Additional experience with dexmedetomidine in pediatric patients.

Purpose: This study evaluates the efficacy of dexmedetomidine in clinical scenarios other than sedation during mechanical ventilation.

Methods: We conducted a retrospective chart review and presentation of case series of children in the pediatric intensive care unit and the postanesthesia care unit who received dexmedetomidine.

Results: Dexmedetomidine was administered by continuous infusion to three patients and as a single bolus dose (0.5 [micro]g/kg) to two patients. In the five clinical scenarios, dexmedetomidine provided effective sedation during spontaneous ventilation in two patients, reversed the clinical signs and symptoms of withdrawal from illicit substances in one patient, and was effective in the treatment of postanesthesia emergence delirium and shivering in two additional patients.

Conclusion: These preliminary data suggest that dexmedetomidine may be an effective agent for sedation in spontaneously breathing patients, in the treatment of drug withdrawal, and in the treatment of two common postanesthesia problems.

Key Words: [[alpha].sub.2]-agonists, clonidine, dexmedetomidine

Dexmedetomidine (Precedex; Abbott Laboratories, Abbott Park, IL) is an [[alpha].sub.2]-adrenergic agonist with an increased specificity for the [[alpha].sub.2]-receptor versus the [[alpha].sub.1]-receptor when compared with clonidine. Although several different physiologic effects have been demonstrated including sedation, anxiolysis, analgesia, a decrease of the minimum alveolar concentration of inhalational anesthetic agents, and blunting of the sympathetic nervous response to surgery, (1-4) to date, the majority of experience and, in fact, its only U.S. Food and Drug Administration-approved use, remains sedation in adults during mechanical ventilation. (5)

We have previously reported our anecdotal experience with dexmedetomidine in infants and children in three different clinical scenarios including sedation during mechanical ventilation, controlled hypotension during spinal fusion, and sedation during upper endoscopy of the gastrointestinal tract. (6) Although we are currently conducting a prospective, randomized trial comparing continuous infusion dexmedetomidine versus midazolam for sedation during mechanical ventilation in infants and children, we have also found this agent to be effective in various other clinical scenarios. The current report outlines our experience with additional applications of dexmedetomidine in the pediatric intensive care unit (ICU) population including the provision of sedation during spontaneous ventilation in two different clinical scenarios, the treatment of withdrawal from ethanol and other illicit substances, the control of postoperative agitation/delirium, and the treatment of shivering after general anesthesia.

Patients and Methods

The Institutional Review Board of the University of Missouri approved this retrospective review. The need for written, informed consent was waived. However, in all of the cases, the use of dexmedetomidine was discussed with the parents and informed consent obtained. From a review of the pediatric ICU admission log, inpatient hospital records, and the authors' recollection, patients were identified who had received dexmedetomidine. The following demographic data were obtained: age, weight, gender, and underlying medical problems. Information concerning dexmedetomidine included the indication for its administration, the initial bolus dose (if used), the initial infusion rate (if used), changes in the infusion during administration, duration of administration, and adverse effects that could be attributed to the medication. Specifically, these adverse effects included bradycardia, hypotension, and alterations in respiratory function as indicated by changes in oxygen requirement, respiratory rate, transcutaneous carbon dioxide ([CO.sub.2]) or arterial [CO.sub.2].

Results

The demographic data and indication for the use of dexmedetomidine are outlined in Table 1. The following are brief descriptions of the individual cases.

Patient 1

A 4-year-old, 22-kg boy was admitted to the pediatric ICU for treatment of status asthmaticus. Therapy included continuous inhalational therapy with albutcrol in a combination of helium and oxygen according to our usual protocol. Significant agitation was present and the child frequently pulled the mask from his face. There was a brief (5-10 min) response to intermittent intravenous (IV) doses of midazolam; however, the patient quickly became agitated and pulled his mask off. The transcutaneous [CO.sub.2] had increased from an admission value of 48 to 54 mm Hg despite maximal medical therapy. Dexmedetomidine was administered as a bolus dose of 0.5 [micro]g/kg over 10 minutes and an infusion started at 0.25 [micro]g/kg/h. The patient became calm and no longer pulled the mask from his face. The transcutaneous [CO.sub.2] values over the next 3 hours were 49, 42, and 37 mm Hg, respectively. The dexmedetomidine infusion was continued lot a total of 34 hours and then discontinued. At that time, the continuous inhalational therapy had been weaned to an every-2-hour administration. The remainder of the hospital course was unremarkable.

