Journal List > J Dent Anesth Pain Med > v.20(1) > 1143336

J Dent Anesth Pain Med. 2020 Feb;20(1):1-8. English.
Published online Feb 28, 2020.  https://doi.org/10.17245/jdapm.2020.20.1.1
Copyright © 2020 Journal of Dental Anesthesia and Pain Medicine
Midazolam use in pediatric dentistry: a review
Shreyans Aditya Jain, Nilesh Rathi, Nilima Thosar and Sudhindra Baliga
Department of Paedodontics and Preventive Dentistry, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences, Sawangi, India.

Corresponding Author: Shreyans Aditya Jain, Department of Paedodontics and Preventive Dentistry, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences, Sawangi, Maharashtra-442001, India. Tel: +91 9762745168, Email: drjainshreyans@gmail.com
Received Jan 15, 2019; Revised Feb 06, 2020; Accepted Feb 08, 2020.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

Behaviour management and dental procedures performed in very young, pre-cooperative, highly anxious, or medically disabled children are challenging tasks. Various drugs and methods have, however, been introduced to facilitate treatment for this patient population. Midazolam is a benzodiazepine used as an adjunct to behavior management techniques in the dental treatment of pediatric patients. Midazolam can be used as a safe and effective drug for conscious sedation, general anesthetic premedication, and treatment of seizures during dental procedures. Nevertheless, further research involving pediatric patients would be beneficial.

Keywords: Benzodiazepines; Conscious Sedation; Midazolam; Pediatric Dentistry

INTRODUCTION

Reducing the level of anxiety and pain in child patients undergoing dental procedures has been an issue for pediatric dentists. The majority of child patients can be managed using conventional behavior management methods; nevertheless, many require pharmacological intervention. Various drugs―namely, sedatives―have been studied to overcome this problem, for which benzodiazepines are commonly used. Midazolam is a benzodiazepine that has been available since 1983 [1]. It has a fast and short duration of action, exerting anxiolytic, anticonvulsive, muscular relaxant, and amnesic effects [1]. Hangover effects are decreased by its short half-life when used as a sedative agent, making midazolam a possible sedative drug for use in pediatric patients undergoing dental procedures.

Sedative drugs, such as benzodiazepines and barbiturates, can be administered by various routes including oral, transmucosal (intranasal, buccal, or sublingual), intravenous, intramuscular, and rectal. Its advantageous role in the management of child dental patients will be discussed and reviewed in detail [2].

MIDAZOLAM: CLASS, PHARMACOKINETICS, AND PHARMACODYNAMICS

Benzodiazepines exert their effects on the central nervous system. Specific benzodiazepine receptors are located in neurons in the brain. All benzodiazepine molecules have a common core shape, which binds to these receptors and, in turn, alter an existing physiological filter. Normal passage of information from the peripheral senses to the brain is filtered by the gamma-aminobutyric acid (GABA) system [2]. GABA is an inhibitory neurotransmitter released from sensory nerve endings as a result of nerve stimuli passing from one neuron to another [2]. GABA binds to receptors on the cell membrane of the post-synaptic neuron and stabilizes it by increasing the threshold for firing. As a result, the number of sensory messages perceived by the brain is reduced. When administered, benzodiazepines prolong the effect of GABA, which reduces the number of stimuli reaching higher centers and results in sedation, muscle relaxation, anxiolysis, amnesia, and anticonvulsant effects [2, 3]. Benzodiazepines need to cross the blood-brain barrier to reach their receptors. Midazolam can reach the brain very quickly due to its high lipophilic property [4]. It is a water-soluble, non-irritant benzodiazepine with a distribution half-life of 6–15 min and an elimination half-life of 1.5–2 h [4]. Therefore, it is a safe and effective medicament in children because its elimination half-life makes it especially suitable for short-duration procedures [5, 6, 7]. It has been shown that children under midazolam conscious sedation have no recollection that of difficult or unpleasant treatment [8].

