Interest in the role of alpha(α)-2-adrenoceptor agonists in anaesthesia and intensive care is growing. These drugs exhibit a wide range of effects that include sedation, anaesthetic-sparing, analgesia and sympatholytic properties. In Europe, clonidine is the most popular drug in this category and it has been used in situations such as ICU sedation, facilitation of regional anaesthesia and control of opioid or alcohol withdrawal syndrome.1 Clonidine is long acting and its use is often associated with rebound hypertension following discontinuation. Dexmedetomidine is a potent and more selective α2-adrenergic agonist than clonidine, with a similarly broad pattern of action on the mammalian brain. A large body of recent work supports its favourable profile in anaesthesia and intensive care.2–5 Cellular effects mediated by signalling pathways other than through α2-adrenoceptors have been reported, and have a role in neuroprotection, both in vitro and in vivo. There is growing appreciation that these brain-protective effects might be clinically important, as dexmedetomidine reduces the number of days of delirium or coma in mechanically ventilated patients in the ICU. In these patients, it does not significantly depress ventilatory drive and may preserve physiological sleep better than any other sedative. In addition, preliminary data suggest that it may reduce mortality in sepsis via attenuation of immunosuppression. Dexmedetomidine has recently found a place as an important adjunct to anaesthesia for certain surgical, endoscopic and imaging procedures. Although α2-adrenoceptor agonists reduce the incidence of major postoperative cardiac events in patients undergoing vascular surgery, uncontrollable hypotension and bradycardia have been reported in those with compromised left ventricular function or heart block.
In this review, we will present new insights into dexmedetomidine, with its promising impact on outcome in anaesthesia and intensive care. We will review the cellular non-α2-adrenoceptor-mediated effects and their implication for neuroprotection. We will comment on recent data supporting its use as an agent for ICU sedation and analgesia. Finally, we will consider the possible development of dexmedetomidine as a first-choice sedative agent for certain procedures and as an adjuvant to regional anaesthesia.
Basic non-alpha-2-adrenoceptor-mediated mechanisms of action of dexmedetomidine and their relevance to neuroprotection
The traditional view of the neuronal effects of dexmedetomidine was that they arose from stimulation of the α2-adrenoceptor inhibitory pathway, something well supported by related research. That this should have applications, particularly in neuroprotection, has generated much interest. Dexmedetomidine increases the phosphorylation of non-receptor tyrosine kinase, focal adhesion kinase, a key cellular enzyme, which may link momentary events, such as action potentials and transmitter release, to long-lasting effects in the brain such as plasticity and survival. In experimental models, this action has proved to be neuroprotective in situations that include neonatal cerebral excitotoxic injury. Elegant experiments indicate that this is mediated via stimulation of the α2-A-adrenoceptor subtype.6
Alternatively, there are several lines of evidence linking dexmedetomidine to important cellular effects mediated via pathways other than that of α2-adrenoceptor adenylate cyclase. It inhibits neuronal sodium and delays potassium inward rectifier currents.7 This mechanism accounts for the inhibitory action of dexmedetomidine on neuronal activity. It increases extracellular signal-regulated kinases (ERK)1/2 phosphorylation, a key mitogen-activated protein kinase involved in cell survival and memory. This effect is mediated via activation of protein kinase C, and probably imidazoline receptors. Dexmedetomidine also increases the expression of growth factors such as epidermal growth factor and brain-derived neurotrophic factors, which participate in neuroprotection. Recently, we have shown that dexmedetomidine exerts both preconditioning and postconditioning effects against ischaemic injury in hippocampal organotypic slice cultures.8 Both tyrosine kinase and ERK1/2 phosphorylation participate in these protective effects. This promises new perspectives for the clinical use of dexmedetomidine, as, theoretically, brain damage may be attenuated even when the drug is administered after injury. Unlike other agents such as volatile anaesthetics, dexmedetomidine was not found to facilitate the apoptotic cascade.9 Preliminary experimental data in a rabbit model of spine trauma failed, however, to show any benefit from dexmedetomidine (1 μg kg−1) in terms of recovery.
Role of dexmedetomidine for sedation and analgesia in mechanically ventilated ICU patients
The goals and standards of care for analgesia and sedation of mechanically ventilated ICU patients have undergone considerable changes in the past 10 years. There is now convincing evidence that an excessively deep level of sedation results in increased morbidity and perhaps mortality due to the prolongation of mechanical ventilation and ICU stay. On the contrary, inadequate sedation is associated with increased risk of accidental extubation and major cardiac events in those at risk for coronary syndrome. Except in specific situations such as severe head trauma and severe acute respiratory distress syndrome, the goal of sedation in the ICU is a calm, but rousable patient, who should be able to communicate his/her needs, particularly for analgesia. Algorithms for sedation and analgesia, based on the evaluation of comfort and pain by nurses using specific sedation and pain scales, have proved to be efficacious in accelerating recovery. Of note, daily awakening trials and active physiotherapy both reduce the duration of mechanical ventilation and ICU stay, and perhaps mortality.
