Comparative study of epidural xylazine or clonidine in horses

Objective To evaluate the cardiorespiratory and behavioural effects of epidural xylazine (XYL) or clonidine (CLO) in horses.Study design Blinded, randomized experimental study.Twelve healthy Arabian yearling horses weighing 117-204 kg were randomly allocated into two groups: XYL (n = 6) and CLO (n = 6).Methods An epidural catheter was inserted and a facial arterial catheter was placed and the next day the horses were restrained in stocks. Baseline values for heart (HR) and respiratory (RR) rates, arterial pressure and behavioural responses were evaluated before (TO) and 10, 20, 30, 45, 60, 90 and 120 minutes after epidural injection (T10-T120). The horses received 0.2 mg kg(-1) of XYL or 5 mu g kg(-1) CLO; adjusted to (3.4 + (body weight in kg x 0.013) mL with saline. Data were analysed by the Kolmogorov-Smirnov test, one-way ANOVA with repeated measures, and one-way ANOVA followed by a Student-Newman-Keuls test or Fisher's exact test, as necessary. Significance was set at p <= 0.05.Results Sedation and ataxia were seen at T10, persisting until T120 in four and three horses, respectively, in XYL and all horses in CLO respectively. Two XYL and one CLO horses became recumbent at T45 and T25 respectively. Penile prolapse occurred in four of five males at T30 and T45, in the XYL and CLO groups, respectively, resolving by T120. Tail relaxation was present from T10 to T120 in all horses in XYL and in four horses in CLO. Head drop was observed from T20 to T60 and from T10 to T120 in XYL and CLO respectively. Respiratory rate decreased significantly only at T45 in the CLO group. Heart rate and arterial blood pressure remained stable.Conclusions and clinical relevance Epidural CLO and XYL produce similar cardiorespiratory and behavioural changes but neither would be safe to use clinically at the doses used in this study.

Study of the contraction induced by norepinephrine and clonidine in the isolated guinea-pig ileum

Norepinephrine (NE) and clonidine produce a phasic, dose-dependent contraction of the isolated guinea-pig terminal ileum. The effect of NE was blocked by prazosin which produced a parallel rightward shift of the concentration-effect curve to NE, with a significant depression of maximum effects. Yohimbine and indomethacin noncompetitively blocked, whereas practolol potentiated, the contractile effect of NE. The contractile effect of clonidine was not antagonized by indomethacin or atropine. These results suggest that the isolated guinea-pig terminal ileum has excitatory receptors sensitive to clonidine stimulation and excitatory alpha receptors sensitive to blockade by prazosin, and that the activation of the latter may be related to the activation of endogenous prostaglandin synthesis.

On a dual role for clonidine stimulation of the ventromedial nucleus of the hypothalamus in sodium and potassium renal excretions of rats

The effects of clonidine on sodium and potassium excretions were examined after previous administration of prazosin (an α 1-adrenergic receptor antagonist) and yohimbine (an α 2-adrenergic receptor antagonist) into the ventromedial nucleus of the hypothalamus of conscious rats. Clonidine injected into the ventromedial nucleus of the hypothalamus induced inhibitory and facilitatory effects on the urinary sodium and potassium excretions. The results suggest that facilitatory effects of clonidine on natriuresis and kaliuresis are mediated through activation of α 1-adrenoceptors and that inhibitory effects require α(2A)-adrenoceptors.

Clonidine and phenylephrine injected into the lateral preoptic area reduce water intake in dehydrated rats

