Pierre Escourrou

Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period.

Objective: To compare compliance with and effectiveness of adaptive servoventilation (ASV) versus continuous positive airway pressure (CPAP) in patients with the central sleep apnoea syndrome (CSA) with Cheyne-Stokes respiration (CSR) and with congestive heart failure in terms of the apnoea–hypopnoea index (AHI), quality of life, and left ventricular ejection fraction (LVEF) over six months. Methods: 25 patients (age 28–80 years, New York Heart Association (NYHA) class II–IV) with stable congestive heart failure and CSA-CSR were randomly assigned to either CPAP or ASV. At inclusion, both groups were comparable for NYHA class, LVEF, medical treatment, body mass index, and CSA-CSR. Results: Both ASV and CPAP decreased the AHI but, noticeably, only ASV completely corrected CSA-CSR, with AHI below 10/h. At three months, compliance was comparable between ASV and CPAP; however, at six months compliance with CPAP was significantly less than with ASV. At six months, the improvement in quality of life was higher with ASV and only ASV induced a significant increase in LVEF. Conclusion: These results suggest that patients with CSA-CSR may receive greater benefit from treatment with ASV than with CPAP.

Induction of rapid eye movement sleep by carbachol infusion into the pontine reticular formation in the rat

Cholinergic regulation of sleep and wakefulness was studied in freely moving rats locally infused with various doses of carbachol into the pontine reticular formation. Induction of REM sleep occurred when carbachol was infused specifically into the posterior oral pontine reticular nucleus (PnO). This effect was observed with 1-10 ng of carbachol, and lasted for at least 6 h. It was antagonized by atropine (100-200 ng) infused into the same site 15 min before carbachol (10 ng), indicating that REM sleep induction resulted from the stimulation of pontine muscarinic receptors. High doses of carbachol (500 ng) did not affect REM sleep but enhanced wakefulness. Cholinergic mechanisms within the PnO may play a critical role in the regulation of REM sleep in the rat.

Contribution of 5-HT2 Receptor Subtypes to Sleep–Wakefulness and Respiratory Control, and Functional Adaptations in Knock-Out Mice Lacking 5-HT2A Receptors

Serotonin (5-hydroxytryptamine; 5-HT) plays key roles in sleep–wakefulness regulation. Evidence indicates that 5-HT2 receptors are involved mainly in non-rapid eye movement sleep (NREMS) regulation and respiratory control. Here, we investigated the relative contribution of 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes to NREMS and breathing during sleep, using 5-HT2 subtype-selective ligands in wild-type (5-HT2A+/+) and knock-out (5-HT2A–/–) mice that do not express 5-HT2A receptors. Acute blockade of 5-HT2A receptors induced an increase in NREMS in 5-HT2A+/+ mice, but not 5-HT2A–/– mutants, which spontaneously expressed less NREMS than wild-type animals. In 5-HT2A+/+ mice, 5-HT2B receptor blockade produced a reduction of NREMS, whereas receptor activation induced an increase in this sleep stage. These effects were less pronounced in 5-HT2A–/– mice, indicating a lower sensitivity of 5-HT2B receptors in mutants, with no change in 5-HT2B mRNA. Blockade of 5-HT2C receptors had no effect on NREMS in both strains. In addition, an increase in EEG power density after sleep deprivation was observed in 5-HT2A+/+ mice but not in 5-HT2A–/– mice. Whole-body plethysmographic recordings indicated that 5-HT2A receptor blockade in 5-HT2A+/+ mice reduced NREMS apneas and bradypneas that occurred after sighs. In contrast, in 5-HT2A–/– mutants, NREMS apneas were not modified, and bradypnea after sighs were more pronounced. Our results demonstrate that 5-HT exerts a 5-HT2B-mediated facilitation of NREMS, and an influence respectively inhibitory on NREMS and facilitatory on sleep apnea generation, via 5-HT2A receptors. Moreover, 5-HT2A gene knock-out leads to functional compensations yielding adaptive changes opposite to those caused by pharmacological blockade of 5-HT2A receptors in 5-HT2A+/+ mice.