USES OF MIDAZOLAM IN PEDIATRIC DENTAL PRACTICE

Midazolam is used for two main purposes in child patients: conscious sedation, and premedication to relieve anxiety before induction of general anesthesia (GA) [4, 9]. It can also be used as an emergency drug to control seizure attacks [9]. In general, the use of midazolam is indicated in children who cannot cope with dental treatment due to high levels of anxiety, young age, learning difficulties, and/or an underlying medical condition. However, midazolam is contraindicated in children with hypersensitivity to benzodiazepines. It is relatively contraindicated in patients with acute or chronic pulmonary disease, pulmonary and/or cardiac insufficiency, and myasthenia gravis [9]. A major drawback of midazolam sedation is the possibility of paradoxical reactions, which include disinhibition, hallucinations, agitation, inconsolable crying, restlessness, and disorientation, especially in younger child patients, although accounting for only 1.4% of reactions [4, 9, 10]. Certain drugs may interact with midazolam, which usually manifest as impeding its metabolism in the liver and increasing or prolonging plasma concentrations. Interacting drugs include erythromycin and clarithromycin, fluconazole and ketoconazole, and some antivirals such as efavirenz, fosamprenavir, and nelfinavir [2, 7, 10]. Midazolam may also enhance the hypotensive effects of calcium channel blockers [9, 11]. These effects should be considered before administering midazolam to patients.

The main side effect of benzodiazepines, which may also lead to complications, is occasional marked respiratory depression. Therefore, it is vital that oxygen and all required equipment for the management of respiratory depression using positive pressure ventilation are available [9]. Decreases in mean arterial pressure, cardiac output, systemic vascular resistance, and stroke volume may also occur, with only a small fall in arterial blood pressure immediately after drug administration [3]. Flumazenil is the drug used to reverse over-sedation, respiratory depression, and/or paradoxical reactions caused by benzodiazepines. No pediatric dose has been recommended by the manufacturer nor is it licensed for use in children. The adult dose is 0.2 mg (intravenous [IV]), administered over 15 s, and additional 0.1 mg IV doses at 60 s intervals if required, up to a maximum of 1 mg. Proportional dosage reduction in children has been recommended with the dose of IV flumazenil as 0.01 mg/kg [9]. It is noteworthy that the half-life of flumazenil is shorter than that of midazolam; therefore, sedation may recur when the patient has returned home [3].

1. Conscious sedation for dental treatment

Conscious sedation has been defined as a technique in which the use of a drug or drugs produces a state of depression of the central nervous system enabling treatment to be administered, but during which verbal contact with the patient is maintained throughout the period of sedation [12]. During conscious sedation, no interventions are required to maintain a patent airway, spontaneous ventilation is adequate, and cardiovascular function is usually maintained [13, 14]. The drugs and techniques used to provide conscious sedation for dental treatment should carry a margin of safety sufficiently wide to render loss of consciousness unlikely [15].

Conscious sedation is used as an adjunct to behavior management techniques for treating child patients in the dental setting. It avoids the major risks associated with GA and aims for behavior improvement, apprehension and anxiety reduction, and an increase in amnesia [1]. In a Cochrane systematic review addressing conscious sedation in anxious pediatric dental patients, the authors were not able to draw a conclusion regarding the most effective drug or method of sedation for anxious children [16]. However, the use of midazolam is a possible option for conscious sedation in pediatric dentistry. Children required to undergo conscious sedation with midazolam should be carefully selected. American Society of Anesthesiologists (ASA) class I or class II patients may be candidates for conscious sedation as outpatients. However, ASA class III and IV patients must undergo conscious sedation in hospital settings along with consultation with their medical doctor [12, 13].

As mentioned above, various routes of administration can be considered for the use of midazolam in conscious sedation. The oral route of administration is the most widely used in children. It is easy to administer and has decreased the risks for allergic reaction. However, when taken orally, the onset and duration of action of midazolam is prolonged, gastric absorption is unpredictable, and a stable sedative level is attained 30 min following drug intake [17, 18, 19]. The bioavailability of midazolam is decreased when it passes the portal circulation to reach systemic circulation. Therefore, a higher oral dosage (0.3–0.5 mg/kg up to 12 mg maximum) is required [9]. The oral route of administration is useful in needle-phobic young children who cannot cope with dental treatment, as well as patients with learning difficulties or other medical conditions. However, oral intake of the drug is completely dependent on the compliance of the child patient and determination of the appropriate dosage is difficult because some of the solution may be spat out [9]; moreover, no oral preparation (i.e., liquid form) is available. Therefore, the IV solution is mixed with juice to mask the strong, bitter taste and improve acceptability in child patients. For optimal sedation, the drug should be administered 10–20 min before commencement of dental treatment. One study compared cola (PepsiCo, Harrison, NY, USA), 10% sodium citrate, pomegranate juice, and grapefruit juice as mixtures with midazolam for oral intake, and concluded that drug ingestion was simpler and sedation was more effective when midazolam was added to sodium citrate because it reduced gastric pH, which facilitated better absorption of the drug [20]. Another study investigating the use of oral midazolam for sedation of child patients reported that the technique was well tolerated by children and accepted by parents [21]. Oral midazolam sedation has been reported to be safe and effective, although some patients became agitated during or after treatment [21].

