Airway Muscle Activity Research Articles

Effects of high dose Fentanyl in combination with hypoxia or ketamine in adult female goats

The worsening opioid epidemic in the United States continues to claim >80,000 lives each year. Synthetic opioids such as fentanyl are highly useful in the clinical management of pain but at high doses are thought to cause death through opioid-induced respiratory depression (OIRD), impairment of the alveolar to arterial oxygen (A-a O2) gradient and though upper airway and respiratory pump muscles activation causing airway dysfunction and/or Wooden Chest Syndrome (WCS). These negative effects of high dose opioids may be exacerbated when individuals use additional drugs such as ketamine or by an existing hypoxia. We have shown previously that low (sub-lethal) doses of fentanyl (25-125 μg/kg; IV) cause transient apnea (<30 sec), a brief suppression of breathing frequency (FB; <5 min), increased tidal volume (VT), upper airway and pump muscle activity, and an increased A-a O2 gradient with an overall stimulatory effect on ventilation for up to 90 min post-injection (PMID: 37885800). Here we tested the hypothesis that the physiological effects of high doses of fentanyl will be exacerbated when combined with pre-treatment of either mild hypoxia (FIO2=0.12) or IV ketamine (10 mg/kg). Adult female goats (n=3) were surgically instrumented with electromyographic (EMG) wires in airway (genioglossus and thyropharyngeal) and respiratory pump (diaphragm, transverse abdominus and intercostal) muscles and the carotid arteries relocated subcutaneously and allowed 2 weeks for recovery. Arterial blood samples were obtained through a carotid catheter and all injections were via a catheter in the jugular. Following a 30-minute control period, goats were given IV saline (vehicle) or fentanyl (50–500 μg/kg). In most goats, fentanyl doses of 200-250 μg/kg cause immediate apnea up to 60 sec in duration and decreased FB (~40%) and PaO2 (~35 mmHg) while increasing PaCO2 (~70mmHg) along with an EMG activation and increased A-a O2 gradient. These effects tended to be less severe at a given dose when injections were performed during mild hypoxia (15 min; n=2) but were exacerbated by pretreatment with ketamine (n=1). These data suggest high doses of fentanyl in goats cause similar life-threatening features as in humans, and that these effects seem to be mitigated by hypoxic ventilatory stimulation but exacerbated by polypharmacy with ketamine. NIH DA050571. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Adaptive responses to chronic intermittent hypoxia: contributions from the European Sleep Apnoea Database (ESADA) Cohort.

Obstructive sleep apnoea (OSA) is a common disease in the general population, and is associated with increased cardiovascular risk and several comorbidities. Obesity favours upper airway collapsibility, but other pathophysiological traits have been identified, i.e. upper airway muscle activity, modulation of the respiratory drive, and the arousal threshold. OSA causes chronic intermittent hypoxia, inflammatory activation and autonomic imbalance with diurnal and nocturnal sympathetic hyperactivity. Disentangling so many components to investigate the pathogenesis of OSA's consequences is very hard clinically. However, albeit imperfect, clinical medicine constitutes a major source of inspiration for basic research, and a mutual exchange of information is essential between clinicians and physiologists to improve our understanding of disease states. OSA is no exception, and this narrative review will summarize the results of clinical studies performed over the years by the European Sleep Apnoea Database (ESADA) Study Group, to explore the variables linked to markers of intermittent hypoxia as opposed to the traditional assessment of OSA severity based on the frequency of respiratory events during sleep (the Apnoea Hypopnoea Index). The results of the clinical studies indicate that intermittent hypoxia variables are associated with several comorbidities, although evidence of a cause-effect relationship is still missing in many cases. It is also possible that adaptive rather than maladaptive responses could be evoked by intermittent hypoxia. The intensity, duration and frequency of intermittent hypoxia episodes causing adaptive rather than maladaptive responses, and their clinical implications, deserve further investigation.

Fentanyl induced disruption of the coordinated reciprocal activity of inspiratory and expiratory respiratory muscles

