Description of the condition
Current advances in diagnostic and invasive imaging technologies have increased the demand for paediatric procedural sedation outside the operating room. The incidence of minor surgical procedures done outside traditional operating rooms has also increased (Krauss 2006).
Children experience anxiety due to separation from parents and fear of injections or physicians. Anxiety can result in postoperative behavioural changes in children (Kain 1999). Hence sedation and anxiolysis play a key role in paediatric anaesthesia. Various interventions have been used to allay anxiety in children such as parental presence during induction, a preoperative preparation programme and preoperative sedative medication (Kain 1998). The most commonly practiced programme is preoperative sedative medication.
The ideal requirements for paediatric sedation include anxiolysis, amnesia, immobility and analgesia with preserved co-operation and haemodynamic stability, without causing any respiratory depression. To provide these requirements we need to use sedatives, analgesics or dissociative drugs. Various drugs have been used via different routes to provide a quiet, co-operative child. Most commonly used drugs include chloral hydrate, ketamine, midazolam and propofol. These drugs are associated with side effects such as respiratory depression, apnoea or bradycardia (Green 2003; Klein 2011; Krauss 2006; Olson 2001). Clonidine is an alpha-2 adrenergic agonist which has been tried as an oral premedicant in paediatric patients (Trevor 2012). The role of clonidine premedication for postoperative analgesia is also being investigated (Lambert 2012). The disadvantage of clonidine is its long duration of action. Dexmedetomidine is a congener of clonidine with a shorter duration of action that has been tried for procedural sedation in children (Aksu 2011; Deutsch 2007). Dexmedetomidine is also used intraoperatively as an adjunct to the inducing agent, to maintain haemodynamics, as a substitute for intraoperative and postoperative opioids, for the management of awake fibreoptic intubation and to reduce emergence agitation (He 2012; Mukhtar 2006; Patel 2010). Advantages of dexmedetomidine over other sedatives are its short duration of action and that it does not cause respiratory depression. Disadvantages are that it can cause transient hypertension followed by hypotension and bradycardia while it is not amnestic. There are case reports of dexmedetomidine triggered convulsions in paediatric patients (Tetsuo 2012; Tosun 2006).
Description of the intervention
Dexmedetomidine is a dextrorotatory enantiomer of medetomidine with selective affinity for the alpha-2 adrenergic receptor. It is eight times more potent than clonidine (Virtanen 1988). It was approved by the Food and Drug Administration (FDA) in 1999 for sedation during mechanical ventilation in intensive care units (ICU), for 24 hours duration; subsequently it was approved, in 2009, for monitored anaesthesia care. Following an intravenous loading dose it has a rapid phase redistribution of seven minutes, with a terminal half life of approximately two hours. It is 94% plasma protein bound and is metabolized by glucuronidation and excreted by the kidneys (Petroz 2006; Vilo 2008). Transient hypertension occurs during bolus administration due to a peripheral vasoconstrictor effect; this is followed by hypotension and bradycardia, the two main adverse effects of dexmedetomidine. Heart rate decreases by 30% in children following a loading dose (Mason 2008). Atipamezole is a specific and selective alpha-2 adrenergic antagonist which has been tried to reverse the pharmacological effects of dexmedetomidine (Karhuvaara 1991)
How the intervention might work
Dexmedetomidine possesses sedative, analgesic, opioid-sparing and anxiolytic properties. It exhibits its physiological effects due to stimulation of post-synaptic alpha-2 adrenergic receptors causing decreased neuronal activity and resulting in sedation and anxiolysis (Mason 2011). In the central nervous system it inhibits sympathetic activity and stimulates parasympathetic outflow in the brainstem thus causing a decrease in the heart rate and arterial blood pressure (Nelson 2003). It exhibits a direct effect on the locus ceruleus resulting in endogenous sleep with a varying depth of sedation. The analgesic effects of dexmedetomidine are due to activation of alpha-2B adrenoceptors at the level of the dorsal horn of the spinal cord and inhibiting the release of substance P, which is a neurokinin responsible for pain perception (Tobias 2007). It has an advantage over other sedatives in that it mimics natural sleep without the risk of