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

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

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

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

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

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

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

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

STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014101.

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

Managing Profound Suffering at the End-of-Life: Should expanding access to continuous deep sedation be the priority?

Commentaire / Commentary

Inhaled linalool-induced sedation in mice

Linalool is a monoterpene often found as a major component of essential oils obtained from aromatic plant species., many of which are used in traditional medical systems as hypno-sedatives. Psychopharmacological evaluations of linalool (i.p. and i.c.v.) revealed marked sedative and anticonvulsant central effects in various mouse models. Considering this profile and alleged effects of inhaled lavender essential oil, the purpose of this study was to examine the sedative effects of inhaled linalool in mice. Mice were placed in an inhalation chamber during 60 min, in an atmosphere saturated with 1% or 3% linalool. Immediately after inhalation, animals were evaluated regarding locomotion, barbiturate-induced sleeping time, body temperature: and motor coordination (rota-rod test). The 1% and 3% linalool increased (p < 0.01) pentobarbital sleeping time and reduced (p<0.01) body temperature. The 3% linalool decreased (p<0.01) locomotion. Motor coordination was not affected. Hence, linalool inhaled for I h seems to induce sedation without significant impairment in motor abilities, a side effect shared by most psycholeptic drugs. (C) 2008 Elsevier GmbH. All rights reserved.

Sedation and analgesia management for mechanically ventilated adults: literature review, case study and recommentations for practice.

The quality of sedation management in mechanically ventilated patients has been a source of concern in recent years. This paper summarises the literature on the principles of optimal sedation, discusses the consequences of over and undersedation, highlighting the importance of appropriate pain management, and presents a case study using the results of an audit of 48 mechanically ventilated adults. As a result of the review and audit, we are implementing changes to practice.

The most important recommendations from the literature are the use of a sedation scale, setting of a goal sedation score, appropriate pain management and implementation of a nurse initiated sedation algorithm. Other recommendations include use of bolus rather than continuous sedative infusions and recommencing regular medications for anxiety, depression and other phychiatric disorders as soon as possible. A recommendation arising from our audit was the need to identify patients at high risk of oversedation and undersedation and adopt a proactive rather than reactive approach to management. The practice goal is to provide adequate and appropriate analgesia and anxiolysis for patients. This will improve patient comfort while reducing length of mechanical ventilation and minimising risk of complications.

Staff perceptions on the use of a sedation protocol in the intensive care setting

Sedation protocols are increasingly being investigated as a method of achieving improved patient outcomes whilst guiding the decision making of both nursing and medical practitioners. However, only a limited number of studies have investigated the perceptions of staff towards a sedation protocol during its implementation. This study was designed to survey the perceptions of staff regarding the implementation of a sedation protocol in an Australian intensive care unit (ICU). Questionnaires were distributed to all multidisciplinary team members who had used the sedation protocol. The response rate was 50% (n=70). The questionnaire combined the use of visual analogue scales plus a comments section to obtain qualitative data.

The results revealed that staff perceived sedation management to be enhanced with the use of a protocol and therefore should be incorporated into routine clinical practice. Staff perceived that providing clear guidelines that facilitated decision making and assisted beginner practitioners enhanced sedation management. In addition, there was a perceived improvement in the patient outcomes, including a decrease in the frequency of over-sedation resulting in a reduced ICU stay.

Positive perceptions may assist in the introduction of other interventional protocols. Other protocols may target areas where variability in clinical decision making exists, despite research evidence that supports specific therapeutic interventions. Further studies addressing protocol implementation for clinical interventions are warranted in other ICU settings.

Patients' experiences of cardiology procedures using minimal conscous sedation

Aim: The study's purpose was to describe patients' experiences of minimal conscious sedation during diagnostic and interventional cardiology procedures.

Methods: Over a 6-week period, 119 consecutive patients (10% of annual throughput) from a major metropolitan hospital in Melbourne, Australia, were interviewed using a modified version of the American Pain Society Patient Outcome Questionnaire. Patients identified pain severity using a 10-point visual analogue scale and rated their overall comfort on a 6-point Likert scale ranging from very comfortable to very uncomfortable.

