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

Introduction

Sedation is ‘a drug-induced depression of consciousness, a continuum culminating in general anaesthesia’. 1 Sedation is a key component of care of critically ill patients, who often need to undergo potentially invasive or uncomfortable procedures such as mechanical ventilation (MV). 2–6 Indications for the use of sedation in the intensive care unit (ICU) include: to alleviate pain; to facilitate use of distressing procedures and minimise patient discomfort; to provide protection from stressful and harmful stimuli; to reduce agitation and control agitation; and to enable nocturnal sleep and, when necessary, amnesia. 6–11 Sedation requirements vary widely between patients and sedative regimens should be tailored to individual patient’s needs [Sheila Harvey, Intensive Care National Audit and Research Centre (ICNARC), 2014].

Evidence from randomised controlled trials (RCTs) and current guidelines supports the use of the minimum possible level of sedation to achieve the desired effects without compromising patient comfort and safety. 12,13 A review of international surveys of critical care clinicians published between 1999 and 2009 confirmed that the trend was towards lighter levels of sedation,4 with only a minority of patients in need of continuous deep sedation. 13–15

The optimal level of sedation varies according to patients’ clinical conditions and treatment requirements. The prevalence of anxiety and agitation in critically ill patients undergoing MV in the ICU has been reported to be > 70%. Hence, assessment of sedation level should be routinely performed in ICUs. 14,16 Sedation level is usually measured by ICU staff by means of scoring sedation scales. Several scales have been developed to monitor sedation levels in critically ill patients. The first standardised measurement for sedation was the Ramsay Sedation Scale (RSS),17 which has been more recently superseded by the Richmond Agitation–Sedation Scale (RASS)18,19 and the Riker Sedation–Agitation Scale (SAS). 20 Scores on the RASS range from 4 (combative) to –5 (cannot be aroused). Riker SAS scores range from 7 (dangerous agitation) to 1 (cannot be aroused). For mechanically ventilated critically ill patients, target scores of between –2 and 0 for the RASS and between 3 and 4 for the Riker SAS are considered appropriate. 13 These scales have been shown to have good reliability and validity in the ICU setting, with neither being definitively superior. 12,14,21 Physiological methods to measure the level of sedation include heart rate variability, auditory-evoked potentials and electroencephalogram. 12,22 Among these, one of the most developed is the bispectral index, which measures the level of consciousness by an algorithmic analysis of the patient’s electroencephalographic and haemodynamic parameters, such as heart rate and arterial pressure. 11,23,24 Current UK and US guidelines do not recommend the use of physiological measures of brain function (e.g. bispectral index) as the primary method to monitor level of sedation in non-comatose, non-paralysed critically ill ICU patients, as these measures cannot adequately replace the existing subjective sedation scoring systems. 12,22

Sedation requirements are often not optimally managed, and poor sedation practice, which encompasses oversedation and undersedation, may have important deleterious effects. 3,6,25 Oversedation can result in cardiorespiratory depression, decreased gastrointestinal motility, immunosuppression and prolonged MV. Undersedation can cause hypertension, tachycardia and discomfort. 6 A variety of strategies have been proposed to address suboptimal management of levels of sedation of critically ill patients in ICUs, including use of sedation guidelines, protocols and goal-directed sedation algorithms,26–29 light target level of sedation and daily sedation interruptions (DSIs),30–34 and regular monitoring of sedation requirements. 35–37

The current Clinical Practice Guidelines from the Society of Critical Care Medicine for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit12 [pain, agitation and delirium (PAD) guidelines] strongly recommend the use of management guidelines and protocols. Protocolised target-based sedation and analgesia may be regarded as the cornerstone of effective sedation practice. 38

The PAD guidelines also recommend DSI or a light level of sedation in mechanically ventilated adults in ICUs. 12 Current evidence on the use of DSIs is far from conclusive. A RCT conducted by Girard and colleagues39 in four tertiary care hospitals found that a strategy comprising both daily spontaneous breathing attempts and daily spontaneous awakening attempts (i.e. DSIs) resulted in better outcomes (such as days breathing without assistance and length of stay in ICUs and hospital) than standard care. A meta-analysis of five trials published in 201140 highlighted the need for further RCTs with long-term survival follow-up before DSI could become standard sedation practice for critically ill patients. A multicentre RCT by Mehta and colleagues36 found that, in mechanically ventilated patients receiving continuous sedation, the combined use of protocol-guided sedation and DSI did not improve the clinical outcomes observed with the use of protocol-guided sedation alone. Similarly, a recent Cochrane systematic review35 did not find strong evidence that DSIs influence the duration of MV, mortality, length of stay, drug consumption, quality of life or adverse events compared with sedation strategies that do not involve the use of DSIs. The authors, however, considered the results to be unstable because of the small number of identified trials, the clinical and statistical heterogeneity observed among them and the marginally significant overall estimate of effect. Moreover, a reduction in duration of MV was detected when the analyses were restricted to trials conducted in North America. 35

Prior to initiating sedation, it is important to provide appropriate analgesia to all critically ill patients. 3,11,15 Adequate pain control can reduce the need for sedative drugs. 41 Pain can be experienced at rest by patients in the ICU42 or because of a number of other factors, including routine care, underlying disease processes, invasive procedures and immobility. 13,43 Pain is reported as the principal stressor by patients and is the most common memory they have of their ICU stay. 13,44,45 The PAD guidelines stress the importance of routine assessment of pain and provision of pre-emptive analgesia. 12 Analgesics and sedatives work in synergy but actually have discrete targets,6 and some analgesics also have a secondary sedative effect. 3 For example, remifentanil (Ultiva^®, GlaxoSmithKline UK Ltd), an opioid, can be administered as a sole agent because of its sedative effects, although it is not commonly used in most ICUs. 13

Clonidine (Catapres^®, Boehringer Ingelheim) also has both sedative and analgesic effects. 46 Patient’s requirements for analgesia and sedation should be thoughtfully balanced11 and sedation should never be given as a substitute for analgesia (Sheila Harvey, ICNARC, 2014).

Alongside assessment of pain, the PAD guidelines recommend the routine monitoring of delirium,12 which occurs in around 60–80% of mechanically ventilated patients in ICUs. 47–50 Delirium is associated with higher mortality, prolonged duration of MV, longer hospital stay and an increased risk of cognitive impairment among adult ICU patients 47,51,52 The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)53 and the Intensive Care Delirium Screening Checklist54 are the two most reliable instruments to assess delirium and their use is recommended by current guidelines. 12

Management of critically ill patients in intensive care units in the UK

A variety of medication is available to treat critically ill patients in ICUs. The choice of sedative or analgesic agents to achieve appropriate levels of sedation and pain relief can be quite challenging and must take account of the pharmacological properties of the different drugs as well as the individual patient’s characteristics and needs. 4,11,55 Sedative agents commonly used in ICUs include propofol (Diprivan^®, AstraZeneca), benzodiazepines [midazolam and lorazepam (Ativan^®, Pfizer)] and alpha-2 adrenergic receptor agonists [clonidine and dexmedetomidine (Dexdor^®, Orion Corporation)]. 34 Commonly used analgesic agents include alfentanil, fentanyl, morphine and remifentanil. 4,15 The current general trend in the UK, and internationally, is a shift from benzodiazepines to propofol and from morphine to alfentanil and fentanyl. 4,56,57 The 2013 PAD guidelines suggest that sedation strategies using non-benzodiazepines (either propofol or dexmedetomidine) may improve clinical outcomes in mechanically ventilated ICU patients over sedation strategies based on benzodiazepines (either midazolam or lorazepam). 12

