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Anxiolytic premedication for children

2020; Elsevier BV; Volume: 20; Issue: 7 Linguagem: Inglês

10.1016/j.bjae.2020.02.006

2058-5357

Shimaa Adel Heikal, Grant Stuart,

Music Therapy and Health

Learning objectivesBy reading this article, you should be able to:•Describe the role of sedative premedication in managing preoperative anxiety in children.•Discuss the considerations for selecting which premedication to use.•Explain that midazolam may cause a paradoxical reaction in some patients.Key points•Preoperative anxiety in children is associated with adverse clinical and behavioural outcomes.•Multiple techniques may be valuable in managing preoperative anxiety.•The need for sedative premedication should be considered during the preoperative assessment of every child.•Many factors may influence the choice premedication, including the pharmacological profile, possible adverse effects and the presence of any comorbid conditions.•More work is required to clarify weight-based dosing in obese patients. By reading this article, you should be able to:•Describe the role of sedative premedication in managing preoperative anxiety in children.•Discuss the considerations for selecting which premedication to use.•Explain that midazolam may cause a paradoxical reaction in some patients. •Preoperative anxiety in children is associated with adverse clinical and behavioural outcomes.•Multiple techniques may be valuable in managing preoperative anxiety.•The need for sedative premedication should be considered during the preoperative assessment of every child.•Many factors may influence the choice premedication, including the pharmacological profile, possible adverse effects and the presence of any comorbid conditions.•More work is required to clarify weight-based dosing in obese patients. A child's preoperative anxiety can pose a significant challenge for the anaesthetic team and can be distressing for parents. Evidence suggests that preoperative anxiety is associated with adverse outcomes, both clinical (increased requirements for analgesics and emergence delirium) and behavioural (sleep disturbances and enuresis).1Fortier M.A. Del Rosario A.M. Martin S.R. Kain Z.N. Perioperative anxiety in children.Paediatr Anaesth. 2010; 20: 318-322Crossref PubMed Scopus (138) Google Scholar,2Kain Z.N. Mayes L.C. Caldwell-Andrews A.A. Karas D.E. McClain B.C. Preoperative anxiety, postoperative pain and behavioural recovery in young children undergoing surgery.Pediatrics. 2006; 118: 651-658Crossref PubMed Scopus (449) Google Scholar Many techniques can be used to reduce anxiety (Table 1). Non-pharmacological techniques must be considered for all anxious children and may be used in conjunction with premedication, or independently. The evidence base for these is growing, but a detailed discussion is beyond the scope of this article.3Manyande A. Cyna A.M. Yip P. Chooi C. Middleton P. Non-pharmacological interventions for assisting the induction of anaesthesia in children.Cochrane Database Syst Rev. 2015; 7: CD006447Google Scholar Sedative premedication is used when alternative techniques have failed, for those needing multiple operative procedures, for those who have previously had a traumatic perioperative experience and for those with special needs (e.g. autistic spectrum disorder) that limit the child's ability to cooperate. It may also be used in conjunction with non-pharmacological techniques.Table 1Alternative methods for managing preoperative anxiety in childrenAnxiolytic strategiesPractical examplesPre-hospital information and preparationInformation leaflets, books, videos, hospital and operating theatre tours, ‘social stories’ and engagement with clinical psychologistsPlay therapyInteraction with trained play therapists using visual aids and toys, and accompanying patient to operating theatreDistraction techniquesBlowing bubbles, toys, videos and gamesEngagement with anaesthetic techniqueHandling/personalising mask, ‘blowing up the balloon’ and building anaesthetic circuitEnvironmental adjustmentLighting, music, minimal extraneous noise, fewest healthcare staff possible and hypnosisActively involving parents/carersParental presence for induction (also dependent on parental anxiety levels)Communication aidsCommunication ‘passports’ (information about the child's needs, routines and communication strategies), use of Makaton and symbol chartsRelaxation techniquesBreathing and relaxation exercises, hypnosis and immersive reality Open table in a new tab Identifying children who are likely to experience preoperative anxiety is an essential step in optimising their care. A number of tools, such as the modified Yale Preoperative Anxiety Scale, can provide an observational measure of anxiety, but these are used for research rather than for clinical purposes.4Kain Z.N. Mayes L.C. Cicchetti D.V. Bagnall A.L. Finley J.D. Hofstadter M.B. The Yale Preoperative Anxiety Scale: how does it compare with a “gold standard”?.Anesth Analg. 