Alpha2-adrenoceptor agonists: analgesia, sedation, anxiolysis, haemodynamics, respiratory function and weaning

BaillieÁre's Clinical Anaesthesiology Vol. 14, No. 2, pp. 433±448, 2000

doi:10.1053/bean.2000.0094, available online at http://www.idealibrary.com on

16 Alpha2-adrenoceptor agonists: analgesia, sedation, anxiolysis, haemodynamics, respiratory function and weaning Jean Mantz

MD, PhD

Professor of Anaesthesia and Critical Care Department of Anaesthesia and Critical Care, Hospital Bichat, 46 rue Henri Huchard, 75018 Paris, France

Over-sedation and subsequent prolonged mechanical ventilation are frequently observed in ICUs and may lead to an increase in morbidity and mortality. No single agent currently used in ICUs incorporates all the properties of an ideal sedative. However, dexmedetomidine, a potent and selective a2-adrenoceptor agonist, possesses most of these: it is a sedative that preserves rousability, it induces analgesia, it has predictable haemodynamic e€ects and it does not cause respiratory depression. Pre-clinical and clinical studies performed on post-operative patients requiring mechanical ventilation for less than 24 hours support that this agent could be safely used as a primary sedative agent in ICUs. Whether dexmedetomidine o€ers a clinically relevant bene®t in terms of outcome over any other agent used for ICU sedation remains to be assessed by large comparative, randomized, double-blind trials. Key words: critically ill; dexmedetomidine; sedation; rousability; analgesia; sympatholysis; respiratory depression.

Appropriate sedation is of extreme importance in ICUs. Critically ill patients are subjected to numerous adverse stimuli inherent to their illness and the environment, which induce both clinical and psychological undesirable e€ects. Pain and anxiety are most commonly felt by ICU patients and may trigger an increase in the plasma level of catecholamines or other stress hormones. It is the responsibility of the physicians in charge to minimize these adverse in¯uences by an appropriate management of the patient's state of tranquillity, anxiety and pain. The need for sedation and analgesia is extremely variable among patients, depending on pre-existing conditions such as drug or alcohol addiction, underlying disease and individual factors. There is also considerable variation in the sedation regimens used in ICUs. A common characteristic shared by ICUs around the world is that a large number of patients spend a large proportion of their ICU stay under an unsuitable level of sedation.1 The recent literature has emphasized the lack of randomized controlled trials for assessing the risk and bene®ts of sedative and analgesic strategies in the critically ill.1 Although the importance of non-pharmacological methods for alleviating agitation and anxiety is universally recognized, drugs are usually necessary to achieve the target level of sedation. The expected pro®le of an `ideal' sedative is that of a short-acting 1521±6896/00/020433‡16 $35.00/00

c 2000 Harcourt Publishers Ltd. *

434 J. Mantz Table 1. Characteristics of an `ideal' agent for ICU sedation. . . . . . . . .

Sedative with maintenance of rousability Analgesic Anxiolytic No accumulation No respiratory depression Haemodynamic stability No nausea or vomiting No constipation

Table 2. Problems with current sedative agents.

Prolonged weaning Respiratory depression Severe hypotension Tolerance Hyperlipidaemia Increased infection Constipation Lack of orientation and co-operation Abuse potential*

Midazolam

Propofol

Opioids

x x x x ± ± ± x x

± ± x ± x x ± x x

x x ± x ± ± x x* x

* High-dose opioids. x ˆ problem exists; ± ˆ no problem exists.

compound with no accumulation during prolonged periods of infusion or in patients with renal failure and easily titrable to the target level of sedation, as determined by a sedation scale (Table 1). This agent should be both sedative and analgesic. Recent data suggest that the maintenance of rousability or a certain level of alertness and cooperation provides a decisive advantage.2,3 The drug should also preserve haemodynamic stability, and induce no signi®cant respiratory depression in order to allow safe weaning from the ventilator. It should not produce nausea or vomiting or reduce intestinal transit. So far, no single agent currently used for ICU sedation achieves all these aims. The most widely used sedatives in ICU ± midazolam and propofol ± both exert signi®cant respiratory depression and potent vasodilatory e€ects, which may result in hypotension in the absence of careful titration. Opioids also potently depress ventilation and may decrease the immune response (Table 2). Interestingly, a2-adrenoceptor agonists show a good theoretical ®t with the pro®le of the ideal sedative agent. Clonidine is a long-acting a2-adrenoceptor agonist that is currently used for ICU sedation in some European countries. It exhibits both sedative and analgesic properties. It is, however, not easily titrable to the target level of sedation and is associated with a rebound of agitation and hypertension, making progressive discontinuation of the infusion necessary. There is currently a growing interest in the ®eld of developing more selective a2adrenoceptor agonists, one of the major reasons being the pharmacological `sympathectomy' achieved by these agents. Indeed, the stimulation of a2-receptors results in a decrease in sympathetic activity and norepinephrine release from both central noradrenergic neurones located in the locus coeruleus and peripheral sympathetic nerve terminals.4 The other reason is that increasing selectivity for a2-receptor

