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Dexmedetomidine: Applications in pediatric critical care andpediatric anesthesiology

Joseph D. Tobias, MD

Dexmedetomidine (Precedex,Hospira Worldwide, Lake For-est, IL) is the pharmacologi-cally active dextro-isomer of

medetomidine. It exerts its physiologic ef-fects via �2-adrenergic receptors. The �2-adrenergic agonists are subclassified intothree groups: imidazolines, phenylethyl-amines, and oxalozepines. Dexmedetomi-dine and clonidine are members of theimidazole subclass, which exhibits a highratio of specificity for the �2 vs. the �1

receptor (Fig. 1). Clonidine exhibits an�2:�1 specificity ratio of 200:1 whereasthat of dexmedetomidine is 1600:1,thereby making it a complete agonist atthe �2-adrenergic receptor (1). Dexme-detomidine has a short half-life (2–3 hrs

vs. 12–24 hrs for clonidine) and is com-mercially available for intravenous ad-ministration. An epidural clonidine for-mulation, although not marketed forintravenous administration, has beenused for this purpose in clinical practicewithout consequences. Dexmedetomi-dine’s end-organ effects are mediated viapostsynaptic �2-adrenergic receptors andsubsequent activation of a pertussis tox-in-sensitive guanine nucleotide regula-tory protein (G protein) (2), which resultsin inhibitory feedback and decreased ac-tivity of adenylyl cyclase (3). A reductionof intracellular cyclic adenosine mono-phosphate and intracellular cyclic adeno-sine monophosphate-dependent proteinkinase activity results in the dephosphor-ylation of ion channels (4). Alterations inion channel function, ion translocation,and membrane conductance lead to de-creased neuronal activation and the clin-ical effects of sedation and anxiolysis (5).Centrally acting �2-adrenergic agonistsalso activate receptors in the medullaryvasomotor center, reducing norepineph-rine with a resultant central sympatho-

lytic effect leading to decreased heart rate(HR) and blood pressure (BP). As the cen-tral presynaptic �2A-adrenergic receptoris a negative feedback receptor, agonistsat this receptor result in decreased cate-cholamine release from the nerve termi-nal. Central nervous system stimulationof parasympathetic outflow and inhibi-tion of sympathetic outflow from the lo-cus ceruleus in the brainstem play aprominent role in the sedation and anxi-olysis produced by these agents. De-creased noradrenergic output from thelocus ceruleus allows for increased firingof inhibitory neurons, most importantlythe �-aminobutyric acid system (6–8).Primary analgesic effects and potentia-tion of opioid-induced analgesia resultfrom the activation of �2-adrenergic re-ceptors in the dorsal horn of the spinalcord and the inhibition of substance Prelease. These interactions with centralnervous system and spinal cord �2-adrenergic receptors mediate dexmedeto-midine’s primary physiologic effects in-cluding sedation, anxiolysis, analgesia, adecrease of the minimum alveolar con-

From the Departments of Anesthesiology and Pe-diatrics, University of Missouri, Columbia, MO.

The author has consulted for and received hono-raria/speaking fees from Hospira.

Copyright © 2007 by the Society of Critical CareMedicine and the World Federation of Pediatric Inten-sive and Critical Care Societies

DOI: 10.1097/01.PCC.0000257100.31779.41

Objective: To provide a general descriptive account of theend-organ effects of dexmedetomidine and to provide an evi-dence-based review of the literature regarding its use in infantsand children.

Data Source: A computerized bibliographic search of the lit-erature regarding dexmedetomidine.

Main Results: The end-organ effects of dexmedetomidine havebeen well studied in animal and adult human models. Adversecardiovascular effects include occasional episodes of bradycardiawith rare reports of sinus pause or cardiac arrest. Hypotensionhas also been reported as well as hypertension, the latter thoughtto be due to peripheral �2B agonism with peripheral vasoconstric-tion. Although dexmedetomidine has no direct effects on myocar-dial function, decreased cardiac output may result from changesin heart rate or increases in afterload. There are somewhatconflicting reports in the literature regarding its effects on ven-tilatory function, with some studies (both human and animal)suggesting a mild degree of respiratory depression, decreasedminute ventilation, and decreased response to CO2 challenge

whereas others demonstrate no effect. The central nervous sys-tem effects include sedation and analgesia with prevention ofrecall and memory at higher doses. Dexmedetomidine may alsoprovide some neuroprotective activity during periods of ischemia.Applications in infants and children have included sedation duringmechanical ventilation, prevention of emergence agitation follow-ing general anesthesia, provision of procedural sedation, and theprevention of withdrawal following the prolonged administrationof opioids and benzodiazepines.

Conclusions: The literature contains reports of the use ofdexmedetomidine in approximately 800 pediatric patients. Givenits favorable sedative and anxiolytic properties combined with itslimited effects on hemodynamic and respiratory function, thereis growing interest in and reports of its use in the pediatricpopulation in various clinical scenarios. (Pediatr Crit Care Med2007; 8:115–131)

KEY WORDS: dexmedetomidine; �2-adrenergic agonist; opioidtolerance and withdrawal; emergence delirium; procedural-sedation

115Pediatr Crit Care Med 2007 Vol. 8, No. 2

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centration of inhalational anestheticagents, decreased renin and vasopressinlevels leading to diuresis, blunting of thesympathetic nervous system, and lower-ing of HR and BP (Fig. 2) (9, 10).

Currently, dexmedetomidine’s onlyFood and Drug Administration (FDA)-approved indication is the provision ofshort-term sedation (�24 hrs) in adultpatients in the intensive care unit (ICU)setting who are initially intubated andreceiving mechanical ventilation (11). Itis available in a water-soluble solutionwithout the addition of lipid or propyleneglycol and is not associated with painfollowing intravenous administration.There are no active or toxic metabolites.Given its favorable physiologic effectscombined with a limited adverse effectprofile reported to date, there is increas-ing use of this agent in the pediatricpopulation. This article reviews the basicpharmacology of dexmedetomidine, itsend-organ effects and adverse effect pro-file, and reports from the literature re-garding its use in various clinical scenar-ios in infants and children.

PHARMACOKINETICS

In healthy adult volunteers, dexme-detomidine’s pharmacokinetic profile in-

cludes a rapid distribution phase (distri-bution half-life of 6 mins), an eliminationhalf-life of 2 hrs, and a steady-state vol-ume of distribution of 118 L (12). In thedosing range of 0.2–0.7 �g/kg/hr deliv-ered via continuous intravenous infusionfor up to 24 hrs, the pharmacokineticsare linear. Dexmedetomidine is 94% pro-tein bound to serum albumin and �1-glycoprotein. It undergoes hepatic me-tabolism with limited unchanged drugexcreted in the urine or stool.

Cunningham et al. (13) evaluateddexmedetomidine pharmacokinetics fol-lowing administration (0.6 �g/kg infusedover 10 mins) in five adults with severe

hepatic failure and compared the resultswith five age-matched controls with nor-mal hepatic function. When comparedwith age-matched controls with normalhepatic function, there was an increasedvolume of distribution at steady state (3.2vs. 2.2 L/kg, p � .05), an increased elim-ination half-life (7.5 vs. 2.6 hrs, p � .05),and a decreased clearance (0.32 vs. 0.64L/hr/kg; p � .05) in patients with hepaticdysfunction. In a subsequent study in sixadult patients with severe renal disease(24-hr creatinine clearance �30 mL/min)who were not receiving dialysis, therewas no statistically significant differencebetween renal disease and control pa-

Figure 1. Representation of the chemical struc-ture of clonidine and dexmedetomidine, �2-adrenergic agonists of the imidazole subclass,which exhibit a high ratio of specificity for the �2

vs. the �1 receptor.

Figure 2. The physiologic end-organ effects of dexmedetomidine.

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tients in the volume of distribution atsteady state (1.81 � 0.55 vs. 1.54 � 0.08L/kg) or the elimination clearance(12.5 � 4.6 vs. 8.9 � 0.7 mL/min/kg)(14). However, the elimination half-lifewas decreased with renal disease (113.4 �11.3 mins vs. 136.5 � 13.0 mins, p �.05). Despite the shorter elimination half-life, there was prolonged sedation in pa-tients with renal disease. The 1-hr postin-fusion visual analog score of sedation(scale of 0 to 100) was 49.2 � 25.4 inpatients with renal disease comparedwith 26.2 � 18.3 in patients with normalrenal function (p � .05). The authorsspeculated that the increased sedationwith renal failure resulted from decreasedprotein binding and an increased freefraction of the drug. Venn et al. (15) eval-uated the impact of acute surgical inter-vention and critical illness on dexmedeto-midine pharmacokinetics in ten adultpatients following complex abdominal orpelvic surgical procedures. Dexmedeto-midine administration included a loadingdose of 0.4 �g/kg over 10 mins followedby an infusion of 0.7 �g/kg/hr. Whencompared with data from healthy volun-teers, there was no difference in half-life,volume of distribution, or clearance.

Data regarding dexmedetomidinepharmacokinetics in the pediatric popu-lation have been presented in one recentmanuscript and two abstracts (16–18).Petroz et al. (16) randomized 36 children,ranging in age from 2 to 12 yrs, to receivedexmedetomidine infused for 10 mins at2, 4, or 6 �g/kg/hr (0.33, 0.6, and 1 �g/kg). Using a two-compartment model,they reported that the pharmacokineticsof dexmedetomidine in children are sim-ilar to adults with no dose-dependent ki-netics, protein binding of 92.6%, weight-adjusted total body clearance of 13 mL/kg/min, a volume of distribution of theperipheral compartment of 1.0 L/kg, anda terminal elimination half-life of 1.8 hrs.Rodarte et al. (17) administered a contin-uous infusion in a dose ranging from 0.2to 0.7 �g/kg/hr for 8–24 hrs to ten chil-dren (0.3–7.9 yrs of age) following cardiacprocedures (n � 9) or craniofacial proce-dures (n � 1). Using a two-compartmentmodel, they reported a volume of distri-bution of 1.53 � 0.37 L/kg, a clearance of0.57 � 0.14 L/kg/hr (approximately 9.5mL/kg/min), and a terminal eliminationhalf-life of 2.65 � 0.88 hrs. They com-mented that their data demonstrated thatthe pharmacokinetics of dexmedetomi-dine in children were predictable andconsistent with results reported in adults.

