Premedication: Is clonidine the answer?

It is generally accepted that apprehension and anxiety should be controlled before children are transported to the operating room for anesthetic induction. Anxiety during the perioperative period has been described as a subjective feeling of apprehension, fear, and nervousness.[12] It may be expressed by children in various forms, including tearfulness, screaming, clinging to parents or caregivers, apathy, and withdrawal. In addition to facilitating the induction of anesthesia and providing a calm perioperative environment, the benefits of effective premedication may be long lasting. Extended postoperative maladaptive behaviors, such as new onset enuresis, feeding difficulties, apathy, withdrawal, and sleep disturbances have been attributed to uncontrolled anxiety before anesthesia and surgery in children.[12] Up to 60% of all children may manifest undesirable behavioral changes at 2 weeks postoperatively and 20% of children continue to exhibit some of those behavioral changes for as long as 6 months following a surgical procedure.[13] In addition to the psychologic complications, inadequate premedication, can also add to the stress response during the perioperative period resulting in a series of hormonal, immunologic, and metabolic changes culminating in a negative nitrogen balance, tissue catabolism, delayed wound healing, and even immunosuppression, which may potentially increase perioperative morbidity and extend the hospital stay.[4-6]

Various factors are involved in the development of preoperative anxiety in children presenting for surgery. The primary mechanism in the developmental scheme of children that results in perioperative anxiety is separation from caregivers. Separation anxiety usually begins after 9 months of age, with children 1–5 years of age having the highest risk for developing extreme anxiety.[12] The level of parental anxiety has also been shown to be an important factor in the development and evolution of the child's anxiety.[2] Previous unpleasant experiences during clinic visits, anesthetic induction, surgery, or hospitalization have a strong association with the development of subsequent preoperative anxiety.[2] Awareness of these factors may help identify the high-risk population and allow for appropriate management with either behavioral or pharmacological therapies to allay preoperative anxiety.

Historically, the rationale for preoperative medication was to minimize the side effects of the commonly used volatile anesthetic agents at the time, including ether and cyclopropane. As such, anticholinergic agents were commonly administered, generally via the intramuscular route, prior to anesthetic induction to prevent salivation and bradycardia.[6] With the advent of sevoflurane for inhalation induction and its decreased incidence of bradycardia and the elimination of the need for an antisialogogue, the focus of premedication has shifted. Additionally, the art of premedication has evolved over time so that in modern anesthetic practice the goal is to ally anxiety, thereby making the experience of anesthesia and surgery more pleasant and less traumatic.[6]

In the United States, the oral route (80%) is the preferred method for the administration of premedication.[2] In selective cases, other routes of administration have been used, including intranasal, sublingual, intramuscular, and rectal.[2] These alternative routes are generally chosen when the patient refuses oral administration or when comorbid conditions preclude the oral route. Although it has been argued that the use of an oral premedication violates the general policy of holding patients nil per os, it has been clearly demonstrated that the use of the oral route for a premedicant does not significantly alter gastric residual volumes.[7] As far as the choice of the agent, midazolam is the most commonly used agent for premedication, being chosen in up to 85% of children. Alternative agents include ketamine, transmucosal fentanyl, meperidine, and the α2-adrenergic agents, such as clonidine.[2]

Introduced into clinical use in the 1980s, midazolam was quickly accepted and became the wonder-drug for premedication, especially in the adult population where it has been suggested that no one enters the operating room without receiving 2 mg of midazolam intravenously. Midazolam, a relatively shorter-acting benzodiazepine when compared with diazepam, has become the most frequently used agent for the premedication of children due to several reasons. The perceived benefits of midazolam as a premedicant in children include its rapid onset, reliability in achieving sedation and anxiolysis, and its availability in an oral formulation with a commercially available liquid, which contains 2 mg/mL of midazolam in a cherry-flavored syrup.[8-10] However, in many centers, when the commercially available solution is not available, the standard intravenous formulation (5 mg/mL) is used via the oral route. In such a practice, the benzyl alcohol which is in the intravenous solution as a preservative makes the solution somewhat unpalatable with the need to mask the flavor by placing it in some type of syrup (acetaminophen) or sweet solution (honey). When this is done, alterations in the absorption characteristics and oral bioavailability may occur due to changes in the ring structure of the parent compound.[11] Therefore, the search for the ideal premedicant continues given the potential concerns of midazolam, such as the bitter taste, intense burning or stinging from nasal administration and side effects, such as hiccoughs, cognitive impairment, delayed awakening from short procedures, long-term behavioral disturbances, and respiratory depression.[1011]