Ideally, the optimal sedative regimen for critically ill patients in ICUs should adequately address pain, sedation and anxiety; have favourable kinetics and clinical effects; be easily titrated and monitored; have a tolerable adverse effects profile; and be affordable. 4 At present, none of the commonly used sedative agents fulfil all of these criteria and none of them has demonstrated to be clearly superior to the others. 4,13,56

Variation in services and/or uncertainty about best practice

A recent UK national survey conducted by the ICNARC among 235 adult general critical care units together with a point-prevalence study conducted among 52 adult general critical care units (Sheila Harvey, ICNARC, 2014) showed that just over half of the surveyed units (57%) reported the use of a written sedation or sedation/analgesia protocol and, of those that did, fewer than one-quarter assessed compliance with the protocol. Level of compliance with sedation protocols varied considerably across units, ranging from 26% to 100%. There was considerable variation with regard to the elements of pain, sedation and delirium management that were included in each protocol and the level of details provided. The majority of the units (94%) used a sedation scale/score for assessing the depth of sedation in patients. The RASS was the most frequently reported scale in use (65% of units), followed by the RSS (25%). Small proportions of units reported the use of the Riker SAS (3.5%), the modified RSS (3%), the Bloomsbury Sedation Scale (1%) and other local or modified scales. Most patients (88%) in the point-prevalence study were assessed using the same sedation scale/score reported in the survey, although variations were observed across units (from 63% to 100%). Seventy per cent of units reported screening for delirium daily and, of these, most (92%) reported using the CAM-ICU tool. Most units (94%) reported that a sedation hold was considered daily for sedated patients. The findings of the point-prevalence study indicate, however, that compliance with sedation holding may be quite low. Overall, only 53% of sedated patients who had been in the unit for at least 24 hours had been considered for a sedation hold during the previous 24 hours.

Despite the existence of numerous published studies and clinical guidelines for sedation and analgesia, there is still a great variation between units in terms of actual intensive care, suggesting that there are still some barriers to the implementation of all relevant recommendations into routine clinical practice.

Relevant national guidelines

The current clinical pathway for analgosedation in the ICU was published by the UK Intensive Care Society in 2014 and recommends sequential assessment and treatment of pain, sedation and delirium, with regular monitoring built into the pathway. 22 These guidelines are in line with the current US12 and German58 guidelines. The UK framework is presented in Figure 1.

FIGURE 1.

General framework for analgosedation in ICUs (the list of drugs is not exhaustive). 22 Reproduced from Grounds M, Snelson C, Whitehouse T, Wilson J, Tulloch L, Linhartova L, et al. Intensive Care Society Review of Best Practice for Analgesia and Sedation in the Critical Care with permission from UK Intensive Care Society (www.ics.ac.uk).

The National Institute for Health and Care Excellence Clinical Guidance Number 103,59 published in July 2010, provides general recommendations for the diagnosis, prevention and management of delirium. The only specific recommendations for people in critical care are that the CAM-ICU should be used if indicators of delirium are identified and that consideration should be given to provision of 24-hour clocks to patients to address cognitive impairment and/or disorientation. The UK Intensive Care Society guidelines also provide recommendations for managing delirium. 22 The suggested framework consists of three stages: assess (pain, discomfort, constipation, hunger, delirium, attempts to communicate); treat (analgesia, aperients, feed, drug withdrawal, change or stop sedative regimen); and prevent (alternative analgesia, sleep, quiet and calm environment, diligent and targeted sedation, communication).

Alpha-2 agonists

Dexmedetomidine is a newer, selective alpha-2 receptor agonist which has sedative, analgesic, anxiolytic and sympatholytic effects. 11,12,60 The sedative effects are mediated through decreased firing of the locus coeruleus, the predominant noradrenergic nucleus, situated in the brainstem. 61 The pattern of sedation of the alpha-2 agonists is quite different from that of other sedative agents in that patients can be aroused readily and their performance on psychometric tests is usually well preserved. 22,62,63 Moreover, dexmedetomidine does not depress the respiratory system, unlike other sedative agents. 64,65

The dexmedetomidine terminal elimination half-life is around 2 hours. 12,13 Main adverse effects related to dexmedetomidine are hypotension and bradycardia. 11,13,66 Transient hypertension may occur during loading infusion. 13

Dexmedetomidine was granted UK marketing authorisation in September 2011 for ‘sedation of adult ICU patients requiring a sedation level not deeper than arousal in response to verbal stimulation (corresponding to RASS 0 to –3)’. 67 According to the summary of product characteristics,61 dexmedetomidine is for hospital use only and should be administrated by a health-care professional skilled in managing patients requiring intensive care. It should be administered by intravenous infusion only, using a controlled infusion device. Doses are adjusted until the required level of sedation is attained. A loading dose is not recommended, as it is associated with increased adverse reactions. The maximum dose of dexmedetomidine is 1.4 µg/kg/hour. During infusion, all patients should undergo continuous cardiac monitoring, and respiration should be monitored in non-intubated patients. Use of dexmedetomidine for > 14 days requires monitoring and regular assessments. The combined use of dexmedetomidine with anaesthetics, other sedatives, hypnotics or opioids is likely to enhance pharmacological effects and, consequently, a reduced dosage of dexmedetomidine or the concomitant drug may be necessary. 61 In the USA, dexmedetomidine is authorised for infusion of up to 24 hours only in intubated and mechanically ventilated patients. 68

In clinical trials, dexmedetomidine has been shown to be similar to midazolam and propofol on the time in target sedation range in a predominantly medical population requiring prolonged light to moderate sedation (RASS score of 0 to –3) in the ICU for up to 14 days. 61,69 In addition, dexmedetomidine reduced the duration of MV compared with midazolam61,70,71 and reduced the time to extubation compared with midazolam and propofol. Compared with both propofol and midazolam, patients receiving dexmedetomidine were more easily aroused, were more co-operative and better able to communicate whether or not they had pain,61,70 and showed a lower rate of post-operative delirium. 20,64,72 The sedative benefits of dexmedetomidine compared with midazolam are, however, not conclusive. A systematic review of six RCTs (1031 intensive care patients) published in 2013 has highlighted the need for further, more robust, research as, so far, the evidence of the advantages of dexmedetomidine compared with midazolam in the ICU setting is limited. 2 A meta-analysis of 14 trials (3029 critically ill patients) published in 2014 showed that the use of dexmedetomidine in ICUs is associated with a significant reduction in the incidence of delirium, agitation and confusion compared with other sedative agents. 73 Another meta-analysis of 27 RCTs, assessing dexmedetomidine compared with any other comparator in 3648 mechanically ventilated ICU patients, indicated that dexmedetomidine could be useful in reducing ICU stay and time to extubation, although heterogeneity was detected among included studies. 73 Similarly, a Cochrane systematic review published in January 2015 and based on seven RCTs with a total of 1624 patients, concluded that, compared with traditional sedative agents, long-term sedation with dexmedetomidine in critically ill patients may reduce the duration of MV and the length of ICU stay. However, the general methodological quality of evidence was low and there was clinical and statistical heterogeneity among studies. 74