The final pharmacokinetic study in chil-dren included infants, ranging in agefrom 1 to 24 months, following surgeryfor congenital heart disease (18). The au-thors reported a median clearance of 27.2mL/kg/min, peripheral volume of distri-bution of 2.5 L/kg, and terminal elimina-tion half-life of 83 mins. They concludedthat infants appear to clear dexmedeto-midine more quickly than adults or olderchildren.

END-ORGAN EFFECTS OFDEXMEDETOMIDINE

Cardiovascular andHemodynamic Effects

Heart Rate, Blood Pressure, CardiacOutput, and Myocardial Contractility. Hy-potension and bradycardia have been re-ported in adult patients, especially in thepresence of comorbid cardiac disease,when administered with other medica-tions that possess negative chronotropiceffects or following large or rapid bolusdoses. In healthy adult volunteers, thereis a biphasic effect following dexmedeto-midine with an initial increase in systolicblood pressure (sBP) and a reflex decreasein HR followed by a stabilization of sBPand HR at values below the baseline (19).Stimulation of peripheral postsynaptic�2B-adrenergic receptors results in vaso-constriction and the initial increase insBP, whereas the eventual decrease in BPand HR results from central presynaptic�2A-adrenergic receptor stimulated sym-patholysis.

In healthy, adult volunteers, dexme-detomidine doses of 0.25, 0.5, 1.0 and 2.0�g/kg administered over 2 mins resultedin a decrease from baseline of the meanarterial pressure (MAP) at 60 mins of14%, 16%, 23%, and 27% (19). Followinga dose of 1 �g/kg, cardiac output, mea-sured by thoracic bioimpedance, was81 � 13% of baseline at 1 min, 88 � 14%of baseline at 10 mins, and 91 � 11% ofbaseline at 60 mins. With a dose of 2�g/kg, cardiac output was 58 � 32% ofbaseline at 1 min, 76 � 33% of baselineat 10 mins, and 85 � 28% of baseline at60 mins.

The potential for adverse hemody-namic effects with dexmedetomidine inpatients with comorbid features is illus-trated in an adult ICU population of 98cardiac and general surgery patients whoreceived dexmedetomidine for sedationduring mechanical ventilation (11).

Dexmedetomidine was dosed as a bolusdose of 1 �g/kg over 10 mins followed byan infusion of 0.2–0.7 �g/kg/hr. Hypo-tension (MAP �60 mm Hg or a �30%decrease from baseline) occurred in 18 of66 patients. Eleven of the episodes oc-curred during the bolus. Hypertensionwas noted in six of the 66 patients duringthe loading dose. Although no morbidityor mortality was noted, the infusion wastemporarily (n � 3) or permanently (n �3) discontinued, and treatment with at-ropine (n � 2) or temporary cardiac pac-ing (n � 4) was necessary.

Bradycardia and sinus arrest havebeen reported with dexmedetomidine(20, 21). In a study combining dexme-detomidine with propofol to induce anes-thesia, two of the first four patients hadbrief and self-limited sinus arrest afterlaryngoscopy (20). Dexmedetomidine wasadministered as a bolus dose of 1 �g/kgover 15 mins followed by an infusion of0.4 �g/kg/hr resulting in the administra-tion of an average dose of 1.47 �g/kgbefore anesthetic induction with propo-fol. The protocol was amended (decreaseof the dexmedetomidine dose to 0.7�g/kg over 15 mins followed by an infu-sion of 0.27 �g/kg/hr), and no subsequentproblems were noted.

We reported bradycardia in a 5-wk-oldinfant with trisomy 21 who was receivingdexmedetomidine for sedation duringmechanical ventilation (22). Concomi-tant medications included digoxin for thetreatment of chronic congestive heartfailure due to an unrepaired atrioventric-ular canal defect. Twelve hours after theinitiation of the dexmedetomidine infu-sion, the infant’s HR decreased to 40–50beats/min with a stable BP. The dexme-detomidine infusion was discontinuedwithout other therapy, and the HR re-turned to baseline within 60 mins.

In a study of 192 patients with Amer-ican Society of Anesthesiologists ratingsof 1 or 2, randomized to receive eitherintramuscular dexmedetomidine and in-travenous saline, intramuscular dexme-detomidine and intravenous fentanyl, orintramuscular midazolam and intrave-nous fentanyl, followed by maintenanceanesthesia (70% nitrous oxide in 30%oxygen, fentanyl, and either enflurane orisoflurane), intraoperative bradycardiaand hypotension were significantly morecommon in the patients who receiveddexmedetomidine compared with thosereceiving midazolam (23). In one patient,bradycardia (HR 35 beats/min) requiredpharmacologic therapy. Khan et al. (24),



in a study of nine male volunteers assess-ing the effects of low (0.3 ng/mL) andhigh (0.6 ng/mL) dexmedetomidineplasma concentrations on isoflurane re-quirements, reported five hypotensiveevents in the low concentration groupand seven in the concentration group.Interventions including crystalloid, crys-talloid and methoxamine, or atropinewere necessary in five patients. The ma-jority of the hemodynamic events (75%)occurred at an end-tidal isoflurane of�1%.

In a cohort of 80 children, ranging inage from 1 to 12 yrs, no clinically signif-icant hypotension or bradycardia oc-curred with the intraoperative adminis-tration of dexmedetomidine (0.5 �g/kg)during anesthesia at 1 minimum alveolarconcentration with either desflurane orsevoflurane (25). However, there was agreater decrease in HR in patients anes-thetized with sevoflurane compared withthose receiving desflurane (104 � 16 vs.120 � 17 beats/min, p � .01).

Lowering of HR and thereby myocar-dial oxygen consumption may providebeneficial effects in patients with coro-nary artery disease. Talke et al. (26) ran-domized 24 adult patients undergoingvascular surgery to placebo or one ofthree plasma concentrations of dexme-detomidine: 0.15 ng/mL (low dose), 0.3ng/mL (medium dose), or 0.45 ng/mL(high dose). Dexmedetomidine wasstarted 1 hr before anesthetic inductionand continued for 48 hrs. Although therewas an increased intraoperative need foratropine and/or phenylephrine withdexmedetomidine, no such difference wasnoted postoperatively. In the placebogroup, there was an increased incidence oftachycardia (23 mins/hr) when comparedwith the low-dose (9 mins/hr, p � .006),medium-dose (0.5 mins/hr, p � .004),and high-dose (2.3 mins/hr, p � .004)dexmedetomidine groups. In an anec-dotal report, the negative chronotropiceffect of dexmedetomidine was used as atherapeutic maneuver during off-pumpcoronary artery bypass surgery whentachycardia was unresponsive to �-adren-ergic blockade (27).

The potential for significant negativechronotropic effects appears to be greaterwhen dexmedetomidine is administeredwith medications that have negativechronotropic effects (propofol, succinyl-choline, digoxin, pyridostigmine) or dur-ing vagotonic procedures (laryngoscopy)(20–22). Animal studies have not demon-strated direct effects on myocardial con-

tractility or intracellular calcium regula-tion (28). When studied in an isolatedright ventricular papillary muscle prepa-ration, dexmedetomidine had no effect onthe amplitude and time variables of iso-metric, isotonic, or zero-loaded-clampedtwitches and intracellular calcium cur-rents (28).

Sympathetic Nervous System and En-dogenous Catecholamine Release. Bio-chemical data from a cohort of eightadult postoperative patients demonstratethe sympatholytic effects of dexmedeto-midine (29). Following a 60-min dexme-detomidine infusion administered by acomputer-controlled infusion protocolto achieve a plasma concentration of600 pg/mL, the plasma norepinephrineconcentration decreased from 2.1 � 0.8to 0.7 � 0.3 nmol/L, the plasma epi-nephrine concentration decreased from0.7 � 0.5 to 0.2 � 0.2 nmol/L, HRdecreased from 76 � 15 to 64 � 11beats/min, and sBP decreased from 158� 23 to 140 � 23 mm Hg. The sameinvestigators evaluated changes inplasma and urinary catecholamines in41 adult patients undergoing vascularsurgery (30). Dexmedetomidine wasstarted intraoperatively and continuedfor the first 48 postoperative hours.When compared with patients receivingdexmedetomidine, plasma norepineph-rine concentrations were two to threetimes higher at the time of trachealextubation and at 60 mins after arrivalin the postanesthesia care unit than inthe control group. Urinary normeta-nephrine levels increased significantlyin the placebo group, whereas nochange was noted in patients receivingdexmedetomidine.

A similar sympatholytic effect hasbeen demonstrated following the intraop-erative administration of dexmedetomi-dine to pediatric patients undergoing car-diopulmonary bypass and surgery forcongenital heart disease (31). Muktar etal. (31) randomized 30 infants and chil-dren to placebo or dexmedetomidine (bo-lus of 10 �g/kg over 10 mins followed byan infusion of 0.5 �g/kg/hr), which wasadministered after anesthetic inductionand placement of arterial and venous can-nulae. Although plasma cortisol, norepi-nephrine, epinephrine, and glucose con-centrations increased in both thedexmedetomidine and the placebo groupsafter sternotomy and following cardiopul-monary bypass, the increase was signifi-cantly less in patients receiving dexme-detomidine. Additionally, when weaning

from cardiopulmonary bypass, less so-dium nitroprusside was required in pa-tients receiving dexmedetomidine (0.3 �0.36 vs. 1.3 � 0.68 �g/kg/min, p � .05).No adverse effects were noted.