Clinical properties of alpha2-agonists 435

agonists should allow a better control of undesirable side-e€ects resulting from the stimulation of various non-a2-receptors. The pre-clinical pro®le of dexmedetomidine identi®es the drug as a potent, selective a2-receptor agonist. Dexmedetomidine has a much shorter elimination half-life (approximately 2 hours) than clonidine and is 1300 times more selective for a2- than a1-adrenoceptors than clonidine. It is also a full agonist in many experimental models in which clonidine displays only partial agonist activity. Its spectrum of activity is unique in that it exhibits sedative, anaesthetic-sparing, analgesic and sympatholytic properties.5,6 The experimental data have been extended to clinical studies in which this agent exhibited sedative, anxiolytic and analgesic properties when administered intravenously. Most interestingly, it does not induce clinically relevant respiratory depression. There is also recent evidence to support a bene®cial role of a2-agonists in improving intra-operative haemodynamic stability and reducing the incidence of perioperative myocardial ischaemia.7±9 Finally, antagonists of the e€ects of a2-adrenoceptors make a quick reversal of sedation an option.9 The aim of this chapter is to review the analgesic, sedative, anxiolytic, haemodynamic and ventilatory e€ects of dexmedetomidine and to discuss its place among the currently available agents used for ICU sedation and analgesia. ANALGESIA There is an increasing recognition of the importance of controlling pain in the critically ill patient. In addition to causing unnecessary su€ering, untreated pain can result in severe anxiety and even delirium, as well as having a detrimental e€ect on patient outcome.10,11 The physiological manifestations of pain result primarily from autonomic stimulation.12 Pain elicits sympathetic responses such as pallor and an increase in respiratory rate, heart rate, blood pressure and muscle tension. In critically ill patients, clinically signi®cant physiological responses to pain can include decreased lung volume, increased myocardial oxygen demand and sleep deprivation.13 Unremitting pain can also compromise patients' ability to communicate with physicians and nurses, as well as comply with diagnostic or therapeutic procedures. The assessment and treatment of pain must therefore be considered the clinician's ®rst priority.11 Although it is often possible to anticipate patients' requirements for analgesia after surgery, determining the need for analgesia in medical patients can be dicult. A large number of pain assessment scales have been developed, but this is no evidence-based medicine recommendation con®rming the preference for one over another.14 Most intravenous sedatives do not provide any degree of pain relief, and even unconscious patients may need additional analgesia. Interestingly, dexmedetomidine exhibits both sedative and analgesic properties. There is strong experimental evidence that the stimulation of a2-receptors leads to the production of analgesia at the spinal cord level.15±19 Animal studies have demonstrated that a2-agonists can potentiate the analgesic properties of opioids, including both a reduction in the amount of opioid required to reach the target level of analgesia and a longer duration of analgesia.20 Such a potentiation has been observed with various combinations of a2-agonists and opioids, occuring independently of the route of administration. Dexmedetomidine induces analgesia by acting on at least two di€erent locations: the brain and brain-stem, and the spinal cord.21 Clinical studies have also demonstrated the analgesic properties of dexmedetomidine in both volunteers and patients. A double-blind, placebo-controlled, cross-over