Opioid induced respiratory depression (OIRD) occurs when respiratory pump and/or airway muscle activity are reduced ostensibly due to reduced output from the brainstem respiratory control system, resulting in central (CA) and/or obstructive apnea (OA) and reduced breathing frequency. Although less commonly reported in the literature, ORID may also result from an inappropriate activation of accessory muscles leading to the “Wooden Chest Syndrome” (WCS) -when airflow is limited due to simultaneous activation of inspiratory and expiratory pump and/or airway respiratory muscles to decrease chest wall compliance and inappropriately increase airway resistance. This phenomenon is difficult to directly study in humans, but here we present data from our large animal model (adult female goats). We tested the hypothesis that IV fentanyl would lead to transient dysfunction in respiratory accessory muscles indicative of WCS. We surgically instrumented goats (n=7) with electromyographic (EMG) wires in inspiratory (diaphragm; DIA) and expiratory (Transversus Abdominus; TA) pump muscles, as well as airway dilator (Thyropharyngeus; Thy) and constrictor (Genioglossus; GG) muscles. After >2 weeks of surgical recovery, responses to saline or various doses of fentanyl citrate (25-125 mcg/kg; IV) were tested for 30 min before and up to 90 min after injection. As described in an adjacent poster, particularly over the first several minutes after fentanyl injection, CA and OA were observed in some goats. However, disruption of airflow was primarily associated with increased simultaneous activation of pump and airway inspiratory and expiratory muscles resembling WCS. For most muscles, the rate of rise in muscle activity (an index of firing intensity) increased within 2 minutes following fentanyl injection and remained significantly (P<0.05) elevated up to 90 minutes. During WCS periods, airflow was oscillatory or interrupted suggesting transient closure of the airway. In addition, there were time- and dose-dependent effects on frequency, duration, and total activity of the pump and airway muscles. By 60 minutes post-injection, there were periods of transient return of muscle activity and airflow to at or below baseline values. There was no significant effect of saline on muscle activity. Overall, these data suggest that following fentanyl injection in awake goats, there was an increase in firing of pump and airway muscles which ultimately disrupts the coordinated reciprocal activity of inspiratory and expiratory muscles and contributes to OIRD. Supported by NIH DA050571 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Physiological responses and perceived comfort to high-flow nasal cannula therapy in awake adults: effects of flow magnitude and temperature.

Clinical use of heated, high-flow nasal cannula (HFNC) for noninvasive respiratory support is increasing and may have a therapeutic role in stabilizing the upper airway in obstructive sleep apnea (OSA). However, physiological mechanisms by which HFNC therapy may improve upper airway function and effects of different temperature modes are unclear. Accordingly, this study aimed to determine effects of incremental flows and temperature modes (heated and nonheated) of HFNC on upper airway muscle activity (genioglossus), pharyngeal airway pressure, breathing parameters, and perceived comfort. Six participants (2 females, aged 35 ± 14 yr) were studied during wakefulness in the supine position and received HFNC at variable flows (0-60 L/min) during heated (37°C) and nonheated (21°C) modes. Breathing parameters via calibrated Respitrace inductance bands (chest and abdomen), upper airway pressures via airway transducers, and genioglossus muscle activity via intramuscular bipolar fine wire electrodes were measured. Comfort levels during HFNC were quantified using a visual analog scale. Increasing HFNC flows did not increase genioglossus muscle activation despite increased negative epiglottic pressure swings (P = 0.009). HFNC provided ∼7 cmH2O positive airway pressure at 60 L/min in nonheated and heated modes. In addition, increasing the magnitude of HFNC flow reduced breathing frequency (P = 0.045), increased expiratory time (P = 0.040), increased peak inspiratory flow (P = 0.002), and increased discomfort (P = 0.004). Greater discomfort occurred at higher flows in the nonheated versus the heated mode (P = 0.034). These findings provide novel insight into key physiological changes that occur with HFNC for respiratory support and indicate that the primary mechanism for improved upper airway stability is positive airway pressure, not increased pharyngeal muscle activity.NEW & NOTEWORTHY This study evaluated upper airway muscle function, breathing, and comfort across different HFNC flows and temperatures. There were no increases in genioglossus muscle activity at higher flows despite greater negative epiglottic pressure swings. Increasing negative pressure swings was associated with increasing discomfort in the nonheated mode. HFNC was associated with ∼7 cmH2O increase in positive airway pressure, which may be the primary mechanism for upper airway stability with HFNC rather than increases in pharyngeal muscle activity.

Dose‐dependent multiple physiologic effects of systemic fentanyl in awake adult goats