Patient 2

A 13-year-old, 52-kg boy was admitted to the pediatric ICU after reoperation and thoracoplasty for repair of a severe pectus excavatum deformity. Routine medications included methylphenidate for attention deficit hyperactivity disorder. Preoperatively, in the preanesthesia holding area, his blood pressure was 160 to 170/110 mm Hg and his parents stated that he was typically anxious when in the hospital. A thoracic epidural catheter (tip at T7 on the postoperative chest radiograph) with a continuous infusion of 0.1% levobupivacaine and fentanyl was in place for postoperative analgesia. Postoperatively, the patient denied pain (pain score, 0-1 using a visual analog scale score of 0-10) but was restless and expressed anxiety, with a blood pressure of 180 to 200/110 to 115 mm Hg. Dexmedetomidine was administered as a bolus dose of 0.5 [micro]g/kg over 10 minutes followed by a continuous infusion of 0.25 [micro]g/kg/h. Over the ensuing 15 to 20 minutes, his blood pressure decreased to 142/64 mm [micro]g. The next morning (17 h later), the infusion was decreased to 0.1 [micro]g/ kg/h and then discontinued 16 hours later (total continuous infusion time, 33 h). During this time, his blood pressure varied from 110 to 120/50 to 70 mm Hg with a heart rate of 70 to 90 beats/min. The remainder of his postoperative course was uneventful.

Patient 3

A 17-year-old, 58-kg male patient was admitted to the pediatric ICU after repair of a coarctation of the aorta. Three years previously, the patient had been involved in a motor vehicle accident that resulted in an injury to his descending aorta that was repaired using a synthetic graft. This graft had now become partially obstructed, resulting in tipper extremity hypertension. He had a history of frequent and excessive use of tobacco, alcohol, and cannabinoids. After the procedure, his trachea remained intubated and mechanical ventilation was provided. During this time, sedation was provided by a continuous infusion of midazolam (0.1 mg/kg/h) and intermittent doses of morphine. Twelve hours postoperatively, his trachea was extubated. During the second postoperative day, he was restless, diaphoretic, and agitated. This agitation and restlessness were not controlled with intermittent doses of lorazepam or morphine. He denied pain, but stated that he could not get comfortable. His heart rate varied from 110 to 130 beats/rain. Hypertension was treated with labetalol and nicardipine. A diagnosis of substance withdrawal was made and dexmedetomidine started as a bolus of 0.5 [micro]g/kg over 10 minutes followed by a continuous infusion of 0.25 [micro]g/kg/h. He was able to rest comfortably, and the diaphoresis and tachycardia resolved and did not recur. The antihypertensive agents were weaned and his blood pressure was controlled with an oral calcium channel blocker (amlodipine). The dexmedetomidine infusion was continued for a total of 40 hours at 0.25 [micro]g/kg/h. Clonidine was started at a dose of 0.1 mg administered orally every 12 hours, and the dexmedetomidine infusion was decreased to 0.12 [micro]g/kg/h for 10 to 12 hours and then discontinued. The clonidine was increased to a maximum dose of 0.1 mg administered orally every 8 hours. Clonidine was gradually weaned during a 2-week period. The remainder of the postoperative course was uneventful.

Patients 4 and 5

The next two patients were cared for during orthopedic surgical trips to the Dominican Republic. Given the clinical environment in which we were working, with a lack of availability of commonly used medications, there were limited options for dealing with these two clinical scenarios. Dexmedetomidine was provided free of charge by Abbott Pharmaceuticals for use during these trips.