436 J. Mantz

study performed in healthy volunteers subjected to an ischaemic pain test found that the analgesic e€ects of single intravenous doses of dexmedetomidine of 0.25, 0.5 and 1.0 mg/kg were similar to that of a 2.0 mg/kg fentanyl dose.22 Both agents signi®cantly decreased the subjective pain score in comparison with placebo. Recently, another randomized, placebo-controlled study performed on volunteers evaluated the sedative, amnesic and analgesic properties of low-dose dexmedetomidine infusion (0.2 or 0.6 mg/ kg per hour). Pain in response to the cold pressor test was reduced by 30% during dexmedetomidine infusion in comparison with placebo.23 On the other hand, the administration of a single pre-operative dose of dexmedetomidine was associated with a reduction in both the intra-operative and post-operative opioid analgesic requirement.24,25 In the post-operative setting, a randomized, double-blind, placebo-controlled study including 96 patients undergoing tubal ligation found that dexmedetomidine signi®cantly relieved moderate-to-severe pain and reduced the need for opioid analgesics.26 The phase III multicentre trial on the ecacy and safety of dexmedetomidine for post-operative sedation lasting less than 24 hours also proved a remarkable analgesic ecacy of dexmedetomidine.27 In this randomized, double-blind, placebo-controlled study, 125 patients representative of the population that usually needs sedation and analgesia after major surgery were enrolled in 13 French institutions. Upon arrival in the post-surgical ICU, they were allocated to receive either dexmedetomidine (6 mg/ kg over 10 minutes followed by a 0.2±0.7 mg/kg per hour over 24 hours) or placebo to maintain a Ramsay sedation score (see Table 3 below) of less than 4. Rescue midazolam or propofol administration was scheduled if required, as was morphine to control postoperative pain. In this study, the number of patients requiring additional morphine boluses post-operatively was signi®cantly reduced in the dexmedetomidine group compared with the placebo group. The morphine dose delivered was markedly reduced in the dexmedetomidine group as well. Taken together, these data demonstrate that dexmedetomidine exerts analgesic properties in the clinical setting, particularly in patients requiring post-operative sedation for less than 24 hours. The dose of dexmedetomidine used here was, however, not potent enough to suppress the need for additional morphine in all ICU patients. Therefore, the analgesic potency of dexmedetomidine in this context and the appropriate dose could be addressed more accurately in further studies comparing the e€ect of dexmedetomidine and opioid administration on the response to painful stimuli such as endotracheal suction or the care of major abdominal wounds by the nursing sta€. SEDATION The sedative e€ects of a2-agonists are well known. The ®rst evidence that clonidine and dexmedetomidine exerted a sedative e€ect was that both agents reduced the anaesthetic requirement for intravenous or volatile anaesthetics in animals.21 These data have been extended to the clinical setting. For example, a 0.6 ng/ml dexmedetomidine concentration reduces the minimal alveolar concentration of iso¯urane by 47%.28 Clonidine administered as a premedicant is also able signi®cantly to decrease the propofol requirement in patients undergoing elective orthopaedic surgery.29 Dexmedetomidine (1.0 mg/kg intramuscularly) produces a signi®cant decrease in the amount of thiopentone required for the induction of anaesthesia, similar to that of midazolam (0.08 mg/kg).30 Furthermore, the pre-operative administration of

Clinical properties of alpha2-agonists 437 Table 3. The Ramsay sedation scale. Clinical score

Level of sedation achieved

1 2 3 4 5 6

Patient anxious, agitated or restless Patient co-operative, orientated and tranquil Patient responds to commands Asleep but with a brisk response to a light glabellar tap or loud auditory stimulus Asleep, sluggish response to a light glabellar tap or loud auditory stimulus Asleep, no response

dexmedetomidine (2.5 mg/kg intramuscularly) produces sedation comparable to that seen with midazolam (0.08 mg/kg) in patients undergoing abdominal hysterectomy, cholecystectomy or intra-ocular cataract surgery.25 In the phase III multicentre trial, the sedative e€ects of dexmedetomidine have been further demonstrated in the critically ill by showing a signi®cant reduction in the amount of rescue hypnotic (midazolam or propofol) administered during the study period.27 The sedative e€ect of dexmedetomidine exhibits original features that make its use potentially very interesting as a sedative for the critically ill. First, its short duration of action facilitates a rapid adaptation of sedation to a target level, such as that assessed by the Ramsay scale.31 Although not perfect (as this is a subjective scale that is dependent on motor function), it has for decades remained the gold standard for assessing sedation at the bedside, and it is the most widely used sedation scale in the world (Table 3). The rapid titrability of the dexmedetomidine dose regimen to the target Ramsay score was one of the most prominent observations of the phase III trial.27 Dexmedetomidine is associated with a pattern of sedation di€erent from that of all the other sedatives currently available. Behavioural studies performed in rats have evaluated the e€ects of dexmedetomidine on motor response, attention and shortterm memory.32,33 The study protocol involved the random presentation of brief ¯ashes of light in one of ®ve di€erent locations to food-deprived rats. The animals were trained to detect and respond to this stimulus to obtain food. Compared with normal saline, a single dose of dexmedetomidine (0.3±3 mg/kg) did not alter the accuracy of choice and did not signi®cantly prolong the latency of response of food collection, although errors of omission increased. These observations suggest that even though dexmedetomidine reduces the background level of arousal and behavioural activity, it preserves such brain functions as attention and short-term memory. The sedation pro®le achieved by dexmedetomidine in both volunteers and patients is also unique. In volunteers, double-blind, placebo-controlled, cross-over studies have examined the sedative e€ects of a single intravenous dose of dexmedetomidine (0.5 or 1.0 mg/kg) using a visual analogue scale of subjects' own estimation of their level of vigilance.34,35 Other measurements of sedation included the Maddox±Wing test, the critical ¯icker fusion frequency threshold and saccadic eye movements.36±38 Dosedependent e€ects were observed on subjective as well as objective measurements. The subjects quickly became sedated. Notably, however, they remained easily rousable while on dexmedetomidine infusion and were able to participate in the visual analogue scale assessment without any need to delay testing. What is unique is that the performance in the critical ¯icker fusion task of the volunteers receiving a dexmedetomidine infusion targeted at a plasma concentration of 1.2 ng/ml was identical to that of the placebo group.