It is well known that opioid analgesics induce life-threatening respiratory depression. A few studies have also documented additional deleterious effects of opioids on multiple physiologic functions. Moreover, there are reports of interindividual variation in susceptibility, magnitude, and duration of physiologic effects of opioids such as fentanyl. Here we tested the dose-dependent effects of intravenous injected fentanyl on physiologic functions in 7 awake, adult goats. Goats were instrumented for recording of multiple cardiorespiratory variables including respiratory pump and airway muscle activity. After a 30-minute control period, 0, 10, 20, or 50 µg/kg fentanyl was infused intravenously. We found that rapid IV infusion of fentanyl over 2 min caused a dose-dependent decrease in minute ventilation due to dramatic suppression of breathing frequency within 5 min after IV injection. These effects were coupled with dose-dependent increases in VT, which represents a more human like ventilatory response to opioids. The major suppression of ventilation occurred in 5 of the 7 goats, whereas in 2 of the goats IV fentanyl injections increased breathing frequency in a dose-dependent manner. This variation in ventilatory response to opioids agrees with findings that in a subset of humans, opioids have an excitatory effect on physiologic functions (Br. J. Anaesth 81, 1998). The suppression of ventilation seen in the majority of goats is transient, lasting for 3-10 minutes post-injection and is accompanied by an increased or normal VT up to 30-90 minutes. Over the initial 10 minutes after injection, there were obstructive and central apneas often exceeding one minute resulting in arterial hypoxemia (PaO2<50 mmHg) and hypercapnia (PaCO2>50mmHg). Heart rate was decreased for up to 15 minutes following 50µg/kg injection, whereas arterial blood pressure was increased for at least 90 minutes post-injection. Particularly over the initial minutes after 50µg/kg, fentanyl infusion decreased the duration but increased the intensity of diaphragm and intercostal muscle activity while increasing tonic activity of abdominal and airway muscles. Infusion of naloxone before or after infusion of fentanyl prevented or reversed the acute and delayed physiologic effects induced by fentanyl. Injection of Naloxone alone had no effect on physiological measures of goats. We conclude that goats have multiple dose- and individual-dependent physiologic responses to systemic infusion of fentanyl. Furthermore, our reversal data suggests the effects of fentanyl in goats are likely mediated by activation of µ-opioid receptors.

After-discharge in the upper airway muscle genioglossus following brief hypoxia.

Genioglossus (GG) after-discharge is thought to protect against pharyngeal collapse by minimizing periods of low upper airway muscle activity. How GG after-discharge occurs and which single motor units (SMUs) are responsible for the phenomenon are unknown. The aim of this study was to investigate genioglossal after-discharge. During wakefulness, after-discharge was elicited 8-12 times in healthy individuals with brief isocapnic hypoxia (45-60 s of 10% O2 in N2) terminated by a single breath of 100% O2. GG SMUs were designated as firing solely, or at increased rate, during inspiration (Inspiratory phasic [IP] and inspiratory tonic [IT], respectively); solely, or at increased rate, during expiration (Expiratory phasic [EP] or expiratory tonic [ET], respectively) or firing constantly without respiratory modulation (Tonic). SMUs were quantified at baseline, the end of hypoxia, the hyperoxic breath, and the following eight normoxic breaths. A total of 210 SMUs were identified in 17 participants. GG muscle activity was elevated above baseline for seven breaths after hyperoxia (p < 0.001), indicating a strong after-discharge effect. After-discharge occurred due to persistent firing of IP and IT units that were recruited during hypoxia, with minimal changes in ET, EP, or Tonic SMUs. The firing frequency of units that were already active changed minimally during hypoxia or the afterdischarge period (p > 0.05). That genioglossal after-discharge is almost entirely due to persistent firing of previously silent inspiratory SMUs provides insight into the mechanisms responsible for the phenomenon and supports the hypothesis that the inspiratory and expiratory/tonic motor units within the muscle have idiosyncratic functions.

Mild Intermittent Hypoxia Reduces the Critical Closing Pressure and Continuous Positive Airway Pressure Resulting in Improved Treatment Adherence