In the present study, we investigated the effect of phenylephrine and clonidine (α1- and α2-adrenoceptor agonists, respectively) injected into the lateral preoptic area (LPOA) on the water intake induced by water deprivation in rats. In addition, the effects of prior injections of prazosin and yohimbine (α1- and α2-adrenoceptor antagonists, respectively) into the LPOA on the antidipsogenic action of phenylephrine and clonidine were investigated. After 30 h of water deprivation, the water intake of rats in a control experiment (saline injection) was 10.5 ± 0.8 ml/h. Injection of clonidine (5, 10, 20, and 40 nmol) into the LPOA reduced water intake to 6.3 ± 0.9, 4.9 ± 0.8, 3.6 ± 1.0, and 2.2 ± 0.7 ml/h, respectively. Similar reductions occurred after injection of 80 and 160 nmol phenylephrine into the LPOA (6.2 ± 1.6 and 4.8 ± 1.3 ml/h, respectively). Pretreatment with prazosin (40 nmol) abolished the antidipsogenic action of an 80-nmol dose of phenylephrine (11.3 ± 1.1 ml/h) and reduced the effect of a 20-nmol dose of clonidine (7.4 ± 1.4 ml/h). Yohimbine (20, 40, and 80 nmol), previously injected, produced no significant changes in the effects of either phenylephrine or clonidine. The present results show that phenylephrine and clonidine injected into the LPOA induce an antidipsogenic effect in water-deprived rat. They also suggest an involvement of α1-adrenoceptors in this effect. A possible participation of imidazole receptors in the effect of clonidine should also be taken into account. © 1993.

Blunted growth hormone response to clonidine in post-traumatic stress disorder

Hyperactivity of the sympathetic and noradrenergic systems is thought to be a feature of post-traumatic stress disorder (PTSD). Assessment of noradrenergic receptor function can be undertaken by measuring the growth hormone (GH) response to the alpha(2)-agonist clonidine. The aim of this study was to examine whether subjects with combat-related PTSD (with or without co-morbid depression) have a blunted growth hormone response to clonidine, compared to a combat-exposed control group. Twenty-three Vietnam veterans suffering from PTSD alone, 27 suffering from PTSD and co-morbid depression, and 32 veteran controls with no psychiatric illness were administered 1.5 mug/kg clonidine i.v. Plasma growth hormone was measured every 20 min for 120 min. The growth hormone response to clonidine was significantly blunted in the non-depressed PTSD group compared to both the depressed PTSD group and the control group as measured by peak growth hormone, delta growth hormone and AUC growth hormone. Subjects with PTSD and no co-morbid depressive illness show a blunted growth hormone response to clonidine. This suggests that post-synaptic alpha(2)-receptors are subsensitive. This finding is consistent with other studies showing increased noradrenergic activity in PTSD. (C) 2003 Elsevier Ltd. All rights reserved.

Clinical Studies on Epidural and Spinal Postoperative Analgesia : With Special Reference to Continuous Techniques of Administration and Adjuvant Drugs

Continuous epidural analgesia (CEA) and continuous spinal postoperative analgesia (CSPA) provided by a mixture of local anaesthetic and opioid are widely used for postoperative pain relief. E.g., with the introduction of so-called microcatheters, CSPA found its way particularly in orthopaedic surgery. These techniques, however, may be associated with dose-dependent side-effects as hypotension, weakness in the legs, and nausea and vomiting. At times, they may fail to offer sufficient analgesia, e.g., because of a misplaced catheter. The correct position of an epidural catheter might be confirmed by the supposedly easy and reliable epidural stimulation test (EST). The aims of this thesis were to determine a) whether the efficacy, tolerability, and reliability of CEA might be improved by adding the α2-adrenergic agonists adrenaline and clonidine to CEA, and by the repeated use of EST during CEA; and, b) the feasibility of CSPA given through a microcatheter after vascular surgery. Studies I IV were double-blinded, randomized, and controlled trials; Study V was of a diagnostic, prospective nature. Patients underwent arterial bypass surgery of the legs (I, n=50; IV, n=46), total knee arthroplasty (II, n=70; III, n=72), and abdominal surgery or thoracotomy (V, n=30). Postoperative lumbar CEA consisted of regular mixtures of ropivacaine and fentanyl either without or with adrenaline (2 µg/ml (I) and 4 µg/ml (II)) and clonidine (2 µg/ml (III)). CSPA (IV) was given through a microcatheter (28G) and contained either ropivacaine (max. 2 mg/h) or a mixture of ropivacaine (max. 1 mg/h) and morphine (max. 8 µg/h). Epidural catheter tip position (V) was evaluated both by EST at the moment of catheter placement and several times during CEA, and by epidurography as reference diagnostic test. CEA and CSPA were administered for 24 or 48 h. Study parameters included pain scores assessed with a visual analogue scale, requirements of rescue pain medication, vital signs, and side-effects. Adrenaline (I and II) had no beneficial influence as regards the efficacy or tolerability of CEA. The total amounts of epidurally-infused drugs were even increased in the adrenaline group in Study II (p=0.02, RM ANOVA). Clonidine (III) augmented pain relief with lowered amounts of epidurally infused drugs (p=0.01, RM ANOVA) and reduced need for rescue oxycodone given i.m. (p=0.027, MW-U; median difference 3 mg (95% CI 0 7 mg)). Clonidine did not contribute to sedation and its influence on haemodynamics was minimal. CSPA (IV) provided satisfactory pain relief with only limited blockade of the legs (no inter-group differences). EST (V) was often related to technical problems and difficulties of interpretation, e.g., it failed to identify the four patients whose catheters were outside the spinal canal already at the time of catheter placement. As adjuvants to lumbar CEA, clonidine only slightly improved pain relief, while adrenaline did not provide any benefit. The role of EST applied at the time of epidural catheter placement or repeatedly during CEA remains open. The microcatheter CSPA technique appeared effective and reliable, but needs to be compared to routine CEA after peripheral arterial bypass surgery.