438 J. Mantz

A recent study performed on volunteers evaluated the sedative and amnesic properties of low-dose dexmedetomidine infusion.23 Dexmedetomidine produced signi®cant sedation associated with an impairment of memory (50%) and psychomotor performance (28±41%). Most interestingly, bispectral index values were signi®cantly higher in the placebo group than in the 0.2 and 0.6 mg/kg per hour groups. However, the bispectral index values were identical in all the groups during cold pressor or cognitive testing. This con®rms and extends the fact that dexmedetomidine preserves rousability, even if the level of performance is impaired. It also supports the fact that dexmedetomidine has an amnesic e€ect, which may be extremely desirable in ICU patients subject to painful procedures such as catheterization, surgery or interventional procedures, or endotracheal intubation and mechanical ventilation. The sedative action of dexmedetomidine has also been demonstrated in ICU patients. In the phase III multicentre trial on the ecacy and safety of dexmedetomidine for sedation and analgesia27, 90% of the 63 patients who received dexmedetomidine did not require additional therapeutic doses of propofol or midazolam to maintain the target Ramsay score. In contrast, only 58% of the patients allocated to the placebo group required the administration of rescue hypnotics. This percentage could have been reduced still further by making the nursing sta€ more familiar with the pattern of sedation of this agent. Patients receiving dexmedetomidine experience a signi®cantly higher level of comfort during sedation than do those taking placebo. They appeared to be in a tranquil state and adapted to the mechanical ventilators. Upon verbal stimulation by the medical or nursing sta€, they were easily able to understand and communicate their needs, particularly their analgesic requirement. This was followed by a rapid restoration of the quiet state. In addition, the particular pro®le of sedation probably allows the physician accurately to evaluate the neuropsychological status of critically ill patients while maintaining the infusion, which is impossible with any other sedative currently used in ICU. The bene®t of avoiding over-sedation has been recently highlighted2 (Table 4). Over-sedation is frequently observed in ICU patients and may contribute to increased morbidity or a prolonged length of stay in ICU.1,2 Dexmedetomidine may allow the evaluation of the neuropsychological status of critically ill patients without discontinuing the infusion. Most interestingly, no rebound or psychiatric disorders were observed in patients receiving dexmedetomidine after cessation of the infusion in this study. Long-term cognitive impairment has been reported to occur frequently after anaesthesia and surgery.39 In contrast, very few data obtained from trials designed using a proper methodology are available on the cognitive and neuropsychological sequelae of an ICU stay, even though the reality of these consequences has been recognized for a long time.40,41 This area represents a very important ®eld of clinical research for the next few years. Dexmedetomidine could exhibit bene®cial e€ects over classical sedatives since it maintains rousability. In addition, trials aimed at demonstrating a bene®t of Table 4. Bene®ts of orientation and rousability in ICU patients. . . . . . .