1997; 85: 783-788Crossref PubMed Google Scholar Factors predictive of poor behavioural compliance during induction include younger age ( 1 yr old2 μg kg−1 (range: 1–4 μg kg−1; maximum 200 μg)2540–135 min (depending on dose)Intranasal option; shorter half-life than clonidineCaution in patients with Grade 2/3 heart block (unless paced), uncontrolled hypertension, and digoxin; intranasal is by mucosal atomisation device (note dead space)Oral clonidine 100 μg tablets or 10 μg ml−1 solutionCentral α2-adrenoceptor agonist6 months–18 yrs4 μg kg−1 (maximum 200 μg)45–6045–90 minTasteless liquid; long ‘window’ of actionCaution in patients with cardiovascular disease/instabilityTemazepam 10 mg tablets or 2 mg ml−1 solutionGABAA receptor agonist12–18 yrs10–20 mg (maximum 10 mg)6012–140 minUseful if maximum dose of midazolam exceededLong time to onsetKetamine oral/i.m. (10 or 50 mg ml−1)Primarily NMDA receptor antagonist2–18 yrsOral: 5–8 or 3 mg kg−1 in combination with midazolam; i.m.: 4–5 mg kg−1; i.v.: 1–2 mg kg−110–153 hQuick onset; useful in combination with midazolamIncreased salivation, hallucinations, emergence delirium, and PONV at higher doses; anaesthetists must be present at all times if i.m./i.v.Morphine (2 mg ml−1 solution)μ-opioid receptors6 months–18 yrs0.2 mg kg−1 (maximum 10 mg)20–301–2 hAnalgesic properties; useful in combinationRarely used as sole agent; risk of respiratory depression and apnoea Open table in a new tab Midazolam is used commonly because of its familiarity, quick onset and brief duration of action. It is an effective preoperative anxiolytic, may cause anterograde amnesia by inducing a dissociation between explicit and implicit memory, and reduces postoperative nausea and vomiting (PONV). However, these amnestic effects may result in children displaying more anxious behaviour in the immediate postoperative period.9Stewart S.H. Buffett-Jerrott S.E. Finley G.A. Wright K.D. Valios Gomez T. Effects of midazolam on explicit vs implicit memory in a surgery setting.Psychopharmacology. 2006; 188: 489-497Crossref PubMed Scopus (29) Google Scholar The oral preparation has a bitter taste, which might make some children refuse it or spit it out. Some practitioners mask this by adding it to a small volume of a flavoured drink. Buccal midazolam has a quick onset, may be better tolerated by some children and does not require them to swallow the medication. Although it is possible to give midazolam by the intranasal route, the low pH of the preparation can cause not only pain, but also bleeding; this route is best avoided. Paradoxical reactions to midazolam occur in a small proportion of children at variable times after dosing. This may present with a brief period of sedation followed by aggression, increased anxiety, agitation, violent crying, disorientation, hallucinations and an inability to be calmed by parents. A paradoxical reaction may be difficult to distinguish from an agitated and anxious child who has received inadequate premedication, but the key features are that distress occurs after the administration of the premedication, after a brief period of sedation, and does not improve with an additional or increased dose of premedication. Children receiving higher doses of midazolam appear to be at increased risk of paradoxical reactions.10Shin Y.H. Kim M.H. Lee J.J. et al.The effect of midazolam dose and age on the paradoxical midazolam reaction in Korean pediatric patients.Korean J Anesthesiol. 2013; 65: 9-13Crossref PubMed Scopus (14) Google Scholar Responder rates suggest that smaller doses (0.25–0.5 mg kg−1 depending on the preparation used) of midazolam are almost as effective as higher doses (0.75–1.5 mg kg−1) and little advantage is gained by increasing the dose.11Manso M.A. Guittet C. Vandenhende F. Granier L. Efficacy of oral midazolam for minimal and moderate sedation of pediatric patients: a systematic review.Paediatr Anaesth. 