In specific clinical scenarios such ashemorrhage, hypovolemia, or conges-tive heart failure, there is the potentialfor dexmedetomidine’s sympatholyticeffect to be detrimental by offsettingthe protective function of the sympa-thetic nervous system. In an animalmodel, Blake et al. (32) evaluated theeffects of dexmedetomidine on the BPresponse during incremental decreasesin intravascular blood volume inducedby a gradual inflation of an inferiorvena cava cuff. In control animals, thegradual reduction of intravascular vol-ume resulted in a progressive increasein HR with peripheral vasoconstrictionto maintain MAP until cardiac indexwas approximately 40% of baseline, atwhich time there was failure of vaso-constriction and a decrease in MAP.Dexmedetomidine, administered intra-venously or directly into the fourthventricle of the central nervous system,resulted in a decrease of HR and MAPfrom baseline and an earlier decompen-sation during inflation of the inferiorvena cava cuff. Similar findings werereported in rabbits treated with doxo-rubicin to induce a chronic congestiveheart failure and then subjected a re-duction of intravascular volume by in-flation of an inferior vena cava cuff (33).

Myocardial Oxygen Consumption andPerioperative Ischemia. Clinical studiesin adults have shown that the periopera-tive administrative of �2-adrenergic ago-nists may modify the incidence of adversecardiovascular events including myocar-dial ischemia (34, 35). In an animalmodel of coronary artery stenosis,dexmedetomidine reduced blood flow inthe nonischemic myocardium and in theischemic epicardial layer; however, therewas no effect on blood flow in the isch-emic mid-myocardial and subendocardiallayers, thereby increasing the ischemic-nonischemic blood flow ratio (36). Myo-cardial oxygen demand also decreasedwith dexmedetomidine, thereby further re-ducing the ischemic myocardium’s oxygendeficiency

Similar findings were reported byWilligers et al. (37) in their animal modelusing graded coronary stenosis to pro-duce lactate release from the poststenoticmyocardium. Lactate production oc-curred in zero of eight dogs receiving



dexmedetomidine compared with four ofseven in the control group (p � .03).With dexmedetomidine, lactate releasewas 46% less during emergence from an-esthesia, and the endocardial/epicardialblood flow ratio increased by 35% com-pared with the control group. Decreasedlevels of plasma epinephrine (158 vs.1909 pg/mL) and norepinephrine (126 vs.577 pg/mL) and decreased HR (123 � 6vs. 160 � 10 beats/min) were noted. Theauthors postulated that this may accountfor the anti-ischemic effect of dexmedeto-midine.

Additional potentially protective ef-fects of dexmedetomidine on myocar-dial performance include preservationof myocardial dysfunction followingischemia and prevention of catechol-amine-induced arrhythmogenesis (38,39). Hypoxia followed by reoxygenationexposes the myocardium to an oxidativestress, resulting in tissue injury/deathand myocardial dysfunction. In rats ex-posed to 60 mins of hypoxia, dexme-detomidine administered before but notafter hypoxia significantly improved leftventricular-developed pressure afterreoxygenation (38). The effect wasblocked by yohimbine, an �2-adrenergicantagonist. In a separate study, dexme-detomidine increased the dysrhythmo-genic dose of epinephrine in halothane-anesthetized dogs (mean dose of 3 �g/kg/min in control animals vs. 6 �g/kg/min inanimals receiving dexmedetomidine) (39).

Pulmonary Vascular Resistance.There is limited information regardingdexmedetomidine’s effects on the pulmo-nary vasculature and pulmonary vascularresistance (PVR). In six instrumentedsheep, dexmedetomidine (2 �g/kg over 1min) transiently increased mean pulmo-nary artery pressure (MPAP) and PVR (40).PVR increased from a baseline of 81 � 16dynes·sec·cm�5 to a maximum of 141 �27 dynes·sec·cm�5, whereas MPAP in-creased from 15 � 1 to 18 � 0 mm Hg.MAP also increased (86 � 2 to 93 � 6mm Hg), as did systemic vascular resis-tance (1416 � 83 to 1889 � 64dynes·sec·cm�5). There was no change inpulmonary artery occlusion pressure.Similar transient pulmonary hemody-namic changes have been reported inhealthy human volunteers with gradeddexmedetomidine infusions to a plasmaconcentration of 1.9 ng/mL (19). Giventhe potential impact of these findings,especially in patients with elevated MPAP

or PVR, future studies are needed to de-fine these effects.

Respiratory Effects

Ventilation. The ventilatory effects ofincreasing doses of dexmedetomidine(0.25, 0.5, 1, and 2 �g/kg over 2 mins)have been evaluated in healthy adult vol-unteers by measurement of oxygen satu-ration, PaCO2, CO2 response curves withCO2 rebreathing, and respiratory induc-tance plethysmography (10, 41). Withdoses of 1 or 2 �g/kg, PaCO2 increasedsignificantly with a maximum effectnoted 10 mins following the dose. Themean PaCO2 increase from baseline was5.0 and 4.2 mm Hg with the 1.0 and 2.0�g/kg doses, respectively. The effect per-sisted for 60 mins following 1 �g/kg andfor 105 mins following 2 �g/kg. Follow-ing 2.0 �g/kg, minute ventilation de-creased from 8.7 � 0.7 to 6.3 � 1.5 L/min(p � .05). The decrease resulted predom-inantly from a decreased tidal volumewith less effect on respiratory rate. Sig-nificant changes were also noted usingCO2 response curves, as minute ventila-tion at an end-tidal CO2 of 55 mm Hg wasdepressed following the both the 1- and2-�g/kg doses. The authors also notedshort episodes of apnea and irregularbreathing in some subjects, which oc-curred more commonly with the twohighest doses (seven of ten patients with2 �g/kg and five of six patients with 1�g/kg vs. one of six with either 0.5 �g/kgor 0.25 �g/kg). Respiratory inductanceplethysmography was used to demon-strate that these problems were obstruc-tive and not central. Although oxygensaturation decreased with the obstructiveepisodes, the average room air oxygensaturation remained 95% following alldoses of dexmedetomidine. The oxygensaturation decrease was greatest at 10mins following 1 �g/kg (decrease from98.5 � 0.7% to 96.2 � 1.3%) and at 60mins following 2 �g/kg (decrease from98.3 � 0.8% to 95.4 � 1.2%). Similarrespiratory effects have been demon-strated in experimental animals althougha paradoxic effect has been noted withmore of an effect on ventilation with 1 vs.10 �g/kg in one study and 10 or 30 �g/kgvs. 50 �g/kg in another (42–44).

Conflicting results were reportedwhen comparing the respiratory effects ofdexmedetomidine with remifentanil insix healthy adult volunteers (45). Whencompared with baseline, a remifentanilinfusion to achieve a stepwise plasma

concentration of 1, 2, 3, and 4 ng/mLresulted in respiratory depression mani-fested as a decrease in respiratory rateand minute ventilation, increased PaCO2,blunting of the CO2 response curve, andapnea with oxygen desaturation. Duringstepwise dexmedetomidine infusions toachieve plasma concentrations of 0.6, 1.2,1.8, and 2.4 ng/mL, there was an increasein respiratory rate, a decrease in the hy-popnea/apnea index, and no change inthe end-tidal CO2 when compared withbaseline values. With dexmedetomidine,some patients demonstrated a periodic in-crease in minute ventilation during CO2

response curves (hypercapnic arousal) thatcorrelated with changes in the BispectralIndex. The authors noted that similarchanges occur during natural sleep andthat these findings may result fromdexmedetomidine’s mechanism of actionin the locus ceruleus and its convergenceon the natural sleep pathway. The au-thors concluded that dexmedetomidinestands apart from other sedatives in thatit appears to be clinically safe from arespiratory point of view even in doseshigh enough to cause unresponsiveness.Similar findings were reported from anevaluation of the respiratory effects ofdexmedetomidine (10 and 30 �g/kg) andalfentanil in an animal model (rats) (46).Neither dose of dexmedetomidine had aneffect on PaO2, PaCO2, or pH, whereas theadministration of alfentanil resulted in adecrease in pH and PaO2 and an increase inPaCO2. Dexmedetomidine had no additionaleffect when administered after alfentanil,and in fact, dexmedetomidine in a dose of30 �g/kg decreased the acidosis and hyper-capnia that occurred following alfentanil.Despite these findings, monitoring of respi-ratory function during the administrationof dexmedetomidine in high-risk patientsor those receiving other agents that maydepress respiratory function appears war-ranted given the recent report of centralapnea after a general anesthetic that in-cluded dexmedetomidine (47).

Airway Reactivity. In mongrel dogs,the intravenous but not the inhalationaladministration of dexmedetomidine hasbeen shown to prevent histamine-in-duced bronchoconstriction (48). Bron-choconstriction was provoked with aero-solized histamine, and its effect on airwaycaliber was evaluated using high-resolu-tion computed tomography with an eval-uation of airway cross-sectional area.Aerosolized histamine constricted theairways to 66 � 27% of baseline com-pared with 87 � 30.4% of baseline when



the animals were pretreated with intrave-nous dexmedetomidine.

Central Nervous System Effects

Sedation. Clinical studies in humansand experimental trials in both humansand animals have demonstrated the sed-ative effects of dexmedetomidine (9, 10,41, 49, 50). In ten healthy adult malevolunteers, sequential 40-min infusionsof dexmedetomidine were administeredto achieve plasma concentrations of 0.5,0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/mL (45).The visual analog sedation score (0 �very alert and 100 � very sedated) in-creased to 36 � 27 and 62 � 18 from abaseline of 0 with the first two targetedinfusion levels (0.5 and 0.8 ng/mL). Thetwo volunteers who received the highestincremental dose (calculated to achieve aplasma concentration of 8.0 ng/mL) werenot arousable even with vigorous shak-ing. Picture recall and recognition werepreserved during the lowest incrementalinfusion (0.5 ng/mL) but were 0% (0 of10) and 20% (2 of 10), respectively, withthe second and third infusion levels (0.8and 1.2 ng/mL).

Dexmedetomidine’s sedative responsehas been shown to have properties thatparallel natural sleep (49, 50). Usingfunctional magnetic resonance imaging(MRI), the blood oxygen level dependentsignal, a correlate of local brain activity,changes with dexmedetomidine-inducedsedation in a similar fashion to that seenduring natural sleep (50). This is differentfrom the pattern that occurs followingthe administration of midazolam. Usingimmunohistochemistry and in situ hy-bridization, dexmedetomidine has alsobeen shown to induce a qualitatively sim-ilar pattern of c-fos expression in sleep-promoting brain nuclei of rats as thatseen during nonrapid eye movementsleep (a decrease in the locus ceruleusand tuberomammillary nucleus and anincrease in the ventrolateral nucleus)(49). These effects were attenuated by ati-pamezole, an �2-adrenergic antagonist,and did not occur in rats that lacked�2-adrenergic receptors. These findingssuggest a clinical advantage of dexmedeto-midine with its pattern of sedation parallel-ing natural sleep when compared withother agents (barbiturates, benzodiaz-epines, and propofol) commonly used forICU sedation. These agents disrupt the nor-mal electroencephalographic patterns ofsleep, and these effects may be responsiblefor the delirium seen in the ICU setting.

