APPLICATIONS OF

DEXMEDETOMIDINE IN
 GOALS
• Understand the pharmacology, physiology,
and clinical properties of dexmedetomidine

• Review clinical experience with

dexmedetomidine for pediatric procedural
sedation
• Adverse Events/Safety Profile
• Coadministrations
• Alternative administration methods

• Discuss practical issues related to use

 BACKGROUND
• Despite recognition of sedation importance,
few agent developments in recent past
• Significant issues with some current agents
• Opiate/benzodiazepine – tolerance, efficacy
• Chloral hydrate - predictability
• Pentobarbital – agitation, duration
• Propofol – limited access in some jurisdictions
• Ketamine – emergence reactions, tolerance
• 2-adrenoreceptor agonism
 BACKGROUND
2 RECPTOR AGONISTS
• Prototype agent is clonidine
• More recent applications in clinical practice
• Sedation
• Behavior disorders (ADHD)
• Drug withdrawal
• Hypertension
• Problem – hypotension, oral = slow
• Solution – 2nd generation -  2 specificity
 DEXMEDETOMIDINE
• Precedex®, Hospira
• Pharmacologically active D- isomer of medetomidine
• 1st synthesized in late 1980’s, Phase 1 studies in
early 1990’s, clinical trials late 1990’s
• ~ 8-fold greater 2:1 selectivity than clonidine
• 1620:1 vs 200:1
• Shorter elimination half-life than clonidine
• 2-3 vs 8-12 hr
• FDA approved for ICU sedation in adults
• Hopefully pediatric clinical trials soon
 PHARMACOKINETICS
• Intravenous:
• Distribution t1/2 = 6 minutes
• Elimination t1/2 = 2 hrs
• VDSS – 118 liters – 94% protein bound
• Intramuscular (2ug/kg):
• Peak plasma conc 13±18 min (variable)
•  70% bioavailability
• Enteral:
• Buccal -  80% bioavailability
• Gastric -  16-20% bioavailability
 PHARMACOKINETICS
PEDIATRIC
• Healthy children:
• Bolus (0.33, 0.6, 1.0 ug/kg)
• No different than adult – t1/2 1.8 hr, Vd 1.0 L/kg

• General post-op population (3 mo-8 yr):

• 8-24 hr infusions – 0.2-0.7 ug/kg/hr
• Similar to adults – t1/2 2.6 hr, Vd 1.5 L/kg

• Infants/toddlers post CV Sx (1-24 mo):

• T1/2 83 min
• more rapid clearance than adults
 METABOLISM
• Almost 100% biotransformation
• Glucuronidation
• Cytochrome P450 mediated
• Metabolites all inactive – urinary elimination

• Significant  t1/2 in hepatic failure (7.5 hr)

• <1% excreted as unchanged
• No significant effect of renal impairment
 MECHANISM
CLINICAL CNS EFFECTS
• Locus ceruleus:
• Brainstem center - modulates wakefulness
• Major site for hypnotic actions (sedation, anxiolysis)
• Mediated via various efferent pathways:
• Thalamus and subthalamus  cortex
• Nociceptive transmission via descending spinal tracts
• Vasomotor center and reticular formation
• Spinal cord:
• Binding to 2 receptors  analgesia via  release of
substance P
 CNS ACTIONS
• Sedation – central, G-proteins (inhibition)
• Analgesia – spinal cord, Substance P

Dexmedetomidine
 MECHANISM – CENTRAL 2
• Presynaptic receptors:
• Location:
• Sympathetic nerve endings
• Noradrenergic CNS neurons
• Mechanism/action:
• Transmembrane receptors
• Coupled to Go- and Gi- type G-proteins
•  adenylate cyclase and cAMP formation
• Hyperpolarization (K+-channels)
•  Ca++ conductance  NE release
CELLULAR MECHANISM
Ca++
Ca++ – Decrease in action
potential due to
Ca++ hyperpolarization

a2A

a2AR

Go Gk K+
– + K+

K+
Decrease in
influx of Ca++
 NON-CNS EFFECTS
• Hypertension:
• peripheral 1-agonism
• Bradycardia/hypotension:
• Sympathetic inhibition - medullary VMC
•  shivering:
• Diuresis:
•  renin, vasopressin;  ANP
 RESPIRATORY EFFECTS
• Promoted as having minimal respiratory
depressing effects
• 0.17% incidence on monogram

