Sebastian Zaremba

Ketamine activates breathing and abolishes the coupling between loss of consciousness and upper airway dilator muscle dysfunction.

Background: Procedural sedation is frequently performed in spontaneously breathing patients, but hypnotics and opioids decrease respiratory drive and place the upper airway at risk for collapse. Methods: In a randomized, controlled, cross-over, pharmaco-physiologic study in 12 rats, we conducted acute experiments to compare breathing and genioglossus electromyogram activity at equianesthetic concentrations of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist that combines potent analgesic with hypnotic action effects, versus propofol. In 10 chronically instrumented rats resting in a plethysmograph, we measured these variables as well as electroencephalography during five conditions: quiet wakefulness, nonrapid-eye-movement sleep, rapid eye movement sleep, and low-dose (60 mg/kg intraperitoneally) and high-dose ketamine anesthesia (125 mg/kg intraperitoneally). Results: Ketamine anesthesia was associated with markedly increased genioglossus activity (1.5 to fivefold higher values of genioglossus electromyogram) compared with sleep- and propofol-induced unconsciousness. Plethysmography revealed a respiratory stimulating effect: higher values of flow rate, respiratory rate, and duty-cycle (effective inspiratory time, 1.5-to-2-fold higher values). During wakefulness and normal sleep, the &dgr; (f = 6.51, P = 0.04) electroencephalogram power spectrum was an independent predictor of genioglossus activity, indicating an association between electroencephalographic determinants of consciousness and genioglossus activity. Following ketamine administration, electroencephalogram power spectrum and genioglossus electroencephalogram was dissociated (P = 0.9 for the relationship between &dgr;/&thgr; power spectrum and genioglossus electromyogram). Conclusions: Ketamine is a respiratory stimulant that abolishes the coupling between loss-of-consciousness and upper airway dilator muscle dysfunction in a wide dose-range. Ketamine compared with propofol might help stabilize airway patency during sedation and anesthesia.

Differential Effects of Isoflurane and Propofol on Upper Airway Dilator Muscle Activity and Breathing

Background:Anesthesia impairs upper airway integrity, but recent data suggest that low doses of some anesthetics increase upper airway dilator muscle activity, an apparent paradox. The authors sought to understand which anesthetics increase or decrease upper airway dilator muscle activity and to study the mechanisms mediating the effect. Methods:The authors recorded genioglossus electromyogram, breathing, arterial blood pressure, and expiratory carbon dioxide in 58 spontaneously breathing rats at an estimated ED50 (median effective dose) of isoflurane or propofol. The authors further evaluated the dose–response relations of isoflurane under different study conditions: (1) normalization of mean arterial pressure, or end-expiratory carbon dioxide; (2) bilateral lesion of the Kölliker-Fuse nucleus; and (3) vagotomy. To evaluate whether the markedly lower inspiratory genioglossus activity during propofol could be recovered by increasing flow rate, a measure of respiratory drive, the authors performed an additional set of experiments during hypoxia or hypercapnia. Results:In vagally intact rats, tonic and phasic genioglossus activity were markedly higher with isoflurane compared with propofol. Both anesthetics abolished the genioglossus negative pressure reflex. Inspiratory flow rate and anesthetic agent predicted independently phasic genioglossus activity. Isoflurane dose-dependently decreased tonic and increased phasic genioglossus activity, and increased flow rate, and its increasing effects were abolished after vagotomy. Impairment of phasic genioglossus activity during propofol anesthesia was reversed during evoked increase in respiratory drive. Conclusion:Isoflurane compared with propofol anesthesia yields higher tonic and phasic genioglossus muscle activity. The level of respiratory depression rather than the level of effective anesthesia correlates closely with the airway dilator muscle function during anesthesia.

Pentobarbital dose-dependently increases respiratory genioglossus muscle activity while impairing diaphragmatic function in anesthetized rats

Background:Anesthetics depress both ventilatory and upper airway dilator muscle activity and thus put the upper airway at risk for collapse. However, these effects are agent-dependent and may involve upper airway and diaphragm muscles to varying degrees. The authors assessed the effects of pentobarbital on upper airway dilator and respiratory pump muscle function in rats and compared these results with the effects of normal sleep. Methods:Tracheostomized rats were given increasing doses of pentobarbital to produce deep sedation then light and deep anesthesia, and negative pressure airway stimuli were applied (n = 11). To compare the effects of pentobarbital with those of natural sleep, the authors chronically instrumented rats (n = 10) with genioglossus and neck electromyogram and electroencephalogram electrodes and compared genioglossus activity during wakefulness, sleep (rapid eye movement and non–rapid eye movement), and pentobarbital anesthesia. Results:Pentobarbital caused a dose-dependent decrease in ventilation and in phasic diaphragmatic electromyogram by 11 ± 0.1%, but it increased phasic genioglossus electromyogram by 23 ± 0.2%. Natural non–rapid eye movement sleep and pentobarbital anesthesia (10 mg/kg intraperitoneally) decreased respiratory genioglossus electromyogram by 61 ± 29% and 45 ± 35%, respectively, and natural rapid eye movement sleep caused the greatest decrease in phasic genioglossus electromyogram (95 ± 0.3%). Conclusions:Pentobarbital in rats impairs respiratory genioglossus activity compared to the awake state, but the decrease is no greater than seen during natural sleep. During anesthesia, in the absence of pharyngeal airflow, phasic genioglossus activity is increased in a dose-dependent fashion.