Wilson et al. [22] performed a randomized, controlled cross-over trial to investigate the effectiveness of 0.5 mg/kg oral midazolam sedation for orthodontic extraction of permanent teeth. They concluded that oral sedation using midazolam was safe and acceptable in patients 10–16 years of age. In another study, involving 5–10-year-old children, oral midazolam was compared with nitrous oxide inhalation sedation. Oral sedation proved to be safe and effective but was not the method of choice for all patients [23]. This may have been due to the unpleasant taste of the oral solution or the emergence of paradoxical reactions. Transmucosal, intranasal route of administration is another effective method in child patients. The sedative effect is observed within 5 min of administration of 0.1–0.2 mg/kg midazolam intranasally or transmucosal (sublingual). Preparations used via the nasal route are made to order and administered using a metered nasal spray. Studies have demonstrated the rapid onset (5–10 min) of intranasal midazolam sedation, as well as the short recovery time following administration [17, 18, 19, 24]. Intranasal midazolam is rapidly absorbed from the nasal mucosa into the circulation and the peak effect occurs sooner compared with the oral route. Therefore, the nasal route could be a better option in children. Despite rapid onset and ease of administration, large volumes of the solution can cause coughing, sneezing, and expulsion of the drug [9]. The use of intranasal midazolam is associated with nasal irritation and unacceptability in children with nasal discharge [25] and could lead to occasional respiratory depression [26]. Karl et al. [27] compared intranasal and sublingual routes of administration of midazolam in child patients 6 months to 10 years of age. Their results revealed that sublingual administration of midazolam was as effective as the intranasal route. However, the sublingual route was better accepted by child patients. The compliance of the 6-month-old patients with sublingual lozenges was not clearly addressed in this study. The IV route is one of the most common routes of administration of midazolam. The general advantages of IV midazolam sedation include rapid onset (3–4 min) with adequate patient cooperation, ability to titrate the dose, and good amnesia of the procedure [28]. In pediatric dentistry, however, it may only serve as a possible option in anxious adolescents [28]. The fact that cannulation must be performed may make it a less favorable route of administration in very young children. The recommended dosage for IV midazolam in children is 0.25–1.5 µg/kg/min. The drug must be administered slowly so that its effects are assessed and overdosage is avoided [4]. Robb et al. [28] reported 18 cases of conscious sedation with IV midazolam in children 11–15 years of age. No loss of consciousness or fall in oxygen saturation levels was observed, which suggested the safe use of this drug for conscious sedation. The intramuscular (IM) route of administration has not been extensively studied in pediatric patients. In children, however, the disadvantages of this technique outweigh its advantages. A stable level of sedation is attained 30 min following drug administration [17, 18, 19] and administering IM injection to a child patient is unpleasant and most probably not acceptable. Rectal administration of midazolam has been demonstrated to be effective and safe for sedating child patients, with an onset of action as short as 5 min [29, 30]. However, interruption of absorption by defecation and lack of patient and parent acceptance are major disadvantages of rectally administered midazolam [24]. Patient sedation using midazolam via any of the above-mentioned routes of administration should be monitored for vital signs, including respiration and blood pressure, especially when midazolam is administered via the oral or IV route [2, 24, 29, 30]. Using pulse oximetry throughout sedation is mandatory in case of any complication. Oxygen saturation levels < 90% should be investigated and the cause corrected.

2. Premedication for induction of GA

Induction of GA may be challenging in a highly anxious or a pre-cooperative patient, as well those with a medically compromising condition or learning difficulty. Various medications have been advocated to ease child-separation anxiety from parents and to mitigate anxiety during different phases of the perioperative period. The ideal premedication agent for children should have an acceptable and atraumatic route of administration, a rapid and reliable onset, minimal side effects, and rapid elimination [31]. It has been reported that midazolam fulfills these criteria and, therefore, can be used as a premedication in child patients undergoing dental treatment under GA [6, 32, 33]. Wilton et al. [34] first described the use of intranasal midazolam as premedication for GA. In a prospective randomized double-blind clinical trial, Weber et al. [35] used the intranasal route of administration for midazolam and concluded that it was an appropriate premedication in preschool children.