Study ObjectivesAdherence to continuous positive airway pressure (CPAP) therapy is low in part because of patient discomfort initiated by high therapeutic pressures (TP). Improved adherence could ultimately lead to more effective treatment of co‐morbidities linked to sleep apnea. Daily exposure to mild intermittent hypoxia (MIH) initiates long‐term facilitation of upper airway (UA) muscle activity. Initiation of this form of plasticity could increase UA patency and as a result decrease the TP required to treat obstructive sleep apnea (OSA). Therefore, we investigated if repeated daily exposure to MIH reduces the TP and UA critical closing pressure (passive = PCRIT, active = ACRIT). Likewise, we examined if reductions in the TP were linked to improved CPAP adherence.MethodsNine hypertensive males with OSA were treated with twelve 2‐minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2‐minute intervals of normoxia each day for a period of 15 days over 3 weeks (i.e. 5 days/week). PETCO2 levels were sustained at 1–3 mmHg above baseline during MIH administration. Five matched participants were exposed to a sham protocol comprised of 2‐minute episodes of room air. Both groups were treated with in‐home CPAP during the 15 day protocol. Prior to exposure to MIH the critical closing pressure and TP were determined. Mid‐way and at the end of the protocol, measures of the critical closing pressure and TP were repeated. If the TP was reduced following measures at the mid‐point of the protocol, the in‐home TP was adjusted accordingly.ResultsFollowing MIH, the TP was reduced (12.3 ± 0.6 to 9.9 ± 0.6 cmH2O (p ≤ 0.001) which was accompanied by a reduction in PCRIT (4.9 ± 0.8 to 1.3 ± 0.7 cmH2O, p ≤ 0.001) and ACRIT (3.6 ± 0.7 to 0.7 ± 0.9, p ≤ 0.01). Additionally, in‐home CPAP adherence improved in the latter half of the study as the hours per night (4.0 ± 0.7 vs 5.5 ± 0.7, hours/night, p ≤ 0.05) and the number of days associated with CPAP therapy greater than 6 hours/night increased following MIH (22.0 ± 8.0 vs 36.0 ± 10.0 percent of available days, p ≤ 0.05). No changes in TP, critical closing pressure, or adherence were found in the sham group. After the protocol, hours per night (5.5 ± 0.7 vs 3.11 ± 0.9, p = 0.06) and the number of days of CPAP therapy greater than 6 hours (3.2 ± 0.9 vs 0.6 ± 0.6, p = 0.06) trended towards significance when compared to sham. However, the MIH group had significantly greater in‐home CPAP use of greater than 4 days when compared to sham following the study protocol (5.3 ± 0.9 vs 1.4 ± 0.7, p ≤ 0.01). A significant correlation between the change in TP (Post‐Pre) and hours of night the CPAP was worn (fraction of baseline) was found following MIH (R2 = 0.8, p ≤ 0.01).ConclusionMIH improved upper airway patency as suggested by the reduction in TP and decrease in critical closing pressures. The reduced TP was coupled to improvements in CPAP adherence. Improved CPAP adherence might ultimately lead to improved treatment of co‐morbidities linked to sleep apnea.Support or Funding InformationDepartment of Veterans Affairs (I01CX000125 &amp; 15SRCS003 JHM, 1IK1RX002945 GSP), and National Institutes of Health (R56HL142757 &amp; R01HL142757 JHM).

Corticomotor control of airway calibre in obstructive sleep apnoea syndrome.

Corticomotor control of airway calibre in obstructive sleep apnoea syndrome.

Targeting Endotypic Traits with Medications for the Pharmacological Treatment of Obstructive Sleep Apnea. A Review of the Current Literature.

Obstructive sleep apnea (OSA) is a highly prevalent condition with few therapeutic options. To date there is no approved pharmacotherapy for this disorder, but several attempts have been made in the past and are currently ongoing to find one. The recent identification of multiple endotypes underlying this disorder has oriented the pharmacological research towards tailored therapies targeting specific pathophysiological traits that contribute differently to cause OSA in each patient. In this review we retrospectively analyze the literature on OSA pharmacotherapy dividing the medications tested on the basis of the four main endotypes: anatomy, upper airway muscle activity, arousal threshold and ventilatory instability (loop gain). We show how recently introduced drugs for weight loss that modify upper airway anatomy may play an important role in the management of OSA in the near future, and promising results have been obtained with drugs that increase upper airway muscle activity during sleep and reduce loop gain. The lack of a medication that can effectively increase the arousal threshold makes this strategy less encouraging, although recent studies have shown that the use of certain sedatives do not worsen OSA severity and could actually improve patients’ sleep quality.

Upper Airway Collapsibility during Dexmedetomidine and Propofol Sedation in Healthy Volunteers: A Nonblinded Randomized Crossover Study.

Dexmedetomidine is a sedative promoted as having minimal impact on ventilatory drive or upper airway muscle activity. However, a trial recently demonstrated impaired ventilatory drive and induction of apneas in sedated volunteers. The present study measured upper airway collapsibility during dexmedetomidine sedation and related it to propofol. Twelve volunteers (seven female) entered this nonblinded, randomized crossover study. Upper airway collapsibility (pharyngeal critical pressure) was measured during low and moderate infusion rates of propofol or dexmedetomidine. A bolus dose was followed by low (0.5 μg · kg · h or 42 μg · kg · min) and moderate (1.5 μg · kg · h or 83 μg · kg · min) rates of infusion of dexmedetomidine and propofol, respectively. Complete data sets were obtained from nine volunteers (median age [range], 46 [23 to 66] yr; body mass index, 25.4 [20.3 to 32.4] kg/m). The Bispectral Index score at time of pharyngeal critical pressure measurements was 74 ± 10 and 65 ± 13 (mean difference, 9; 95% CI, 3 to 16; P = 0.011) during low infusion rates versus 57 ± 16 and 39 ± 12 (mean difference, 18; 95% CI, 8 to 28; P = 0.003) during moderate infusion rates of dexmedetomidine and propofol, respectively. A difference in pharyngeal critical pressure during sedation with dexmedetomidine or propofol could not be shown at either the low or moderate infusion rate. Median (interquartile range) pharyngeal critical pressure was -2.0 (less than -15 to 2.3) and 0.9 (less than -15 to 1.5) cm H2O (mean difference, 0.9; 95% CI, -4.7 to 3.1) during low infusion rates (P = 0. 595) versus 0.3 (-9.2 to 1.4) and -0.6 (-7.7 to 1.3) cm H2O (mean difference, 0.0; 95% CI, -2.1 to 2.1; P = 0.980) during moderate infusion of dexmedetomidine and propofol, respectively. A strong linear relationship between pharyngeal critical pressure during dexmedetomidine and propofol sedation was evident at low (r = 0.82; P = 0.007) and moderate (r = 0.90; P < 0.001) infusion rates. These observations suggest that dexmedetomidine sedation does not inherently protect against upper airway obstruction.