Given that delirium has been shown to bean independent risk factor of mortality inthe adult ICU setting, avoidance of the dis-ruption of the natural sleep cycle may the-oretically prevent such problems.

Intracranial Pressure and CerebralPerfusion Pressure. The effects of dexme-detomidine on intracranial pressure(ICP) and cerebral perfusion pressure(CPP) were evaluated by Talke et al. (51)during the immediate postoperative pe-riod following transphenoidal resectionof a pituitary tumor in adults. Thedexmedetomidine infusion was startedpostoperatively and administered by acomputer-controlled infusion to achievea plasma concentration of 600 pg/mL. Alumbar intrathecal catheter was used tomeasure ICP. Although dexmedetomi-dine had no effect on ICP (highest ICPvalues in the dexmedetomidine patientswere 19 and 20 mm Hg), CPP decreasedfrom baseline of 95 � 8 to a low of 78 �6 mm Hg (p � .05). Similar effects onICP have been reported in an animalstudy with escalating doses of dexmedeto-midine (20, 80, and 320 �g/kg) (52).Dexmedetomidine had no effect on ICP inthe baseline state or in animals with in-tracranial hypertension (mean startingICP of 16.8 mm Hg) induced by a cryo-genic lesion. Dexmedetomidine has alsobeen shown to lower intraocular pressurein animals with both normal and elevatedintraocular pressure (53).

Animal and human studies have dem-onstrated a reduction in cerebral bloodflow (CBF) following dexmedetomidine(54, 55). Karlsson et al. (54) demon-strated a reduction of CBF in dogs anes-thetized with 0.9% halothane; however,the authors could not determine whetherdexmedetomidine directly constricted thecerebral vasculature or blunted the cere-bral vasodilatation induced by halothane.Prielipp et al. (55) evaluated changes inCBF in nine healthy adult volunteers us-ing positron emission tomography scan-ning. Dexmedetomidine dosing includeda bolus dose of 1 �g/kg followed by aninfusion of either 0.2 (low dose) or 0.6(high dose) �g/kg/hr. Global CBF (mL/100 g/min) decreased from 91 mL/100 g/min at baseline to 64 mL/100 g/min and61 mL/100 g/min with the low and highdoses, respectively.

Seizure Threshold. Reports in the lit-erature regarding the effects of dexme-detomidine on potential anticonvulsantor proconvulsant effects of dexmedetomi-dine are mixed (56–59). A lowering of theseizure threshold (proconvulsant effect)

with doses of 100 and 500 �g/kg, but not20 �g/kg, was noted in rats treated withthe epileptogenic agent, pentylenetetra-zol (56). The effect was blocked by atipa-mezole. The authors noted that their datawere consistent with previous data dem-onstrating that medications which in-hibit central noradrenergic transmissionfacilitate seizure expression. Dexmedeto-midine (doses of 10 and 100 �g/kg, butnot 1 �g/kg) also reduced the seizurethreshold during enflurane anesthesia incats (57). Anticonvulsant effects weredemonstrated by other investigators (58,59). Dexmedetomidine (20 �g/kg fol-lowed by an infusion of 1 �g/kg/min)increased the dose of cocaine required tocause seizures in Sprague-Dawley rats(58). With a cocaine infusion at 1.25 mg/kg/min, rats treated with dexmedetomi-dine manifested seizures at 49.3 � 14.8mins vs. 25.0 � 7.7 mins in controls. InSprague-Dawley rats, the dose of eitherlevobupivacaine or bupivacaine requiredto induce seizures was higher in ratstreated with dexmedetomidine than incontrols (59).

Neuroprotection. Various animalmodels with complete and incomplete aswell as transient and permanent ischemicinjury have attempted to define dexme-detomidine’s protective effects duringcentral nervous system injury. Hoffmanet al. (60) evaluated the effect of dexme-detomidine on neurologic and his-topathologic outcome from incompletecerebral ischemia in rats. Dexmedetomi-dine (10 or 100 �g/kg) was administeredintraperitoneally, 30 mins before isch-emia, produced by 30 mins of unilateralcarotid occlusion combined with phlebot-omy-induced hypotension. After 30 mins,the carotid occlusion was removed andthe withdrawn blood reinfused. Dexme-detomidine blunted the endogenous re-lease of epinephrine and norepinephrineand improved both histopathologic andneurologic outcome scores when com-pared with either controls or animalstreated with both dexmedetomidine andatipamezole. Serum glucose concentra-tions were significantly higher in animalsreceiving dexmedetomidine, which theauthors attributed to the �2-adrenergicinhibition of insulin release.

In a subsequent study, dexmedetomi-dine (3 or 30 �g/kg) was administeredeither before and then for 48 hrs after theinjury or only following the injury ingerbils exposed to 5 mins of bilateral ca-rotid occlusion (61). Neuronal cells in thehippocampus (CA1 and CA3 regions) and



the dentate gyrus were examined 1 wkfollowing the injury. When comparedwith controls, there was a significant de-crease in the number of ischemic cells inthe CA3 region of the hippocampus inrats that received 3 �g/kg but not 30�g/kg of dexmedetomidine before the in-jury. No effect was noted with either doseif administered after the injury. In thedentate hilus, there were decreased num-bers of ischemic cells in rats that received3 �g/kg of dexmedetomidine before theinjury and those that received 30 �g/kg ofdexmedetomidine after the injury. Theauthors concluded that low-dose dexme-detomidine had neuroprotective effects ifadministration was started before theischemic insult and continued for 48 hrsfollowing it.

The same group of investigators eval-uated dexmedetomidine in a model com-paring transient (90 mins) and perma-nent ischemia using occlusion of themiddle cerebral artery (62). Dexmedeto-midine (bolus of 3 �g/kg followed by a2-hr infusion of either 3 or 6 �g/kg/hr)was administered after middle cerebralartery occlusion. No effect was noted inthe animals subjected to a permanentischemic injury; however, the authorssuggested that although not statisticallysignificant, there was a trend toward de-creased infarct size following transientischemia with the higher dose of dexme-detomidine. Infarct volumes in the cortexand the brainstem were 20–30% less indexmedetomidine-treated animals com-pared with the controls. In term, 5-day-old mice, dexmedetomidine decreased in-farct size and histopathologic evidence ofneuronal death induced by the intracere-bral injection of the N-methyl-D-aspartateagonist, ibotenate (63). An N-methyl-D-aspartate agonist was chosen because ofthe evidence implicating glutamate as acausative agent in hypoxic-ischemic en-cephalopathy and periventricular whitematter lesions in preterm infants.

The preliminary work assumed thatdexmedetomidine’s neuroprotective ef-fect was the result of its blunting of en-dogenous catecholamine release duringischemia. Although dexmedetomidinesuppresses plasma catecholamine con-centrations following cerebral ischemiain rats, it does not alter brain norepi-nephrine or glutamate levels (64).Dexmedetomidine’s neuroprotective ef-fects may be mediated by a reduction incaspase-3 expression (a pro-apoptotic fac-tor) and increased expression of active(autophosphorylated) focal adhesion ki-

nase, a nonreceptor tyrosine kinase thatplays a role in cellular plasticity and sur-vival (65).

Miscellaneous CNS Effects. Additionaleffects on the central and peripheral ner-vous system include prevention of opioid-induced muscle rigidity and attenuationof shivering. Using hindlimb electromyo-graphic activity, dexmedetomidine abol-ished increased electromyographic activ-ity associated with alfentaniladministration in rats (46). A decreasedincidence of fentanyl-induced muscle ri-gidity during anesthetic induction wasdemonstrated following dexmedetomi-dine in adults undergoing coronary ar-tery bypass grafting (15 of 40 or 37.5% vs.33 of 40 or 82.5%) (66). In the samestudy, postoperative shivering occurredin 13 of 40 (32.5%) patients who receiveddexmedetomidine vs. 23 of 40 (57.5%)patients who received placebo. In healthyadult volunteers, the shivering thresholdwas 36.7 � 0.3°C in control patients, 36.0� 0.5°C with dexmedetomidine (p � .001compared with control), 35.5 � 0.6°Cwith meperidine (p � .001 comparedwith control), and 34.7 � 0.6°C withdexmedetomidine and meperidine (p �.001 compared with control) (67).

Miscellaneous End-OrganEffects

Gastrointestinal Motility. Using radio-labeled sodium chromate in a whole an-imal model (rat), Asai et al. (68) evaluatedthe effects of clonidine, dexmedetomi-dine, and morphine on gastrointestinaltransit time and gastric emptying. Al-though all three drugs strongly inhibitedgastrointestinal transit time in a dose-dependent manner, morphine’s effect ongastric emptying was greater than that ofeither clonidine or dexmedetomidine,which only weakly inhibited gastric emp-tying time. Gastric emptying evaluated asthe percentage of radioactivity that hadentered the small intestine at 30 minswas 88.2% in the control group, 70.9%with clonidine, 78% with dexmedetomi-dine, and 23% with morphine. Herbert etal. (69) compared the effects of clonidineand dexmedetomidine in an in vitromodel using an isolated segment ofguinea pig ileum with an assessment ofthe pressure required to induce peristal-sis. Inhibition of gastrointestinal motil-ity, defined by the requirement for anincreased pressure to stimulate peristal-sis, was increased with both clonidineand dexmedetomidine; however, the ef-

fect was markedly greater with dexme-detomidine.