A placebo-controlled trial investigated the reaction time and psycho-motor coordination of children undergoing GA before discharge and at 48 h when premedicated with 0.2 mg/kg buccal mucosa injection of midazolam to a maximum dose of 10 mg [36]. Premedication with midazolam requires a low dose (0.2 mg/kg) for anxiolysis; however, for oral sedation, a higher dose (0.5 mg/kg) is required for anxiolysis as well as sedation. A total of 179 children participated in this study, each receiving buccal midazolam or placebo before induction of GA. Results revealed that reaction time was significantly slower and psychomotor coordination was also significantly impaired in the midazolam group. Midazolam was also associated with anterograde amnesia before discharge and at 48 h [36]. This indicates that impairment of children's cognitive function and amnesia lasting for up to 48 h post-GA should be expected when midazolam is used for premedication.

A more recent study, however, demonstrated that 0.2 mg/kg buccal midazolam reduced anxiety in most patients but did not have an effect on psychological morbidity, induction behavior, and subsequent dental attendance [37]. Kain et al. [38] reported that children premedicated with oral midazolam exhibited less negative behavioral changes during the first postoperative week compared to those in the placebo group. It has been suggested that high levels of trait anxiety could be a contraindication to the use of oral midazolam as a premedication for GA. In addition, the use of midazolam before GA for a child with low state baseline anxiety is deemed unnecessary [39]. Regarding recovery and discharge times, Viitanen et al. [40] reported that the use of oral midazolam as premedication for propofol-induced GA in 1–3-year-old children delayed early recovery but did not affect discharge time. The authors also concluded that oral midazolam did not improve the quality of recovery. A literature review of available randomized controlled trials investigating midazolam oral premedication studied the effects of midazolam on separation anxiety, induction anxiety, emergence agitation, recovery times, long-term outcomes, and dose and timing of the drug. The authors concluded that premedication with oral midazolam reduced anxiety in children at separation from parents and anesthesia induction. However, there appeared to be no evidence supporting the moderation of emergence agitation, and awakening times were slightly delayed, although no serious side effects were reported [41]. Finally, midazolam could be used as an emergency drug in the dental setting.

CONTROL OF ACUTE SEIZURES IN EPILEPTIC CHILDREN IN THE DENTAL SETTING

A prolonged convulsive seizure is the most common neurological medical emergency with poor outcome. An ideal anticonvulsant should be easy to administer, effective, and safe, as well as having a long-lasting effect. IV or rectally administered benzodiazepines have generally been used as first-line drugs. In young children, however, gaining IV access on the dental chair and during a seizure attack is exceedingly difficult, if not impossible.

Transmucosal midazolam has recently been suggested as a possible drug for the management of seizure attacks on the dental chair and at home [42]. Transmucosal (intranasal and buccal) route of administration has mainly been studied and compared with IV or rectal diazepam. In a prospective randomized study involving 358 patients, Holsti et al. [43] compared the use of intranasal midazolam with rectal diazepam at home for the treatment of seizures in children with epilepsy. There was no difference among the two drugs in terms of efficacy as a rescue medication. However, ease of administration and overall satisfaction was higher with intranasal midazolam.

Another recent study involving 98 participants compared the use of buccal midazolam with rectal diazepam. Results revealed that midazolam was as effective as diazepam. However, midazolam was less time consuming, and more parents were satisfied with the buccal route of administration [42]. The buccal administration dose of 0.3 mg/kg (Epistat) has been recommended and the effects are observed within 5 min [36]. A Cochrane review concluded that buccal midazolam was successful in the treatment of seizures at a rate almost double that for rectal diazepam. The authors reported that intranasal midazolam was as effective as IV diazepam in the treatment of prolonged febrile convulsions, suggesting that when IV access is unavailable, buccal midazolam is the treatment of choice [44]. It is noteworthy that only four studies were included in this systematic review. However, more studies have been performed since then, and the use of midazolam for seizures has been proven to be effective [45].

Midazolam can be used to help child patients cope with dental treatment and undergo GA, as well as being a life-saving drug in case of a seizure attack. Midazolam, similar to any other drug, has its own side effects that could lead to very serious complications such as respiratory depression. Therefore, clinicians should be familiar with the administration of midazolam and management of its complications in case of an emergency. Monitoring vital signs at all times during sedation is vital so that appropriate action can be taken to reverse over-sedation. The midazolam reversal drug flumazenil should always be present in dental settings where midazolam sedation is performed.

Notes

AUTHOR CONTRIBUTIONS:

  • Shreyans Aditya Jain: Conceptualization, Data curation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

  • Nilesh Rathi: Supervision, Writing – review & editing.

  • Nilima Thosar: Writing – review & editing.

  • Sudhindra Baliga: Supervision, Writing – review & editing.

DECLARATION OF INTEREST:No potential conflict of interest was reported by the authors.

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