Role of G protein coupled inwardly rectifier K+ channels (GIRK) on the neurobiology depression

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Avaliação da função endotelial em pacientes com hipertensão arterial resistente

A hipertensão arterial resistente (HAR) é definida pela persistência da pressão arterial (PA)≥140/90mmHg a despeito do uso de 3 anti-hipertensivos em doses plenas, incluindo diurético. Revisão recente da literatura mostra poucos estudos avaliando o perfil e o comportamento da função endotelial em pacientes com HAR. Objetiva avaliar a função endotelial em pacientes hipertensos resistentes. Estudo transversal com 60 pacientes que foram avaliados em uma visita (V3) de um estudo longitudinal, onde numa primeira fase todos pacientes tiveram padronização do tratamento anti-hipertensivo. Foram incluídos pacientes (V0) com PA>160/100mmHg e <220mmHg e todos receberam clortalidona 25mg/dia e enalapril 20mg 2x/dia ou losartana 50mg 2x/dia (intolerantes ao enalapril). Visita 1: se PA>140/90mmHg acrescentou-se anlodipino 5mg/dia, foi realizado avaliação laboratorial de rotina do hipertenso e monitorização ambulatorial da PA-24h (MAPA). Visita 2: se PA>140/90mmHganlodipino foi titulado para 10mg/dia. Visita 3: todos os pacientes receberam avaliação clínica, da pressão arterial por MAPA, laboratorial de rotina e da função endotelial. Formaram-se dois grupos: os que controlaram a PA, grupo hipertensão arterial controlada (HAC); e os que permaneceram com PA de consultório>140/90mmHg e PA na MAPA-24h>130/80mmHg, foram considerados resistentes. O grupo HAR recebeu aleatoriamente espironolactona ou clonidina por mais 12 semanas para tentar controlar a PA e o grupo HAC teve assistência farmacológica mantida no mesmo período. A PA foi avaliada por método oscilométrico com aparelho digital semi-automático Microlife modelo BP3AC1-1PC e MAPA por aparelho SpaceLabs 90207. A função endotelial avaliada através de tonometria arteriolar periférica (PAT) pelo Endo-PAT2000 e por biomarcadores (I-CAM-1, V-CAM-1, VEGF, MCP-1, IL-6, adiponectina) através da técnica LuminexTMxMAP. Dos 60 pacientes avaliados, 36 controlaram a PA, grupo HAC, e 24 permaneceram resistentes ao tratamento, grupo HAR, na visitaV3. Na avaliação da PA pela MAPA-24h observamos que no grupo HAC a PAS-24h foi de 121,1+1,7mmHg e no grupo HAR 147+3,3mmHg, enquanto a PAD-24h no grupo HAC foi de 76,64+1,5mmHg e no grupo HAR 88,58+2,4mmHg (p<0,0001). O descenso noturno, apesar de maior no grupo HAC, não apresentou significância estatística entre os dois grupos (p> 0,05). A função endotelial avaliada através do PAT mostrou índice de hiperemia reativa de 1,850,056 e 1,65+0,074 nos grupos HAC e HAR respectivamente (p= 0,036) e quando avaliada através dos biomarcadores observamos: ICAM-1 (HAC= 186,6+12,65 vs HAR= 240,9+23,76ng/ml, p= 0,038), VCAM-1 (HAC= 627,137,09vs HAR= 706,086,10ng/ml, p= 0,372),VEGF (HAC= 403,394,91 vs HAR= 612,788,27pg/ml, p= 0,123) e MCP-1 (HAC= 694,969,09 vs HAR= 787,052,80pg/ml, p= 0,315). Na avaliação dos biomarcadores inflamatórios, observamos IL-6 no grupo HAC= 1,8970,2165pg/mle no HAR= 9,7934,421pg/ml (p= 0,027) e adiponectina no grupo HAC= 105701516pg/ml e HAR= 84221295pg/ml (p=0,301). A razão de prevalência do comprometimento da função endotelial no grupo HAR foi de 54% (OR= 3,55; 95% IC 1,18- 10.67; p= 0,029). No presente trabalho, as análises das variáveis estudadas na visita V3, mostraram que os pacientes com HAR têm maior comprometimento da função endotelial que os pacientes com HAC.