Currently, propofol and benzodiazepines are the most frequently used agents for continuous ICU sedation in the United States and Europe, respectively. Dexmedetomidine has become available in the United States, Asia, Middle East, Japan, Australia, but not yet in Europe. However, it represents only 4% of the drugs used in the United States for ICU sedation.10 From the point of view of the intensivist, the agent has an interesting profile, as it preserves rousability, does not depress spontaneous ventilation and may facilitate weaning from the ventilator. Support for this comes from a volunteer study that measured bispectral index scores associated with an Observer Assessment of Alertness/Sedation score of 2 or less, and found them significantly lower with dexmedetomidine compared with propofol (46 vs. 67).11 At the same time, dexmedetomidine exhibits favourable properties towards brain protection, confirmed in two recent major trials on ICU sedation: MENDS, Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction12 and Efficacy of Dexmedetomidine Compared With Midazolam.13 In these prospective, controlled, randomised trials, dexmedetomidine for ICU sedation was compared with lorazepam. Although no difference in overall mortality was found, the number of days free of coma or delirium, a major complication in ICU patients, was markedly increased in the dexmedetomidine group. A recent meta-analysis9 of five studies confirms and extends these findings by showing a significant reduction in the risk of delirium with dexmedetomidine compared with control (relative risk 0.45; 95% confidence interval 0.32 to 0.64). A subgroup analysis of the MENDS trial included 19 septic patients in the dexmedetomidine group and 20 in the lorazepam group.12 Baseline characteristics, ICU type and admission diagnosis of the sepsis were similar in both groups. Dexmedetomidine-treated patients had more days that were free of delirium or ventilatory support. In septic patients, the risk of death at 28 days was reduced by 70% in the dexmedetomidine group compared with the lorazepam group (P = 0.04). Although these preliminary results need confirmation in larger prospective studies, it is possible that dexmedetomidine improves survival in septic patients by either specific immunologic mechanisms or by avoidance of lorazepam.14 Several lines of evidence suggest that dexmedetomidine prolongs survival in experimental models of sepsis. This effect may be mediated via reduction in the inflammatory process and cytokine production.15 Other possible contributing factors are lack of apoptosis induction by dexmedetomidine compared with other sedative/anaesthetics, and improved macrophage function. Interestingly, in a pilot study conducted in ICU patients with postoperative abdominal complications, blood levels of tumour necrosis factor-alpha, and interleukins 1 and 6 were found to be lower at 24 h after surgery in patients sedated with dexmedetomidine compared with those who had received propofol. Large differences in favour of the dexmedetomidine group were also observed in intraabdominal pressure at 24 h (12.4 ± 5.8 vs. 18.1 ± 2.8 mmHg, P < 0.05) and 48 h (13.9 ± 6.2 vs. 18.7 ± 3.5 mmHg, P < 0.05).16 A follow-up study13 has recently shown that in comparison with midazolam, patients sedated with dexmedetomidine had fewer secondary infections in the ICU.
Mechanically ventilated ICU patients experience disorganisation of their sleep pattern resulting from the busy nature of the ICU environment, the impact of certain drugs and mechanical ventilation.17,18 Patients interviewed after discharge from the ICU complain particularly of sleep deprivation. Sleep fragmentation due to the multiple episodes of awakening during the frequent disturbances that occur every night is another problem in those mechanically ventilated patients. Even several weeks after discharge, ICU patients continue to experience disturbance of sleep. What effect this might have on outcome in terms of morbidity or even mortality remains to be seen. Indirect experimental and clinical evidence exists to support the case that sleep disorders may interfere with weaning from the ventilator or might predispose to post-ICU cognitive dysfunction.19 Dexmedetomidine seems to better preserve quality and quantity of sleep compared with other sedative regimens.20 There is clinical evidence that the electroencephalography pattern associated with dexmedetomidine sedation mimics that of non-rapid eye movement sleep.21 This unique property makes this agent an excellent candidate for exploring attenuation of sleep disturbance and its putative consequences on long-term cognitive functions in ICU patients. Interestingly, the relationship between sleep deprivation and delirium has been studied for many years, and has been regarded as reciprocal.22 We might, therefore, speculate that dexmedetomidine may also reduce delirium by restoring, at least in part, sleep quality in ICU patients. In relation to this, dexmedetomidine was found to reduce the duration, but not the incidence, of delirium after cardiac surgery, with effective analgesia/sedation, less hypotension and requirements for vasopressors, but more bradycardia in comparison with morphine.23
The lack of experimental neurotoxicity and presence of neuroprotection in experimental models of perinatal excitotoxic injury suggest that dexmedetomidine might have a particularly appropriate role as a sedative and analgesic in the paediatric ICU. It has been successfully used for analgesia and sedation of preterm infants. The sedation target concentration is similar to that in adults but changes in clearance during the first years of life dictate that infusion rates are adjusted for age.16
Use of dexmedetomidine as a sedative/anaesthetic for miscellaneous procedures and as an adjuvant to local anaesthetics
Dexmedetomidine has been successfully used as the primary sedative/anaesthetic agent in various surgical, endoscopic and radiologic procedures. Recent evidence obtained from a prospective, randomised, double-blind, multicentre trial indicates that it is an effective and well tolerated baseline sedative for surgical patients requiring monitored anaesthesia care. It may be useful in patients with chronic obstructive pulmonary disease (COPD) undergoing percutaneous endovascular procedures requiring sedation and may be particularly suitable for sedation of children with obstructive sleep apnoea undergoing MRI.24,25 In a recent study,17 dexmedetomidine provided an acceptable level of anaesthesia for this procedure, and fewer interventions for airway obstruction were necessary compared with propofol sedation.