Patient 4. An 8-year-old, 36-kg boy was admitted to the postanesthesia care unit (PACU) after a femoral osteotomy. Anesthesia included sevoflurane in oxygen/air, fentanyl (2 [micro]g/kg), and a fascia iliaca block at the completion of the procedure for postoperative analgesia. In the PACU, the patient demonstrated emergence delirium that failed to respond to a total of 4 mg of nalbuphine. After 0.5 [micro]g/kg of dexmedetomidine, the patient's agitation ceased and he rested comfortably. The remainder of the postoperative course was uneventful.

Patient 5. A 14-year-old, 54-kg boy was admitted to the PACU alter hip surgery. Anesthesia included sevoflurane in oxygen/air, fentanyl (2 [micro]g/kg), and a lumbar plexus block at the completion of the procedure for postoperative analgesia. In the PACU, the patient had persistent shivering. His postoperative temperature was 36[degrees]C. After 0.5 [micro]g/kg dexmedetomidine, the patient's shivering ceased and he rested comfortably. The remainder of the postoperative course was uneventful.

Discussion

The a2-agonists are divided into three groups: imidazolines, phenylethylamines, and oxazepines. Both dexmedetomidine and clonidine are imidazole compounds and possess a high ratio of specificity for the [[alpha].sub.2]-versus the [[alpha].sub.1]-receptor (200:1 for clonidine and 1,600:1 for dexmedetomidine). Additional differences include a half-life of 12 to 24 hours for clonidine and 2 to 3 hours for dexmedetomidine.

The [[alpha].sub.2]-agonists activate receptors in the medullary vasomotor center, thereby reducing norepinephrine turnover and decreasing central sympathetic outflow. Additional effects result from the central stimulation of parasympathetic outflow and inhibition of sympathetic outflow from the locus ceruleus in the brainstem. The latter effect plays a prominent role in the sedation and anxiolysis produced by these agents, as decreased noradrenergic output from the locus ceruleus allows for increased firing of inhibitory neurons including the [gamma]-aminobutyric acid system.

Although the only current Food and Drug Administration-approved indication for dexmedetomidine remains sedation for up to 24 hours in adults during mechanical ventilation, given its beneficial properties, we have found it effective in other clinical scenarios as demonstrated in our five patients. In our first two patients, dexmedetomidine provided sedation and proved to be an effective anxiolytic in the non-intubated, spontaneously breathing patient. In our first patient, dexmedetomidine controlled the agitation and allowed for an appropriate level of sedation to permit delivery of continuous inhalational therapy for status asthmaticus. Although sedation of patients with respiratory insufficiency can be problematic, given the previous studies demonstrating that dexmedetomidine has limited effects on respiratory function (see below), we felt that it was the optimal agent for this patient. Similar efficacy was noted in our second patient who, despite effective postoperative analgesia, demonstrated significant anxiety with hypertension.

Regardless of the clinical scenario, sedative agents including dexmedetomidine can have deleterious effects on cardiorespiratory function. The latter may be particularly worrisome in the patient with underlying respiratory insufficiency or during the immediate postoperative period, given the potential respiratory depressant effects of residual anesthetic agents. To date, the potential for respiratory depression with dexmedetomidine appears to be limited. Hall et al (1) demonstrated sedation, impairment of memory, and decreased psychomotor performance during dexmedetomidine infusions (0.6 [micro]g/kg followed by either 0.2 or 0.6 [micro]g/kg/h) in healthy volunteers (age range, 23-31 yr). In their study, limited changes were noted in hemodynamic variables or respiratory function (end-tidal [CO.sub.2], oxygen saturation, respiratory rate). Similar effects on respiratory function have been reported with clonidine. Dupeyrat et al (7) noted no difference in postoperative respiratory effects (respiratory rate, transcutaneous C[O.sub.2], oxygen saturation) in children who received caudal epidural clonidine (1 [micro]g/kg) when compared with the control group. Although Benhamou et al (8) noted no effects on tidal volume and respiratory rate after oral clonidine (300 [micro]g), there were three patients that developed an obstructive pattern to their breathing with a decrease in oxygen saturation.