apnoea or respiratory depression. It also causes decreased emergence agitation (crying, thrashing and disorientation experienced by children during emergence from anaesthesia), which is advantageous in children (Patel 2010). Dexmedetomidine has been used as an intravenous bolus (Lam 2013) and is also administered via the intramuscular (Mason 2012), buccal (Cimen 2012) and nasal routes (Yuen 2012) and is found to be effective. It has been used to treat iatrogenic withdrawal and to facilitate weaning of opioids and benzodiazepines in paediatric patients with cardiac disease (Baddigam 2005). Dexmedetomidine combined with ketamine preserves the haemodynamics and provides effective sedation (Koruk 2010). A meta-analysis on the use of dexmedetomidine for tonsillectomy and adenoidectomy found that dexmedetomidine was as effective as opioids in preventing postoperative pain and emergence agitation in children (He 2013). Another meta-analysis on the efficacy of intraoperative dexmedetomidine for acute postoperative pain in children concluded that there was low risk of postoperative pain following intraoperative dexmedetomidine (Schnabel 2013). There is no meta-analysis regarding the efficacy of dexmedetomidine for procedural sedation in children, hence this topic warrants a systematic review.
Why it is important to do this review
The presence of parents at induction of anaesthesia has not been shown to reduce anxiety or distress in children (Yip 2009). Hence pharmacological measures are essential to allay anxiety in children.
Paediatric sedation is no longer managed by anaesthesiologists alone. Medications once only used by anaesthesiologists are now utilized by non-anaesthesiologists to provide sedation to children (Havidich 2012). The efficacy and safety of dexmedetomidine in paediatric patients aged less than 18 years has not been established. Although not an FDA approved drug, more than 1000 paediatric patients have received dexmedetomidine for a variety of clinical applications inside and outside operating rooms (Easley 2008). Dexmedetomidine is expected to lose patent protection in the United States in 2013 and the acquisition cost of this drug is likely to decrease (Wunsch 2012). It will be available at affordable prices in developing countries following which there will be greater usage.
The primary objective of this review is to evaluate and compare the efficacy and safety of dexmedetomidine as a sedative with other pharmacological methods for procedural sedation in children.
Criteria for considering studies for this review
Types of studies
We will consider published and unpublished randomized and quasi-randomized controlled trials (allocation done on the basis of a pseudo-random sequence).
Types of participants
We will include children aged one month to 18 years who are undergoing any diagnostic, therapeutic or invasive procedure requiring sedation, analgesia or anaesthesia outside the operating room.
Types of interventions
Dexmedetomidine versus any sedative or opioid
We will not include studies where dexmedetomidine has been used as an adjunct to another anaesthetic agent.
Types of outcome measures
- Adequate sedation (Appendix 1) (as described by the study group)
- Haemodynamic response: a) heart rate response to dexmedetomidine (magnitude of heart rate change from baseline following administration of drug); b) blood pressure response to dexmedetomidine (magnitude of blood pressure change from baseline following administration of drug)
- Adverse events: a) bradycardia requiring intervention; b) hypotension requiring intervention; c) respiratory depression requiring intervention
- Need for additional sedation or analgesia, or both (Appendix 2)
- Duration of stay in post-sedation care unit (in hours) or delay in discharge
- Incidence of emergence agitation (Appendix 3)
- Incidence of convulsions
Search methods for identification of studies
We will conduct electronic searches of the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, most recent issue), MEDLINE (1966 to date) through Ovid, EMBASE (1988 to date) and Web of Science (1945 to date).
We will use the sensitivity maximizing search strategies described in section 6.4 of the Cochrane Handbook to search for randomized controlled trials (RCTs) in MEDLINE and EMBASE. We will not impose any language restriction in the search strategy.
We will use free text and explode associated MeSH terms as found in Appendix 4
Searching other resources
For ongoing trails, we will search the World Health Organization (WHO) International Clinical Trials Registry Platform. This includes clinicaltrials.gov, the meta.Register of Controlled Trials, and other national trial registries.