β2-Containing Nicotinic Receptors Contribute to the Organization of Sleep and Regulate Putative Micro-Arousals in Mice

The cholinergic system is involved in arousal and in rapid eye movement sleep (REMS). To evaluate the contribution of nicotinic acetylcholine receptors (nAChRs) to these functions, we studied with polygraphic recordings the regulation of sleep in mice lacking the β2 subunit gene of the nAChRs, a major component of high-affinity nicotine binding sites in the brain. Nicotine (1-2 mg/kg, i.p.) increased wakefulness in wild-type but not knock-out animals, indicating that β2-containing nAChRs mediate the arousing properties of nicotine. Under normal conditions, the β2-/- mice displayed the same amounts of waking, non-REM sleep (NREMS) and REMS as their wild-type counterparts. However, they exhibited longer REMS episodes and a reduced fragmentation of NREMS by events characterized notably by a transient drop in EEG power and frequently associated with EMG activation, tentatively referred to as micro-arousals. Respiration monitoring showed that these events were accompanied with, but not caused by, breathing irregularities. Sleep deprivation of β2-/- mice resulted in a normal increase in REMS episode duration and NREMS δ power but yielded a reduction of the number of micro-arousals in NREMS. In contrast, in β2-/- mice, a 1 hr immobilization stress failed to produce the normal rebound in REMS in the following 12 hr and, instead, was associated with increased NREMS fragmentation and sustained corticosterone levels. Our results show that the β2-containing nAChRs contribute to the organization of sleep by regulating the transient phasic activity in NREMS, the REMS onset and duration, and the REMS-promoting effect of stress.

Auto-servoventilation in heart failure with sleep apnoea: a randomised controlled trial

We tested the hypotheses that in patients with congestive heart failure (CHF) and sleep disordered breathing (SDB) auto-servoventilation (ASV) improves cardiac function and quality of life. Between March 2007 and September 2009, patients with stable CHF (left ventricular ejection fraction (LVEF) ≤40%) and SDB (apnoea/hypopnoea index ≥20 events·h−1) were randomised to receive either ASV (BiPAP ASV (Philips Respironics, Murrysville, PA, USA), n=37) and optimal medical management, or optimal medical management alone (n=35). Outcomes were assessed at baseline and 12 weeks. The apnoea/hypopnoea index assessed with polysomnography scored in one core laboratory was significantly more reduced in the ASV group (-39±16 versus -1±13 events·h−1; p<0.001) with an average use of 4.5±3.0 h·day−1. Both groups showed similar improvements of the primary end-point LVEF (+3.4±5 versus +3.5±6%; p=0.915) assessed with echocardiography. In the ASV group, reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) was significantly greater (-360±569 versus +135±625 ng·mL−1; p=0.010). No differences were observed between the groups in subjective quality of life. In patients with CHF and SDB, ASV reduced NT-proBNP levels, but improvement of LVEF or quality of life was not greater than in the control group. The data support that such patients can be randomised in large-scale, long-term trials of positive airway pressure therapy versus control to determine effects on cardiovascular outcome. Patients with heart failure and sleep apnoea can be randomised in long-term trials of positive airway pressure therapy http://ow.ly/nQnVg

Vasoactive intestinal polypeptide microinjections into the oral pontine tegmentum enhance rapid eye movement sleep in the rat.

Rapid eye movement sleep can be elicited in the rat by microinjection of the cholinergic agonist carbachol into the oral pontine reticular nucleus. Intracerebroventricular administration, during the light period, of vasoactive intestinal peptide enhances rapid eye movement sleep in several species. Since this peptide is co-localized with acetylcholine in many neurons in the central nervous system, it was assumed that the oral pontine tegmentum could also be one target for vasoactive intestinal peptide to induce rapid eye movement sleep. This hypothesis was tested by recording the sleep-wakefulness cycle in freely-moving rats injected with vasoactive intestinal peptide or its fragments (1-12 and 10-28) directly into the oral pontine reticular nucleus. when administered into the posterior part of this nucleus, vasoactive intestinal peptide at 1 and 10 ng (in 0.1 microliter of saline), but not its fragments, induced a 2-fold enhancement of rapid eye movement sleep during 4 h, at the expense of wakefulness. At the dose of 10 ng, a significant increase in rapid eye movement sleep persisted for up to 8 h. Moreover, when the peptide was injected into the centre of the positive zone, rapid eye movement sleep was enhanced during three to eight consecutive days. These data provide the first evidence that rapid eye movement sleep can be elicited at both short- and long-term by a single intracerebral microinjection of vasoactive intestinal peptide. Peptidergic mechanisms, possibly in association with cholinergic mechanisms, within the caudal part of the oral pontine reticular nucleus may play a critical role in the long-term regulation of rapid eye movement sleep in rats.

