Background

The anesthesia aspect of the surgical experience creates anxiety for patients.1 The thought of having anesthesia and being put to sleep is associated with a feeling of loss of control that is both uncomfortable and unfamiliar.1 Fear and anxiety are intense emotions that can affect the mind and change both pre- and postoperative behaviors.1 The treatment of anxiety is especially challenging in the pediatric population. Up to 65% of pediatric surgical patients develop severe anxiety in the preoperative holding area, as well as during induction of anesthesia.1 Children with anxiety preoperatively and during anesthetic induction experience a greater degree of agitation and distress in the post-anesthesia care unit.2 Preoperative anxiety is an independent predictor of postoperative negative behaviors, including nightmares, waking up crying, separation anxiety and temper tantrums. Increased levels of anxiety are directly correlated with the incidence of emergence delirium (ED).1,2

Emergence delirium is defined as a cognitive disturbance during emergence from general anesthesia resulting in hallucinations, delusions and confusion manifested by agitation, restlessness, involuntary physical movement and extreme flailing about in bed.3 Postoperative ED develops in 12-18% of all children undergoing general anesthesia for surgery.1 Emergence delirium creates an inability of the child to recognize his or her parents, surroundings and/or other familiar objects.4 This post-anesthetic phenomenon changes cognitive and psychomotor behavior, and puts pediatric patients and healthcare personnel at risk of injury. Unintentional self-injury can occur in a patient experiencing ED due to multiple causes including the removal of catheters and drains, falls, wound dehiscence and blunt trauma to extremities from hitting nearby bed rails or other equipment.3 Adverse events arising from ED can involve prolonged recovery, increased hospital length of stay, caregiver role strain, patient/parent dissatisfaction and the need for surgical re-exploration to repair injuries. Other risk factors for ED include children less than six years of age, postoperative pain and administration of inhalational anesthetic agents.4 Emergence delirium can be measured through a variety of standardized scoring systems for postoperative agitation or the newer, more sensitive Pediatric Anesthesia Emergence Delirium (PAED) scale.3

The intense preoperative anxiety relating to surgery requires the anesthesia practitioner to administer premedication to help calm the child. The currently accepted standard treatment of preoperative anxiety is administration of midazolam, a benzodiazepine class drug, with the primary function of anxiolysis. Midazolam is effective in the treatment of preoperative anxiety, but has not been shown to reduce the incidence of ED.5

Multiple studies in the literature link oral midazolam to the incidence of postoperative ED.5,6 Multiple studies demonstrate that midazolam has undesirable side effects including restlessness, paradoxical reactions and negative postoperative behavioral changes.5,6 Drugs that act on gamma-aminobutyric acid (GABA) receptors, such as midazolam, can produce a hazy state of consciousness which puts the patient at risk of ED.7 Another study links midazolam with delayed recovery after brief sevoflurane anesthesia by a few minutes.8 Delayed recovery from anesthesia may increase the interval at which the child is at an increased risk of complications such as acute airway obstruction, such as laryngospasm, due to an inability to protect his or her airway.8

A newer drug, dexmedetomidine, is a selective alpha-2 agonist which works in the brain and spinal cord that has sedative, analgesic and anxiolytic properties. Dexmedetomidine also has the ability to lower the overall anesthetic requirements by reducing sympathetic outflow in response to painful surgical stimulation.4,9 Dexmedetomidine use in children and neonates has expanded in recent years to include the prevention and treatment of ED, postoperative pain control, procedural sedation and opioid withdrawal management.4 Even though the use of dexmedetomidine in this patient population has increased, the Food and Drug Administration has not yet approved this drug as a first-line treatment for preoperative anxiety and prevention of ED in pediatric patients.

The development of ED is associated with multidimensional factors including the interruption of the physiologic sleep cycle, use of volatile anesthetics, presence of pain postoperatively and the presence of preoperative anxiety. It is important to conduct this systematic review to discover if dexmedetomidine may provide a better outcome, compared with oral midazolam, for premedication of pediatric surgical patients.

Martin et al.6 compared the electroencephalograms in children who developed ED to those who did not through assessment of cortical functional connectivity. Children who awoke from anesthesia in a calm controlled state showed characteristics of typical sleep patterns (theta and delta waves) just prior to their arousal from anesthesia. Slow wave sleep seen with delta waves is a restful dream-free sleep state, characterized by decreased sympathetic activity and muscle tone.7 On the other hand, children who experienced ED awoke from an "indeterminate state", characterized by mixed alpha and beta waves, which are associated with a more active cerebral cortex as that of an awake state of consciousness.6

Dexmedetomidine is unique because the sedation it produces mimics that of a normal sleep cycle, a property that drugs which act on GABA (midazolam) are unable to produce.7,10 Benzodiazepines, such as midazolam, can actually disrupt sleep cycles and attenuate rapid eye movement sleep.5 In addition, the anterograde amnesia caused by midazolam may contribute to disorientation and agitation postoperatively in younger children.5

Volatile anesthetics, particularly sevoflurane, have been widely accepted as risk factors in the development of ED.11 Sevoflurane is associated with up to 67% more incidences of ED following general anesthesia.9 Dexmedetomidine has been shown to decrease the minimum alveolar concentration (MAC) of inhaled anesthetics between 17 and 50% depending on the dose.4 A single MAC (1.0) of inhaled anesthetics is the concentration at 1 atmosphere required to prevent skeletal muscle movement in response to a supramaximal painful stimulus in 50% of individuals.12