We will search the reference lists of all articles retrieved by the searches. We will also contact the individual researchers working in this field, organizations and pharmaceutical companies in order to identify unpublished and ongoing studies. We will present this information in a table along with the dates when this was done.
Data collection and analysis
Selection of studies
Two authors (SS and AR) will independently screen all citations and abstracts identified by the search strategy and include all eligible studies. We will assess the reports of all studies for inclusion in the review. If eligibility is unclear, we will seek more data or information from the study authors. The authors will resolve any differences regarding the eligibility of studies through discussion or consultation with a third author (SR). If a study is not eligible for inclusion, we will exclude it and document the reasons for exclusion.
We will exclude studies concerning sedation for dental procedures as there is a Cochrane review in process (Pauline 2001).
Data extraction and management
Two review authors (SS and AR) will independently extract the data from all the included studies using pre-tested data extraction forms (Appendix 5).
- Baseline characteristics (randomized controlled trial (RCT), single or multicentre, etc)
- Method of sequence generation
- Method of allocation concealment
- Blinding (of participants, personnel and outcome assessors)
- Number of participants randomized, as well as those excluded or lost to follow-up
- Whether an intention-to-treat analysis was done
- Whether a power calculation was done
- Duration, timing and location of the study
- Source of funding
- Type of diagnostic or therapeutic procedure
- Inclusion criteria
- Exclusion criteria
Details of the interventions, including the dose, route and duration, and other medical interventions
We will extract data for the outcomes as listed in the Types of outcome measures section.
We will compare interventions individually and versus other interventions.
Assessment of risk of bias in included studies
We (SS and AR) will independently extract the data on the following domains (Cochrane Handbook):
- random sequence generation (selection bias);
- allocation concealment (selection bias);
- blinding of participants and personnel (performance bias);
- blinding of outcome assessment (detection bias);
- incomplete outcome data (attrition bias);
- selective reporting (reporting bias);
- other bias.
We will assess the risk of bias in each included studies using the Cochrane 'Risk of bias' tool (Cochrane Handbook). We will resolve any disagreements by discussion with the third review author (SR). We will judge each domain in the risk of bias tool as 'Low risk' of bias, 'High risk' of bias, or 'Unclear risk' of bias because of either lack of information or uncertainty over the potential for bias.
Measures of treatment effect
For dichotomous outcomes, primary outcomes 1, 3 (adequate sedation, adverse events); secondary outcomes 1, 3, 4 (need for additional sedation or analgesia, incidence of emergence agitation, incidence of convulsions), we will use the risk ratio (RR) with the 95% confidence interval (CI). For continuous outcomes, primary outcome 2 (haemodynamic response); secondary outcome 2 (duration of stay in post-anaesthesia care unit (in hours) or delay in discharge), we will use the mean difference (MD) with the 95% CI. If continuous data have been summarized using geometric means, we shall combine them on the log scale using the generic inverse variance method and report them on the linear scale.
For some dichotomous outcomes (for example the proportion of patients having adverse events), a higher proportion represents a negative consequence of that treatment; and for other outcomes a higher proportion is considered a benefit of treatment. We will make this distinction between the categorizing of outcomes clear when we construct the summary graphs for the meta-analysis. Thus, for some of the dichotomous outcomes a treatment benefit will be displayed as risk ratio (RR) with 95% CI to the left of the centre line, while for others a treatment benefit will be displayed to the right of the centre line. For clarification, we will label the forest plots for each outcome.
If time to event outcomes are reported, we will extract the estimates of the log hazard ratio and its standard error (SE). If standard errors are not available, we will use alternative statistics that are reported in the studies to compute the SE by following the methods described in the Cochrane Handbook.
Unit of analysis issues
We anticipate that there will not be any cluster randomized studies.
If outcomes are reported both at baseline and at follow-up, or at trial endpoints, we will extract the mean change from baseline and the standard deviation of this mean for each group, as well as for the endpoint data. If count data are reported in trials, we will extract the total number of events in each group and the total person-time risk in each group. If count data are presented as continuous outcomes or as time to event outcomes, we will extract the same information for the respective outcomes.