Adrenocortical Function. As demon-strated by the classic problems with eto-midate, compounds that contain an imi-dazole ring can inhibit hydroxylaseenzymes involved in the production ofadrenocorticosteroids. As dexmedetomi-dine contains an imidazole ring, there aretheoretical concerns regarding its effectson steroidogenesis. In a series of in vitroand in vivo animal studies, the effects ofdexmedetomidine on steroidogenesis,binding to glucocorticoid receptors, andadrenocorticotrophic hormone (ACTH)-stimulated release of corticosterone wereinvestigated (70). In the concentrationsthat are used clinically, there was no ev-idence to suggest that dexmedetomidinedepressed adrenocortical function to theextent that occurs with etomidate. How-ever, the studies did demonstrate thathigh doses of dexmedetomidine are capa-ble of inhibiting steroidogenesis. In 20adult patients who required sedation dur-ing mechanical ventilation randomizedto receive either propofol or dexmedeto-midine, there was no difference in corti-sol, ACTH, prolactin, and glucose con-centrations between the two groups (71).However, some of the dexmedetomidinepatients had abnormal ACTH stimulationtests, although these were attributed totheir acute surgical illness and notdexmedetomidine. None of the patientswere felt to be at risk for adrenocorticalfailure or manifested clinical symptomsof adrenal dysfunction. The failure tomeet the criteria for an acceptable ACTHstimulation test varied according to thecriteria used. If an acceptable responsefollowing ACTH administration was apeak cortisol concentration �400nmol/L, nine of ten patients had a normalresponse. If the peak cortisol level follow-ing ACTH administration was increasedto �550 nmol/L, eight of ten had a nor-mal response. However, if there was arequirement to increase the serum corti-sol by 200 nmol/L from baseline follow-ing ACTH, only five of ten patients metthe criterion. The authors concluded thatdexmedetomidine does not inhibit adre-nal steroidogenesis when used for short-term sedation after surgery and that thepattern of serum cortisol and ACTH levelswas not similar to what had been re-ported with etomidate.

White Blood Cell Function and In-flammatory Response. In an in vitrostudy, dexmedetomidine was shown tohave no effect on white blood cell chemo-



taxis, phagocytosis, or superoxide anionproduction leading (72). The authorsconcluded that there is no concern withits use in patients with acute infectiousprocesses (72). They also noted that theirdata did not demonstrate any beneficialeffects in disease processes that involveauto-tissue injury due to neutrophils. De-spite this, other data suggest that dexme-detomidine may modify the inflammatoryresponse. In the study by Venn et al. (71),in which patients were randomized toreceive either propofol or dexmedetomi-dine, there was a decrease in interleu-kin-6 levels from baseline in patients re-ceiving dexmedetomidine with no changein patients receiving propofol. A similareffect has been demonstrated in labora-tory animals (72). Additional work hasdemonstrated that dexmedetomidine mayblunt the systemic inflammatory re-sponse during endotoxemia (73). In astudy that randomized rats to one of fourgroups (endotoxin administration, salinecontrol, dexmedetomidine, or endotoxinand dexmedetomidine), the mortalityrates at 8 hrs after endotoxin administra-tion were 94%, 10%, 0%, and 44%, re-spectively, in the four groups. Hypoten-sion, increases in tumor necrosis factorand interleukin-6 concentrations, andthe infiltration of neutrophils into theairspaces and vessel walls were less in therats that received dexmedetomidine afterendotoxin than in rats that received en-dotoxin alone.

Neuromuscular Blockade. An animalstudy and a human study have investi-gated the effects of dexmedetomidine onneuromuscular blockade (74, 75). In a ratmodel, vecuronium was administered bycontinuous infusion to produce a steady-state depression of the first twitch (T1) ofthe train-of-four to 53 � 2% of baseline(74). Dexmedetomidine (10, 30, or 100�g/kg) had no effect on the T1 heightduring the initial 30 mins following ad-ministration. After 30 mins, there wereminor differences between the groups;however, the authors concluded thatthese effects were unlikely to be of clini-cal significance. Similar findings were re-ported by Talke et al. (75) in ten healthyadult volunteers anesthetized with alfen-tanil and propofol. Rocuronium was ad-ministered by continuous infusion toproduce a 50% decrease from baseline ofthe T1 of the train-of-four, followed bydexmedetomidine administered by acomputer-controlled infusion to a plasmaconcentration of 0.6 ng/mL. There was astatistically significant decrease in the T1

height from 51 � 2% to 44 � 9% (p �.0001) and an increase in plasma rocuro-nium concentrations. The authors con-cluded that dexmedetomidine’s effects onneuromuscular function are related to al-terations of rocuronium pharmacokinet-ics and not a direct effect on the neuro-muscular junction. The authors alsoemphasized that the effect is small andunlikely to be of clinical significance.

CLINICAL APPLICATIONS

Preliminary Reports

The two initial reports regarding theuse of dexmedetomidine in pediatric pa-tients were retrospective case series (76).The first report, involving four pediatricpatients, outlined dexmedetomidine useto provide sedation during mechanicalventilation, dexmedetomidine combinedwith remifentanil as an adjunct for con-trolled hypotension during posterior spi-nal fusion, and dexmedetomidine for pro-cedural sedation (76). Althoughdexmedetomidine was effective in thefirst two scenarios, dexmedetomidine wasineffective as the sole agent during uppergastrointestinal endoscopy. The secondreport outlined the use of dexmedetomi-dine in three patients in the pediatric ICUsetting and two in the postanesthesia careunit (77). In the pediatric ICU setting,dexmedetomidine was used for sedationduring spontaneous ventilation withoutairway control in a 4-yr-old with statusasthmaticus whose agitation preventedthe delivery of inhalational therapy, a 13-yr-old who had significant anxiety follow-ing pectus excavatum surgery despite ef-fective pain management with a thoracicepidural catheter, and a 17-yr-old withwithdrawal from the recreational use ofillicit drugs. In the other two patients, asingle bolus dose of dexmedetomidine(0.4–0.5 �g/kg) controlled postoperativeemergence delirium and postoperativeshivering.

Prevention of EmergenceDelirium Following Anesthesia

Five prospective, randomized trials de-tail the successful use of dexmedetomi-dine to prevent emergence delirium fol-lowing general anesthesia in a total of288 pediatric patients (Table 1) (78–82).The first of these studies randomized 90children to placebo, dexmedetomidine0.15 �g/kg, or dexmedetomidine 0.3�g/kg following anesthetic induction

with sevoflurane (78). The incidence ofemergence delirium was 37% in the pla-cebo group, 17% with 0.15 �g/kg ofdexmedetomidine, and 10% with 0.3 �g/kg. Similar efficacy was reported in theother four studies using dexmedetomi-dine in doses ranging from 0.5 to 1 �g/kgas a bolus dose or an infusion of 0.2�g/kg/hr (79–82). These studies note upto an eight- to ten-fold decrease in theincidence of emergence delirium whencompared with placebo. Dexmedetomi-dine was effective regardless of the anes-thetic used (sevoflurane or desflurane)and the type of surgical procedure. Al-though four of the studies reported nodifference in time to emergence and tra-cheal extubation (78, 79, 81, 82), Guler etal. (80) noted that both time to emer-gence (5.03 � 2.3 vs. 3.30 � 1.3 mins, p� 0.05) and time to extubation (9.30 �2.9 vs. 7.20 � 2.7 mins, p � .05) werelonger with dexmedetomidine vs. pla-cebo.

Sedation in the Pediatric ICU(Mechanical Ventilation andSpontaneous Ventilation)

There is currently only one prospec-tive, randomized trial evaluating dexme-detomidine for sedation during mechan-ical ventilation in infants and children(Table 2). Thirty infants and children re-quiring sedation during mechanical ven-tilation were randomized to receive ei-ther a continuous infusion of midazolamstarting at 0.1 mg/kg/hr or a continuousinfusion of dexmedetomidine starting ateither 0.25 �g/kg/hr or 0.5 �g/kg/hr (83).Morphine (0.1 mg/kg) was provided asneeded with an increase of the midazo-lam or dexmedetomidine infusion in 20%increments if necessary. The efficacy ofthe sedation regimens was assessed usingthe Ramsay sedation score and the needfor supplemental morphine, whereas thedepth of sedation was compared using theBispectral Index. Dexmedetomidine at0.25 �g/kg/hr was as effective as midazo-lam at 0.22 mg/kg/hr, whereas the higherdose of dexmedetomidine (0.5 �g/kg/hr)was more effective. With the higher doseof dexmedetomidine, although sedationscores and the Bispectral Index wereequivalent, there was a decreased needfor supplemental morphine (0.28 � 0.12vs. 0.74 � 0.5 mg/kg/24 hrs). Two of tenpatients receiving dexmedetomidine at0.5 �g/kg/hr had a Ramsay score of 1 atany time vs. six of ten patients receivingmidazolam. There was a decrease in the



number of Ramsay scores of 1 (five withdexmedetomidine at 0.5 �g/kg/hr vs. 14with midazolam at a mean dose of 0.22mg/kg/hr). The authors speculated thatdexmedetomidine may be less effective inyounger patients, as five of the six pa-tients who manifested a Ramsay score of1 in either of the two dexmedetomidinegroups (0.25 or 0.5 �g/kg/hr) were �12months of age.

One retrospective case series andtwo other case reports detailed the useof dexmedetomidine for sedation dur-ing mechanical ventilation (Table 2)(84 – 86). The first of these outlined theuse of dexmedetomidine as part of arotating sedation regimen in an at-tempt to prevent the development oftolerance and withdrawal during pro-longed sedation regimens (84). The sec-ond remains the only report of the ad-ministration of a dexmedetomidineinfusion for 24 hrs for sedation dur-ing mechanical ventilation in a child(85). The final of these reports detailsthe use of dexmedetomidine to transi-tion from fentanyl/midazolam sedationbefore extubation in a 12-yr-old whowas status post heart transplantation andrequired mechanical ventilation for respi-ratory failure (86).