In our third patient, we found that dexmedetomidine effectively controlled the signs and symptoms of withdrawal from substance abuse (alcohol, tobacco, and cannabinoids). Although there is only anecdotal information regarding the use of dexmedetomidine in this scenario, there is experience with clonidine in relieving the clinical manifestations of opioid withdrawal from abuse or after prolonged administration in the ICU setting. (9, 10) The mechanism of action of the [[alpha].sub.2]]-agonists in this setting is provided by demonstration that naloxone administration to opiate-dependent laboratory animals increases the rate of firing from neurons in the locus ceruleus (see previous discussion of dexmedetomidine's effects on the central nervous system). (11) Subsequent studies in laboratory animals have demonstrated that the [[alpha].sub.2]]-agonists decrease the physical manifestations that result from electrical stimulation of the locus ceruleus. (12) Additional studies have demonstrated the efficacy of the [[alpha].sub.2]]-agonists in the treatment of withdrawal from other substances including benzodiazepines, alcohol, and tobacco. (13-15)

Our final two patients demonstrate other potential applications of dexmedetomidine in the PACU arena. With the introduction of short-acting anesthetic agents such as sevoflurane, emergence behavior and agitation after general anesthesia has become a more frequently recognized problem, with up to 30% of patients exhibiting this problem during their PACU time. (16) Bock et a1 (17) demonstrated that the administration of either IV or caudal clonidine (3 [micro]g/kg) was effective in decreasing the incidence of agitation after sevoflurane anesthesia. Other investigators have reported a similar effect after using a 2-[micro]g/kg IV dose of clonidine. (18) We noted similar efficacy with dexmedetomidine administered as a single IV dose of 0.5 [micro]g/kg in treating postoperative agitation in our one patient.

An additional problem frequently encountered in the PACU is postoperative shivering. The possible mechanisms responsible and various options for treatment have been reviewed previously. (19) Schwarzkopf et al (20) compared the efficacy of three different agents (meperidine 25 mg, clonidine 0.15 mg, and urapidil 25 mg) in treating postoperative shivering in a total of 60 adult patients. Clonidine was effective in all 20 patients, meperidine was effective in 18 of 20 patients with the remaining two patients requiring a second dose, and urapidil was effective in 6 patients after the first dose and in another 6 after the second dose. We report for the first time the effective use of a single bolus dose of dexmedetomidine (0.5 [micro]g/kg) to treat postanesthesia shivering.

With the decreased central sympathetic outflow and the potential augmentation of parasympathetic function, adverse cardiovascular effects may also occur. Although several of the studies demonstrate limited effects such as mild bradycardia and a modest (10-15%) decrease in blood pressure in patients with normal cardiovascular function, more significant bradycardia and hypotension have been reported in other patient populations, especially with larger bolus dosing regimens. Venn et al (5) evaluated the efficacy of dexmedetomidine to sedate adult patients during mechanical ventilation after cardiac surgery. Dexmedetomidine was administered as a loading dose of 1 [micro]g/kg over 10 minutes followed by an infusion rate of 0.2 to 0.7 [micro]g/kg/h. Significant hemodynamic changes were noted in 18 of the 66 patients that received dexmedetomidine. These changes included either bradycardia or hypotension (mean arterial pressure less than 60 mm Hg or a greater than 30% decrease in mean arterial

pressure from baseline). In 11 patients, these changes occurred during the initial bolus dosing. In three of these patients, the infusion was temporarily discontinued and an additional three patients were withdrawn from the study. No long-term sequelae occurred related to the hemodynamic changes.

Talke et al (4) evaluated the efficacy of dexmedetomidine infusion during vascular surgery in 41 adults. In the 22 patients that received the dexmedetomidine infusion, there was a lower heart rate, less tachycardia, and decreased norepinephrine levels during emergence from anesthesia. Adverse effects related to dexmedetomidine included one episode of postoperative hypotension and one patient that had a 5-to 10-second sinus pause after anesthetic induction with thiopental and fentanyl followed by endotracheal intubation. In the study of Peden et al, (3) two patients who had received dexmedetomidine experienced a brief episode of sinus arrest after laryngoscopy and propofol administration, thereby suggesting the possibility of potentiation of heart rate slowly by procedures with vagal stimulation (laryngoscopy) or medications (propofol, fentanyl). In our ongoing pediatric trial, an infant who was concomitantly receiving digoxin developed bradycardia (heart rate, 40 beats/min) during dexmedetomidine infusion. (21) Therefore, despite the efficacy of this agent, ongoing cardiorespiratory monitoring is suggested during its administration.