When studies have reported the outcome using a per protocol analysis, we intend to perform the analysis based on intention to treat (ITT) by assuming the best case scenario.
Dealing with missing data
We will attempt to obtain all missing data from the study investigators. Where possible, we will extract data to allow an ITT analysis in which all randomized participants are analysed in the groups to which they were originally assigned. If there is a discrepancy between the number analysed and the number randomized, we will calculate the percentage lost to follow-up in each group and report this loss. For dichotomous outcomes, if dropouts exceed 10% for any study we will assign the worst outcome to those lost from that group and assess the impact in a sensitivity analysis by comparing the result with the result from the participants who completed the study. For continuous data, if standard deviations (SDs) are missing we will calculate them from other available data, such as SEs, or impute them using the suggested methods (Cochrane Handbook). We will not make assumptions about losses to follow-up for continuous data and will analyse the results for those who completed the study.
Assessment of heterogeneity
We will visually inspect the forest plot for overlapping confidence intervals along with applying the Chi
When substantial heterogeneity is found, we will explore the reason by Subgroup analysis and investigation of heterogeneity. When considerable heterogeneity is present we will not perform a meta-analysis.
Assessment of reporting biases
Apart from addressing the risk of reporting bias, we will assess the likelihood of publication bias using funnel plots (provided there are at least 10 studies). We will combine multiple reports of a single study under a single study identifier. We will check for discrepancies between the outcomes in published protocols against the actual reported outcomes at the end of the study (outcome reporting bias).
The included studies may present the data for evaluation in different ways, as dichotomous outcome data or ordinal scales (for example sedation scales, measured as the Ramsay Scale, Richmond Agitation Sedation Scale; analgesia scales, visual analogue scale (VAS), a numeric scale or behaviour scale; and for emergence agitation, scales such as agitation score etc). Therefore, in the case of dichotomous data we will use risk ratio and, where possible, we plan to use the standardized mean difference (SMD) for continuous outcomes. If this is not possible, we will not pool the data but will analyse the studies separately. Similarly, we will not pool data from studies which measure outcomes using different scales.
If we undertake a meta-analysis we will use the fixed-effect model when there is no heterogeneity. Where heterogeneity is significant (I
For dichotomous data, we will use a Mantel-Haenszel fixed-effect model to calculate the risk ratio with 95% CI.
Subgroup analysis and investigation of heterogeneity
We plan the following subgroup analyses as a means of investigating heterogeneous results and also to answer specific questions about the above types of interventions.
- Route of administration of dexmedetomidine - intravenous, intramuscular, nasal, oral.
- Age group of children - one month to one year, one year to three years, and three years to 18 years.
- Type of procedure - invasive or noninvasive, diagnostic or therapeutic.
- Children with neurocognitive impairment.
- Different dosing regimens of dexmedetomidine.
If we are able to include sufficient data, we will perform the following sensitivity analyses.
- Studies with a low risk of bias versus those with a high risk of bias.
- Studies with or without a power calculation.
- Studies assessing the outcome objectively versus those assessing the outcome subjectively or indirectly, as explained above.
- Studies with number of dropouts less than 10% versus those with more than 10% dropouts.
Summary of findings
We will summarize the results by importing the data from RevMan 5.2 to GRADEprofiler software to create summary of findings tables.
By making judgements for each domain, using the methods described in the GRADEprofiler software, we will grade each outcome described in the Primary outcomes for the quality of the evidence.
This document is the result of a workshop organized by the South Asian Cochrane Network at The Christian Medical College Vellore.
We would like to thank Ronan O'Sullivan (Content editor), Marialena Trivella (Statistical editor), Anuradha Patel, Hannah Wunsch and Paul Lamber (Peer reviewers) for their help and editorial advice during the preparation of this protocol for the systematic review.
Appendix 1. Sedation
The American Society of Anesthesiologists defines the continuum of sedation as the following.