Results: Patients were aged 67.6 years (standard deviation 11.1), 70.8% were male, and the mean body mass index was 27.7 (standard deviation 4.8). Patients underwent diagnostic coronary angiography (67.5%), percutaneous coronary interventions (13.3%), or combined procedures (19.2%). Most patients (65%) were comfortable in the context of low-dose conscious sedation. Slight discomfort was reported by 26% of patients; 9% reported feeling uncomfortable primarily as a result of a combination of musculoskeletal pain, angina, and vasovagal symptoms experienced during the procedure. There was significant correlation (rho = .25, P = .01) between procedure length and patients' report of overall comfort, suggesting longer procedures were less comfortable for patients.

Conclusions: The minimal sedation protocol was effective for the majority of patients; however, 9% of patients experienced significant discomfort related to preexisting conditions, highlighting the need for individual patient assessment before, during, and after the procedure.

A randomized trial of protocol-directed sedation management for mechanical ventilation in an Australian intensive care unit

Objective: To compare protocol-directed sedation management with traditional non-protocol-directed practice in mechanically ventilated patients. Design: Randomized, controlled trial. Setting: General intensive care unit (24 beds) in an Australian metropolitan teaching hospital. Patients: Adult, mechanically ventilated patients (n = 312). Interventions: Patients were randomly assigned to receive sedation directed by formal guidelines (protocol group, n = 153) or usual local clinical practice (control, n = 159). Measurements and Main Results: The median (95% confidence interval) duration of ventilation was 79 hrs (56-93 hrs) for patients in the protocol group compared with 58 hrs (44-78 hrs) for patients who received control care (p = .20). Lengths of stay (median [range]) in the intensive care unit (94 [2-1106] hrs vs. 88 (14-962) hrs, p = .58) and hospital (13 [1-113] days vs. 13 (1-365) days, p = .97) were similar, as were the proportions of subjects receiving a tracheostomy (17% vs. 15%, p = .64) or undergoing unplanned self-extubation (1.3% vs. 0.6%, p = .61). Death in the intensive care unit occurred in 32 (21%) patients in the protocol group and 32 (20%) control subjects (p = .89), with a similar overall proportion of deaths in hospital (25% vs. 22%, p = .51). A Cox proportional hazards model, after adjustment for age, gender, Acute Physiology and Chronic Health Evaluation II score, diagnostic category, and doses of commonly used drugs, estimated that protocol sedation management was associated with a 22% decrease (95% confidence interval 40% decrease to 2% increase, p = .07) in the occurrence of successful weaning from mechanical ventilation. Conclusions: This randomized trial provided no evidence of a substantial reduction in the duration of mechanical ventilation or length of stay, in either the intensive care unit or the hospital, with the use of protocol-directed sedation compared with usual local management. Qualified high-intensity nurse staffing and routine Australian intensive care unit nursing responsibility for many aspects of ventilatory practice may explain the contrast between these findings and some recent North American studies. (C) 2008 Lippincott Williams & Wilkins, Inc.

A critical review of daily sedation interruption in the intensive care unit

Background. Daily sedation interruption (DSI) has been proposed as a method of improving sedation management of critically ill patients by reducing the adverse effects of continuous sedation infusions.

Aim. To critique the research regarding daily sedation interruption, to inform education, research and practice in this area of intensive care practice.

Design. Literature review.

Method. Medline, CINAHL and Web of Science were searched for relevant key terms. Eight research-based studies, published in the English language between 1995–December 2006 and three conference abstracts were retrieved.

Results. Of the eight articles and three conference abstracts reviewed, five originated from one intensive care unit (ICU) in the USA. The research indicates that DSI reduces ventilation time, length of stay in ICU, complications of critical illness, incidence of post-traumatic stress disorder and is reportedly used by 15–62% of ICU clinicians in Australia, Europe, USA and Canada.

Conclusions. DSI improves patients' physiological and psychological outcomes when compared with routine sedation management. However, research relating to these findings has methodological limitations, such as the use of homogenous samples, single-centre trials and retrospective design, thus limiting their generalisability.

Relevance to clinical practice. DSI may provide clinicians with a simple, cost-effective method of reducing some adverse effects of sedation on ICU patients. However, the evidence supporting DSI is limited and cannot be generalised to heterogeneous ICU populations internationally. More robust research is required to assess the potential impact of DSI on the physical and mental health of ICU survivors.

Assessing the reliability of the sedation-agitation scale between nurses and doctors in a New Zealand ICU

The aim of the study was to determine whether nurses and doctors rate “real world” intensive care unit (ICU) patients similarly using the Sedation–Agitation Scale (SAS) in a generalist ICU context outside USA