Improved co-operation with diagnostic procedures Better compliance with therapeutic measures Facilitation of critical assessments (such as evaluations of neurological function) Patient is able to communicate needs to health-care providers and participate in the care process Patient is able to communicate with and o€er reassurance to family members Enhancement of patient's sense of control

Clinical properties of alpha2-agonists 439

dexmedetomidine over midazolam or propofol in reducing the length of ICU stay and the duration of mechanical ventilation should be initiated based on the experience reported by Kress et al.2 ANXIOLYSIS One of the primary goals of ICU sedation is the relief of anxiety. It not only contributes to greater patient comfort, but also facilitates medical care.42 Anxiety is characterized by a subjective feeling of fear and uneasy anticipation or apprehension and is associated with hormonal and physiological manifestations of stress.43 Major causes of anxiety in the ICU include monitoring equipment, mechanical ventilation, the rapid pace of the ICU, the high noise level, sleep deprivation and drug therapies that alter the mental state.44 Data reporting speci®cally on the anxiolytic e€ects of a2-adrenoceptor agonists are scarce. Dexmedetomidine appears to have anxiolytic e€ects in the peri-operative period. Following the intramuscular injection of 2.5 mg/kg dexmedetomidine, the reduction in anxiety assessed using a visual analogue scale was comparable to that observed after the intramuscular injection of midazolam in patients receiving general anaesthesia.25,34 Also, the administration of 1.0 mg/kg intravenous dexmedetomidine 10 minutes before exsanguination of the arm reduced patient apprehension during minor hand surgery under regional anaesthesia.45 In another double-blind study, the anxiolytic e€ect of dexmedetomidine was examined in 192 patients undergoing hysterectomy, cholecystectomy or intra-ocular surgery.25 Results indicated that dexmedetomidine produced a degree of anxiolysis comparable to that achieved with benzodiazepines. The assessment of anxiety in ICU patients is particularly dicult. Indeed, no speci®c tool has been validated for measuring this highly subjective feeling in those who are mechanically ventilated and critically ill. The Ramsay scale was not designed adequately to address this point. Other anxiety scales have been developed, most of them for use in medical outpatient clinics.46 Developing and validating simple, easy-to-use anxiety scales for ICU remains a challenge for the future, one which could contribute greatly to the quality of care. Dexmedetomidine may have potential to achieve satisfactory anxiolysis in ICU patients. This should, however, be further investigated and assessed. HAEMODYNAMICS Haemodynamic stability also represents an important goal in ICU patients. Increasing stress results in an elevation of the plasma catecholamine concentration as a result of stimulation of the sympathetic nervous system. When activated, the sympathetic nervous system triggers the release of norepinephrine from pre-synaptic nerve endings and of epinephrine from the adrenal medulla.47 The surge of catecholamines produces a hyperdynamic state associated with tachycardia and an increase in blood pressure. Tachycardia has been identi®ed as a critical factor in this situation since blood ¯ow in the myocardium is a function of the diastolic interval. In addition, the myocardial oxygen demand is related to the sympathetic nervous system's e€ect on heart rate, contractility and myocardial wall stress. The latter is strongly a€ected by both ventricular pre-load and the in¯uence of systemic vascular resistance on afterload. In this situation, myocardial ischaemia may result from impaired coronary blood ¯ow, an