Participação dos fatores derivados do endotélio no efeito vasodilatador da clonidina

Os mecanismos envolvidos na ação vasodilatadora da clonidina ainda não foram completamente elucidados. Investigamos os mecanismos potencialmente envolvidos utilizando o leito arterial mesentérico (LAM) isolado de rato. No LAM pré-contraído, clonidina (10-300 pmol) induz relaxamento dose-dependente, que foi significativamente inibido pela remoção do endotélio (ácido deoxicólico) e pelos inibidores do receptor α2-adrenérgico, ioimbina (1-3 μM) e rauwolscina (1 μM). A vasodilatação endotélio-dependente induzida pela clonidina foi reduzida pelo inibidor da oxido nítrico sintase (NOS), L-NAME (0.3 mM) e pelo inibidor da guanilato ciclase, ODQ (10 μM), mas não foi alterada pela indometacina (3-10 μM). Na presença do L-NAME, o efeito vasodilatador da clonidina foi adicionalmente reduzido pela solução de potássio elevado (45 mM). Os inibidores dos canais de K⁺ dependentes de cálcio (K_ca), caribdotoxina (ChTx; 0.1 μM) e apamina (0.1 μM) também reduziram a vasodilatação induzida pela clonidina, contudo, esta resposta não foi adicionalmente inibida na presença de L-NAME, como foi observado para acetilcolina (10 pmol). Na presença do bloqueador dos canais de K⁺ dependentes de ATP, glibenclamida (10 μM), o efeito inibitório da associação ChTx, apamina e L-NAME foi aumentado. Em contraste, a vasodilatação induzida pela clonidina não foi afetada pelo inibidor dos canais de potássio dependentes de voltagem (K_v), 4-aminopiridina (4-AP, 1 mM). Concluindo, nossos resultados demonstram que clonidina ativa receptores α2-adrenérgicos no LAM e que a vasodilatação dependente de endotélio é mediada pela ativação da via NO-GMPc e também envolve a ativação de canais de KC_{a e KATP.} Um fator hiperpolarizante derivado do endotélio (EDHF) também parece participar do efeito vasodilatador da clonidina.