Genioglossus activation during maximal sniff manoeuvres: Is upper airway function relevant in the clinical assessment of inspiratory and expiratory muscle strength?

Genioglossus activation during maximal sniff manoeuvres: Is upper airway function relevant in the clinical assessment of inspiratory and expiratory muscle strength?

Effect of Sustained Hypoxia on Autophagy of Genioglossus Muscle-Derived Stem Cells.

BackgroundPrevious studies have demonstrated that sustained hypoxia in people with obstructive sleep apnea (OSA) impairs upper airway muscle activity, but the underlying mechanism remains poorly understood. As autophagy acts as an important regulator under hypoxia stress, we performed an in vitro investigation of the effects of sustained hypoxia on autophagy of genioglossus muscle-derived stem cells (GG MDSC), an important component of the upper airway muscle.Material/MethodsGenioglossus MDSCs were obtained from Sprague-Dawley (SD) rats and identified by using immunofluorescence staining for CD34, Sca-1, and desmin. GG MDSCs were incubated under normoxic or sustained hypoxic conditions for different periods of time. Western blotting was used to detect LC3 and Beclin 1, which are 2 important proteins in autophagy flux, and autophagolysosomes accumulation was observed by transmission electron microscopy (TEM). The mRNA and protein levels of HIF-1α and BNIP3 were evaluated by RT-PCR and Western blot analysis, respectively.ResultsOur study shows that sustained hypoxia promotes the expression of LC3BII and Beclin 1 in GG MDSCs in a time-dependent manner. TEM showed an increased number of autophagolysosomes in GG MDSCs under sustained hypoxia for 12 and 24 h. In addition, hypoxia activated the HIF-1α/BNIP3 signal pathway both at protein levels (shown by Western blot) and at mRNA levels (shown by RT-PCR).ConclusionsOur study shows that sustained hypoxia promotes autophagy in GG MDSCs, and the HIF-1α/BNIP3 signal pathway was involved in this process.

Mild Intermittent Hypoxia Significantly Reduces the Critical Closing Pressure and Continuous Positive Airway Pressure

PurposeAdherence to continuous positive airway pressure (CPAP) therapy is low in part because of patient discomfort initiated by high therapeutic pressures (TP). Improved adherence could ultimately lead to more effective treatment of co‐morbidities linked to sleep apnea. Acute and repeated daily exposure to mild intermittent hypoxia (MIH) initiates long‐term facilitation of upper airway muscle activity. Initiation of this form of plasticity could increase upper airway patency and as a result decrease the therapeutic pressure required to treat obstructive sleep apnea (OSA). Therefore, we investigated if repeated daily exposure to MIH reduces the upper airway critical closing pressure (PCRIT) and therapeutic CPAP pressure. Likewise, we examined if reductions in the therapeutic pressure were linked to improved adherenceMethodsFive hypertensive male participants newly diagnosed with OSA were treated with twelve 2‐minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2‐minute intervals of normoxia each day for a period of 15 days over 3 weeks (i.e. 5 days/week). PETCO2 levels were sustained at 3 mmHg above baseline during MIH administration. Prior to exposure to MIH the critical closing pressure and therapeutic CPAP was determined. Thereafter, participants were treated with CPAP at home each night throughout the 15 day protocol. Mid‐way and at the end of the protocol measures of the critical closing pressure and therapeutic pressure were repeated.ResultsMid way through the MIH protocol the therapeutic pressure was reduced from 12.6 ± 0.93 to 11.2 ± 0.97 cmH2O (P ≤ 0.05) accompanied by a reduction in passive PCRIT from 4.2 ± 0.92 to 2.5 ± 0.95 cmH2O (P ≤ 0.03). Similar modifications were also evident at the end of the protocol. The frequency of breathing events recorded remotely from participants treated with CPAP at home was not altered following reductions in TP (AHI: 1.48 ± 0.4 vs 2.30 ± 1.6, P ≥ 0.2) indicating that the participants were effectively treated despite a decrease in TP. Adherence to CPAP increased in 4 of 5 participants. An increase in adherence to CPAP was not evident in one individual because treatment throughout a given sleep period was uninterrupted from the onset to the end of the protocol (7.7 vs. 7.4 hours/night). In the remaining participants adherence increased from 4.9 ± 0.87 to 6.1 ± 0.37 hours per night. In addition, the number of days participants used CPAP for less than 6 hours significantly decreased before compared to after the TP was reduced (5 to 2.4 days, P ≤ 0.02). A correlation between the change in TP and number of hours of use trended toward significance (R2 = 0.89, P ≤ 0.06).ConclusionMIH improves upper airway patency as suggested by the decrease in PCRIT and the reduction in TP. The reduced TP was coupled to improvements in CPAP adherence. Improved CPAP adherence might ultimately lead to improved treatment of co‐morbidities linked to sleep apnea.Support or Funding InformationThis material is based upon work supported by the Department of Veterans Affairs, Veterans Health 507 Administration, Office of Research and Development (I01CX000125 &amp; 15SRCS003 ‐ JHM).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Kinesthetic stimulation for obstructive sleep apnea syndrome: An \u201con-off\u201d proof of concept trial