2019; 29: 1094-1106Crossref PubMed Scopus (16) Google Scholar Midazolam is also associated with an increased incidence of postoperative agitation. Dexmedetomidine is a highly selective α2-adrenoceptor agonist that provides anxiolysis and sedation, whilst providing additional benefits, including analgesic effects and avoidance of respiratory depression. The sedation provided by dexmedetomidine resembles a natural sleep, and meta-analyses show it to be at least as effective in decreasing preoperative anxiety when compared with midazolam.12Pasin L. Febres D. Testa V. et al.Dexmedetomidine vs midazolam as preanaesthetic medication in children: a meta-analysis of randomized controlled trials.Paediatr Anaesth. 2015; 25: 468-476Crossref PubMed Scopus (57) Google Scholar However, dexmedetomidine does not provide any amnestic effects and has a longer time to onset and longer duration of action than oral midazolam. Bradycardia, or decrease in resting heart rate, is a predictable response to dexmedetomidine, and it should be used with caution in patients with severe ventricular dysfunction and advanced atrioventricular block, and those taking medications, such as digoxin or beta blockers. A biphasic effect on arterial pressure may also be seen, and so it should be avoided in patients with uncontrolled hypertension. Clonidine is another α2-adrenoceptor agonist that is more widely available at most hospitals. It has many of the advantages and disadvantages of dexmedetomidine. It is given orally, usually by giving the i.v. preparation, which is tasteless. It has a slow onset of action and long duration of action, and so provides a long ‘window’ of sedation before surgery, but prolonged sedation after surgery. It should be used with due caution, as it may induce hypotension and bradycardia. Ketamine has sedative, anxiolytic and analgesic properties, and a rapid onset of action. It may cause hallucinations, random limb movements, increased salivation, hyperventilation and significant emergence reactions, particularly when given at the higher doses required when using as a sole premedication. It is also emetogenic. Children receiving ketamine should be nursed with close observation in a quiet area. Giving midazolam in combination with ketamine allows a lower dose to be given. Ketamine can be given i.m. in cases where all other methods of managing perioperative anxiety sufficiently to achieve safe anaesthesia have failed and the procedure is felt to be necessary, or if alternative drugs are not available. It is highly lipid soluble and is rapidly absorbed after i.m. administration. This may be painful and traumatic for the child, and may also require physical restraint for the injection. The parents should be counselled about this beforehand. Flumazenil competitively antagonises the effects of benzodiazepines. It may be given as a reversal agent in patients who develop significant respiratory depression or apnoea after iatrogenic benzodiazepine oversedation, provided there are no contraindications (in particular, flumazenil may precipitate seizures in patients taking prolonged benzodiazepine therapy for epilepsy).13Shannon M. Albers G. Burkhart K. et al.Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. The Flumazenil Pediatric Study Group.J Pediatr. 1997; 131: 582-586Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar It is given i.v. at an initial dose of 10 μg kg−1 over 15 s (up to a maximum dose of 200 μg). The peak effect of a single dose occurs 6–10 min after administration. The duration of action of flumazenil is brief and re-sedation may occur, requiring further doses. Infusions of flumazenil are unlicensed in children, but can be given. It is also not licensed for use in children aged <1 yr. It is worth noting that flumazenil does not consistently reverse the central respiratory depression that occurs after benzodiazepine overdose. The use of flumazenil to reverse paradoxical agitation as a result of midazolam administration has also been described.14Massanari M. Novitsky J. Reinstein L.J. Paradoxical reactions in children associated with midazolam use during endoscopy.Clin Pediatr (Phila). 