• Most data suggests SaO2 and PaCO2

unaffected

• Numerous reports during spontaneous

ventilation
 RESPIRATORY EFFECTS
Belleville JP et al, Anesthesiology 1992;77:1125
• 37 healthy, male volunteers - 0.25-1 ug/kg over 2 min
• SaO2, PaCO2, ETCO2, CO2 response
Results:
• Irregular breathing/obstruction in 1.0, 2.0 ug/kg groups
• Mild  SaO2, and VE; mild  PaCO2; blunted CO2 response

PARAMETER BASELINE 10 MIN 60 MIN

SpO2 (% saturation) 98.3 + 0.8 96.2 + 1.5* 95.4 + 1.2*
PaCO2 (mmHg) 41.9 + 2.3 46.1 + 5.0* 45.3 + 3.5*
Ventilation (l/min) 8.73 + 0.71 7.14 + 3.04* 6.28 + 1.53*
VE @ PETCO2 55 mmHg 22.50 + 7.32 13.82 + 8.01* 12.89 + 3.22*
 OR/PERIOPERATIVE
OBSERVATIONS
•  hypotension vs propofol
• Blunted tachycardia during controlled
hypotension
•   PACU analgesia requirements
• Blunted catecholamine response
• Potential importance with vascular procedures
• Respiratory - non-intubated
 CLINICAL USE – PICU
Tobias JD, Berkenbosch JW, South Med J 2004;97:451
• PRT in 30 ventilated PICU patients
• Crossover (24 hr) comparison dex (0.25, 0.5 ug/kg/hr) vs
midazolam (0.1 mg/kg/hr)
• Morphine (0.1 mg/kg) prn agitation
• Outcomes: sedation quality, adjunct meds

Midazolam Dexmedetomidine Dexmedetomidine

(0.22 mg/kg/) (0.25 µg/kg/) (0.5 µg/kg/)

Morphine 0.74 + 0.5 0.55 + 0.38 0.28 + 0.12*

(mg/kg/24)

RSS = 1 14 & 6/10 11 & 4/10 5 & 2/10**

(points, pts)

*: p<0.05 vs. midazolam group

**: p=0.08 vs. midazolam group
 CLINICAL USE – PICU
Chrysostomou et al, Ped Crit Care Med 2006:7:126
• Retrospective description of dex use in 38 post-
cardiac surgical patients
• 5 intubated, 33 spontaneously ventilating
• Used as primary sedative/analgesic agent
• No defined rescue regimen
• Mean infusion rate 0.3 ug/kg/ (0.1-0.75) x 155 hrs
• No loading dose
• Sedation and analgesia adequate 93% and 83% of
the time
• 1.3 rescue boluses/pt, increased in <1 yr (3.2 boluses/pt)
• Hypotension in 6 pts (16%), easily managed
• No respiratory events
 CLINICAL USE – PICU
Buck et al, Pharmacotherapy 2008:7:51

• Prospective, observational series of dex in 17

PICU patients (20 courses)
• cardiac surgical (13), medical (3), other surg (1)
• Dose range 0.2-0.7 ug/kg/ x 3221 hr
• No loading dose
• Primary agent in 15, adjunct in 5 (failed conv)
• periextubation agent in 13 - all successful
• No reported significant cardiovascular events
 ICU OBSERVATIONS
• Limited available data
• Peds doses may be slightly higher, esp infants
• Parent satisfaction high
• Lighter but less agitated
•  sedation/recovery-related “wooziness”
• Appears useful in non-intubated pts
• Effective bridge through extubation
• Not necessarily 1st line
• reserve for difficult, long-term
• Analgesic effects probably not insignificant
 PROCEDURAL SEDATION
• Most recently reported application but more
published information compared with ICU
• Expansion developed based on confirmation of
limited resp depression
• Nichols DP, et al Pediatr Anaesth 2005;15:199
• Sedation of 5 children failing chloral hydrate/midazolam
• Dex bolus (0.80.4 ug/kg) over 10 min, gtt 0.6ug/kg/hr
• Procedures completed
• Modest  HR, BP; no significant respiratory effects
 PROCEDURAL SEDATION
Berkenbosch JW, Pediatr Crit Care Med 2005;6:435