Obstructive sleep apnea (OSA) occurs when the upper airway narrows or collapses due to the loss of upper airway muscle activation at sleep onset. This study investigated the effectiveness of triggered kinesthetic stimulation in patients with OSA. This proof-of-concept, open-label, multicenter prospective study was conducted on 24 patients with severe OSA. During a one night evaluation, kinesthetic stimulation was intermittently delivered in 30 minute periods. The duration of apneas and hypopneas during Stimon and Stimoff periods were compared. Five hospital-based university centers in France participated. Sleep studies were evaluated by a single scorer at a core laboratory (CHU Grenoble). Results show that during the Stimon phases, statistically significant decreases in durations of apneas and hypopneas were observed in 56% and 46% of patients, respectively. Overall, 75% of patients showed an improvement in apneas or hypopneas durations. The mean reduction in durations for patients with a significant decrease was 4.86 seconds for apneas and 6.00 seconds for hypopneas. This proof of concept study is the first to identify kinesthetic stimulation as a potentially effective therapy for OSA. These data justify evaluation in a controlled study.

Sleep-Disordered Breathing in People with Multiple Sclerosis: Prevalence, Pathophysiological Mechanisms, and Disease Consequences.

Sleep problems are common in people with multiple sclerosis (MS). Reported prevalence rates of sleep-disordered breathing (SDB) vary between 0 and 87%. Differences in recruitment procedures and study designs likely contribute to the wide variance in reported prevalence rates of SBD in MS. This can make attempts to compare SDB rates in people with MS to the general population challenging. Little is known about the pathophysiological mechanisms that contribute to SDB in people with MS or whether MS contributes to SDB disease progression. However, compared to the general obstructive sleep apnea (OSA) population, there are clear differences in the clinical phenotypes of SDB in the MS population. For instance they are typically not obese and rates of SDB are often comparable or higher to the general population, despite the high female predominance of MS. Thus, the risk factors and pathophysiological causes of SDB in people with MS are likely to be different compared to people with OSA who do not have MS. There may be important bidirectional relationships between SDB and MS. Demyelinating lesions of MS in the brain stem and spinal cord could influence breathing control and upper airway muscle activity to cause SDB. Intermittent hypoxia caused by apneas during the night can increase oxidative stress and may worsen neurodegeneration in people with MS. In addition, inflammation and changes in cytokine levels may play a key role in the relationship between SDB and MS and their shared consequences. Indeed, fatigue, neurocognitive dysfunction, and depression may worsen considerably if both disorders coexist. Recent studies indicate that treatment of SDB in people with MS with conventional first-line therapy, continuous positive airway pressure therapy, can reduce fatigue and cognitive impairment. However, if the causes of SDB differ in people with MS, so too may the optimal therapy. Thus, many questions remain concerning the relationship between these two disorders and the underlying mechanisms and shared consequences. Improved understanding of these factors has the potential to unlock new therapeutic targets.

Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem.