- Minimal sedation - normal response to verbal stimuli.
- Moderate sedation - purposeful response to verbal/tactile stimulation (conscious sedation).
- Deep sedation - purposeful response to repeated or painful stimulation.
- General anesthesia - unarousable even with painful stimulus.
The different scales used to measure sedation include:
- Ramsay Scale - numeric scale;
- Richmond Agitation Sedation Scale (RASS);
- Minnesota Sedation Assessment Tool (MSAT);
- University of Michigan Sedation Scale (UMSS);
- Observer's Assessment of Alertness and Sedation (OAA/S).
Appendix 2. Analgesia
Definition: absence of the spontaneous report of pain or pain behaviours in response to stimulation that would normally be expected to be painful (Bonica's 2010).
Measurement of pain intensity, the most commonly used scales to assess pain intensity are the following.
- Visual analogue scale (VAS).
- Numerical rating scale (NRS).
- Verbal (Categorical) Rating Scale.
Behaviour observation method, the commonly used scales are:
- Faces Pain Scale - Revised (FPS-R);
- Face, Legs, Activity, Cry and Consolability (FLACC) Scale;
- Children's Hospital of Eastern Ontario Pain Scale (CHEOPS);
- CRIES Scale;
- Children and Infants' Postoperative Pain Scale (ChIPPS).
Appendix 3. Emergence delirium
Emergence delirium is a transient state of marked irritation and disassociation after the discontinuation of anaesthesia in some patients, which does not respond to consoling measures.
Some scales used for measuring emergence delirium are:
- Paediatric Anaesthesia Emergence Delirium (PAED);
- Watcha scale;
- Cravero scale;
- 4 Point Agitation scale.
Appendix 4. MEDLINE (OvidSP) search strategy
1. exp Dexmedetomidine/ or Adrenergic alpha-Agonists/ or (Precedex or Dexmedetomidin*).af. or ((adren?ergic or alpha) adj3 agonist*).mp.
2. exp Conscious Sedation/ or (procedural adj3 sedation).mp. or Perioperative Period/ or (perioperative adj3 (period or use*)).mp.
3. 1 and 2
4. (child* or pediatr*).af.
5. 3 and 4
Appendix 5. Data extraction form
Data collection form
1. General Information
2. Study Eligibility
DO NOT PROCEED IF STUDY EXCLUDED FROM REVIEW
3. Population and setting
5. Risk of Bias assessment
7. Intervention groups
Intervention Group 1
Primary Outcome 1
Primary Outcome 2
Primary Outcome 3
Secondary Outcome 1
Secondary outcome 2
Secondary outcome 3
Secondary outcome 4
10. Other information
Contributions of authors
Sampangiramaiah Shailaja (SS), Amita Ray (AR), Sujoy Ray (SR), Richard Kirubakaran (RK)
Conceiving the review: SS, AR
Co-ordinating the review: SS, AR, SR
Undertaking manual searches: SS, AR
Screening search results: SS, AR
Organizing retrieval of papers: SS, AR
Screening retrieved papers against inclusion criteria: SS, AR
Appraising quality of papers: SS, AR, SR
Abstracting data from papers: SS, AR
Writing to authors of papers for additional information: SR, SS
Providing additional data about papers: SS, AR
Obtaining and screening data on unpublished studies: SS, SR
Data management for the review: SS, AR, RK
Entering data into Review Manager (RevMan 5.2 ): SS, AR, SR
RevMan statistical data: RK, SR
Other statistical analysis not using RevMan: RK
Interpretation of data: RK, SS
Statistical inferences: RK, AR
Writing the review: SS, AR, SR, RK
Securing funding for the review: none
Performing previous work that was the foundation of the present study: none
Guarantor for the review (one author) SS
Person responsible for reading and checking review before submission: SS, AR, SR, RK
Declarations of interest
Sampangiramaiah Shailaja: none known
Amita Ray: none known
Sujoy Ray: none known
Richard Kirubakaran: none known
Sources of support
- No source of support provided, Not specified.
- No sources of support supplied