• First reported prospective series

• non-invasive procedures
• Candidates:
• >4 y.o.
• Previous chloral hydrate failure/poor candidate
• Rescue from failed sedation
• Induction bolus: 0.5 ug/kg over 5 min
• Maintenance: started at 0.5 ug/kg/hr - titrate
• Monitor - Physiologic
- Effectiveness
- Recovery-related behavior
 PROCEDURAL SEDATION
Berkenbosch JW, Pediatr Crit Care Med 2005;6:435

• 48 patients, 6.9±3.7 yrs - 15 “rescues”

Group Induction Ind Time Maintenance Recovery

(ug/kg) (min) (ug/kg/hr) (min)

Overall 0.92±0.36 10.3±4.7 0.69±0.32 84±42

(48)
Primary 0.95±0.35 10.8±5.0 0.67±0.30 69±34
(33)
Rescue 0.83±0.33 9.3±3.8 0.73±0.38 117±41*
(15)
 PROCEDURAL SEDATION
Berkenbosch JW, Pediatr Crit Care Med 2005;6:435

Group  BP  HR  RR  SaO2
(mmHg) (BPM) (Br/min) (%)
Overall 19.0±18.4 12.9±12.3 3.0±3.5 2.6±2.0
(n=48) (16.6±14.0) (12.4±12.6) (13.4±16.1) (2.6±2.1)
Primary 15.5±14.6 12.2±12.0 3.3±3.7 2.1±2.0
(n=33) (13.8±12.9) (12.0±14.0) (14.8±17.3) (2.1±2.0)
Rescue 31.1±29.4 14.5±13.0 2.3±2.9 3.2±1.6
(n=15) (26.7±21.4) (13.0±9.4) (10.4±12.8) (3.3±1.6)

• Modest  in HR, BP, RR - always normal for age

• ET-CO2 >50 in 1.7% (max 52 mmHg)
• No recovery-related agitation
 PROCEDURAL SEDATION
• Only 2 comparative trials to date:
• Koroglu A, Br J Anaesth 2005;94:821
• Dex vs midazolam for MRI sedation
• 80 patients, 1-7 yrs
• Dex: 1ug/kg bolus, then 0.5 ug/kg/hr
• Midazolam: 0.2 mg/kg, then 0.36 mg/kg/hr
• Efficacy: 32/40 (dex) vs 8/40 (midazolam)
• Onset: 19 min (dex) vs 35 min (midazolam)
• Similar CV effects - nothing significant
• Concl: dex > efficacy vs midazolam
• Problem – midaz rarely sole agent for MRI
 PROCEDURAL SEDATION
• Koroglu A, Anesth Analg 2006;103:63
• Dex vs propofol for MRI sedation
• 60 patients aged 1-7 yrs
• Dex: 1ug/kg bolus, then 0.5 ug/kg/hr
• Propofol: 3 mg/kg bolus, then 6 mg/kg/min
• Efficacy similar: 83% (dex) vs 90% (propofol)
• Onset – 11 min (dex) vs 4 min (propofol)
•  rec time with dex (27 vs 18 min)
•  hypoxia with dex (0% vs 13%)
• Concl: Consider as alternative to propofol
 PROCEDURAL SEDATION
• Preceding series with limited power – small n
• Mason K, Pediatr Anaesth 2008;18;393
• Dex for CT scan sedation – protocolized
• Bolus 2 ug/kg over 10 min or until RSS 4-5
• ± maintenance dose 1 ug/kg/hr as needed
• N=250 pts, 2.9±1.9 yrs
• Induction – 2.2 ±0.6 ug/kg over 10.5±4.2 min
• Recovery - 27±16 min
• Modest dec HR (15-30% in 54%, >30% in 20%)
and BP (15-30% in 24%, >30% in 7%)
• No information on interventions
• Most pronounced toward procedure conclusion
 PROCEDURAL SEDATION
Mason K et al, Pediatr Anaesth 2008;18;403
• High dose dex as sole agent for MRI sedation
• Bolus + infusion, rescue with pentobarb
• 747 patients over 2 year period
• Progressive increase in doses over time (n=3)
• Induction: 23 ug/kg over 10 min
• Maintenance: 12 ug/kg/hr
• Success: 91.8% (dose 1) vs 97.6% (dose 3)
• Dec pentobarb use: 8.2 vs 10.4% vs 2.4%
• Modest bradycardia (n=120)
• >20 below NL in 28 (3.7%) – no intervention
• Mean rec time ~34 min vs 72 min with pentobarb
 CLINICAL EXPERIENCE
Lubisch N, Berkenbosch JW (submitted, 2008)