Hypnotics are contraindicated in obstructive sleep apnoea (OSA) because of concerns of pharyngeal muscle relaxation and delayed arousal worsening hypoxaemia. However, human data are lacking. This study aimed to determine the effects of three common hypnotics on the respiratory arousal threshold, genioglossus muscle responsiveness and upper airway collapsibility during sleep.21 individuals with and without OSA (18-65 years) completed 84 detailed sleep studies after receiving temazepam (10 mg), zolpidem (10 mg), zopiclone (7.5 mg) and placebo on four occasions in a randomised, double-blind, placebo-controlled, crossover trial (ACTRN12612001004853).The arousal threshold increased with zolpidem and zopiclone versus placebo (mean±sd -18.3±10 and -19.1±9 versus -14.6±7 cmH2O; p=0.02 and p<0.001) but not with temazepam (-16.8±9 cmH2O; p=0.17). Genioglossus muscle activity during stable non-REM sleep and responsiveness during airway narrowing was not different with temazepam and zopiclone versus placebo but, paradoxically, zolpidem increased median muscle responsiveness three-fold during airway narrowing (median -0.15 (interquartile range -1.01 to -0.04) versus -0.05 (-0.29 to -0.03)% maximum EMG per cmH2O epiglottic pressure; p=0.03). The upper airway critical closing pressure did not change with any of the hypnotics.These doses of common hypnotics have differential effects on the respiratory arousal threshold but do not reduce upper airway muscle activity or alter airway collapsibility during sleep. Rather, muscle activity increases during airway narrowing with zolpidem.

Exposure to intermittent hypoxia and sustained hypercapnia reduces therapeutic CPAP in participants with obstructive sleep apnea.

Our purpose was to determine whether exposure to mild intermittent hypoxia leads to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events. Ten male participants were treated with twelve 2-min episodes of hypoxia ([Formula: see text] ≈50 mmHg) separated by 2-min intervals of normoxia in the presence of [Formula: see text] that was sustained 3 mmHg above baseline. During recovery from the last episode, the positive airway pressure was reduced in a stepwise fashion until flow limitation was evident. The participants also completed a sham protocol under normocapnic conditions, which mimicked the time frame of the intermittent hypoxia protocol. After exposure to intermittent hypoxia, the therapeutic pressure was significantly reduced (i.e., 5 cmH2O) without evidence of flow limitation (103.4 ± 6.3% of baseline, P = 0.5) or increases in upper airway resistance (95.6 ± 15.0% of baseline, P = 0.6). In contrast, a similar decrease in pressure was accompanied by flow limitation (77.0 ± 1.8% of baseline, P = 0.001) and an increase in upper airway resistance (167.2 ± 17.5% of baseline, P = 0.01) after the sham protocol. Consistent with the initiation of long-term facilitation of upper airway muscle activity, exposure to intermittent hypoxia reduced the therapeutic pressure required to eliminate apneic events that could improve treatment compliance. This possibility, coupled with the potentially beneficial effects of intermittent hypoxia on comorbidities linked to sleep apnea, suggests that mild intermittent hypoxia may have a multipronged therapeutic effect on sleep apnea.NEW & NOTEWORTHY Our new finding is that exposure to mild intermittent hypoxia reduced the therapeutic pressure required to treat sleep apnea. These findings are consistent with previous results, which have shown that long-term facilitation of upper muscle activity can be initiated following exposure to intermittent hypoxia in humans.

Effect of 4-Aminopyridine on Genioglossus Muscle Activity during Sleep in Healthy Adults.

The reduction in upper airway muscle activity from wakefulness to sleep plays a key role in the development of obstructive sleep apnea. Potassium (K+) channels have been recently identified as the downstream mechanisms through which hypoglossal motoneuron membrane excitability is reduced both in non-rapid eye movement (NREM) sleep and REM sleep. In animal models, the administration of 4-aminopyridine (4-AP), a voltage-gated K+ channel blocker, increased genioglossus activity during wakefulness and across all sleep stages. We tested the hypothesis that administration of a single dose of 4-AP 10 mg extended release would increase genioglossus activity (electromyography of the genioglossus muscle [EMGGG]) during wakefulness and sleep, and thereby decrease pharyngeal collapsibility. We performed a randomized controlled crossover proof-of-concept trial in 10 healthy participants. Participants received active treatment or placebo in randomized order 3 hours before bedtime in the physiology laboratory. EMGGG during wakefulness and NREM sleep and upper airway collapsibility measured during NREM sleep were unchanged between placebo and 4-AP nights. Tonic but not phasic EMGGG during REM sleep was higher on the 4-AP night when measured as a percentage of maximal voluntary activation (median [interquartile range] 0.3 [0.5] on placebo vs. 0.8 [1.9] %max on 4 AP; P = 0.04), but not when measured in μV or as a percentage of wakefulness value. A single dose of 4-AP 10 mg extended release showed only a small increase in tonic EMGGG during REM sleep in this group of healthy subjects. We speculate that a higher dose of 4-AP may further increase EMGGG. However, given the potentially severe, dose-related adverse effects of this drug, including seizures, the administration of 4-AP does not appear to be an effective strategy to increase genioglossus activity during sleep in humans. Clinical Trial registered with clinicaltrials.gov (NCT02656160).