Clonidine is an alpha-2 agonist agent that produces a reduction in sympathetic tone and resultant fall in diastolic and systolic blood pressure and heart rate. 75 Originally marketed as an antihypertensive agent, clonidine has demonstrated sedative and analgesic-sparing properties. The current therapeutic indications include the treatment of hypertensive crises,76 the prophylactic management of migraine or recurrent vascular headache and the management of vasomotor conditions commonly associated with the menopause and characterised by flushing. 75 There is no current marketing authorisation for clonidine as a sedative agent and no dosage recommendation for sedation in the summary of product characteristics. 76

In the ICU setting, clonidine has been used as a treatment for delirium and as a second-line sedative agent. 77–79 The pharmacodynamics pattern of clonidine is broadly similar to that of dexmedetomidine, but clonidine is less specific for alpha-2 receptors and has a lower affinity for alpha-2 receptors than dexmedetomidine. 60,78 Clonidine has been shown to be effective in controlling delirium and withdrawal symptoms from opioids, benzodiazepines, nicotine and alcohol. 78,80–83 Clonidine is a very lipid-soluble agent. Its peak action occurs after 10 minutes and lasts for 3–7 hours after a single intravenous dose. 84 Clonidine is metabolised in the liver and is eliminated primarily through the kidney. The elimination of the half-life of clonidine is 6–23 hours (average 7.7 hours) (Sheila Harvey, ICNARC, 2014), a key difference from dexmedetomidine which has an elimination half-life of around one-quarter the length of clonidine. 85 Sudden cessation of clonidine after prolonged use may cause a withdrawal syndrome leading to rebound hypertension and tachycardia in susceptible patients. 15,77,86 The main adverse effects of clonidine include bradycardia, hypotension and xerostomia (dry mouth). 15

Evidence on the use of clonidine in ICU settings is limited. A recent placebo-controlled RCT found a significant reduction in the need for benzodiazepines and opioids, but not propofol, in mechanically ventilated ICU patients treated with clonidine compared with those receiving placebo. No significant differences in the incidence of adverse events were observed between the groups. 87

A retrospective review of mechanically ventilated ICU patients’ clinical records showed a significantly lower mortality index and no important adverse effects for patients receiving clonidine rather than other sedatives. 88 A prospective study assessing the effects of clonidine among mechanically ventilated ICU patients with withdrawal symptoms after sedation interruption for ventilator weaning showed that the majority responded positively to clonidine and were weaned in a median of 2 days. In addition, clonidine decreased the haemodynamic, metabolic and respiratory parameters to near those observed with sedation. 82

The role of alpha-2 agonists (clonidine and dexmedetomidine) in the sedation of ICU patients has yet to be fully established.

Intravenous anaesthetic agents

Propofol is a short-acting intravenous general anaesthetic agent commonly used in ICUs since the 1980s. It activates gamma-aminobutyric acid (GABA) receptors and has shown a considerable array of effects including anxiolysis, anticonvulsant activity, antiemesis and the ability to reduce intracranial pressure. 13,89–93 Propofol is a lipid-soluble compound with a rapid onset of action (from seconds to minutes) and a short duration of effect following short-term administration. 12,90,94 Owing to its short duration of sedative effect, propofol may be indicated for patients who require frequent awakening and DSIs. 12,95 The half-life of propofol ranges from 30 to 60 minutes after short-term infusion, but is longer after prolonged infusion (up to 50 ± 18.6 hours). 12,13 The rapid onset and offset are specific features of propofol compared with other common sedative drugs. 96 The most significant side effects of propofol include hypotension as a result of systemic vasodilation and dose-dependent respiratory depression.

Other side effects include hypertriglyceridaemia, acute pancreatitis, arrhythmia, bradycardia and cardiac arrest. 11–13 Propofol administration may rarely cause propofol infusion syndrome, an adverse reaction characterised by lactic acidosis, hypertriglyceridaemia, hypotension and arrhythmia. 12

A systematic review of 16 RCTs with a total of 1386 critically ill adult patients, which compared propofol with alternative sedative agents for medium- or long-term sedation, concluded that propofol is safe and can reduce the duration of MV. In addition, propofol also reduced the length of ICU stay when compared with long-acting benzodiazepines but not when compared with midazolam. 97

Benzodiazepines

Benzodiazepines bind to the GABA receptor complex modulating GABA release in the central nervous system, causing downregulation of neuronal excitation (neurons become less excitable). 11 Depending on the dose used, they can cause sedation, anxiolysis or hypnosis (Sheila Harvey, ICNARC, 2014). Benzodiazepines vary in their potency, onset and duration of effect, uptake, distribution, metabolism and presence or absence of active metabolites. 15,94 Lorazepam is more potent than midazolam, which, in turn, is more potent than diazepam (Diazemuls^®, Actavis UK Ltd). As midazolam and diazepam are more lipid soluble than lorazepam, they cross the blood–brain barrier quicker and result in a more rapid onset of action (from 2 to 10 minutes) than lorazepam (from 5 to 20 minutes). 11,13,98–100 The half-life of midazolam is 3–11 hours, compared with 8–15 hours for lorazepam and 20–120 hours for diazepam. 12,13 Midazolam and diazepam metabolites are active and tend to accumulate with prolonged administration, especially in patients with renal dysfunction. 11,101 Lorazepam metabolites are not active and, for this reason, it is the preferred benzodiazepine in patients with renal failure. 11 As all benzodiazepines are metabolised predominantly in the liver, clearance is reduced in patients with hepatic dysfunction. 12 Adverse effects of benzodiazepines include hypotension, respiratory depression, paradoxical agitation, tolerance with acute discontinuation and delirium. 13,15,102

A recent systematic review of six trials (1235 patients) concluded that the use of a dexmedetomidine- or propofol-based sedation regimen rather than a benzodiazepine-based regimen in critically ill patients may reduce ICU length of stay and duration of MV. 103 Indeed, current PAD guidelines suggest that sedation strategies using non-benzodiazepines (either propofol or dexmedetomidine) may be preferred over sedation with benzodiazepines (either midazolam or lorazepam) to improve outcomes in mechanically ventilated adult ICU patients. 12

Identification of important subgroups

Specific subgroups of interests are usually based on severity of disease, primary reasons for admission to the ICU (e.g. admission after elective surgery) and duration of MV. Severity of disease is usually assessed by means of severity scores and risk prediction models. One of the most commonly used methods is the Acute Physiology and Chronic Health Evaluation (APACHE) II severity score system, which uses a point score based on initial values of 12 routine physiological measurements, age and previous health status to provide a general measure of severity of disease. Scores can range from 0 to 71, with higher scores indicating more severe disease and a higher risk of mortality. This severity index has been used to evaluate the use of hospital resources and compare the efficacy of intensive care over time and across different hospitals. The APACHE II scores combined with an accurate description of disease can also be used to stratify, prognostically, acutely ill patients and compare the success of new or differing forms of therapy. 104

Identification of studies (search strategy and information sources/dates)

Highly sensitive literature searches, using an appropriate combination of controlled vocabulary and text word terms, were developed to identify reports of published, ongoing and unpublished studies reporting the clinical effectiveness of dexmedetomidine or clonidine in comparison with propofol and benzodiazepines (e.g. midazolam, lorazepam and diazepam) in mechanically ventilated adults admitted to ICUs. Literature searches were carried out from 12 to 15 November 2014 for publications from 1999 onwards. Details of the search strategies are reported in Appendix 1. Major electronic databases were searched including MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Science Citation Index, Bioscience Information Service and the Cochrane Central Register of Controlled Trials. Reports of relevant evidence synthesis were sought from the Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects. The World Health Organization International Clinical Trials Registry Platform, metaRegister of Controlled Trials and ClinicalTrials.gov were searched for evidence of ongoing studies.