440 J. Mantz

imbalance between myocardial oxygen demand and supply, or a combination of the two. As an additive factor, multiple organ failure in the critically ill patient may impair oxygen delivery to the myocardium and also contribute to haemodynamic instability. Furthermore, subtle signs of myocardial ischaemia may be missed or recognized too late in ICU. As a result, factors that increase sympathetic discharge and produce haemodynamic instability represent potentially adverse factors. Common conditions that can favour a hyperadrenergic state include untreated pain and anxiety, fever, interventional procedures and recovery from surgery and anaesthesia. Attempts to counteract the sympathetic hyperactivity in this subpopulation have often used sedative hypnotics such as benzodiazepines or propofol. Careful titration of these agents is, however, mandatory in order to avoid hypotension, which results in organ hypoperfusion and can precipitate as well myocardial ischaemia or cerebral vascular disease. Several lines of evidence suggest that decreasing the activity of the sympathetic nervous system in the peri-operative period provides protection against myocardial ischaemia. Long ago, Roizen ®rst described the results of published studies that supported the pharmacological manipulation of the sympathetic nervous system and its bene®cial e€ect in the peri-operative period.48 Stone et al investigated the e€ects of a single pre-operative dose of one of several b-blockers (labetalol, atenolol or oxprenolol) on the incidence of peri-operative ischaemic episodes in hypertensive patients.49 They detected brief, self-limited episodes of myocardial ischaemia during tracheal intubation and/or emergence from anaesthesia in 11 out of 39 untreated patients but only 2 out of the 89 patients receiving b-blockers. In another study, Mangano et al emphasized the importance of blocking the sympathetic system in order to prevent myocardial ischaemia and subsequent mortality, and severe cardiovascular complications after non-cardiac surgery. In a randomized, double-blind, placebo-controlled study of 200 patients, they compared the e€ect of atenolol with that of placebo on overall survival and cardiovascular morbidity in patients with or at risk of coronary artery disease. Compared with placebo recipients, patients receiving b-blockers had a signi®cantly lower average heart rate (75 versus 87 bpm) and maximal heart rate (113 versus 130 bpm). Over the 5 months following hospital discharge, the overall mortality from hospital was signi®cantly lower in the atenolol-treated patients than in those given placebo (0% versus 8%).50 These results have been supported by recent data showing the ecacy of atenolol in improving survival in high-risk coronary patients undergoing vascular surgery.51 Interestingly, it has been elegantly demonstrated that it is the reduction of heart rate, rather than the b-adrenergic receptor blockade per se, that is bene®cial in terms of improving cardiovascular morbidity in the peri-operative setting.52 There are no published reports of any anaesthetic, sedative or analgesic drug and/or any strategy that can improve cardiovascular morbidity.53 The eciency of a2adrenoceptor agonists in blocking the sympathetic nervous system and the subsequent reduction in heart rate may, however, confer on them the same protective e€ect as bblockers to prevent myocardial ischaemia in particular subpopulations of patients.54 Both clonidine and mivazerol have been shown to reduce the incidence of perioperative myocardial ischaemia in large, multicentre, randomized trials.55,56 In these studies, mivazerol was found to be safe and not associated with signi®cant hypotension or adverse e€ects.8,56 No clear bene®t in terms of mortality was, however, observed in the mivazerol-treated group.

Clinical properties of alpha2-agonists 441

Dexmedetomidine's haemodynamic e€ects have been well documented in numerous experimental models. At its usual concentration, dexmedetomidine has no direct e€ect on heart rate or on contractile force, as was shown in isolated heart and heart±lung preparations as well as on autonomically denervated dogs.57,58 The sympatholytic e€ect exerted by dexmedetomidine appears to decrease the myocardial energy requirement and oxygen consumption.59 In addition, large intravenous doses of dexmedetomidine produce moderate regional coronary vasoconstriction without any metabolic signs of myocardial ischaemia in the pig.60 The haemodynamic-stabilizing e€ect of dexmedetomidine in patients is well documented in a number of studies using healthy subjects as well as post-surgical patients.25,26,47,61±63 In a double-blind, randomized, placebo-controlled trial performed on volunteers, only a mild change in heart rate and blood pressure was observed for plasma concentrations of up to 2.0 ng/ml.64 Dexmedetomidine therefore has a predictable and potentially bene®cial haemodynamic pro®le and may decrease the incidence of cardiac ischaemia and related morbidity in surgical patients.65,66 In a study of patients with severe coronary disease undergoing coronary artery bypass surgery, the administration of dexmedetomidine led to an attenuation of the hypertensive and tachycardic e€ects.63 This is important in so far as tachycardia has been recognized as a major risk factor for developing myocardial ischaemia in patients undergoing myocardial revascularization.53 The characteristic biphasic e€ects of dexmedetomidine re¯ect the dominance of the central versus peripheral sympatholytic e€ects of a2-adrenoceptor agonists. The initial response to a rapid dexmedetomidine infusion is stimulation of the peripheral a2adrenoceptors located in vascular smooth muscle, leading to an increase in contractility and a subsequent rise in blood pressure.61 This is, however, a transient event that is superseded by the dominant central sympatholytic e€ects of decreased blood pressure and heart rate (Figure 1). In the ICU, data collected from clinical sedation studies also con®rm the predictable haemodynamic pro®le of dexmedetomidine.27,65 In the phase III study, dexmedetomidine-treated patients typically exhibited a slight, non-signi®cant increase in blood pressure following the 10 minute loading infusion. This was followed by a more gradual, moderate decrease in blood pressure and heart rate that was observed during the whole dexmedetomidine infusion period. Upon cessation of the dexmedetomidine administration, the restoration of base-line values occurred progressively. Interestingly, 1) Initial effect—receptors on peripheral blood vessels RESULTS Blood pressure Blood pressure Heart rate 2) Sympatholytic effect at higher doses leading to: • Vasodilation • Decreased heart rate Figure 1. Vascular e€ects of dexmedetomidine.