Our dosing has been extrapolated from the initial reports in the adult population combined with the experience gained from our prospective trial. We chose to use a continuous infusion in three patients because the reason for which dexmedetomidine was being used was long term (sedation, withdrawal), whereas a single bolus was used in the final two patients because the problem was thought to be short term (emergence delirium, shivering).

Conclusion

We found dexmedetomidine to be an effective agent fur sedation in spontaneously breathing patients, in the treatment of the clinical signs and symptoms of drug withdrawal, and in the treatment of two common postanesthesia problems (emergence delirium and postoperative shivering). Prospective, randomized trials are needed to demonstrate the true efficacy of dexmedetomidine in these new clinical scenarios and to determine its advantages and disadvantages when compared with other agents.

Key Points

* Dexmedetomidine is a novel [[alpha].sub.2]-adrenergic agonist that has been demonstrated to provide sedation, anxiolysis, and analgesia; to decrease intraoperative anesthetic requirements; to potentiate opioid-induced analgesia; and to blunt the sympathetic nervous response to surgery.

* To date, the majority of clinical experience with dexmedetomidine has been to provide sedation in adults during mechanical ventilation.

* Clinical investigations have demonstrated limited effects of dexmedetomidine on respiratory function.

* We found dexmedetomidine to be an effective agent for providing sedation in spontaneously breathing patients, in the treatment of the clinical signs and symptoms of drug withdrawal, and in the treatment of two common postanesthesia problems: emergence delirium and postoperative shivering.

Table 1. Demographic data and indications for dexmedetomidine therapy

Patient no.    Age (yr)    Weight (kg)    Sex

     1             4           22          M
     2            13           52          M
     3            17           58          M
     4             8           36          M
     5            14           54          M

Patient no.                          Indication

     1         Sedation during administration of continuous inhalatio-
                 nal therapy with albuterol for status asthmaticus
     2         Sedation after thoracoplasty for pectus excavatum
                 deformity
     3         Control of agitation from substance (alcohol, tobacco,
                 cannabinoids) withdrawal after repair of aortic
                 coarctation after previous repair of traumatic arch
                 injury
     4         Control of postoperative emergence delirium
     5         Control of postoperative shivering

Table 2. ETS conditions (% of total acute problems)
seen by treatment location (a)

                           UCC          RCC          ER

Total acute problems    549          269          518
Total ETS conditions    302 (55%)    104 (39%)     89 (17%)
ENT                      88 (16%)     17 (16%)     19 (4%)
Urology                  43 (8%)      10 (4%)      14 (3%)
Dermatology              41 (7%)      11 (4%)      11 (2%)
Ophthalmology            25 (5%)       7 (3%)      10 (2%)
Orthopedics             105 (19%)     59 (22%)     35 (7%)

(a) ETS, educationally targeted specialty; UCC, urgent care center;
RCC, resident continuity clinic; ER, emergency room.

Table 3. Most frequent problems seen in the UCC (a)

ENT
  Intra-oral pain
  Ear pain
  Facial pain
  Vertigo
  Nasal discharge/congestion
Ophthalmology
  Decreased vision
  Eye pain
  Red eye
Urology
  Painful/difficulty voiding
  Penile discharge
  Testicular pain
  Penile pain
  Penile lesion
Orthopedics
  Back pain
  Knee pain
  Shoulder pain
  Foot pain
  Hip/leg pain
Dermatology
  Rash
  Skin lesion
  Acne
General medicine
  Headache
  Abdominal pain
  Chest pain
  Cough
  Vomiting

(a) UCC, urgent care center.

References

(1.) Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000; 90:699-705.

(2.) Khan ZP, Munday IT, Jones RM, et al. Effects of dexanedetomidine on isoflurane requirements in healthy volunteers: Part I. Pharmacodynamic and pharmacokinetic interactions. Br J Anaesth 1999;83:372-380.