树（左鼠右句）前额叶皮层神经元信息处理功能的alpha-2去甲肾上腺素能受体机制研究

本研究采用微电极胞外记录技术和微电泳技术探讨了树（左鼠右句）前额叶神经元的电生理及其alpha-2去甲肾上腺素能受体的性质发现：1.树（左鼠右句）前额叶神经元的自发放电以中频(1-10次/秒)为主。2.树（左鼠右句）前额叶存在多模和单模感觉相关神经元。3.树（左鼠右向）前额叶存在clonidine敏感神经元。4.在树（左鼠右向）前额叶多模神经元中，有较高比例的clonidine敏感神经元。本研究提示：树（左鼠右句）前额叶的clonidine敏感神经元大多为单模和多模神经元。推测这些感觉相关神经元的信息处理功能可能与alpha-2受体有关。此外，本研究表明树（左鼠右句）前额叶神经元电活动具有前额叶的特征。

去甲肾上腺素参与吗啡神经适应性改变的中枢机制

That relapse still exists even after prolonged withdrawal is a difficult issue in the medical cure of drug addiction. Neuro-adaptation induced by prolonged exposure to addictive drugs is the neural mechanisms of both compulsive drug seeking and relapse.Neuro-adaptation caused by addictive drugs increases the individuals’ response to drugs and on the other hand, it reduces the response to natural reward in withdrawn individuals.There must be common neural mechanisms between the co-existing phenomena, and there must also be unique neural mechanisms in the drugs.To reveal the neuro-adaptation arising in the process from random, controllable drug-use to uncontrollable compulsive drug seeking is of great significance both theoretically and practically.Based on the above hypothesis, in order to reveal the function of alpha adrenergic receptor in compulsive drug-seeking motivation during the process of drug addiction, using sensitization of morphine-induced psychomotor activity as behavioral model, through the method of behavioral pharmacology, the neural mechanisms of alpha adrenergic receptor’s involvement in the process of addiction has been studied.The adjustment function caused by alpha receptors in medial prefrontal cortex and nucleus accumbens to morphine-induced psychomotor activity has been compared in the period of first use of drugs and in repetitive-use period. Furthermore, the effect on novelty seeking caused by alpha-receptors in relevant brain areas has also been compared. Major results are as follow: 1 After prolonged morphine exposure, rats’ response to morphine-induced psychomotor activity is strengthened and response to novel object induced reward weakened. 2 Injection of prazosin in medial prefrontal cortex will block morphine-induced psychomotor activity of naïve rats, however, it will not block that of morphine-withdrawn rats, but it will block the novelty seeking behavior of morphine-withdrawn rats. 3 Injection of clonidine in medial prefrontal cortex will block morphine-induced psychomotor effect of both naïve rats and morphine-withdrawn rats, and will block the novelty seeking behavior of morphine-withdrawn rats. 4 Injection of prazosin in nucleus accumbens will not affect the morphine-induced psychomotor effect of either naïve rats or morphine-withdrawn rats, nor will it affect the novelty seeking behavior of morphine-withdrawn rats. 5 Injection of clonidine in nucleus accumbens will block morphine-induced psychomotor effect of naïve rats, however, it will not block that of morphine-withdrawn rats, nor will it affect the novelty seeking behavior of morphine-withdrawn rats. These results show: 1 The weakening of the function of alpha1 receptors in medial prefrontal cortex and alpha2 receptors in nucleus accumbens caused by repetitive exposure to morphine is probably the cause of compulsive drug-seeking activity. 2 Blocking alpha1 receptors in medial prefrontal cortex accelerates the loss of interest in natural reward after morphine withdrawal. 3 Blocking alpha2 receptors in medial prefrontal cortex not only restrains drug-seeking motivation, but also blocks the individual’s seeking motivation for novelty stimulus, which suggests that, while selecting medicine for curing addiction, it should be considered to reduce the influence on natural reward as much as possible and to avoid major side-effect.