Mild Intermittent Hypoxia with Sustained Hypercapnia Improves Airflow, Reduces Therapeutic CPAP and Blood Pressure in Participants with Obstructive Sleep Apnea

Intermittent hypoxia (IH) elicits long term facilitation of ventilation and upper airway muscle activity. The latter form of plasticity could contribute to stabilizing the upper airway. Based on this possibility, we examined if administration of mild IH accompanied by sustained hypercapnia reduces the continuous positive airway pressure (CPAP) required to treat obstructive sleep apnea (OSA). In addition, we investigated if daily exposure to mild IH would elicit changes in the autonomic nervous system, leading to a decrease in blood pressure in individuals with OSA.MethodsTen male participants with OSA initially visited the laboratory to confirm the presence of sleep apnea, while a second visit was used to determine the therapeutic CPAP (TP). On a third visit, the participants completed a sham protocol (i.e. normoxic and normocapnic conditions), which mimicked the timeframe of the IH protocol that would be introduced in a subsequent visit, while being treated with TP. During the sham recovery period, the CPAP was reduced in a step‐wise fashion to measure the change in flow and upper airway resistance. On a fourth visit participants were treated with TP. PETCO2 levels were increased and sustained 3 mmHg above baseline. Subsequently, twelve 2‐minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2‐minute intervals of normoxia were administered. During recovery, the CPAP was reduced in a step‐wise fashion until flow limitation was evident. In a separate set of experiments two subjects with OSA underwent daily exposure to IH on 15 occasions over 3 weeks.ResultsFollowing exposure to intermittent hypoxia minute ventilation (P &lt; 0.001) and tidal volume (P &lt; 0.001) during end‐recovery and the step‐downs in positive pressure were greater compared to B2 (P &lt; 0.001). Inspiratory flow and resistance remained at baseline levels following exposure to intermittent hypoxia after TP was reduced by 5 cmH2O. In contrast, after completion of the sham protocol inspiratory flow was reduced (P &lt; 0.001) and resistance was increased (P &lt; 0.01) in response to the 5 cmH2O reduction in positive airway pressure. Preliminary data in two participants showed that daily exposure to IH over a 3 week period led to a decrease in systolic (144 ± 1 vs. 128 ± 5 mmHg) blood pressure and an increase in baroreceptor sensitivity (6.5 ± 0.06 vs. 17.9 ± 1.7 ms/mmHg). CPAP compliance data was retrieved from one individual. CPAP use increased from 2 h 52 minutes in the 1st week to 5 h 52 minutes in the 3rd week.ConclusionThe administration of mild IH and sustained hypercapnia decreases the CPAP required to eliminate apneic events. Additionally, increases in resistance and decreases in flow following CPAP step‐downs were significantly mitigated following IH with sustained hypercapnia. Preliminary data from 2 individuals showed that mild IH could effectively treat cardiovascular co‐morbidities directly and indirectly by increasing CPAP compliance via reductions in TP.Support or Funding InformationVA Merit Award ‐ Department of Veterans Affairs

Mechanisms of the deep, slow-wave, sleep-related increase of upper airway muscle tone in healthy humans

Upper airway muscle activity is reportedly elevated during slow-wave sleep (SWS) when compared with lighter sleep stages. To uncover the possible mechanisms underlying this elevation, we explored the correlation between different indices of central and reflex inspiratory drive, such as the changes in airway pressure and end-expiratory CO2 and the changes in the genioglossus (GG) and tensor palatini (TP) muscle activity accompanying transitions from the lighter N2 to the deeper N3 stage of non-rapid eye movement (NREM) sleep in healthy young adult men. Forty-six GG and 38 TP continuous electromyographic recordings were obtained from 16 men [age: 20 ± 2.5 (SD) yr; body mass index: 22.5 ± 1.8 kg/m2] during 32 transitions from NREM stages N2 to N3. GG but not TP activity increased following transition into N3 sleep, and the increase was positively correlated with more negative airway pressure, increased end-tidal CO2, increased peak inspiratory flow, and increased minute ventilation. None of these correlations was statistically significant for TP. Complementary GG and TP single motor unit analysis revealed a mild recruitment of GG units and derecruitment of TP units during the N2 to N3 transitions. These findings suggest that, in healthy individuals, the increased GG activity during SWS is driven primarily by reflex stimulation of airway mechanoreceptors and central chemoreceptors.NEW & NOTEWORTHY The characteristic increase in the activity of the upper airway dilator muscle genioglossus during slow-wave sleep (SWS) in young healthy individuals was found to be related to increased stimulation of airway mechanoreceptors and central chemoreceptors. No evidence was found for the presence of a central SWS-specific drive stimulating genioglossus activity in young healthy individuals. However, it remains to be determined whether a central drive exists in obstructive sleep apnea patients.