442 J. Mantz

no hypertensive and/or tachycardic rebound was observed after discontinuation of the dexmedetomidine infusion. The decrease in blood pressure was generally easily correctable using ¯uid challenge and/or atropine or short-acting vasopressors such as ephedrine. No mortality was attributable to dexmedetomidine in this trial. However, severe hypotension was observed in some situation, mostly uncorrected hypovolemia and severe cardiac failure. In both of these, turning o€ the sympathetic activity may result in collapse since these patients exhibit maximal compensatory sympathetic hyperactivity. Therefore, dexmedetomidine should probably be avoided in these patients. In addition, careful titration of the dexmedetomidine infusion is mandatory in patients more prone to developing hypotension than the general population. This subpopulation of patients includes elderly subjects, patients with pre-existing severe heart block or receiving either bradycardic and/or vasodilatory medication, and diabetic patients with dysautonomia. Based on these considerations, dexmedetomidine may have the potential to reduce cardiovascular morbidity in critically ill patients. Further studies are, however, needed to assess the haemodynamic safety of speci®c subpopulations of critically ill patients, such as shock or trauma patients. In addition, the e€ect of long-term infusions on sedative and analgesic ecacy and haemodynamic safety should be examined before this agent can be recommended for routine ICU sedation. RESPIRATORY FUNCTION AND WEANING Improving respiratory function and weaning from mechanical ventilation, as well as reducing the number of complications associated with mechanical ventilation, remain a major challenge in ICU patients and deserve considerable e€orts at the present time. Barotrauma, for example, has been identi®ed as a major cause of mortality in mechanically ventilated patients.67 Strategies have therefore been designed to minimize the consequences of barotrauma on outcome in patients with acute respiratory disease syndrome (ARDS). In a randomized trial performed on 53 patients with ARDS, a protective strategy including limitation of driving pressure, permissive hypercapnia, the use of a low tidal volume and a pulmonary end-expiratory pressure above the in¯ection point of a static pressure±volume curve produced an improvement in survival at day 28 and a higher rate of weaning from mechanical ventilation.68 Very similar strategies failed, however, to demonstrate an improvement in outcome for patients at risk of developing ARDS within the ®rst 24 hours after intubation.69 In a recent multicentre, randomized trial, the bene®t for in-ICU mortality provided by a 6 ml/kg versus a 12 ml/kg tidal volume mechanical ventilation could be demonstrated in these patients.70 In addition, the number of days without ventilator use from day 1 to day 28 was reduced in the 6 ml/kg tidal volume group. Therefore, the use of low tidal volumes can be strongly recommended as part of the therapeutic procedure in the management of ARDS, although the causal relationship between pneumothorax and mortality has been challenged in ARDS.71,72 On the other hand, a recent large study has focused on the improvement in weaning from the ventilator in critically ill patients.73 Several lines of evidence support the fact that mechanical ventilation can be safely discontinued in patients who meet screening criteria and tolerate trials of unassisted breathing.74±76 Although some techniques, such as the use of pressure support ventilation, may be bene®cial in some subpopulations of ICU patients, no clear-cut bene®t of one technique over another