Evidence for the presence of G-proteins, adenylyl cyclase and phospholipase C activities in lymphatic smooth muscle cell membranes

In plasma membranes derived from bovine mesenteric lymphatic smooth muscle cells, guanine nucleotide and forskolin stimulated adenylyl cyclase (AC) activity in a concentration-dependent manner, indicative of the presence of the stimulatory G-protein G(s) linked to AC. There was no significant enzyme inhibition by low concentrations of guanine nucleotide and no effect on basal or guanine nucleotide-stimulated activity following pertussis toxin treatment of cells, suggesting the absence of G(1) linked to inhibition of AC. Furthermore, there was no effect of adrenaline, isoprenaline or clonidine on basal or forskolin-stimulated activities, nor was there any specific binding of the beta-adrenoceptor ligand [I-125]cyanopindolol to membranes, suggesting that cate-cholamine receptors do not modulate AC activity in these membranes. Pertussis toxin-mediated ADP ribosylation of membrane proteins and Western immunoblotting analysis revealed the presence of G-protein subunits G(alpha l2), G(alpha q), G(alpha 11) and G(beta 1). In experiments designed to identify a possible effector enzyme for these G-proteins, membranes were screened with a range of antibodies raised against phospholipase C (PLC) beta, gamma and delta isozymes. Though no evidence was obtained by Western blotting for any of these proteins, PLC activity was concentration-dependently stimulated by Ca2+, but not by AlF4-, GTP[S], or purified G(beta gamma) subunits. Finally, no specific binding to membranes of the alpha(1)-adrenoceptor ligand [H-3]prazosin or the alpha(2)-adrenoceptor ligand [H-3]yohimbine was obtained. In conclusion, this study provides evidence for a G(s)-dependent stimulation of AC, and for the presence of G(2) and G(q11), which do not appear to regulate a PLC activity also identified in lymphatic smooth muscle cell membranes. Furthermore, neither AC nor PLC appear to be associated with catecholamine receptors. Copyright(C) 1996 Elsevier Science Inc.

α-Adrenergic agonism enhances the growth hormone (GH) response to GH-releasing hormone through an inhibition of hypothalamic somatostatin release in normal men

The purpose of this study was to investigate the precise mechanism by which central a-adrenergic pathways modulate GH secretion in humans. In 10 normal subjects we compared the pattern of clonidine-induced GH release to that elicited by GH-releasing hormone (GHRH) given at a time of presumably similar responsiveness of the somatotrope. We also evaluated the effect of stimulation by GHRH (either endogenous, by administration of clonidine, or exogenous) on the GH response to a further exogenous GHRH stimulation. In 2 experiments the administration of clonidine (0.150 mg, orally) at 0 or 60 min was followed by a GHRH [GRF-(1-29); 1 µg/kg, iv] challenge at 180 min. In other experiments subjects received on separate occasions placebo or clonidine at 0 min, followed by GHRH at 60 min and again at 180 min. In a further experiment the administration of clonidine at 0 min was followed by 2 GHRH challenges (60 and 180 min later). The administration of clonidine 60 or 120 min, but not 180 min, before the GHRH bolus significantly (P <0.01) increased the GH responses to this challenge compared to those elicited by GHRH when given after placebo in a period of a similar somatotrope responsiveness. These, in turn, were significantly (P <0.05) higher than those elicited by clonidine alone. The close relationship between pre-GHRH plasma GH values and GHRH-elicited GH peaks, not observed for clonidine, was lost after pretreatment with this drug. These data indicate that clonidine was able to disrupt the intrinsic hypothalamic-somatotroph rhythm, suggesting that a-adrenergic pathways have a major inhibitory effect on somatostatin release. Our data also indicate that GH responses to a GHRH bolus administered 120 min after a prior GHRH challenge are dependent on two parameters: the intrinsic hypothalamic-somatotroph rhythm at the time of the second GHRH bolus, and the magnitude of GH secretion elicited by the previous somatotroph stimulation. In summary, a-adrenergic agonism appears to act primarily in GH control by inhibiting the hypothalamic release of somatostatin, rather than by stimulating GHRH secretion.

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review

BACKGROUND: Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents.

OBJECTIVES: To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs.

DATA SOURCES: We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014.

METHODS: Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis.

RESULTS: Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001).

LIMITATIONS: Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors.

CONCLUSIONS: Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014101.