In another potential application forthe pediatric ICU setting, Chrysosto-

mou et al. (87) retrospectively reviewedtheir experience with dexmedetomidineinfusions following cardiac and tho-racic surgical procedures in 38 patientswith a mean age of 8 � 1 yrs. Sevenpatients (18%) were �1 yr of age and 33(87%) were extubated and breathingspontaneously. The dexmedetomidineinfusion without a loading dose wasstarted following the surgical proce-dure at 0.1– 0.5 �g/kg/hr (0.32 � 0.15�g/kg/hr). The infusion was continuedfor 3–26 hrs (14.7 � 5.5 hrs) at 0.1–0.75 �g/kg/hr (0.3 � 0.05 �g/kg/hr).Mild to moderate sedation was achieved93% of the time and no to mild pain83% of the time. Forty-nine doses ofrescue agents were required for eithersedation or analgesia (1.3 � 0.26 bo-luses per patient). Twenty-nine (60%)were required during the first 5 hrs ofthe dexmedetomidine infusion. Therewas a trend toward a requirement for ahigher dexmedetomidine infusion andmore rescue doses in patients �1 yr ofage compared with those 1 yr of age(0.4 � 0.13 vs. 0.29 � 0.17 �g/kg/hr).Bradycardia occurred in one patient, 15mins after starting the dexmedetomi-dine infusion, and resolved with its dis-continuation. Transient hypotensionwas noted in six patients (15%) andresolved with decreasing the dexme-

detomidine infusion in three and withdiscontinuation of the infusion inthree.

Procedural Sedation(Noninvasive Procedures)

Reports of dexmedetomidine for non-invasive procedural sedation are summa-rized in Table 3. Preliminary data wereprovided by Nichols et al. (88), who useddexmedetomidine for “rescue sedation”during radiologic imaging (computed to-mography and MRI) in five patients rang-ing in age from 11 months to 16 yrs whena combination of chloral hydrate and mi-dazolam was ineffective. Four prospectivetrials have evaluated the efficacy ofdexmedetomidine for sedation duringnoninvasive radiologic imaging (89–92).

Koroglu et al. (89) randomized 80children (1–7 yrs of age) to dexmedeto-midine or midazolam during MRI.Dexmedetomidine was administered as aloading dose of 1 �g/kg over 10 minsfollowed by an infusion of 0.5 �g/kg/hr,whereas midazolam was administered asa loading dose of 0.2 mg/kg followed byan infusion of 6 �g/kg/hr. The quality ofsedation was better and the need for res-cue sedation was less (8 of 40 vs. 32 of 40)with dexmedetomidine compared withmidazolam.

Table 1. Dexmedetomidine to prevent emergence delirium following general anesthesia

Author and ReferenceType of Study and

No. of Patients Dexmedetomidine Dosing Findings

Ibacache et al. (78) Prospective,randomizedtrial, n � 90

Placebo or one of two doses ofdexmedetomidine (0.15 or0.3 �g/kg) following theinduction of generalanesthesia.

No difference in the time to awakening and tracheal extubation.The incidence of emergence delirium with sevoflurane was37% in the placebo group, 17% with 0.15 �g/kgdexmedetomidine, and 10% with 0.3 �g/kg.

Hanafy et al. (79) Prospective,randomizedtrial, n � 46

Placebo or dexmedetomidine(0.5 �g/kg) following theinduction of generalanesthesia.

Dexmedetomidine patients were less likely to exhibit agitation,were less likely to require treatment for agitation, and hadlower pain scores. There was no difference in recovery time.

Guler et al. (80) Prospective,randomizedtrial, n � 60

Placebo or dexmedetomidine(0.5 �g/kg) prior toemergence.

Dexmedetomidine patients had a decreased incidence of severeagitation, pain, and coughing during recovery. Times totracheal extubation and emergence were longer withdexmedetomidine.

Shukry et al. (81) Prospectiverandomizedtrial, n � 50

Placebo or dexmedetomidine(infusion of 0.2 �g/kg/hr)started after anestheticinduction and continued for15 mins into the recoveryphase.

The incidence and the number of episodes of emergencedelirium were decreased with dexmedetomidine comparedwith placebo. There were no differences in pain scores andthe times to tracheal extubation and discharge from therecovery room.

Isik et al. (82) Prospectiverandomizedtrial, n � 42

Placebo or dexmedetomidine(1 �g/kg) after theinduction of generalanesthesia for magneticresonance imaging.

No differences in hemodynamic variables. Times to removal ofthe laryngeal mask airway and eye opening with verbalstimuli were shorter with placebo. No difference in recoveryroom and hospital discharge time. The incidence ofemergence agitation was 4.8% with dexmedetomidine and47.6% with placebo.



Similar efficacy was reported by Berken-bosch et al. (90) in an open-label trial dur-ing MRI in 48 pediatric patients ranging inage from 5 months to 16 yrs. Dexmedeto-midine was administered as a loading doseof 0.5 �g/kg over 5 mins and repeated asneeded to achieve the desired level of seda-tion. Following this, a continuous infusionwas started at a rate in �g/kg/hr, which wasequivalent to the loading dose. Fifteen pa-tients had failed chloral hydrate and/or mi-dazolam, and 33 patients received dexme-detomidine as the primary agent. The meanloading dose was 0.92 � 0.36 �g/kg fol-lowed by an infusion of 0.69 � 0.32 �g/kg/hr. Effective sedation was achieved in allpatients, and the scan was completed with-out other agents. Recovery time was longerin patients who had received other agentsbefore dexmedetomidine than in those whoreceived dexmedetomidine as a primaryagent (117 � 41 vs. 69 � 34 mins).

A second study by Koroglu et al. (91)randomized 60 children to dexmedeto-midine or propofol during MRI. Dexme-detomidine was administered as a load-ing dose of 1 �g/kg over 10 minsfollowed by an infusion of 0.5 �g/kg/hr,whereas propofol was administered as a

loading dose of 3 mg/kg followed by aninfusion of 100 �g/kg/hr. Althoughequally effective in providing sedation,induction time, recovery time, and dis-charge times were shorter with propo-fol. Adverse effects including hypoten-sion and oxygen desaturation weremore common with propofol. Oxygendesaturation requiring intervention(chin lift, discontinuation of the infu-sion, and supplemental oxygen) oc-curred in four children receivingpropofol vs. none of those receivingdexmedetomidine.

In a retrospective review of prospec-tive data from their quality assurancedatabase, Mason et al. (92) presenteddata regarding dexmedetomidine for se-dation in 62 children during radiologicimaging. Dexmedetomidine was admin-istered as a loading dose of 2 �g/kg over10 mins and repeated to achieve effec-tive sedation, after which an infusionwas started at 1 �g/kg/hr. The meanloading dose was 2.2 �g/kg, with 52patients requiring only the initial doseof 2 �g/kg. The time to achieve sedationwas 9.9 � 2.4 mins (range 6 –20 mins).Sinus arrhythmias were noted in ten

patients (16%). Although HR and BPdecreased in all patients, no treatmentwas necessary and no value was lessthan the fifth percentile for age. Nochanges were observed in end-tidalCO2, and no patient developed oxygendesaturation while breathing room air.Two patients manifested significant ag-itation during the administration of theloading dose and were switched to othersedative agents (propofol or pentobar-bital).

Anecdotal case reports have also dem-onstrated the efficacy of dexmedetomi-dine for sedation during cardiac MRI andradiation therapy (93–96). A final reportregarding the use of dexmedetomidinefor noninvasive procedural sedation de-scribes the combination of dexmedeto-midine and ketamine for three patientswith trisomy 21 and obstructive sleepapnea requiring sedation during staticand dynamic cine MRI (97). Effectivesedation was provided by an initial bo-lus dose of ketamine (1 mg/kg) anddexmedetomidine (1 �g/kg) followed bya continuous infusion of dexmedetomi-dine (1 �g/kg/hr).

Table 2. Dexmedetomidine for sedation in the pediatric intensive care unit



Tobias andBerkenbosch (83)

Prospectiverandomizedtrial, n � 30

Midazolam at 0.1 mg/kg/hr vs. dexmedetomidineat either 0.25 or 0.5�g/kg/hr with doses ofmorphine as required.

Dexmedetomidine at 0.25 �g/kg/hr was as effective as midazolamat 0.22 mg/kg/hr, whereas dexmedetomidine at 0.5 �g/kg/hrwas more effective. Patients receiving dexmedetomidine at 0.5�g/kg/hr had a decreased need for supplemental morphine(0.28 � 0.12 vs. 0.74 � 0.5 mg/kg/24 hrs), and fewer patientsmanifested a Ramsay score of 1 (two of ten vs. six of ten).

Wheeler et al. (84) Retrospective casereport, n � 2,compared withhistoricalcontrols, n � 5

Rotating sedation(continuous infusion ofmidazolam, fentanyl, ordexmedetomidine) inpatients who requiredsedation for 5 days.

Patients who received the rotating sedation regimen did notdevelop tolerance or manifest withdrawal symptoms and weredischarged earlier (days 6–7 vs. 8–10 days) when comparedwith patients who received a single agent for 5 days.

Hammer et al. (85) Case report, n � 1 Continuous infusion of0.2–0.5 �g/kg/hr.

Dexmedetomidine infusion provided effective sedation duringmechanical ventilation when escalating doses of midazolamand fentanyl were ineffective.

Chrysostomou et al.(86)

Case report, n � 1 Dexmedetomidine infusionof 0.2 �g/kg/hr to start;later increased to0.4 �g/kg/hr.

12-year-old status post cardiac transplantation with respiratoryfailure. Infusion started 20 hrs prior to tracheal extubationand continued for 6 hrs afterward to provide sedation andallow for transition from fentanyl/midazolam sedation tospontaneous ventilation in a patient who had failed twoprevious attempts at extubation.

Chrysostomou et al.(87)

Retrospectivereview, n � 38

Cohort of patientsfollowing cardiacsurgery. No loadingdose. Initial infusionstarted at 0.32 � 0.15�g/kg/hr followed by amean infusion at 0.3 �0.05 �g/kg/hr.

Mild to moderate sedation achieved 93% of the time, whereas noto mild pain was reported 83% of the time. A total of 49rescue doses of a sedative or analgesic were required (1.3 �0.26 boluses per patient). Bradycardia occurred in one patientand resolved with its discontinuation. Transient hypotensionwas noted in six patients (15%) and resolved with decreasingthe dexmedetomidine infusion in three and withdiscontinuation in three.