Serial polysomnography in hypnic headache.

Background: Hypnic headache (HH) is a rare primary headache disorder characterized by strictly sleep-related headache attacks. Most patients are over the age of 50 and usually awake at the same time at night with dull bilateral head pain. The pathophysiology of this headache disorder is still enigmatic but association with rapid eye movement (REM) sleep and sleep-disordered breathing (SDB) has been suggested. Methods: Six patients with HH according to the current International Classification of Headache Disorders (ICHD-II) criteria (code 4.5) were investigated. Serial polysomnography (PSG) was performed in each patient for four consecutive nights. Results: A total of 22 HH attacks were recorded from all patients during PSG. Six of the monitored headache attacks arose from REM sleep; 16 attacks, however, arose from different non-REM (NREM) sleep stages. Five patients showed an increased apnoea/hypopnoea index (>5), indicating obstructive sleep apnoea (OSA) on some but not the majority of nights. Headache onset and occurrence of SDB were not temporally connected. Conclusions: This prospective study shows that the onset of HH was not associated with sleep stage. These results contradict the current belief that REM sleep and SDB play a crucial role in the pathophysiology of HH.

Elevated Upper Body Position Improves Pregnancy-Related OSA Without Impairing Sleep Quality or Sleep Architecture Early After Delivery

BACKGROUND During pregnancy, upper airway resistance is increased, predisposing vulnerable women to pregnancy-related OSA. Elevation of the upper body increases upper airway cross-sectional area (CSA) and improves severity of OSA in a subgroup of nonpregnant patients (positional-dependent sleep apnea). We tested the hypothesis that elevated position of the upper body improves OSA early after delivery. METHODS Following institutional review board approval, we conducted a randomized, crossover study on two postpartum units of Massachusetts General Hospital. Women during the first 48 h after delivery were included. Polysomnography was performed in nonelevated and 45° elevated upper body position. Upper airway CSA was measured by acoustic pharyngometry in nonelevated, 45° elevated, and sitting body position. RESULTS Fifty-five patients were enrolled, and measurements of airway CSA obtained. Thirty patients completed polysomnography in both body positions. Elevation of the upper body significantly reduced apnea-hypopnea index (AHI) from 7.7 ± 2.2/h in nonelevated to 4.5 ± 1.4/h in 45° elevated upper body position (P = .031) during sleep. Moderate to severe OSA (AHI > 15/h) was diagnosed in 20% of postpartum patients and successfully treated by elevated body position in one-half of them. Total sleep time and sleep architecture were not affected by upper body elevation. Change from nonelevated to sitting position increased inspiratory upper airway CSA from 1.35 ± 0.1 cm2 to 1.54 ± 0.1 cm2 during wakefulness. Position-dependent increase in CSA and decrease in AHI were correlated (r = 0.42, P = .022). CONCLUSIONS Among early postpartum women, 45° upper body elevation increased upper airway CSA and mitigated sleep apnea. Elevated body position might improve respiratory safety in women early after delivery. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01719224; URL: www.clinicaltrials.gov.

Continuous Positive Airway Pressure Mitigates Opioid-induced Worsening of Sleep-disordered Breathing Early after Bariatric Surgery.

Background:Bariatric surgery patients are vulnerable to sleep-disordered breathing (SDB) early after recovery from surgery and anesthesia. The authors hypothesized that continuous positive airway pressure (CPAP) improves postoperative oxygenation and SDB and mitigates opioid-induced respiratory depression. Methods:In a randomized crossover trial, patients after bariatric surgery received 30% oxygen in the postanesthesia care unit (PACU) under two conditions: atmospheric pressure and CPAP (8 to 10 cm H2O). During 1 h of each treatment, breathing across cortical arousal states was analyzed using polysomnography and spirometry. Arousal state and respiratory events were scored in accordance with American Academy of Sleep Medicine guidelines. Data on opioid boluses in the PACU were collected. The primary and secondary outcomes were the apnea hypopnea index (AHI) and apnea after self-administration of opioids in the PACU. Linear mixed model analysis was used to compare physiologic measures of breathing. Results:Sixty-four percent of the 33 patients with complete postoperative polysomnography data demonstrated SDB (AHI greater than 5/h) early after recovery from anesthesia. CPAP treatment decreased AHI (8 ± 2/h vs. 25 ± 5/h, P < 0.001), decreased oxygen desaturations (5 ± 10/h vs. 16 ± 20/h, P < 0.001), and increased the mean oxygen saturation by 3% (P = 0.003). CPAP significantly decreased the respiratory-depressant effects observed during wakefulness–sleep transitions without affecting hemodynamics. The interaction effects between CPAP treatment and opioid dose for the dependent variables AHI (P < 0.001), inspiratory flow (P = 0.002), and minute ventilation (P = 0.015) were significant. Conclusions:This pharmacophysiologic interaction trial shows that supervised CPAP treatment early after surgery improves SDB and ameliorates the respiratory-depressant effects of opioids without undue hemodynamic effects.