FUNDING: The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

Rhythmic Masticatory Muscle Activity during Sleep: Etiology and Clinical Perspectives

L’activité rythmique des muscles masticateurs (ARMM) pendant le sommeil se retrouve chez environ 60% de la population générale adulte. L'étiologie de ce mouvement n'est pas encore complètement élucidée. Il est cependant démontré que l’augmentation de la fréquence des ARMM peut avoir des conséquences négatives sur le système masticatoire. Dans ce cas, l'ARMM est considérée en tant que manifestation d'un trouble moteur du sommeil connue sous le nom de bruxisme. Selon la Classification Internationale des Troubles du Sommeil, le bruxisme est décrit comme le serrement et grincement des dents pendant le sommeil. La survenue des épisodes d’ARMM est associée à une augmentation du tonus du système nerveux sympathique, du rythme cardiaque, de la pression artérielle et elle est souvent en association avec une amplitude respiratoire accrue. Tous ces événements peuvent être décrits dans le contexte d’un micro-éveil du sommeil. Cette thèse comprend quatre articles de recherche visant à étudier i) l'étiologie de l’ARMM pendant le sommeil en relation aux micro-éveils, et à évaluer ii) les aspects cliniques du bruxisme du sommeil, du point de vue diagnostique et thérapeutique. Pour approfondir l'étiologie de l’ARMM et son association avec la fluctuation des micro-éveils, nous avons analysé le patron cyclique alternant (ou cyclic alternating pattern (CAP) en anglais), qui est une méthode d’analyse qui permet d’évaluer l'instabilité du sommeil et de décrire la puissance des micro-éveils. Le CAP a été étudié chez des sujets bruxeurs et des sujets contrôles qui ont participé à deux protocoles expérimentaux, dans lesquels la structure et la stabilité du sommeil ont été modifiées par l'administration d'un médicament (la clonidine), ou avec l'application de stimulations sensorielles (de type vibratoire/auditif) pendant le sommeil. Dans ces deux conditions expérimentales caractérisées par une instabilité accrue du sommeil, nous étions en mesure de démontrer que les micro-éveils ne sont pas la cause ou le déclencheur de l’ARMM, mais ils représentent plutôt la «fenêtre permissive» qui facilite l'apparition de ces mouvements rythmiques au cours du sommeil. Pour évaluer la pertinence clinique du bruxisme, la prévalence et les facteurs de risque, nous avons effectué une étude épidémiologique dans une population pédiatrique (7-17 ans) qui était vue en consultation en orthodontie. Nous avons constaté que le bruxisme est un trouble du sommeil très fréquent chez les enfants (avec une prévalence de 15%), et il est un facteur de risque pour l'usure des dents (risque relatif rapproché, RRR 8,8), la fatigue des muscles masticateurs (RRR 10,5), les maux de tête fréquents (RRR 4,3), la respiration bruyante pendant le sommeil (RRR 3,1), et divers symptômes liés au sommeil, tels que la somnolence diurne (RRR 7,4). Ces résultats nous ont amenés à développer une étude expérimentale pour évaluer l'efficacité d'un appareil d'avancement mandibulaire (AAM) chez un groupe d'adolescents qui présentaient à la fois du bruxisme, du ronflement et des maux de tête fréquents. L'hypothèse est que dans la pathogenèse de ces comorbidités, il y a un mécanisme commun, probablement lié à la respiration pendant le sommeil, et que l'utilisation d'un AAM peut donc agir sur plusieurs aspects liés. À court terme, le traitement avec un AAM semble diminuer l'ARMM (jusqu'à 60% de diminution), et améliorer le ronflement et les maux de tête chez les adolescents. Cependant, le mécanisme d'action exact des AAM demeure incertain; leur efficacité peut être liée à l'amélioration de la respiration pendant le sommeil, mais aussi à l'influence que ces appareils pourraient avoir sur le système masticatoire. Les interactions entre le bruxisme du sommeil, la respiration et les maux de tête, ainsi que l'efficacité et la sécurité à long terme des AAM chez les adolescents, nécessitent des études plus approfondies.