Websites of regulatory bodies and Health Technology Assessment agencies were checked for relevant unpublished reports, while websites of relevant pharmaceutical companies and professional organisations were searched for further pertinent information and reports.

In addition, reference lists of all included studies were perused for further citations.

Inclusion and exclusion criteria

Data extraction strategy (study selection and data collection)

One reviewer (MC) screened all titles and abstracts identified by the search strategies. A second reviewer (MB) independently double-screened the first 100 abstracts and titles of the 2011–14 list. Agreement between the two reviewers was 100%.

All potentially relevant reports were retrieved in full and assessed independently by one reviewer (MC). A total of 40 reports were double-assessed by a second reviewer (Pawana Sharma or MB). Any disagreements were resolved by consensus. The full-text screening form is presented in Appendix 2. A data extraction spreadsheet (Microsoft Excel^®, 2013; Microsoft Corporation, Redmond, WA, USA) was developed specifically for the purpose of this assessment, piloted and amended as necessary. From each study, one reviewer (MC) extracted information on geographical location, sponsor, study design, participants’ characteristics, setting and characteristics of ICU practice, characteristics of sedative intervention and outcome measures. Data extraction was double-checked by a second reviewer (MB). Any disagreements were resolved by discussion.

Critical appraisal strategy

The risk of bias of included RCTs was initially assessed by one reviewer (MC) using Cochrane’s risk-of-bias tool106 and, subsequently, cross-checked by a second reviewer (MB). The following domains were assessed: sequence generation, allocation concealment, blinding of participants and medical personnel, blinding of outcome assessors, incomplete outcome data and selective outcome reporting. Assessment of ‘other bias’ was based on the funding source, and a study was judged to be at high risk of bias if it was funded by the manufacturer(s) of the sedative agent(s) under investigation. Individual outcomes were judged as being at ‘high’, ‘low’ or ‘unclear’ risk of bias. Overall, risk of bias for each study was based on the findings of three key domains: sequence generation, allocation concealment and blinding of outcome assessor.

Studies were classified as follows: (1) high risk of bias if one or more key domains were at high risk; (2) unclear risk of bias if one or more key domains were judged to be at unclear risk; and (3) low risk of bias if all key domains were judged to be at low risk. Any disagreements between reviewers were resolved by discussion.

Method of analysis/synthesis

The general approach recommended by Cochrane was used for data analysis and synthesis. 106 For binary outcomes, the Mantel–Haenszel approach was used to pool risk ratios (RRs) derived from each study. A random-effects model was used to calculate the pooled estimates of effect. For continuous outcomes (duration of MV, ICU length of stay, hospital length of stay, time to extubation, time in target sedation range and ventilator-free days), mean differences between groups were pooled when possible using the inverse variance weighted mean difference method and a random-effects model. Random-effects methods, rather than fixed-effects methods, as outlined in the original protocol, were chosen because of the clinical and statistical heterogeneity observed among included studies.

For each continuous outcome, an initial analysis was conducted using only studies where the mean and standard deviation (SD) were provided. In studies that did not report a mean and SD [and we could not derive these summary measures from reported p-values, standard errors or confidence intervals (CIs)], we tried to impute these from the data reported. The imputation strategy was as follows:

1. Where the median, range and n for each group were available, we used the formulae reported by Hozo and colleagues107 to estimate the mean and SD.

2. Where this method proved unfeasible, we imputed a SD from the available data using the methods outlined by Furukawa and colleagues. 108

3. In studies where a median and interquartile range were reported, we used two methods to calculate the mean. If the sample size was < 25, then first the median was used and second the value midway between the lower quartile and upper quartile was used. If the two methods yielded results that reversed the direction of treatment effect for a certain outcome within a study, then the study was excluded from the pooled analysis of that outcome.

For each outcome where the above provided extra data, a second analysis was done using the imputed data.

Heterogeneity across studies was explored by visual inspection of forest plots and using the chi-squared test and I²-statistics.

When data were available, subgroup analyses were performed according to type of comparator intervention.

Quantity of the evidence (studies included and excluded)

The literature searches identified 1182 potentially relevant citations, of which 83 were selected for full-text assessment and 107 for background information. Of these, 59 were subsequently excluded because the patient population, study design, outcomes reported or publication type were not eligible. A total of 18 RCTs published in 24 papers with a total of 2489 people were included in this assessment. 5,52,69–72,102,109–125 It is worth noting that the results of the two large multicentre trials of PROpofol compared with DEXmedetomidine (the PRODEX trial) and of MIdazolam compared with DEXmedetomidine (the MIDEX trial) were published in a single report by Jakob and colleagues70 for the Dexmedetomidine for Long-Term Sedation investigators. Figure 2 presents the flow chart of the selection process. Appendix 3 provides the details of the 18 included trials and related secondary publications. Appendix 4 categorises the excluded studies according to the main reasons for their exclusion.

FIGURE 2.

Flow chart of the study selection process.

Study characteristics

Appendix 5 details the study characteristics of the 18 included trials. All 18 trials were published in full. Four different comparators were assessed. One trial, with a total of 70 randomised patients, compared the effects and safety of dexmedetomidine with clonidine;55 nine trials, with a total of 1134 randomised patients, compared dexmedetomidine with propofol;70,109–111,114,117,120,122,123 four trials, with a total of 939 randomised patients, compared dexmedetomidine with midazolam;70,71,112,116 one trial, with a total of 118 randomised patients, compared dexmedetomidine with propofol or midazolam (three arms);72 two trials, with a total of 122 randomised patients, compared dexmedetomidine with ‘standard care’ (i.e. propofol and/or midazolam);69,121 and one trial with a total of 106 randomised patients, compared dexmedetomidine with lorazepam. 102 A total of 2446 patients were analysed in the 18 included trials.

Six trials assessed dexmedetomidine in patients admitted to ICUs following elective surgery,72,110,111,114,120,123 whereas the remaining trials included general ICU patients.

Four trials were conducted in the USA,72,102,110,116 two in India,55,120 three in Turkey,112,117,122 two in Egypt,109,111 one in the UK,123 one in North America (USA and Canada),114 one in Finland and Switzerland,69 and one in Australia and New Zealand. 121 The MIDEX multicentre trial70 was conducted in nine European countries; the PRODEX multicentre trial70 was conducted in six European countries and in Russia; and the SEDCOM71 (Safety and Efficacy of Dexmedetomidine COmpared with Midazolam) multicentre trial was conducted in the USA, Argentina, Brazil, Australia and New Zealand. All included trials involved prospective collection of data.