• Dex in patients with neurobehavioral disease

• Many need EEG, MRI but sedation options limited

• Combined databases from 2 Institutions

• Demographics, adjuncts, procedures, efficacy
• Limited by differences between databases

• 315 pts, KCH (n=74), CECH (n=241)

• Age: 6.8 ± 3.9 yrs (8 mo-24 yr)
• 1° Dx = autism (83.1%)
• 1° procedure = MRI (78%)
 CLINICAL EXPERIENCE
Lubisch N, Berkenbosch JW, (submitted, 2008)

• Sedation:
• Dex alone (n= 32), dex + midaz (n=283)
• Induction - 1.40.6 ug/kg,
• Total - 2.71.7 ug/kg
• Efficiency: Ind - 8.24.7 min, rec - 4727 min
• Adverse:
• >30%  SBP (n=30, 9.6%), HR (n=64, 20.3%)
• Glycopyrollate x4, NS bolus x1
• UAObstr in 1 - nasal trumpet
• Sedation failures (n=4, 1.3%)
• Recovery-related agitation – severe: n=2 (0.6%)
 PSRC EXPERIENCE
Berkenbosch JW, Lubisch N, PSRC (in preparation)

• Major limitation of single Institution studies is

sample size and power.
• Pediatric Sedation Research Consortium – 37
institution collaborative
• July 1, 2004 – Data collection begun
• Through 9/2007 – 90,000+ sedation entries
• Database queried from 7/1/2004 – 9/1/2007 for
all sedations using dexmedetomidine
 PSRC EXPERIENCE
Berkenbosch JW, Lubisch N, PSRC (in preparation)

• 2309 sedations, 7 Institutions

• Age: 5747 mos (median 36 mos)
• 221 (9.6%) 12 mos, 96 (4.2%) 6 mos
• ASA I=618, ASA II=738, ASA III=431 (n=1803)
• Co-morbidities in 1038 (47%)
• 1 diagnoses:
• Neurologic (n=1389, 60%), Hem-Onc (n=328, 14%)
• 1 procedures = radiology (n=2026, 88%)
• MRI (1469, 64%), CT (460, 20%), NM (133, 6%)
 PSRC EXPERIENCE
Berkenbosch JW, Lubisch N, PSRC (in preparation)
• Administration: Bolus alone: n=164 (7.1%)
Infusion alone: n=360 (15.6%)
PO alone: n=215 (9.3%)
Bolus+infusion: n=1566 (68%)
• Total dose – 3.12.1 ug/kg
• Adjunct midazolam in 1535 (66.4%)
• Analgesic (n=42), Sedatives (n=107)
• Administration: Physician: n=112 (4.8%)
APRN: n=1485 (64.3%)
RN: n=1347 (58.3%)
 PSRC EXPERIENCE
Berkenbosch JW, Lubisch N, PSRC (in preparation)

Conditions produced: Complication # %

• Ideal (2212, 95.7%)
• Suboptimal (80, 3.4%) Inad/agitation 48 2.1
>30%  VS 44 1.9
Failures (n=17, 0.7%)
• Inadequate (n=8) Respiratory 7 0.3
• Complications (n=3) desat 3
• Unrelated (n=6) obstruction 4
Resp Assist 3 0.1
 Level of Care (n=2, 0.1%)
• PICU (n=2) Nausea/vomit 5 0.5
• Underlying Dx (n=2)
Seizure 1 0.1
 PSRC EXPERIENCE
Berkenbosch JW, Lubisch N, PSRC (in preparation)

• Highly effective
• Dex alone – 724/729 (99.3%)
• Dex + Midazolam – 1334/1440 (99.6%)
• Dex + any adjunct – 2298/2309 (99.5%)
• Adverse events favorable compared to PSRC
• Respiratory – 1:329 vs 1:49
• Airway Intervention – 1:770 vs 1:89
• Failed sedation – 1:210 vs 1:338
• Availability to/administration by non-physicians
 NON-IV USE – ORAL
Zub et al, Pediatr Anesth 2005;932