Clonidine, an α2-adrenergic agonist, has emerged as a potential alternative to midazolam as premedication in pediatric patients.[12-14] Since the first report of its use as a premedicant in the pediatric population in 1993,[13] there have been numerous reports in the pediatric population demonstrating its efficacy in this clinical scenario.[15-19] Various authors have expounded on the virtues of clonidine as a premedicant for children. Nishina et al. stated that clonidine when used as a premedication in pediatric patients reliably produced sedation and anxiolysis.[1819] It has also been shown to provide excellent quality of separation from parents and blunting of the response to placement of the mask at the time of inhalational induction.[1520] Pretreatment with clonidine decreases the minimum alveolar concentration of the inhalational agents for induction, endotracheal intubation, and maintenance of anesthesia.[16192122] Additional perioperative advantages include attenuation of the reflex tachycardia and hemodynamic responses to tracheal intubation and prevention of intraoperative hemodynamic instability and swings in hemodynamic parameters.[2223] Benefits beyond the intraoperative period include a decreased postoperative incidence of nausea, vomiting, shivering, and emergence delirium, as well as a reduction of postoperative requirements for opioids.[14171824-26] Unlike midazolam, clonidine does not accentuate opioid-induced respiratory depression.[27]

In this issue of the Saudi Journal of Anaesthesia, Trevor et al. provide additional information comparing clonidine with the commonly used premedicant, oral midazolam.[28] The authors compared premedication with standard doses of oral midazolam (0.5 mg/kg) and clonidine (4 μg/kg) in a cohort of 60 pediatric patients (ASA I–II) undergoing elective surgery. Their protocol demonstrates some of the challenges with oral premedication in the pediatric population as with both medications, some extra steps were necessary, including the use of honey to mask the flavor of midazolam as they used the standard intravenous preparation with benzyl alcohol and the need to compound the oral clonidine by crushing adult tablets of 0.1 mg. Additionally, one of the major drawbacks to clonidine use was noted as the authors administered clonidine 90 min prior to anesthetic induction given its slow onset of action. This practice is likely not feasible in many operating rooms given the timing of patient arrivals in the preoperative holding area and the rapidity of turnover of the operating rooms. Also of note was the fact that although clonidine effectively prevented separation anxiety (80% of those receiving clonidine vs only 30% with midazolam, neither drug was particularly effective during venipuncture for placement of an intravenous cannula (33.3% with clonidine vs 23.3% with midazolam) or during placement of the mask for anesthetic induction (26.6% with clonidine vs 20.0% with midazolam). However, the level of anxiolysis was judged to be better with midazolam than with clonidine at all 3 critical junctures (separation from parents, venipuncture, and mask application). Although statistically significant differences were noted in the blood pressure between the two groups with a lowering blood pressure with clonidine, no clinically significant hemodynamic effects were noted. The authors concluded that although clonidine was an excellent sedative with other beneficial effects, which have been outlined above, it is not a better anxiolytic alternative to midazolam.

Given the results of this study, it is evident that we still need future studies to determine the optimal premedication or perhaps combination of premedicants for children. The current study demonstrates successful premedication in only approximately 1/3rd of the patients. This may be related to the long onset time of clonidine or the erratic absorption due to the administration of the intravenous preparation of midazolam in honey. More importantly, we have no information on the long-term behavioral outcomes of these patients or the amnestic effects of the premedicants. At least in the pediatric population, although effective and easy separation and tolerance of the mask is desirable, perhaps the goal should be to ensure amnesia for the perioperative process.

The ideal preanesthetic medication should provide a quick onset, have short-lived effects while enabling easy separation of the child from the caregivers. Given the experience in the operating room and the issues noted in this editorial, the ideal premedicant has not been identified. Although frequently used, midazolam frequently falls short of the mark suggesting that novel agents or more appropriately, combinations of agents should be studied. Although the literature is replete with head-to-head comparisons of various agents, it seems that perhaps we should start studying combinations of agents. The α2-adrenergic agonists, such as clonidine, have many beneficial properties throughout the perioperative period, although the onset time of sedation is such that it is likely not the ideal agent by itself to provide ideal preoperative sedation. However, as noted above, there are numerous other benefits, such as decreasing the minimum alveolar concentration of the inhalational agents for induction, endotracheal intubation, and maintenance of anesthesia. Clonidine also attenuates the surgical stress response, blunts the hormonal response to surgery, and prevents intraoperative hemodynamic instability and swings in hemodynamic parameters. Benefits beyond the intraoperative period include a decreased postoperative incidence of nausea, vomiting, shivering, and emergence delirium as well as a reduction of postoperative requirements for opioids. These are provided without potentiating opioid-induced respiratory depression. These beneficial effects could be utilized if the undesirable properties of clonidine could be masked or covered with an additional agent. Ongoing work is currently evaluating the newest α2-adrenergic agonist, dexmedetomidine, as a potential agent for premedication with its use by nonparenteral routes.[29-32] Although we are getting closer, we still believe that we have not found the ideal agent for premedication of children in the perioperative setting. It is likely that the question may not be which agent, but rather, which combination of agents.