Three trials assessed patients up to 45 days69,70 and one up to 90 days. 121 In one trial,102 participants were observed in the hospital from enrolment until discharge from hospital or death, and survivors were observed for vital status until 1 year after enrolment using hospitals’ electronic record systems and a commercial version of the Social Security Death Master File (http://ssdi.rootsweb.com). One trial114 followed up patients for 24 hours after discharge from ICUs and another trial71 for 48 hours after study drug cessation. One trial72 reported that patients were followed up for 3 days post operatively. In one trial,109 length of follow-up was reported to be 6 hours, in two trials55,120 it was 24 hours and in another trial123 it was 48–72 hours. Two trials reported follow-up in terms of time post extubation: one trial110 assessed patients at least 24 hours post extubation and another trial116 at least 72 hours post extubation. Length of follow-up was not reported in four trials. 111,112,117,122

Appendix 6 presents details of dosage and route of administration of the respective sedative agents.

In general, dexmedetomidine was initiated with a loading dose of 1 µg/kg, administered intravenously over a period of 10–20 minutes. 109,110,112,114,117,120,122 Some trials involved lower55,72,102,116 or higher111,123 loading doses, four trials did not use a loading dose69,70,121 and, in one trial, the loading dose was optional. 71 Dexmedetomidine maintenance doses were fixed in two trials: 0.4 µg/kg/hour110 or 0.7 µg/kg/hour. 112 The remaining trials specified lower and upper limits for maintenance doses, with lower limits ranging from 0 µg/kg/hour121 to 0.015 µg/kg/hour,102,116 0.2 µg/kg/hour,55,70,72,111,114,117,120,122,123 0.4 µg/kg/hour,110 0.5 µg/kg/hour109 and 0.7 µg/kg/hour. 112 The maximum allowable dose was 2.5 µg/kg/hour. 117,122,123

Clonidine was used in one trial. Patients received an infusion of clonidine at 1 µg/kg/hour. Titration was achieved with dosage increments up to 2 µg/kg/hour. 55

Of the 12 trials that included a propofol arm, four trials reported a loading dose: an initial bolus dose of 1 mg/kg in one trial111 and 1 mg/kg over 10–15 minutes in three trials. 117,122,123 Six trials did not use a loading dose69,70,72,109,110,120 and two trials did not provide information on dosage. 114,121 Maintenance infusions of propofol ranged from 0.5–1 mg/kg/hour111 to 4 mg/kg/hour across trials. 69,70

Out of the seven trials that included a midazolam arm, one trial reported a loading dose of 0.05 mg/kg112 and another trial reported an optional loading dose of the same level. 71 The remaining trials did not use a loading dose. One trial did not specify dosage of midazolam. 121 Maintenance doses of midazolam were between 0.03 mg/kg/hour70 and 10 mg/hour across trials. 116

In one trial, lorazepam infusion started at 1 mg/hour and was titrated to a maximum of 10 mg/hour. 102

All trials titrated sedatives to a target sedation level. 55,69–72,102,109–112,114,116,117,120–123 Target sedation level was measured by means of the RSS score in 11 trials,55,72,109–112,114,117,120,122,123 the RASS in six trials69–71,102,121 and the Riker SAS score in one trial. 116

The main characteristics of the 18 included studies are shown in Table 1.

Participant characteristics

The 18 included trials randomised a total of 1283 participants to dexmedetomidine and 1206 participants to a control intervention. The sample sizes of included studies ranged from 23 to 501 participants.

There was some doubt whether or not the trial by Memis and colleagues (40 patients in total)117 and that by Tasdogan and colleagues (40 patients in total)122 were mutually exclusive with regard to participants. Even though a number of similarities between the two trials were observed, the characteristics of the two patient populations were clearly not identical and, therefore, we treated them as two separate trials. Correspondence with the trials investigators (Dr Dilek Memis named as corresponding author for both trials) proved unsuccessful and did not elicit any response.

The mean age was reported in 12 trials. 71,72,109–112,114,116,117,120–122 With the exception of one trial112 that focused exclusively on young pregnant women (mean age 25.1 years in the dexmedetomidine group and 26.8 years in the control intervention group), the 11 remaining trials mean age ranged from 43 to 65 years for dexmedetomidine and from 40 to 67 years for the comparator interventions. The median age was reported in six trials55,69,70,102,123 and ranged from 49 to 65 years for dexmedetomidine and from 46 to 67 years for the comparator interventions.

Sixteen studies reported information regarding the sex of participants. 55,69–72,102,109,110,112,114,116,117,120–122 Study populations tended to involve more men than women, with the exception of one trial that involved only pregnant women112 (see Appendix 5 for further details).

The severity of illness at baseline was reported in eight trials55,71,102,112,117,121–123 by means of the APACHE II scores or APACHE III scores (one trial). 116 The APACHE II scores have a possible range of 0–71, whereas the APACHE III scores can range from 0 to 299. In both cases, higher scores indicate more severe disease and a higher risk of death. 104 Across the eight trials that used APACHE II, scores ranged from a mean of 5.1112 to a mean of 22 for dexmedetomidine117 and a mean of 6112 to a mean of 20117 for the control sedative intervention. One trial102 reported a median APACHE II score of 29 for dexmedetomidine and of 27 for the control sedative intervention. The trial116 that assessed severity of disease using the APACHE III scores reported mean scores of 74.1 for dexmedetomidine and of 70.4 for midazolam.

Table 2 presents an overview of the participants’ characteristics of the 18 included trials. It is worth noting that not all trials provided the same participant details or used the same measures to assess them.

Risk-of-bias assessment of included studies

Figure 3 presents the summary of the risk-of-bias assessments for all included trials. The risk of bias of individual studies is presented in Figure 4.

FIGURE 3.

Summary of risk-of-bias assessments of all included trials.

FIGURE 4.

Risk-of-bias assessments of individual studies. CLON, clonidine compared with dexmedetomidine, LORAZ, lorazepam compared with dexmedetomidine; MIDAZOLAM, midazolam compared with dexmedetomidine; PROPOFOL, propofol compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

Overall, out of the 18 included trials, four were judged to be at low risk of bias70,71,102 and seven at high risk of bias. 72,111,114,117,120–122 For the remaining seven trials, there was not sufficient information to make an overall judgement. 55,69,109,110,112,116,123

With regard to the assessment of selection bias, around half of the trials were judged to be at low risk (i.e. adequate sequence generation and allocation concealment),55,70,71,102,110,112,116,117,122 whereas the remaining eight trials did not provide sufficient information to formulate a proper judgement. 69,72,109,111,114,120,121,123

In eight of the included trials, participants were reported to be blinded to the intervention received,69–71,102,109,111,116 whereas in six trials they were not. 72,114,117,120–122 The remaining four trials did not report information on blinding of participants. 55,110,112,123 Blinding of outcome assessor was addressed adequately in five trials,69–71,102 not adequately in seven trials72,111,114,117,120–122 and not reported in six trials. 55,109,110,112,116,123

With regard to ‘incomplete outcome data’,10 trials had low withdrawal/discontinuation rates, which were balanced between intervention groups and, therefore, judged to be at low risk of bias. 69,71,72,102,112,116,117,120–122 Two trials reported significantly higher discontinuation rates, owing to lack of efficacy, among people treated with dexmedetomidine, and were judged to be at high risk of bias. 70 The remaining six trials did not provide sufficient information on which to make a definitive judgement. 55,109–111,114,123

There was no evidence of selective reporting in any of the included trials, with the exception of one trial111 in which data on hypotension and bradycardia were mentioned only in the discussion section of the published paper and not properly reported in the results section. For this reason, the study was judged to be at high risk of selective reporting.