Procedural Sedation (InvasiveProcedures)

There have been mixed results whenusing dexmedetomidine for invasive pro-cedures (Table 4). Although Tobias andBerkenbosch (76) reported that dexme-detomidine was not effective for uppergastrointestinal endoscopy in an 11-yr-old boy, Jooste et al. (98) reported suc-cessful sedation with dexmedetomidineduring fiberoptic intubation in two pedi-atric patients, both of whom were 10 yrsold, who presented for operative proce-dures and evidence of cervical spinal cord

compromise. Similar success withdexmedetomidine for sedation during fi-beroptic intubation of the trachea hasbeen reported in adults (99, 100).

In the first prospective evaluation ofdexmedetomidine as the lone agent duringan invasive procedure in infants and chil-dren, Munro et al. (101) reported their ex-perience with dexmedetomidine duringcardiac catheterization. Following premed-ication with midazolam and the placementof intravenous access with the inhalation ofsevoflurane, the inhalational anestheticagent was discontinued and dexmedetomi-

dine administered (1 �g/kg over 10 minsfollowed by an infusion of 1 �g/kg/hr ti-trated up to 2 �g/kg/hr as needed). Theaverage maintenance infusion rate was 1.15� 0.29 �g/kg/hr (range, 0.6–2.0 �g/kg/hr).Five patients (25%) moved during local in-filtration of the groin, which did not re-quire treatment or interfere with cannulaeplacement. Twelve (60%) patients receiveda propofol bolus during the procedure formovement, an increasing Bispectral Indexnumber, or anticipation of a stimulus. Noadverse hemodynamic or respiratory effectswere noted.

Table 3. Dexmedetomidine for noninvasive procedural sedation in infants and children



Koroglu et al. (89) Prospective,randomized trial,n � 80

Dexmedetomidine (loading dose of 1 �g/kg over10 mins 3 an infusion of 0.5 �g/kg/hr) vs.midazolam (loading dose of 0.2 mg/kgfollowed by an infusion of 6 �g/kg/hr).

The quality of sedation during radiologicimaging was better and the need forrescue sedation was less (eight of 40vs. 32 of 40) with dexmedetomidinecompared with midazolam.

Berkenbosch et al.(90)

Prospective, open-label trial, n � 48

Loading dose of 0.5 �g/kg over 5 mins, repeatedas needed to achieve an acceptable level ofsedation. Continuous infusion equal to loadingdose.

Dexmedetomidine was effective eitherafter other agents had failed (n � 15)or as a primary agent (n � 33) forradiologic imaging. Sedation initiatedwith 0.92 � 0.36 �g/kg followed byan infusion of 0.69 � 0.32 �g/kg/hr.

Koroglu et al. (91) Prospective,randomized trial,n � 60

Dexmedetomidine (loading dose of 1 �g/kg over10 mins 3 an infusion of 0.5 �g/kg/hr) vs.propofol (3 mg/kg followed by an infusion of100 �g/kg/hr).

Onset of sedation, recovery, anddischarge times were significantlyshorter with propofol. Hypotensionand oxygen desaturation noted withpropofol but not dexmedetomidine.

Mason et al. (92) Prospective, open-label trial, n � 62

Dexmedetomidine (loading dose of 2 �g/kg over10 mins and repeated as needed followed by aninfusion of 1 �g/kg/hr).

Effective sedation in all but two patientswho required alternative sedationwhen they became increasinglyagitated during the loading dose.

Shukry andRamadhyani (93)

Case report, n � 1 Loading dose of 1 �g/kg 3 infusion of 0.7–0.8�g/kg/hr.

Dexmedetomidine as sole agent forsedation during radiation therapy innine of 12 procedures, with additionalsedation (propofol 5–10 mg) requiredin three.

Young (94) Case report, n � 1 Loading dose of 1 �g/kg 3 infusion of 0.5�g/kg/hr.

Additional propofol (5 mg) needed afterloading dose to induce somnolenceotherwise effective sedation wasachieved.

Fahy and Okumura(95)

Case report, n � 1 Infusion of 0.3–0.7 �g/kg/hr for first course oftherapy. Loading dose of 1 �g/kg 3 infusionup to 1.4 �g/kg/hr for second course.

In both cases, propofol (20 �g/kg/hr)required to provide effective sedation.

Kunisawa and Iwasaki(96)

Case report, n � 1 Premedication with diazepam and atropine orallyfollowed by dexmedetomidine (1 �g/kg 3 0.7�g/kg/hr).

Successful sedation. Patient was notfully awake for 210 mins.

Luscri and Tobias(97)

Case series, n � 3 Loading dose of ketamine (1 mg/kg) anddexmedetomidine (1 �g/kg) 3 infusion of 1�g/kg/hr.

One patient required a repeat of thebolus doses of ketamine anddexmedetomidine and an increase ofthe infusion to 2 �g/kg/hr. Briefepisode of upper airway obstruction inone patient, which responded torepositioning of the airway. Themaximum end-tidal CO2 values were49, 53, and 52 mm Hg in the threepatients.



However, dexmedetomidine has failedas the sole agent for sedation in otherscenarios in the adult population.Jalowiecki et al. (102) found dexmedeto-midine to be ineffective during colonos-copy, to be associated with a high inci-dence of adverse effects, and to delaydischarge in adults, and the authorstherefore abandoned the study beforecompletion. Similar issues were encoun-tered when dexmedetomidine was com-pared with midazolam for monitored an-esthesia care in adults during cataractsurgery (103).

Given its limited analgesic effects,dexmedetomidine may not be the idealagent for painful procedures. Anecdotalexperience suggests that a combinationof dexmedetomidine with ketamine maybe effective in such scenarios. Scher andGitlin (104) reported the successful use ofdexmedetomidine (bolus of 1 �g/kg fol-lowed by an infusion of 0.7 �g/kg/hr) andketamine (15 mg followed by an infusionof 20 mg/hr) for procedural sedation(awake fiberoptic intubation in an adult

patient). Tosun et al. (105) compared adexmedetomidine-ketamine combinationwith a propofol-ketamine combination in44 children (4 months to 16 yrs) withacyanotic congenital heart disease under-going cardiac catheterization. Ketamine(1 mg/kg) and dexmedetomidine (1 �g/kg) were administered over 10 mins fol-lowed by an infusion at 0.7 �g/kg/hr ofdexmedetomidine and 1 mg/kg/hr of ket-amine. In the other arm of the study,propofol (1 mg/kg) and ketamine (1 mg/kg) were administered as the loading dosefollowed by an infusion of propofol (100�g/kg/hr) and ketamine (1 mg/kg/hr).Supplemental ketamine (1 mg/kg) wasgiven as needed. Although sedation wasmanaged effectively with both regimens,patients sedated with ketamine-dexme-detomidine required more ketamine(2.03 � 1.33 vs. 1.25 � 0.67 mg/kg/hr, p� .01) and more supplemental doses ofketamine (10/22 vs. four of 22) and hadlonger recovery times (median time of 45vs. 20 mins, p � .01) than patients se-dated with a propofol-ketamine combina-

tion. No clinically significant differenceswere noted in hemodynamic and respira-tory variables. During the maintenancesedation phase, two patients receiving thedexmedetomidine-ketamine combinationhad convulsions. Neither had a history ofprevious neurologic problems, and theauthors could not determine the cause ofthe seizure activity.

Despite the limited data, the combina-tion of dexmedetomidine with ketaminemakes pharmacologic sense as the twomedications have the potential to balancethe hemodynamic and adverse effects ofthe other. Dexmedetomidine may preventthe tachycardia, hypertension, salivation,and emergence phenomena from ket-amine, whereas ketamine may preventthe bradycardia and hypotension thathave been reported with dexmedetomi-dine (106). Additionally, ketamine as partof the sedation induction may speed theonset of sedation and eliminate the slowonset time when dexmedetomidine isused as the sole agent and the loadingdose is administered over 10 mins.

Table 4. Dexmedetomidine for invasive procedural sedation in children



Tobias andBerkenbosch (76)

Case report, n � 1 Dexmedetomidine 0.6 �g/kg 30.5 �g/kg/hr. BIS numberdecreased to 89. Bolusrepeated. BIS numberdecreased to 42.

With the introduction of the endoscope into the patient’smouth, the BIS number increased to 98 and thepatient became distressed. Procedure completed withmidazolam/ketamine sedation.

Jooste et al. (98) Case report, n � 2 Incremental doses of midazolamto 0.1 mg/kg followed bydexmedetomidine (1 �g/kg 30.7 �g/kg/hr). The sedationregimen was supplementedwith topical anesthesia of theairway using 1% lidocaine.

Adequate sedation to allow for fiberoptic intubation ofthe trachea without patient movement or coughing intwo 10-year-old pediatric patients with cervical spineabnormalities and cervical spinal cord compromise.

Munro et al. (101) Prospective, open-label trial, n � 20

Dexmedetomidine (1 �g/kg over10 mins followed by aninfusion of 1 �g/kg/hr andtitrated up to 2 �g/kg/hr asneeded).

Average dexmedetomidine infusion rate of 1.15 � 0.29�g/kg/hr (range, 0.6–2.0 �g/kg/hr). Five patients(25%) moved during local infiltration of the groin.Twelve (60%) received a propofol bolus during theprocedure for movement, an increasing BIS number,or anticipation of a stimulus. No adverse hemodynamicor respiratory effects noted.

Tosun et al. (105) Prospective,randomized trial,n � 44

Ketamine (1 mg/kg) dexmedetomidine (1 �g/kg)administered over 10 minsfollowed by dexmedetomidine(0.7 �g/kg/hr) and ketamine(1 mg/kg/hr) or propofol (1mg/kg) and ketamine (1 mg/kg) followed by propofol (100�g/kg/hr) and ketamine (1mg/kg/hr). Supplementalketamine (1 mg/kg) asneeded.

Patients sedated with ketamine and dexmedetomidinerequired more ketamine and had longer recoverytimes (median time of 45 vs. 20 mins) than patientssedated with propofol and ketamine. No clinicallysignificant difference was noted in hemodynamic andrespiratory variables. Convulsions occurred during themaintenance sedation phase in two patients receivingthe dexmedetomidine-ketamine combination; however,the exact etiology could not be determined.