Bench testing of auto-adjusting positive airway pressure devices

Continuous positive airway pressure devices are routinely used to treat sleep breathing disorders. Automated devices that adjust the therapeutic pressure have recently been proposed. The utility of such devices is still controversial, as rigorous clinical comparisons are difficult to perform as a result of patient and device differences. The current authors studied automated devices in a respiratory model that was able to mimic upper airway mechanics and to interact with pressure adjustment in a closed loop. Five auto-adjusted devices were submitted to this model, in order to determine their ability to detect respiratory events and adjust pressure accordingly. All apnoeas were suppressed, whilst the reaction to repetitive hypopnoeas was dependent on the airflow shape. In some devices, repetitive hypopnoeas were changed to flow limitation. Artificial snoring caused a pressure increase in four devices, and constant mask leak was not systematically compensated. Only one device did not raise pressure in response to central apnoeas with opened upper airways. These findings show that, in some devices, event classification failed and normal airflow was not fully restored, resulting in elevated residual event indices. In conclusion, this model is useful in order to reproducibly compare diagnostic and therapeutic capacities of commercial devices as a first step, before costly clinical studies.

Outcome of acetylcholinesterase deficiency for neuromuscular functioning

Acetylcholinesterase (AChE) plays an essential role in neuromuscular transmission, therefore it is surprising that AChE knockout (KO) mice could live to the adulthood. Neuromuscular functioning in KO and normal (wild type, WT) mice were studied, at different age (1.5-, 4- and 9-month-old). Hindlimb muscle force productions in response to nerve or muscle electric stimulation were recorded in situ and in vitro. Our results show that contrary to WT mice, 1.5-, 4- and 9-month-old KO mice exhibited a decreased in tetanic force during short periods (500 ms) of repetitive nerve stimulations (tetanic fade). Nevertheless submaximal muscle forces in response to single or repetitive nerve stimulation were increased (potentiation) in 1.5-, 4- and 9-month-old KO mice as compared to WT mice (p<0.05). Tetanic fade and potentiation were absent when muscles were directly stimulated, indicating neuromuscular transmission alterations in KO mice. Contrary to younger mice, muscle weight and maximal tetanic force in response to repetitive nerve stimulation were not reduced in 4- and 9-month-old KO mice as compared to WT mice (p>0.05). In conclusion AChE deficit leads to marked neuromuscular alterations in hind limb muscle functioning and a prominent symptom is the lack of resistance to fatigue.

Increased ventilation and CO2 chemosensitivity in acetylcholinesterase knockout mice

To investigate the effects of a permanent excess of acetylcholine (AChE) on respiration, breathing and chemosensitivity were analyzed from birth to adulthood in mice lacking the AChE gene (AChE-/-), in heterozygotes, and in control wild-type (AChE+/+) littermates. Breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O2) and hypercapnia (3-5% CO2) were measured by whole-body plethysmography. At rest AChE-/- mice show larger tidal volumes (VT, + 96% in adults), overall ventilation (VE, + 70%), and mean inspiratory flow (+270%) than wild-type mice, with no change in breathing frequency (fR). AChE-/- mice have a slightly blunted response to hypoxia, but increased VE and fR responses to hypercapnia. Heterozygous animals present no consistent alterations of breathing at rest and chemosensitivity is normal. Adult AChE-/- mice have an increased VE/VO2 and a marginally higher normalized VO2. The results suggest that the hyperventilation and altered chemosensitivity in AChE-/- mice largely reflect alterations of central respiratory control.

Quelle approche clinique et quelle procédure diagnostique pour le SAHOS

Hôpital Antoine Béclère, Clamart, France. b Département de Pneumologie, CHU, Angers, France. c Service de Physiologie et d’Exploration Fonctionnelle, Hôpital Ambroise Paré, Groupement hospitalier universitaire Ouest, Boulogne-Billancourt, France. d Service de Pneumologie, CHRU, Montpellier, France. e Cabinet médical, Mornac, France. f Service de Pneumologie, CHU Bretonneau, Tours, France. g Service de Neurophysiologie, CHU, Poitiers, France. h Service de Pneumologie, CH, Le Mans, Paris, France. i Service de physiologie-explorations fonctionnelles respiratoires, Hôpital Pitié-Salpêtrière, Paris, France.