Cluster headache shows no association with rapid eye movement sleep

Background: The connection of cluster headache (CH) attacks with rapid eye movement (REM) sleep has been suggested by various studies, while other authors challenge this assumption. We performed serial polysomnography to determine the association of nocturnal CH attacks and sleep. Methods: Five patients diagnosed with CH (two with the episodic and three with the chronic subtype) were included and studied over four consecutive nights to evaluate connections between attacks onset and sleep stage. Results: Twenty typical CH attacks were reported. Thirteen of these attacks arose from sleep. Seven attacks were reported after waking in the morning or shortly before going to sleep. The beginnings of sleep-related attacks were distributed arbitrarily between different non-REM sleep stages. No association of CH attacks with REM or sleep disordered breathing was observed. Increased heart rate temporally associated with transition from one sleep state to another was observed before patients awoke with headache. Total sleep time, total wake time, arousal index and distribution of non-REM sleep stages were different between chronic and episodic CH. Conclusion: CH attacks are not associated with REM sleep. Brain regions involved in sleep stage transition might be involved in pathophysiology of CH. Differences in sleep characteristics between subgroups might indicate adaptation processes or underlying pathophysiology.

Effects of obstructive sleep apnoea risk on postoperative respiratory complications: protocol for a hospital-based registry study.

Introduction Obstructive sleep apnoea (OSA), the most common type of sleep-disordered breathing, is associated with significant immediate and long-term morbidity, including fragmented sleep and impaired daytime functioning, as well as more severe consequences, such as hypertension, impaired cognitive function and reduced quality of life. Perioperatively, OSA occurs frequently as a consequence of pre-existing vulnerability, surgery and drug effects. The impact of OSA on postoperative respiratory complications (PRCs) needs to be better characterised. As OSA is associated with significant comorbidities, such as obesity, pulmonary hypertension, myocardial infarction and stroke, it is unclear whether OSA or its comorbidities are the mechanism of PRCs. This project aims to (1) develop a novel prediction score identifying surgical patients at high risk of OSA, (2) evaluate the association of OSA risk on PRCs and (3) evaluate if pharmacological agents used during surgery modify this association. Methods Retrospective cohort study using hospital-based electronic patient data and perioperative data on medications administered and vital signs. We will use data from Partners Healthcare clinical databases, Boston, Massachusetts. First, a prediction model for OSA will be developed using OSA diagnostic codes and polysomnography procedural codes as the reference standard, and will be validated by medical record review. Results of the prediction model will be used to classify patients in the database as high, medium or low risk of OSA, and we will investigate the effect of OSA on risk of PRCs. Finally, we will test whether the effect of OSA on PRCs is modified by the use of intraoperative pharmacological agents known to increase upper airway instability, including neuromuscular blockade, neostigmine, opioids, anaesthetics and sedatives. Ethics and dissemination The Partners Human Research Committee approved this study (protocol number: 2014P000218). Study results will be made available in the form of manuscripts for publication and presentations at national and international meetings.

Perioperative sleep apnea: a real problem or did we invent a new disease?

Depending on the subpopulation, obstructive sleep apnea (OSA) can affect more than 75% of surgical patients. An increasing body of evidence supports the association between OSA and perioperative complications, but some data indicate important perioperative outcomes do not differ between patients with and without OSA. In this review we will provide an overview of the pathophysiology of sleep apnea and the risk factors for perioperative complications related to sleep apnea. We also discuss a clinical algorithm for the identification and management of OSA patients facing surgery.

Elevated body position early after delivery increased airway size during wakefulness, and decreased apnea hypopnea index in a woman with pregnancy related sleep apnea.

We report a patient with pregnancy related obstructive sleep apnea ([OSA]; apnea hypopnea index [AHI] 18/h) early after delivery, with improvement of AHI by 87% following 45-degree elevation in body position compared with the non-elevated position. Improvement associated with this position may be explained, at least in part, by an increased upper airway diameter (as measured during wakefulness). Sleep apnea in this patient resolved at 9 months postpartum. This observation suggests that 45-degree elevated body position may be an effective treatment of pregnancy related OSA during the postpartum period.