BIS, Bispectral Index.


Petition for Inter Partes Review of US 8,455,527 Amneal Pharmaceuticals LLC – Exhibit 1061 – 6

Intraoperative Applications

In addition to the report of Tobias andBerkenbosch (76), which reported theuse of dexmedetomidine combined withremifentanil to provide controlled hypo-tension during posterior spinal fusion,two other reports have described the in-traoperative use of dexmedetomidine,both of which entail its use for awakeneurosurgical procedures in pediatric pa-tients (107, 108). Ard et al. (107) useddexmedetomidine to provide sedationduring awake craniotomy in two patients,both of whom were 12 yrs old. Anesthesiafor skin incision, craniotomy, and duralopening were provided by sevoflurane,fentanyl, and nitrous oxide via a laryngealmask airway. Dexmedetomidine (0.1–0.3�g/kg/hr) provided sedation during thetumor resection and provided an awakeand cooperative patient to allow identifi-cation of critical language areas. For thispart of the procedure, the other anes-thetic agents were discontinued and thelaryngeal mask airway was removed. Sim-ilar success was reported by Everett et al.(108) in two additional pediatric patientsundergoing awake craniotomy, both ofwhom were 16 yrs of age.

Treatment of Withdrawal

Regardless of the agent responsible forwithdrawal, the potential role of dexme-detomidine in treating such problems issupported by animal studies (109–112),case reports in adults and children (113–

117), and one retrospective case series ininfants (Table 5) (118). The largest seriesreported in either the adult or pediatricpopulation regarding the use of dexme-detomidine to control withdrawal is a ret-rospective review of seven infants rangingin age from 3 to 24 months (118). Thepatients had received a continuous fent-anyl infusion supplemented with inter-mittent doses of midazolam for duringmechanical ventilation. Withdrawal wasdocumented by a Finnegan score �12.Dexmedetomidine was administered as aloading dose of 0.5 �g/kg/hr followed byan infusion of 0.5 �g/kg/hr. The loadingdose was repeated and the infusion in-creased to 0.7 �g/kg/hr in the two pa-tients who had received the highest dosesof fentanyl (8.5 � 0.7 vs. 4.6 � 0.5 �g/kg/hr, p � .0005). Withdrawal was con-trolled, and subsequent Finnegan scoreswere �7.

Miscellaneous Applications

Four additional reports have appearedin the literature describing the use ofdexmedetomidine in the pediatric popu-lation (119–122). Khasawinah et al. (119)reported the successful use of dexmedeto-midine in three patients to control thesigns and symptoms of cyclic vomitingsyndrome, a disorder thought to be re-lated to alterations in the central controlof the sympathetic nervous system,which manifests as recurrent bouts ofvomiting. Zub et al. (120) evaluated thepotential efficacy of oral dexmedetomi-

dine in 13 patients ranging in age from 4to 14 yrs. Oral dexmedetomidine in dosesranging from 1.0 to 4.2 �g/kg was used aspremedication before inhalational anes-thetic induction or to facilitate intrave-nous cannula placement before proce-dural sedation in nine patients withneurobehavioral disorders. Effective se-dation was achieved in 11 of the 13 pa-tients. An anecdotal report in a 14-yr-oldsuggested the potential efficacy of dexme-detomidine in the treatment of chronicregional pain syndrome type I (121). Thefinal report in the pediatric populationdescribes the postoperative administra-tion of dexmedetomidine to control shiv-ering following general anesthesia (122).Dexmedetomidine (0.5 �g/kg over 3–5mins) was administered in a prospective,open-label fashion to 24 children rangingin age from 7 to 16 yrs of age. Shiveringbehavior ceased within 5 mins with amean onset time of 3.5 � 0.9 mins.

SUMMARY

Dexmedetomidine (Precedex) is an �2-adrenergic agonist that shares physio-logic similarities with clonidine. It is cur-rently approved by the FDA forcontinuous infusions for up to 24 hrs inadult ICU patients who are initially intu-bated and receiving mechanical ventila-tion. To date, there are no FDA-approvedindications for its use in children, butwith ongoing encouragement from themedical community, it is hoped that themanufacturers will seek FDA approval for

Table 5. Anecdotal reports of dexmedetomidine to control withdrawal in infants and children

Authors and Reference Patient Demographics Dexmedetomidine Dosing Regimen

Finkel and Elrefai(115)

8-month-old infant with Hurler syndrome who requiredprolonged sedation during mechanical ventilation.Using a Bispectral Index monitor, the authorstitrated the dexmedetomidine infusion afterdiscontinuation of midazolam and fentanyl infusions.

Dexmedetomidine (0.2–0.7 �g/kg/hr) was continued for 7days and then tapered over a 24-hr period. Thisallowed for withdrawal of benzodiazepines and opioids.

Baddigam et al. (116) 17-year-old with infected aortic valve. History ofcannabinoid, tobacco, ethanol, and other substanceabuse. Manifested withdrawal symptoms duringpostoperative period.

Dexmedetomidine, loading dose of 0.5 �g/kg 3 infusionof 0.25 �g/kg/hr, controlled the withdrawal behavior(diaphoresis, agitation, tachycardia, and hypertension).

4-month-old infant, status post repair of congenitalheart disease. Withdrawal behavior after fentanylsedation during mechanical ventilation.

Dexmedetomidine, loading dose of 0.5 �g/kg 3 infusionof 0.25 �g/kg/hr, controlled withdrawal behavior.Dexmedetomidine weaned over 48–72 hrs.

55-day-old infant, status post palliation of congenitalheart disease. Withdrawal behavior after fentanyl forsedation during mechanical ventilation.

Dexmedetomidine, loading dose of 0.5 �g/kg 3 infusionof 0.25 �g/kg/hr, controlled withdrawal behavior.

Finkel et al. (117) Two pediatric patients (6-month-old and 7-year-old)who were status post cardiac transplantation.Withdrawal behavior following the prolongedadministration of opioids and benzodiazepines.

Dexmedetomidine, loading dose of 1 �g/kg 3 infusion of0.8–1.0 �g/kg/hr, controlled the withdrawal behavior.Dexmedetomidine infusions administered and thenweaned for a total duration of use of 8 and 16 days inthe two patients.



various clinical scenarios within the pe-diatric population (123).

As with any sedative agent, the poten-tial exists for adverse end-organ effectswith dexmedetomidine. Although thecurrent literature suggests that theseevents are relatively uncommon withdexmedetomidine, the hemodynamic orrespiratory effects should they occur havethe potential for significant morbidity oreven mortality in critically ill infants andchildren (Table 6). Potential cardiovascu-lar effects include bradycardia with rarereports of sinus pause or cardiac arrest.Hypotension has also been reported aswell as hypertension, the latter thoughtto be due to peripheral �2B agonist withperipheral vasoconstriction. Hypotensionand bradycardia occur more commonlywith the initial loading dose, with comor-bid cardiovascular disease, and when co-administered with other medications thathave negative chronotropic effects. A sin-gle animal study (n � 6) suggested thatMPAP and PVR may be transiently ele-vated following dexmedetomidine. Thereare conflicting reports in the literatureregarding effects on ventilatory function,with some studies (both human and ani-mal) demonstrating respiratory depres-sion with mild increases of PaCO2 (4–5mmHg), decreased minute ventilation,decreased response to CO2 challenge us-ing CO2 response curves, or upper airwayobstruction following bolus doses of 1 or2 �g/kg. Despite these reports, other an-

imal and human studies have suggestedno effect on respiratory function. Al-though dexmedetomidine has no directeffect on ICP, its hemodynamic effectsmay decrease CPP. Both animal and hu-man studies have demonstrated cerebralvasoconstriction with a decrease of CBF.Mixed results have been noted in animalstudies regarding the anticonvulsant orproconvulsant effects of dexmedetomi-dine. As with any agent used for sedationand/or analgesia, failures will occur, andat times it may be necessary to switch toalternative agents. Despite these con-cerns, anecdotal evidence demonstratesthe potential safety of this drug evenwhen drug errors occur such as infusingthe medication in �g/kg/min instead of�g/kg/hr (124). If there is a concern re-garding the potential adverse effect pro-file of dexmedetomidine in critically illinfants and children, various precautionsshould be considered including omittingthe loading dose, using a lower loadingdose, administering the loading dose overa longer period of time, and using a con-tinuous infusion starting at the lower endof the recommended dosing range.

Dexmedetomidine is available as a2-mL, 100-�g/mL solution that can be

diluted in 50 mL of saline to provide a4-�g/mL solution that can be adminis-tered via a peripheral or central vein.Acquisition costs vary from $50 to $80per vial. To date, the literature containsreports of its use in approximately 800pediatric patients. Given is favorable sed-ative and anxiolytic properties combinedwith its limited effects on hemodynamicand respiratory function, there is grow-ing interest in the use of dexmedetomi-dine in the pediatric population in vari-ous clinical scenarios, including sedationduring mechanical ventilation, proce-dural sedation, the treatment of with-drawal, and prevention of emergence ag-itation (Table 7). It may also be aneffective agent for the provision of seda-tion and anxiolysis in situations wherethe maintenance of spontaneous ventila-tion is required, and therefore it may playa role in combination with regional an-esthetic techniques or patient-controlledanalgesia following major surgical proce-dures. Although dexmedetomidine maynot be effective as the sole agent, theremay be a role for the combination ofdexmedetomidine with analgesic agentssuch as ketamine for painful invasive pro-cedures.

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Table 7. Reported applications of dexmedetomi-dine in pediatric patients

Sedation during mechanical ventilationAdjunct for controlled hypotension during

orthopedic surgeryProcedural sedation

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Table 6. Potential adverse effect profile of dexme-detomidine

CardiovascularBradycardia or sinus pause/arrestHypotensionDecreased cardiac outputHypertensionSinus arrhythmiaDecreased central sympathetic nervous

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RespiratoryIncreased resting PaCO2

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Irregular breathing patternApnea (obstructive)

Central nervous systemIneffective sedation and/or analgesiaParadoxical agitationPotentiation of neuromuscular blockade

(clinically insignificant)Proconvulsant effect (animal study)Decreased cerebral perfusion due to effect on

mean arterial pressure



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