Adding dexmedetomidine to ropivacaine increased the duration of a peripheral nerve block.18 The mechanisms involved in this increased potency of the local anaesthetic may include first, a hyperpolarisation of nerve fibres to the inhibitory effect of α2-adrenoceptor agonists on Ih currents in peripheral nerves, and second, to anti-inflammatory properties of dexmedetomidine.26 These findings represent an encouraging first step for future studies in humans. Sedation has gained growing acceptance during regional anaesthesia as it improves the comfort of the patient.19 There is also the potential benefit of adding dexmedetomidine into a local anaesthetic solution intended for intravenous regional anaesthesia.27 What role there might be for dexmedetomidine in this context remains to be further investigated.
A recent review20 of 31 randomised controlled trials including 4578 patients considered the impact of α2-adrenoceptor agonists on the risk of undesirable major cardiac events and death in patients undergoing non-cardiac surgery. Although the trials were of variable quality, both the overall mortality and the risk of myocardial infarction were significantly reduced in patients receiving α2-adrenoceptor agonists. The protective effect was the most prominent in those undergoing vascular surgery but occurred at the expense of a significantly increased risk of bradycardia and hypotension.20 Although these data are encouraging, the risk/benefit balance of introducing dexmedetomidine perioperatively has to be considered cautiously, taking into account both the rare, but severe episodes of bradycardia and hypotension in patients with compromised left ventricular function, and preexisting heart block.21,28,29 This caution also applies to the use of dexmedetomidine in combination with continuous epidural analgesia when hypotension is the main concern. Also, the coadministration of other cardioprotective medications (beta-blockers and statins) has to be taken into account. Large randomised controlled trials are necessary to address this issue.
Key learning points
- Dexmedetomidine exerts both α2-adrenoceptor-mediated and α2-adrenoceptor-independent effects in the central nervous system.
- Dexmedetomidine's neuroprotective effects have extensive experimental support. Preconditioning and postconditioning against ischaemic injury represent properties that may be clinically important.
- As an agent for sedation in the ICU, dexmedetomidine is superior to benzodiazepines in decreasing the duration of mechanical ventilation, and increasing the number of days that are free of coma and delirium.
- Dexmedetomidine may increase survival in septic ICU patients. Hypotheses that may account for this are a decreased immunosuppressive action compared with other sedatives/analgesics and an opioid-sparing effect.
- Dexmedetomidine has a potential as a sedative/anaesthetic in a broad pattern of surgical, endoscopic and radiologic procedures, particularly in patients with COPD and in children.
- Dexmedetomidine as an adjuvant to local anaesthetics may prolong the duration of the anaesthetic and motor block.
When compared with other sedative and analgesic drugs, dexmedetomidine has unique properties that have led us to reevaluate its place in the perioperative period as well as in the ICU. The potential brain-protective properties of this agent are novel and promise interesting applications. The possibility of decreasing the incidence of long-term adverse effects such as cognitive impairment and posttraumatic stress disorder due to sedation of ICU patients offers a particularly interesting challenge. The occurrence of severe bradycardia and hypotension when dexmedetomidine is administered to those in whom no increase in sympathetic tone is possible, such as preexisting severe left ventricular failure, remains the major concern with its use. Future research should aim at a better understanding of the risk/benefit ratio of dexmedetomidine in the clinical setting.
This work was carried out solely with institutional funding.
J.M. has received an honorarium from Orionpharma for his advise on dexmedetomidine clinical development. S.H. and J.J. have no conflicts of interest.
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