1997; 36: 681-684Crossref PubMed Scopus (88) Google Scholar,15Jackson B.F. Beck L.A. Losek J.D. Successful flumazenil reversal of paradoxical reaction to midazolam in a child.J Emerg Med. 2015; 48: e67-e72Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Common adverse effects of flumazenil include anxiety, nausea, vomiting, headache and palpitations. Sedative premedication in children with obstructive sleep apnoea (OSA) may cause pre- and postoperative airway obstruction and desaturation. However, a safe and non-traumatic induction of anaesthesia is not possible without premedication for some children. Thus, the appropriate sedatives should be used with due caution and when indicated, with support from anaesthetists. Midazolam may increase supraglottic airway resistance, induce central apnoeas and decrease the arousal response to hypoxia and hypercarbia.16Montravers P. Dureuil B. Desmonts J.M. Effects of i.v. midazolam on upper airway resistance.Br J Anaesth. 1992; 68: 27-31Abstract Full Text PDF PubMed Scopus (103) Google Scholar Therefore, it should be used with caution.17Ankichetty S. Wong J. Chung F. A systematic review of sedatives and anesthetics with obstructive sleep apnea.J Anaesthesiol Clin Pharmacol. 2011; 27: 447-458Crossref PubMed Scopus (67) Google Scholar Dexmedetomidine causes a decrease in minute ventilation and increases arterial carbon dioxide, but this occurs at a level similar to ‘profound sleep’, suggesting a theoretical advantage over midazolam. Airway patency and tone are also maintained.18Mahmoud M. Radhakrishman R. Gunter J. et al.Effect of increasing depth of dexmedetomidine anaesthesia on upper airway morphology in children.Paediatr Anaesth. 2010; 20: 506-515Crossref PubMed Scopus (87) Google Scholar Ketamine may also offer a theoretical advantage over midazolam as upper airway patency is maintained, although the associated hypersalivation may cause problems. Obesity is associated with a number of conditions that need to be considered when prescribing sedative premedications, including OSA and gastro-oesophageal reflux. Achieving optimal drug dosing in obese children is challenging. The physiological changes that occur can affect the pharmacokinetics of many drugs, and failure to adjust drug dosing appropriately may result in inadvertent toxicity or therapeutic failure. There remains a lack of pharmacokinetic studies in obese children, and the available evidence is complicated by variations in the BMI percentile thresholds used to define obesity. Drug dosing guidance (where available) is typically derived from data in obese adults. There are some key pharmacokinetic principles:(i)Absorption appears unaltered (based on limited data in obese adults).(ii)Drug distribution alters as both fat mass and lean body mass increase, but not proportionally.(iii)Dose adjustments are determined by the physicochemical properties of the drug:(a)Ideal body weight should be used for relatively hydrophilic drugs (e.g. morphine).(b)Adjusted body weight may be used for those medications that partially distribute to adipose tissue (e.g. dexmedetomidine and clonidine).(c)Initial doses of lipophilic drugs may need to be increased for an adequate response and should be based on total body weight (e.g. benzodiazepines and ketamine).(iv)Changes in protein binding are not significant clinically.(v)The impact of obesity on drug metabolism may differ greatly, depending on the metabolic pathway and the drug. It can be challenging to apply these principles in practice. For example, in obese adult patients, the volume of distribution of midazolam is increased, and it is suggested that a loading or initial dose is based on total body weight, with maintenance doses calculated on ideal body weight.19De Baerdemaeker L.E.C. Mortier E.P. Struys M.M.R.F. Pharmacokinetics in the obese patients.Contin Educ Anaesth Crit Care Pain. 2004; 4: 152-155Abstract Full Text Full Text PDF Scopus (101) Google Scholar As clearance is unchanged, prolonged sedation may occur from the larger dose required to achieve initial adequate plasma concentrations. Information regarding its dosing in obese paediatric patients is limited. Although dosing on ideal body weight may result in a reduced clinical response, this approach has been advocated to minimise the risk of significant respiratory depression.20Mortensen A. Lenz K. Abildstrøm H. Lauritsen T.L.B. Anesthetizing the obese child.Paediatr Anaesth. 