Dexmedetomidine acts on spinal noradrenergic neurons to the dorsal horn by hyperpolarizing potassium channels causing inhibition of the release of nociceptive neurotransmitters such as substance P, which contribute to pain modulation.13-15 The drug also acts at the site of the locus ceruleus by amplifying the activity of inhibitory neurons (GABA), which decreases central sympathetic output contributing to sedation and analgesia.3,13-15 The actions on both the spinal cord and supraspinal mechanisms give dexmedetomidine both analgesic qualities and the ability to augment the effects of exogenous opioids, reducing the perioperative narcotic requirement by 30-50%.7,14

Martin et al.6 hypothesized that pain inhibits a child from progressing to a normal sleep state during anesthesia, thus increasing the chance of the child awakening when in a deep plane of anesthesia. Inadequate pain control is a risk factor for ED particularly in brief surgical procedures, since the peak analgesic effect of the drug is delayed until after emergence has already occurred.2 Acute pain can manifest as significant emotional, behavioral or social abnormalities.13 It is vital to incorporate pain into the prevention of ED because newborns and young children have decreased pain thresholds and exaggerated responses to pain.13

One meta-analysis conducted by Peng et al.16 reviewed dexmedetomidine as a premedication in pediatric patients. Peng et al. compared dexmedetomidine with both ketamine and midazolam but did not specifically look at intranasal dexmedetomidine and oral midazolam. The review also did not have set standards for measuring ED. Another meta-analysis performed by Pasin et al.17 reviewed 13 randomized control trials and obtained data from 1033 pediatric patients. This analysis considered all administration routes of both dexmedetomidine and midazolam, but lacked a single standardized tool for measuring ED. A third meta-analysis conducted by Sun et al.18 had the same issues: multiple routes were considered with both dexmedetomidine and midazolam, with the lack of a consistent scale to measure ED. Most of the studies included in these meta-analyses did not clearly define ED as it is still a relatively new phenomenon.

This review will specifically look into whether preoperative intranasal administration of dexmedetomidine has an effect on the incidence of ED when compared with oral midazolam in pediatric patients aged three to seven years. This review will focus on the use of a single, standardized scale that specifically measures ED to provide a more reliable conclusion that may contribute to clinical decision making.

Inclusion criteria

Types of participants

The current review will consider studies that include pediatric patients aged three to seven years, with an American Society of Anesthesiologists (ASA) classification of I or II19 and who are undergoing general anesthesia for elective/ambulatory surgery. This review will exclude studies that include patients who have special needs including developmental delay, chronic pain issues and/or any preexisting mental or physical health disorders which categorize them above an ASA II. The ASA is a classification system that evaluates the preoperative health status of an individual. An ASA I status constitutes a healthy individual, and an ASA II status labels an individual with mild disease and no functional limitations.

Types of intervention(s)/phenomena of interest

Since both oral midazolam and intranasal dexmedetomidine provide effective preoperative sedation, a focused look into the safest alternative of the two drugs is warranted.17,18 Therefore, this review will consider studies that compare preoperative intranasal administration of dexmedetomidine with preoperative oral administration of midazolam for the prevention of ED.

Outcomes

The current review will consider studies that include the presence of postoperative ED. The PAED scale is currently the only scale used to measure ED that is sensitive to the pediatric population.3 The PAED scale consists of five characteristics that are each ranked by a five-point Likert scale.3 The highest levels of sensitivity and specificity to detecting ED have been achieved when a scale score of 10 or higher has been reported.3 Thus, only studies that use the PAED scale to quantify the degree of ED will be included in the review. Adverse events other than ED will not be considered as part of the outcomes inclusion criteria; however, they will be included in the discussion. While other studies have reviewed the effectiveness of dexmedetomidine's ability to provide sedation and pain reduction, they do not appropriately measure the presence of ED through the use of a pediatric sensitive delirium scale. Therefore, these studies will not be included in the review.

Types of studies

The review will consider both experimental and non-experimental study designs including randomized controlled trials, non-randomized control trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies for inclusion.

Search strategy

The search strategy aims to discover both published as well as unpublished studies on the phenomena of interest. A three-step approach will be undertaken in the search for literature. An initial limited search of Ovid/Medline and CINAHL will be undertaken. An analysis of text words contained in the title and abstract as well as index terms used to describe the article will be identified in MeSH and added to the search string. A second search using all identified keywords and index terms will be explored through all included databases. Third, the reference lists of all identified articles will be searched for any studies missed by the initial searches. Only studies available in English or English translation will be included in the review. If appropriate studies are discovered in languages other than English, authors will be contacted to identify if they have an English translation available. Studies published after 1999 will be considered for inclusion in this review. The year 1999 was chosen as a date when dexmedetomidine was invented and started being used for testing on human subjects.20

The databases to be searched include CINAHL, Ovid/MEDLINE, Scopus and EMBASE. The search for unpublished studies will include ProQuest Dissertations and Theses (PQDT) and clinicaltrials.org. All identified studies will be assessed for relevance to the review based on information provided in the title, abstract and descriptor terms. Full reports will then be retrieved and reviewed for all studies that appear to meet inclusion criteria.

Initial keywords to be used to develop full search strategies will be emergence delirium; emergence agitation; postoperative delirium; postoperative agitation; behavior; pediatric; children; dexmedetomidine; precedex; midazolam; versed; oral; preoperative and intranasal.

Assessment of methodological quality

Quantitative papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through a discussion or with a third reviewer.

Data extraction

Quantitative data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. The authors of primary studies will be contacted for any missing or unclear data. Multiple, independent data extractors will be used to minimize errors during the extraction process.

Data synthesis

Quantitative data will be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also examined via subgroup analysis based on the different study designs included in this review. When statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation when appropriate.

Appendix I: MAStARI appraisal instruments

Appendix II: MAStARI extraction instruments

References