• Dex (vs of midaz) as premed for OR/IV

• Planned IV dex d/t EEG in 9, OR premed in 4
• 7/9 - prior failed attempts with other po
• 13 pts, 8.3±3 yrs (4-14)
• po dose - 2.6±0.8ug/kg (1-4.2 ug/kg)
• Undiluted (100 ug/ml), slowly (buccal >> gastric)
• Time to IV placement – 30-50 min
• Success in all, minimal distress
•  efficacy, efficiency with 3-4 ug/kg
 NON-IV USE – ORAL
Schmidt et al, Pediatr Anesth 2007;667

• Pre-op po midaz vs po clonidine vs TM dex on

post-op pain/anxiety
• Midaz – 0.5 mg/kg 30 min preop (n=22)
• Clonidine – 4 ug/kg 90 min preop (n=18)
• Dex – 1 ug/kg 45 min preop (n=20)
• Various elective, ambulatory surgeries
• Anesthetic time – 116 min, surgical time 83 min
• Similar recovery/discharge times
• Similar anxiety but  pain, htn in 2 agonist grp
 NON-IV USE – INTRANASAL
Yuen et al, Anesth Analg 2008;1715
• DBRCT IN dex vs po midaz for OR premed
• 96 pts, 2-12 yrs old – elective minor surgery
• po midaz - 0.5 mg/kg
• IN dex - 0.5 or 1.0 ug/kg (diluted to 0.4 ml/pt)
• Modest resistance to IN admin (5.2%)
• No c/o pain/burning with IN
•  sedation in dex at separation (22/59/75%*)
• No diff in separation ease, induction behavior
• Trend to dec HR, BP with dex – sig in D1 grp
• Paradoxical rxn – n=9 with midaz, 0 with dex
 COADMINISTRATIONS
Tosun et al, J Cardiovasc Vasc Anesth, 2006
• Dex or propofol + ketamine in CHD cath lab
• 44 children with acyanotic CHD – 4 mo-16 yr
• Dex/ketamine (n=22)
• Induction - 1 ug/kg dex, 1 mg/kg ketamine – 10 min
• Maint – 0.7 ug/kg/hr dex/1 mg/kg/hr ketamine
• Propofol/ketamine (n=22)
• Induction - 1 mg/kg prop, 1 mg/kg ketamine (? time)
• Maint – 100 ug/kg/min prop/1 mg/kg/hr ketamine
•  ketamine (2.0 vs 1.3 mg/kg/hr) and rec time
(45 vs 20 min) in dex group
• Similar changes in HR/BP, minimal resp effects
 COADMINISTRATIONS
Mester et al, Am J Therap, 2008
• Dex/ketamine in cath lab – case series
• 16 pts with acyanotic CHD
• Ind: 1 ug/kg dex, 2 mg/kg ketamine – 3 min
• Maint: 21 ug/kg/hr dex, ketamine 1 mg/kg prn
• No response to cannulation
• Early  dex dose in 2 d/t HR
• No clinically sig HR/BP changes, no tachycardia
• Mild UAO in 2 – reposition; no hypercarbia
• Concl – good analgesia, minimal CV-resp
• Likely 2° inc dex dose vs prior study (Tosun)
 CONCLUSIONS
• Effective for non-invasive procedures
• Coadmin with analgesics for invasive??
• Dose moderately higher than for ICU sedation
• 2-3 ug/kg/hr well tolerated medium-term
• Lack of recovery-related agitation significant
• Minimal compared to chloral, barbiturates
• Role of adjunct benzodiazepines unclear
• Similar CV,  resp vs propofol
•  availability vs propofol in many venues
• Ongoing paucity of comparative reports/trials
 PRACTICAL POINTS
• IV use:
• Dilute to 4 ug/ml in 0.9% saline
• Infusion usually req for lengthy procedures
• Use pump for induction bolus – 12 ug/kg/hr = 1
ug/kg over 5 min
• Coadmin with midazolam
• Appears to  induction time, ?  rec time
• Buccal/transmucosal
• Use undiluted (100 ug/ml) drug
• Slow drip into oral cavity  efficacy, efficiency
by  swallowing and, therefore, gastric absorption