With regard to ‘other sources of bias’, nine trials declared financial support by manufacturers of sedative agents and were, therefore, judged to be at high risk of bias. 69–71,102,116,120,121,123 One trial was judged at low risk of bias, as the authors clearly stated that no funding was received from manufacturers. 55 The remaining eight studies were judged to be at unclear risk of bias, as the authors did not explicitly report their source of funding. 72,109–112,114,117,122

Primary outcomes

Mortality

Nine trials reported mortality data (Figure 5). 69–71,102,116,117,120,121 A total of 196 out of 909 (22%) patients who received dexmedetomidine and 162 out of 783 (21%) of patients who received a control intervention died. Compared with alternative sedative agents, dexmedetomidine had no significant effects on mortality (RR 1.03, 95% CI 0.85 to 1.24, I² = 0%; p = 0.78).

FIGURE 5.

Meta-analysis for mortality. df, degrees of freedom; IV, inverse variance; LORAZ, lorazepam compared with dexmedetomidine; MIDAZOLAM, midazolam compared with dexmedetomidine; PROPOFOL, propofol compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

Two trials assessing patients after elective surgery reported mortality data. 72,123 In one trial,72 two deaths not attributable to sedation occurred among patients who received the control intervention (propofol), whereas in the other trial123 two patients receiving dexmedetomidine died, compared with one patient receiving the control intervention (propofol).

Duration of mechanical ventilation

Two trials reported mean duration of MV (Figure 6). 70 There were no significant differences in the duration of MV between dexmedetomidine and control interventions (mean difference –0.36, 95% CI –1.59 to 0.86, I² = 0%; p = 0.56).

FIGURE 6.

Meta-analysis for duration of MV. df, degrees of freedom; IV, inverse variance.

Similarly, there was no difference (mean difference –0.30, 95% CI –1.70 to 1.11; p = 0.68) in the duration of MV between dexmedetomidine and control interventions (Figure 7) when all available data suitable for the analysis were considered (including transformed and imputed data). Statistical heterogeneity was observed among trials (I² = 70%).

FIGURE 7.

Meta-analysis for duration of MV: all available data (including transformed and imputed data). df, degrees of freedom; IV, inverse variance; PROPOFOL, propofol compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

One trial that assessed patients after elective surgery110 reported no difference between dexmedetomidine and propofol (p > 0.05) with regard to length of intubation.

Ventilator-free days

One trial provided suitable data for ventilator-free days (Figure 8). 121 There was no evidence of a statistically significant difference (mean difference 1.20, 95% CI –5.12 to 7.52; p = 0.71) between patients who received dexmedetomidine and those who received standard care (propofol or midazolam).

FIGURE 8.

Meta-analysis for ventilator-free days. IV, inverse variance; SC, standard care compared with dexmedetomidine.

When all available data suitable for the analysis were considered (including transformed and imputed data) (Figure 9), the mean difference was 3.28 ventilator-free days (95% CI 0.06 to 6.49 ventilator-free days, I² = 0%; p = 0.046) favouring dexmedetomidine.

FIGURE 9.

Meta-analysis for ventilator-free days: all available data (including transformed and imputed data). df, degrees of freedom; IV, inverse variance; LORAZ, lorazepam compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

Intensive care unit length of stay

One trial provided mean length of ICU stay data (Figure 10). 117 There was no evidence of a significant difference between sedative agents (mean difference 2.00 days, 95% CI –3.12 to 7.12 days; p = 0.44).

FIGURE 10.

Meta-analysis for ICU length of stay. IV, inverse variance; PROPOFOL, propofol compared with dexmedetomidine.

However, Figure 11 shows that when all available data suitable for the analysis were considered (including transformed and imputed data), ICU length of stay was significantly shorter among patients who received dexmedetomidine than among those who received an alternative sedative agent (mean difference –1.26 days, 95% CI –1.96 to –0.55 days, I² = 31%; p = 0.0004).

FIGURE 11.

Meta-analysis for ICU length of stay: all available data (including transformed and imputed data). IV, inverse variance; LORAZ, lorazepam compared with dexmedetomidine; MIDAZOLAM, midazolam compared with dexmedetomidine; PROPOFOL, propofol compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

Hypotension

Five trials provided suitable data to assess the incidence of hypotension (Figure 12). 69–71,116 There were no statistically significant differences between participants who received dexmedetomidine (232 out of 789, 29%) and those who received an alternative sedative agent (137 out of 675, 20%) (RR 1.28, 95% CI 0.93 to 1.75, I² = 55%; p = 0.12).

FIGURE 12.

Meta-analysis for incidence of hypotension. IV, inverse variance; MIDAZOLAM, midazolam compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

The proportion of patients who developed hypotension was reported in two trials that assessed patients after elective surgery. 110,114 No statistically significant differences were found. In one trial,110 35 out of 43 patients who received dexmedetomidine experienced severe hypotension, compared with 31 out of 46 of those who received propofol (p = 0.132). In the other trial,114 hypotension occurred in 36 out of 148 (24%) participants who received dexmedetomidine and in 24 out of 147 (16%) participants who received propofol (p = 0.111).

Hypertension

Three trials reported the incidence of hypertension during sedation (Figure 13). 70,71 There was no evidence of statistically significant differences (RR 1.09, 95% CI 0.89 to 1.33, I² = 21%; p = 0.43) between dexmedetomidine (211 out of 737, 29%) and alternative sedative agents (143 out of 619, 23%).

FIGURE 13.

Meta-analysis for incidence of hypertension. IV, inverse variance; MIDAZOLAM, midazolam compared with dexmedetomidine.

In one trial, in which patients were sedated after elective coronary artery bypass graft (CABG) surgery,114 hypertension occurred more frequently among patients who received dexmedetomidine than among those who received propofol (p = 0.018).

Bradycardia

Six trials assessed the incidence of bradycardia during sedation (Figure 14). 69–71,102,116 Significantly more participants who received dexmedetomidine (189 out of 841, 22%) experienced bradycardia than those who received alternative sedative agents (70 out of 726, 10%) (RR 1.88, 95% CI 1.28 to 2.77, I² = 46%; p = 0.001).

FIGURE 14.

Meta-analysis for incidence of bradycardia. IV, inverse variance; LORAZ, lorazepam compared with dexmedetomidine; MIDAZOLAM, midazolam compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

In one trial, which enrolled patients after elective coronary artery bypass graft surgery,114 the frequency of bradycardia was similar between intervention groups [5 out of 148 (3%) in the dexmedetomidine group, compared with 2 out of 147 (1%) in the propofol group; p = 0.448].

Delirium

Seven trials reported the proportion of patients who experienced episodes of delirium during sedation. 69–71,102,116,121 A total of 234 out of 862 (27%) participants who received dexmedetomidine and 209 out of 742 (28%) participants who received an alternative sedative agent experienced delirium (Figure 15). The difference between sedatives was not statistically significant (RR 0.83, 95% CI 0.65 to 1.06, I² = 60%; p = 0.14). Statistical heterogeneity was observed among trials (I² = 60%).