Clinical properties of alpha2-agonists 443

could be demonstrated.74,77 Also, such techniques as non-invasive ventilation via a facemask represent an elegant alternative in some subpopulations of critically ill patients.78 The role of sedation in residual respiratory depression and weaning diculties has now become a major topic of interest. Indeed, there is convincing evidence that oversedation prolongs the duration of mechanical ventilation in critically ill patients.1,2 Most of the agents currently available for ICU sedation depress spontaneous ventilation and may therefore delay extubation. Interestingly, several lines of evidence suggest that dexmedetomidine does not signi®cantly depress spontaneous ventilation. Pre-clinical studies have shown that dexmedetomidine administered to rats in doses of 10±30 mg does not a€ect the respiratory rate or PaCO2. In addition, it did not potentiate the respiratory depressant e€ects of alfentanil in this species.79 In dogs, the slope of the carbon dioxide response curve was only minimally depressed for clinical doses of dexmedetomidine, while no e€ect was observed on the hypoxic ventilatory drive.80 Interestingly, hypercarbia induced by dexmedetomidine in rabbits could be promptly reversed by idazoxan, a selective a2-adrenergic agonist.81 The e€ects of dexmedetomidine on re-breathing carbon dioxide curves has been studied in volunteers.82 Only a very small increase in the slope of the carbon dioxide response curve was observed at clinical concentrations. In the phase III trials on the ecacy and safety of dexmedetomidine, no extensive measurement of the e€ect of dexmedetomidine on ventilatory parameters was performed. However, no change in either respiratory rate or PaCO2 was detected in spontaneously breathing patients still receiving a dexmedetomidine infusion following extubation.27,65 It is remarkable that patients could be extubated while being still administered dexmedetomidine, which is not possible with any other sedative used in ICU. Therefore, the potential bene®ts of maintaining the infusion after extubation (the maintenance of a quiet state and the analgesic e€ect) represent a decisive advantage of dexmedetomidine over other agents. In addition, the possibility of rapidly antagonizing the e€ects of this agent is very interesting. More speci®c data on the e€ects of dexmedetomidine on respiratory function (tidal volume and airway occlusion pressure) are, however, needed. Furthermore, whether the lack of respiratory depression achieved by this agent represents a bene®t in terms of clinical outcome (a reduction in the duration of mechanical ventilation) remains to be determined. It can be anticipated, however, that dexmedetomidine could be particularly suitable for facilitating weaning processes of long duration, such as those of patients with chronic obstructive pulmonary disease.

CONCLUSION Dexmedetomidine exhibits unique properties in comparison with any other sedative used in ICU at the present time: it is both sedative and analgesic, it maintains rousability, it has a moderate, predictable and in some circumstances potentially bene®cial haemodynamic sympatholytic e€ect, and it does not induce clinically signi®cant respiratory depression, allowing extubation while maintaining infusion. Dexmedetomidine should be considered to be not an adjuvant but a primary agent of sedation. Additional information, as detailed in the research agenda below, is, however, still needed, but for the investigators who have used it during the phase III trial, the bene®t-to-risk ratio of this agent used as a sedative in mechanically ventilated post-operative patients appears to be positive.

444 J. Mantz

SUMMARY There is growing interest in developing novel approaches, both pharmacological and non-pharmacological, to the sedation of critically ill patients. The importance of maintaining rousability in critically ill patients has recently been emphasized, potentially improving quality of care and decreasing cost. The ideal agent of sedation should be both sedative and analgesic, should provide haemodynamic stability and induce no respiratory depression, and should be anxiolytic. No single agent currently used for the sedation of critically ill patients ®ts all these criteria. Dexmedetomidine is a potent, selective, short-acting adrenergic a2-receptor agonist. Its selectivity confers on it fewer undesirable side-e€ects than are seen with Practice points . in contrast with any sedative agent currently used in ICU, dexmedetomidine exhibits both sedative and analgesic properties . the pattern of sedation achieved by dexmedetomidine is unique in so far as it preserves rousability . the haemodynamic e€ects of dexmedetomidine are moderate and predictable, consisting of a mild decrease in blood pressure and heart rate resulting from sympatholysis . dexmedetomidine induces no clinically relevaant respiratory depression . the bene®t-to-risk ratio of dexmedetomidine in ICU patients with respect to length of stay or duration of mechanical ventilation remains to be established Research agenda . the analgesic e€ect of dexmedetomidine should be assessed in comparison with that of an opioid. Particular painful stimuli, such as endotracheal suction or ®bre-optic bronchoscopy with bronchoalveolar lavage, could be used . the short- and long-term cognitive and neuropsychological sequelae of an ICU stay should be assessed in prospective trials comparing dexmedetomidine as a primary agent of sedation to midazolam or propofol . prospective, double-blind, randomized trials aiming at demonstrating a bene®t of long-term dexmedetomidine infusion over midazolam or propofol in reducing the length of ICU stay and the duration of mechanical ventilation should be initiated . the EEG pattern and the e€ect of dexmedetomidine on REM sleep should be investigated . the unique sedative pro®le of dexmedetomidine, preserving rousability, should be demonstrated against a comparator (midazolam or propofol) using measurements of cognitive performance . extensive haemodynamic data could be obtained from studies in which dexmedetomidine is used for the sedation of cardiac surgical patients requiring Swan±Ganz catheters and transoesophageal echocardiography . the bene®cial e€ect of dexmedetomidine on respiratory function (respiratory rate, airway occlusion pressure and incidence of obstructive apnoea) compared with the e€ect of midazolam should be assessed in post-surgical patients

Clinical properties of alpha2-agonists 445

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