(3.) Peden CJ, Cloote AH, Stratford N, et al. The effect of intravenous dexmedetomidine premedication on the dose requirement of propofol to induce loss of consciousness in patients receiving alfentanil. Anaesthesia 2001 ;56:408-413.

(4.) Talke P, Chen R, Thomas B, et al. The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery. Anesth Analg 2000;90:834-839.

(5.) Venn RM, Bradshaw CJ, Spencer R. et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthexia 1999;54:1136-1142.

(6.) Tobias JD, Berkenbosch JW. Initial experience with dexmedetomidine in paediatric-aged patients. Paediatr Anaesth 2002;12:171-175.

(7.) Dupeyrat A, Goujard E, Muret J, et al. Transcutaneous [CO.sub.2] tension effects of clonidine in paediatric caudal analgesia, Paediatr Anaesth 1998;8:145-148.

(8.) Benhamou D, Veillette Y, Narchi P, et al. Ventilatory effects of premedication with clonidine. Anesth Analg 1991;73:799-803.

(9.) Deutsch ES, Nadkarni VM. Clonidine prophylaxis for narcotic and sedative withdrawal syndrome following laryngotracheal reconstruction. Arch Otolaryngol Head Neck Surg 1996;122:1234-1238.

(10.) Gold MS, Pottash AL, Sweeney DR, el al. Efficacy of clonidine in opiate withdrawal: A study of thirty patients. Drug Alcohol Depend 1980;6: 201-208.

(11.) Vetulani J, Bednarczyk B. Depression by clonidine of shaking behavior elicited by nalorphine in morphine-dependent rats. J Pharm Pharmacol 1977;29:567-569.

(12.) Redmond DE Jr, Huang YH. The primate locus ceruleus and effects of clonidine on opiate withdrawal. Drug Alcohol Depend 1980;6:201-208.

(13.) Ashton H. Benzodiazepine withdrawal: Outcome in 50 patients. Br J Addict 1987;82:665-671.

(14.) Cushman P Jr, Sowers JR. Alcohol withdrawal syndrome: Clinical and hormonal responses to [[alpha].sub.2]]-adrenergic treatment. Alcoholism 1989;13: 361-364.

(15.) Glassman AH, Jackson WK, Walsh BT, et al. Cigarette craving, smoking withdrawal, and clonidine. Science 1984;226:864-866.

(16.) Cole JW, Murray DJ, McAllister JD, et al. Emergence behaviour in children: Defining the incidence of excitement and agitation following anaesthesia. Paediatr Anaesth 2002;12:442-447.

(17.) Bock M, Kunz P, Schreckenberger R, et al. Comparison of caudal and intravenous clonidine in the prevention of agitation after sevoflurane in children. Br J Anaesth 2002;88:790-796.

(18.) Kulka PJ, Bressem M, Tryba M. Clonidine prevents sevoflurane-induced agitation in children. Anesth Analg 2001;93:335-338.

(19.) Kranke P, Eberhart LH, Roewer N, et al. Pharmacological treatment of postoperative shivering: A quantitative systematic review of randomized controlled trials. Anesth Analg 2002;94:453-460.

(20.) Schwarzkopf KR, Hoff It, Hartmann M, et al. A comparison between meperidine, clonidine and urapidil in the treatment of postanesthetic shivering. Anesth Analg 2001 ;92:257-260.

(21.) Berkenbosch JW, Tobias JD. Development of bradycardia during sedation with dexmedetomidine in an infant concurrently receiving digoxin. Pediotr Crit Care Mud 2003:4:203-205.

Joseph D. Tobias, MD, John W. Berkenbosch, MD, and Pierantonio Russo, MD

From the Departments of Child Health, Anesthesiology, and Cardiothoracic Surgery, University of Missouri, Columbia, MO.

Dr. Tobias serves on the speaker board of and as a constant to Abbott Pharmaceuticals, the manufacturers of dexmedetomidine (Precedex).

Reprint requests to Joseph D. Tobias, MD, Department of Anesthesiology, University of Missouri, 3W40H One Hospital Drive, Columbia, MO 65212. Email: [e-mail]

Accepted October 2, 2002.

It is easier for parents to have children than for children to have parents.

--Pope John XXIII