FIGURE 15.

Meta-analysis for incidence of delirium. IV, inverse variance; LORAZ, lorazepam compared with dexmedetomidine; MIDAZOLAM, midazolam compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

Two trials, which enrolled patients after elective surgery, reported the proportion of patients with episodes of delirium. 72,110 In one trial,110 the number of patients with episodes of delirium was similar in both intervention groups (1 out of 43 in the dexmedetomidine group compared with 1 out of 46 in the propofol group). In the other trial,72 the incidence of delirium was 10% (4 out of 40) among patients who received dexmedetomidine, 44% (16 out of 36) among those who received propofol and 44% (17 out of 40) for those who received midazolam.

Self-extubation

Four trials reported episodes of self-extubation during sedation (Figure 16). 70,102,121 Self-extubation occurred in 12 out of 566 (2%) of patients who received dexmedetomidine and 3 out of 564 (< 1%) of those who received an alternative sedative agent. There was no clear evidence of a statistically significant difference between sedative interventions (RR 2.95, 95% CI 0.96 to 9.06, I² = 0%; p = 0.06).

FIGURE 16.

Meta-analysis for episodes of self-extubation. IV, inverse variance; LORAZ, lorazepam compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

One trial, which assessed patients after elective surgery,110 reported one episode of self-extubation among participants who received propofol (1 out of 46) and none among those who received dexmedetomidine (0 out of 43).

Tachycardia

Five trials assessed the incidence of tachycardia among patients receiving sedation (Figure 17). 70,71,102,116 There was no evidence of a significant difference (RR 0.93, 95% CI 0.63 to 1.39; p = 0.73) between sedative interventions [187 out of 800 (23%) of those who received dexmedetomidine compared with 178 out of 682 (26%) of those who received alternative sedative agents]. Substantial statistical heterogeneity was observed among trials (I² = 82%).

FIGURE 17.

Meta-analysis for incidence of tachycardia. IV, inverse variance; LORAZ, lorazepam compared with dexmedetomidine; MIDAZOLAM, midazolam compared with dexmedetomidine.

Secondary outcomes and other reported outcomes

It is worth noting that no data were available from the included trials for extubation readiness, discharge readiness and quality of life.

Time in target sedation range

Three trials provided data on percentage of total time in target sedation range (Figure 18). 70,71 There was no evidence of a significant difference between sedative interventions (mean difference 1.94% of total time in target sedation range, 95% CI –1.70 to 5.57% of total time in target sedation range, I² = 0%).

FIGURE 18.

Meta-analysis for time in target sedation range. IV, inverse variance; MIDAZOLAM, midazolam compared with dexmedetomidine.

Similarly, Figure 19 shows that no significant differences were evident between dexmedetomidine and alternative sedative agents (mean difference 2.53% of total time in target sedation range, 95% CI –0.82 to 5.87% of total time in target sedation range, I² = 0%; p = 0.14) when all available data suitable for the analysis (including transformed and imputed data) were considered.

FIGURE 19.

Meta-analysis for time in target sedation range: all available data (including transformed and imputed data). IV, inverse variance; LORAZ, lorazepam compared with dexmedetomidine; MIDAZOLAM, midazolam compared with dexmedetomidine; SC, standard care compared with dexmedetomidine.

Two trials, which enrolled patients after elective surgery, assessed time in target sedation range. 111,123 Both trials showed that the proportion of time spent at adequate depth of sedation was similar for sedative interventions (46.3% for dexmedetomidine and 49.1% for propofol in one trial,123 and 93% for dexmedetomidine and 92% for propofol in the other trial). 111

Time to extubation

Two trials reported time to extubation (Figure 20). 70 Time to extubation was significantly shorter among patients who received dexmedetomidine than among those who received an alternative sedative agent (mean difference –1.83 days, 95% CI –2.70 to –0.95 days, I² = 0%; p < 0.0001).

FIGURE 20.

Meta-analysis for time to extubation. IV, inverse variance.

Similarly, time to extubation was significantly shorter for patients who received dexmedetomidine than for those who received an alternative sedative agent (Figure 21) when all available data suitable for the analysis (including transformed and imputed data) were considered (mean difference –1.85 days, 95% CI –2.61 to –1.09 days, I² = 0%; p < 0.00001).

FIGURE 21.

Meta-analysis for time to extubation: all available data (including transformed and imputed data). IV, inverse variance; MIDAZOLAM, midazolam compared with dexmedetomidine.

Three trials, which enrolled patients after elective surgery, assessed time to extubation. 111,114,123 All three trials showed that times to extubation were similar between sedative interventions. Elbaradie and colleagues111 reported mean times to extubation of 30 minutes (SD 15 minutes) for dexmedetomidine compared with 35 minutes (SD 12 minutes) for propofol. Herr and colleagues114 reported median times to extubation of 410 minutes (25th–75th percentiles 310 to 584 minutes) for dexmedetomidine and 462 minutes (25th–75th percentiles 323–808 minutes) for propofol. In the trial by Venn and Grounds,123 mean extubation times were 29 minutes (range 15–50 minutes) for dexmedetomidine and 28 minutes (range 20–50 minutes) for propofol (p = 0.63).

Clinical effectiveness

This assessment is based on evidence from 18 RCTs with a total of 2489 critically ill mechanically ventilated ICU patients. Only 1 of the 18 identified trials compared dexmedetomidine directly with clonidine, while the remaining trials assessed the effects and safety of dexmedetomidine compared with propofol or compared with benzodiazepines (i.e. midazolam or lorazepam). Not all trials provided data for the assessment of all primary and secondary outcomes under consideration. Clinical heterogeneity among trials was mostly because of type of patient population (e.g. general ICU patients and patients admitted to ICU following elective surgical); type of comparator treatment (i.e. propofol, midazolam or lorazepam); type of outcome measures; and length of follow-up. Overall, trials were at high or unclear risk of bias.

Uncertainties from the assessment

This assessment was conducted according to current methodological standards and the methods were specified a priori in a research protocol, which was informed by an advisory group established for the purpose of this assessment. In particular, we performed comprehensive literature searches of the major electronic databases and we contacted experts in the field to identify all existing relevant evidence. We reviewed all potential eligible studies for inclusion and assessed their methodological quality using the best recommended risk-of-bias tool. We developed specific data extraction forms on prespecified outcome parameters and data extraction was performed by one reviewer and chekced by a second reviewer. Despite all these efforts, there is still the possibility that some relevant evidence may have been missed. Furthermore, we need to acknowledge the following limitations:

• This assessment provides mainly evidence on the use of dexmedetomidine as sedative agent in ICUs. The evidence on the effects of clonidine in ICUs was scant (only one trial comparing clonidine with dexmedetomidine was identified in our included studies). Nevertheless, one-third of UK ICUs have reported frequent or very frequent use of clonidine and nearly two-thirds have reported occasional or rare use of clonidine to sedate critically ill adults (Sheila Harvey, ICNARC, 2014). Clonidine appears to be used off-label and evidence regarding its effectiveness and safety profile is clearly needed.

• The included trials were clinically heterogeneous. In particular, patient populations, comparator interventions, dose of sedative agents, length of follow-up assessments, and choice and definitions of outcome measures varied considerably across trials.

