity on high-fat diet, but hepatic BChE gene transfer rescues normal food intake and obesity resistance. However, these mice lack brain BChE and still develop hyperinsulinemia and insulin resistance, suggesting essential interactions between BChE and ghrelin within the brain. METHODS: To test the hypothesis we used four experimental groups: (1) untreated wild-type mice, (2) BChE KO mice with LUC delivered by adeno-associated virus (AAV) in combined intravenous (i.v.) and intracerebral (i.c.) injections, (3) KO mice given AAV for mouse BChE (i.v. only) and (4) KO mice given the same vector both i.v. and i.c. All mice ate a 45% calorie high-fat diet from the age of 1 month. Body weight, body composition, daily caloric intake and serum parameters were monitored throughout, and glucose tolerance and insulin tolerance tests were performed at intervals. RESULTS: Circulating ghrelin levels dropped substantially in the KO mice after i.v. AAV-BChE delivery, which led to normal food intake and healthy body weight. BChE KO mice that received AAV-BChE through i.v. and i.c. combined treatments not only resisted weight gain on high-fat diet but also retained normal glucose and insulin tolerance. CONCLUSIONS: These data indicate a central role for BChE in regulating both insulin and glucose homeostasis. BChE gene transfer could be a useful therapy for complications linked to diet-induced obesity and insulin resistance.

Modelling of subarachnoid space width changes in apnoea resulting as a function of blood flow parameters.

During apnoea, the pial artery is subjected to two opposite physiological processes: vasoconstriction due to elevated blood pressure and vasorelaxation driven by rising pH in the brain parenchyma. We hypothesized that the pial artery response to apnoea may vary, depending on which process dominate. Apnoea experiments were performed in a group of 19 healthy, non-smoking volunteers (9 men and 10 women). The following parameters were obtained for further analysis: blood pressure, the cardiac (from 0.5 to 5.0Hz) and slow (<0.5Hz) components of subarachnoid space width, heart rate, mean cerebral blood flow velocity in the internal carotid artery, pulsatility and resistivity index, internal carotid artery diameter, blood oxygen saturation and end-tidal carbon dioxide. The experiment consisted of three apnoeas, sequentially: 30s, 60s and maximal apnoea. The breath-hold was separated for 5minute rest. The control process is sophisticated, involving internal cross-couplings and cross-dependences. The aim of work was to find a mathematical dependence between data. Unexpectedly, the modelling revealed two different reactions, on the same experimental procedure. As a consequence, there are two subsets of cardiac subarachnoid space width responses to breath-hold in humans. A positive cardiac subarachnoid space width change to apnoea depends on changes in heart rate and cerebral blood flow velocity. A negative cardiac subarachnoid space width change to apnoea is driven by heart rate, mean arterial pressure and pulsatility index changes. The described above two different reactions to experimental breath-hold provides new insights into our understanding of the complex mechanisms governing the adaptation to apnoea in humans. We proposed a mathematical methodology that can be used in further clinical research.

Respiratory responses to progesterone and allopregnanolone following chronic caffeine treatment in newborn female rats.

We recently showed that in 12-day-old male rats exposed to caffeine for 10 consecutive days, progesterone inhibits the respiratory response to hypoxia and increases apnea frequency (Uppari et al., 2016). This was partly due to a higher inhibitory response of GABAa receptor to allopregnanolone, the neuroactive metabolite of progesterone. In the present study, we addressed whether similar effects occur in females. We used newborn female rats daily gavaged with water (control) or caffeine (15mg/kg) between the postnatal (P) days 3-12. At P12, we recorded ventilation, metabolic rate, and apnea frequency and duration in normoxia and in response to moderate hypoxia, following an intraperitonial injection of progesterone (4mg/kg) or allopregnanolone (10mg/kg). In control rats, progesterone had no effect on breathing in normoxia and in hypoxia, and in rats treated with caffeine it decreased the initial increase in respiratory frequency in hypoxia. In both groups, allopregnalone decreased breathing frequency in normoxia and in hypoxia and increased the frequency of apnea in normoxia in control rats and in rats treated with caffeine. Injection of bicuculline (a specific GABAa receptor antagonist) prevented the inhibitory effects of allopregnanolone on breathing in both groups. These data indicate that chronic caffeine treatment unmasked an inhibitory effect of progesterone on the hypoxic response but this was weaker than in males, and contrasting to what was observed in male rats (Uppari et al., 2016), GABAa receptors are not significantly affected by chronic caffeine treatment in newborn female rats.

Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) in children: a randomized controlled trial.

BACKGROUND: Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) was introduced to adult anaesthesia to improve the safety of airway management during apnoea before intubation. The objective of our study was to determine whether THRIVE safely prolongs apnoeic oxygenation in children. METHODS: This was a randomized controlled trial in 48 healthy children, with normal airways and cardiorespiratory function, in age groups 0-6 and 7-24 months, 2-5 and 6-10 yr old, presenting for elective surgery or imaging under general anaesthesia. All children were induced with sevoflurane, O2, and N2O, followed by muscle relaxation with rocuronium, and standardized preoxygenation with bag-and-mask ventilation. The control arm received jaw support during apnoea, whereas the THRIVE arm received jaw support during apnoea and age-specific flow rates. The primary outcome was to demonstrate that children allocated to THRIVE maintain transcutaneous haemoglobin saturation at least twice as long as the expected age-dependent apnoea time in the control group. RESULTS: Both study arms (each n=24) were similar in age and weight. The apnoea time was significantly shorter in the control arm: average 109.2 (95% CI 28.8) s in the control arm and 192 s in the THRIVE arm (0-6 months), 147.3 (95% CI 18.9) and 237 s (7-24 months), 190.5 (95% CI 15.3) and 320 s (2-5 yr), and 260.8 (95% CI 37.5) and 430 s (6-10 yr), respectively. Average transcutaneous haemoglobin saturation remained at 99.6% (95% CI 0.2) during THRIVE. Transcutaneous CO2 increased to a similar extent in both arms, with 2.4 (95% CI 0.5) mm Hg min-1 for the control arm and 2.4 (95% CI 0.4) mm Hg min-1 for the THRIVE arm. CONCLUSION: Transnasal humidified rapid-insufflation ventilatory exchange prolongs the safe apnoea time in healthy children but has no effect to improve CO2 clearance. CLINICAL TRIAL REGISTRATION: ACTRN12615001319561.