2011; 21: 623-629Crossref PubMed Scopus (58) Google Scholar The paucity of evidence and guidance means that the experience and judgement of the clinician in managing these patients are vital. The necessity to achieve therapeutic effect must be balanced against the risks posed by overdosage. For some children, preoperative sedation may not have been adequate or effective. Factors that may lead to inadequate sedation include the timing of administration relative to induction of anaesthesia, the agent used, the route, the dose and the possibility of paradoxical agitation, especially with midazolam. If the child previously spat out oral medication, giving a drug by the intranasal route may ensure better drug delivery. Where a low dose was previously used unsuccessfully, a higher dose of the same agent or a combination of synergistic agents can be effective. Useful combinations include:(i)Benzodiazepine (e.g. midazolam) and ketamine.(ii)Benzodiazepine and α-2 agonist (clonidine or dexmedetomidine).(iii)Benzodiazepine or α-2 agonist and an opioid. The common practice in our institution is to use buccal or oral midazolam in combination with intranasal dexmedetomidine. It is important to apply caution when using combined agents in patients at risk of airway obstruction or respiratory depression, as the combination of synergistic medications may increase the risk of overdosage. The combination of midazolam and opioids in particular is associated with an increased risk of respiratory depression.21Kennedy R.M. Porter F.L. Miller J.P. Jaffe D.M. Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic emergencies.Pediatrics. 1998; 102: 956-963Crossref PubMed Scopus (204) Google Scholar Melatonin has been used for both sedation and sleep regulation. In adults, melatonin may be effective in reducing preoperative anxiety.22Hansen M.V. Halladin N.L. Rosenberg J. Gögenur I. Møller A.M. Melatonin for pre- and postoperative anxiety in adults.Cochrane Database Syst Rev. 2015; 4: CD009861Google Scholar Its safety profile makes it an appealing alternative to other drugs, as it is associated with a lower incidence of post-anaesthetic sleep disturbance than midazolam or placebo, and produces less post-anaesthetic excitation than midazolam.23Kain Z.N. MacLaren J.E. Herrmann L. et al.Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery.Anesthesiology. 2009; 111: 44-49Crossref PubMed Scopus (77) Google Scholar,24Samarkandi A. Naguib M. Riad W. et al.Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study.Eur J Anaesthesiol. 2005; 22: 189-196Crossref PubMed Google Scholar Trials assessing the effects of melatonin in paediatric patients have produced conflicting results. Some studies suggest that it may be as effective an anxiolytic as midazolam.24Samarkandi A. Naguib M. Riad W. et al.Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study.Eur J Anaesthesiol. 2005; 22: 189-196Crossref PubMed Google Scholar,25Impellizzeri P. Vinci E. Gugliandolo M.C. et al.Premedication with melatonin vs midazolam: efficacy on anxiety and compliance in paediatric surgical patients.Eur J Pediatr. 2017; 176: 947-953Crossref PubMed Scopus (35) Google Scholar However, others contradict this.23Kain Z.N. MacLaren J.E. Herrmann L. et al.Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery.Anesthesiology. 2009; 111: 44-49Crossref PubMed Scopus (77) Google Scholar This may relate to the differing dosing regimens used, differences in outcome measures used, and the potential for inter-rater reliability. Those studies that did demonstrate the equivalence of melatonin to active controls used higher dosing regimens than studies that did not. There is limited evidence to support the routine use of melatonin for premedication. The authors declare that they have no conflicts of interest. The associated MCQs (to support CME/CPD activity) are accessible at www.bjaed.org/cme/home for subscribers to BJA Education. Sarah Heikal MCEM FRCA is a specialty registrar in anaesthesia in the Severn Deanery. She has also completed a year of advanced training in paediatric anaesthesia at Great Ormond Street Hospital for Children. Grant Stuart FRCA is a consultant paediatric anaesthetist at Great Ormond Street Hospital. His major interests include anaesthesia for rare diseases, particularly metabolic illness; TIVA; spinal surgery; and sedation, particularly the clinical use and applications for dexmedetomidine in children.