• The overall risk of bias was high or unclear in the majority of included trials. Only four trials were judged to be at low risk of bias. In particular, blinding of outcome assessors was reported in only 5 of the 18 included trials.

• Length of follow-up after discharge from ICUs varied among included trials. Apart from one trial in which survivors were followed up for 1 year after discharge from ICUs, none of the remaining trials reported the long-term outcomes of patients receiving dexmedetomidine (generally, length of follow-up ranged from 24 to 72 hours in most trials).

• Units of measurement, especially for continuous data, varied considerably among trials. This required data transformation and imputation, and it hampered our ability to combine data across trials reliably.

• Subgroup analyses according to type of comparator were not very informative as subgroups were too small. There were not enough data to perform subgroup analyses according to type of patient population, which is likely to impact on the effects of sedation (e.g. elective ICU setting compared with general ICU setting).

• There was substantial variation in the choice and definitions of outcome measures among included trials. No trials reported information on extubation readiness, discharge readiness or quality of life.

• A number of trials and, in particular, all the largest included trials excluded patients with bradycardia and hypotension. This may impact on the generalisability of our findings.

• In two large multicentre trials (MIDEX and PRODEX, with a total of 1001 patients), discontinuation because of a lack of efficacy was observed significantly more frequently among patients treated with dexmedetomidine. However, patients in these trials received standard sedation prior to randomisation and this may have potentially masked the benefits of dexmedetomidine because a change of sedative drug (from that received prior to randomisation) might have negatively affected the subsequent efficacy of dexmedetomidine.

Search strategy

1. Conscious Sedation/

2. exp Respiration, Artificial/ use medf

3. exp artificial ventilation/ use emef

4. exp Critical Care/ use medf

5. Intensive Care/ use emef

6. Critical Illness/

7. (sedation or sedate?).tw.

8. ((mechanical$ or artificial$) adj5 ventilat$).tw.

9. or/1-8

10. Dexmedetomidine/

11. (dexmedetomidine or dexdor or precedex or primadex or dexdomitor or mpv1440 or mpv 1440).tw,rn.

12. Clonidine/

13. (clonidine or clofenil or klofenil or m5041t or m 5041t or catapres$ or st155 or st 155).tw,rn.

14. or/10-13

15. exp clinical trial/ use emef

16. randomized controlled trial.pt.

17. controlled clinical trial.pt

18. randomization/ use emef

19. randomi?ed.ab.

20. placebo.ab.

21. drug therapy.fs.

22. randomly.ab.

23. trial.ab.

24. groups.ab.

25. or/15-24

26. exp animals/ not humans/

27. nonhuman/ not human/

28. exp child/ not exp adult/

29. (conference abstract or letter).pt.

30. 25 not (26 or 27 or 28 or 29)

31. 9 and 14 and 30

32. limit 30 to yr=“1999 -Current”

33. remove duplicates from 31

Search strategy

1. (TS=critical illness) AND DOCUMENT TYPES: (Article)

2. (TS=critical care) AND DOCUMENT TYPES: (Article)

3. (TS=intensive care) AND DOCUMENT TYPES: (Article)

4. (TS=(sedation or sedate*)) AND DOCUMENT TYPES: (Article)

5. (TS=((mechanical* or artificial*) NEAR/3 ventilat*)) AND DOCUMENT TYPES: (Article)

6. #5 OR #4 OR #3 OR #2 OR #1

7. (TS=(dexmedetomidine or dexdor or precedex or primadex or dexdomitor or mpv1440 or “mpv1440”)) AND DOCUMENT TYPES: (Article)

8. (TS=(clonidine or clofenil or klofenil or m5041t or “m 5041t” or catapres$ or  st155 or “st 155”)) AND DOCUMENT TYPES: (Article)

9. #8 OR #7

10. #9 AND #6

11. (TS=trial*) AND DOCUMENT TYPES: (Article)

12. (TS=randomized) AND DOCUMENT TYPES: (Article)

13. (TS=randomised) AND DOCUMENT TYPES: (Article)

14. (TS=randomly) AND DOCUMENT TYPES: (Article)

15. #14 OR #13 OR #12 OR #11

16. #15 AND #10 Refined by: [excluding] WEB OF SCIENCE CATEGORIES: (PEDIATRICS)

Search strategy

#1 (Dexmedetomidine or Clonidine).ti [In press articles].

Search strategy

1. MeSH descriptor: [Conscious Sedation] explode all tree

2. MeSH descriptor: [Respiration, Artificial] explode all trees

3. MeSH descriptor: [Critical Care] explode all trees

4. MeSH descriptor: [Critical Illness] explode all trees

5. (sedation or sedate*):ti,ab,kw (Word variations have been searched)

6. ((mechanical* or artificial*) near/5 ventilat*):ti,ab,kw (Word variations have been searched)

7. #1 or #2 or #3 or #4 or #5 or #6

8. MeSH descriptor: [Dexmedetomidine] explode all trees

9. MeSH descriptor: [Clonidine] explode all trees

10. dexmedetomidine or dexdor or precedex or primadex or dexdomitor or mpv1440 or “mpv1440”:ti,ab,kw (Word variations have been searched)

11. clonidine or clofenil or klofenil or m5041t or “m 5041t” or catapres$ or st155 or “st 155”:ti,ab,kw (Word variations have been searched)

12. #8 or #9 or #10 or #11

13. #7 and #12

14. MeSH descriptor: [Child] explode all trees

15. MeSH descriptor: [Adult] explode all trees

16. #14 not #15

17. #13 not #16

Search strategy

1. MeSH DESCRIPTOR Conscious Sedation

2. MeSH DESCRIPTOR Respiration, Artificial EXPLODE ALL TREES

3. MeSH DESCRIPTOR Critical Illness

4. MeSH DESCRIPTOR Critical Care EXPLODE ALL TREES

5. #1 OR #2 OR #3 OR #4

6. MeSH DESCRIPTOR Clonidine EXPLODE ALL TREES

7. MeSH DESCRIPTOR D exmedetomidineEXPLODE ALL TREES

8. #6 OR #7

9. #5 AND #8

Search strategy

Interventions=Dexmedetomidine or Clonidine

Search strategy

Intervention= Dexmedetomidine or Clonidine

Secondary reports

Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care 2010;14:R38.

Fine PG. Sedation in mechanically ventilated patients. J Pain Palliat Care Pharmacother 2008;22:15.

Secondary reports

Lachaine J, Beauchemin C. Economic evaluation of dexmedetomidine relative to midazolam for sedation in the intensive care unit. Can J Hosp Pharm 2012;65:103–10.

Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW, et al. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med 2010;38:2311–18.

Riker R, Shehabi Y, Wisemandle W, Bokesch PM, Rocha MG, Bradt J. Dexmedetomidine improves outcomes for long term ICU sedation when compared to midazolam: the Sedcom study. Chest 2008;134:34003s.

Secondary report

Takala J, Nunes S, Parviainen I, Jakob S, Kaukonen M, Shepherd S. Comparison of dexmedetomidine with propofol/midazolam in sedation of long-stay intensive care patients: a prospective randomized, controlled, multicenter trial. Crit Care 2007;11:P423.

Secondary report

Venn RM, Bryant A, Hall GM, Grounds RM. Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in post-operative patients needing sedation in the intensive care unit. Br J Anaesth 2001;86:650–6.