APPLICATIONS OF DEXMEDETOMIDINE IN PEDIATRIC PROCEDURAL SEDATION

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APPLICATIONS OF DEXMEDETOMIDINE IN PEDIATRIC
PROCEDURAL SEDATION

• John Berkenbosch, MD
• Director, University Childrens Sedation Service
  Associate Professor
• Pediatrics/Pediatric Critical Care
• University of Louisville
• john.berkenbosch_at_louisville.edu

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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

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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

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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

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DEXMEDETOMIDINE

• Precedex, Hospira
• Pharmacologically active D- isomer of
  medetomidine
• 1st synthesized in late 1980s, Phase 1 studies
  in early 1990s, clinical trials late 1990s
• 8-fold greater ?2?1 selectivity than clonidine
• 16201 vs 2001
• Shorter elimination half-life than clonidine
• 2-3 vs 8-12 hr
• FDA approved for ICU sedation in adults
• Hopefully pediatric clinical trials soon

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PHARMACOKINETICS

• Intravenous
• Distribution t1/2 6 minutes
• Elimination t1/2 2 hrs
• VDSS 118 liters 94 protein bound
• Intramuscular (2ug/kg)
• Peak plasma conc 1318 min (variable)
• ? 70 bioavailability
• Enteral
• Buccal - ? 80 bioavailability
• Gastric - ? 16-20 bioavailability

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PHARMACOKINETICSPEDIATRIC

• 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

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METABOLISM

• Almost 100 biotransformation
• Glucuronidation
• Cytochrome P450 mediated
• Metabolites all inactive urinary elimination
• Significant ? t1/2 in hepatic failure (7.5 hr)
• lt1 excreted as unchanged
• No significant effect of renal impairment

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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

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CNS ACTIONS

• Sedation central, G-proteins (inhibition)
• Analgesia spinal cord, Substance P

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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

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CELLULAR MECHANISM
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NON-CNS EFFECTS

• Hypertension
• peripheral ?1-agonism
• Bradycardia/hypotension
• Sympathetic inhibition - medullary VMC
• ? shivering
• Diuresis
• ? renin, vasopressin ? ANP

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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

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RESPIRATORY EFFECTSBelleville JP et al,
Anesthesiology 1992771125

• 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 _at_ PETCO2 55 mmHg 22.50 7.32 13.82 8.01
  12.89 3.22

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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

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CLINICAL USE PICU Tobias JD, Berkenbosch JW,
South Med J 200497451

• 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

plt0.05 vs. midazolam group p0.08 vs.
midazolam group
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CLINICAL USE PICU Chrysostomou et al, Ped Crit
Care Med 20067126

• 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 lt1 yr (3.2
  boluses/pt)
• Hypotension in 6 pts (16), easily managed
• No respiratory events

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CLINICAL USE PICU Buck et al, Pharmacotherapy
2008751

• 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

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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

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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 200515199
• 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

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PROCEDURAL SEDATION Berkenbosch JW, Pediatr
Crit Care Med 20056435

• First reported prospective series
• non-invasive procedures
• Candidates
• gt4 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

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PROCEDURAL SEDATION Berkenbosch JW, Pediatr
Crit Care Med 20056435

• 48 patients, 6.93.7 yrs - 15 rescues

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PROCEDURAL SEDATION Berkenbosch JW, Pediatr
Crit Care Med 20056435

• Modest ? in HR, BP, RR - always normal for age
• ET-CO2 gt50 in 1.7 (max 52 mmHg)
• No recovery-related agitation

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PROCEDURAL SEDATION

• Only 2 comparative trials to date
• Koroglu A, Br J Anaesth 200594821
• 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 gt efficacy vs midazolam
• Problem midaz rarely sole agent for MRI

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PROCEDURAL SEDATION

• Koroglu A, Anesth Analg 200610363
• 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

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PROCEDURAL SEDATION

• Preceding series with limited power small n
• Mason K, Pediatr Anaesth 200818393
• 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
• N250 pts, 2.91.9 yrs
• Induction 2.2 0.6 ug/kg over 10.54.2 min
• Recovery - 2716 min
• Modest dec HR (15-30 in 54, gt30 in 20) and BP
  (15-30 in 24, gt30 in 7)
• No information on interventions
• Most pronounced toward procedure conclusion

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PROCEDURAL SEDATION Mason K et al, Pediatr
Anaesth 200818403

• 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 (n3)
• 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 (n120)
• gt20 below NL in 28 (3.7) no intervention
• Mean rec time 34 min vs 72 min with pentobarb

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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 (n74), CECH (n241)
• Age 6.8 3.9 yrs (8 mo-24 yr)
• 1 Dx autism (83.1)
• 1 procedure MRI (78)

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CLINICAL EXPERIENCE Lubisch N, Berkenbosch JW,
(submitted, 2008)

• Sedation
• Dex alone (n 32), dex midaz (n283)
• 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
• gt30 ? SBP (n30, 9.6), HR (n64, 20.3)
• Glycopyrollate x4, NS bolus x1
• UAObstr in 1 - nasal trumpet
• Sedation failures (n4, 1.3)
• Recovery-related agitation severe n2 (0.6)

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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

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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 I618, ASA II738, ASA III431 (n1803)
• Co-morbidities in 1038 (47)
• 1? diagnoses
• Neurologic (n1389, 60), Hem-Onc (n328, 14)
• 1? procedures radiology (n2026, 88)
• MRI (1469, 64), CT (460, 20), NM (133, 6)

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PSRC EXPERIENCE Berkenbosch JW, Lubisch N, PSRC
(in preparation)

• Administration Bolus alone n164 (7.1)
• Infusion alone n360 (15.6)
• PO alone n215 (9.3)
• Bolusinfusion n1566 (68)
• Total dose 3.1?2.1 ug/kg
• Adjunct midazolam in 1535 (66.4)
• Analgesic (n42), Sedatives (n107)
• Administration Physician n112 (4.8)
• APRN n1485 (64.3)
• RN n1347 (58.3)

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PSRC EXPERIENCE Berkenbosch JW, Lubisch N, PSRC
(in preparation)

• Conditions produced
• Ideal (2212, 95.7)
• Suboptimal (80, 3.4)
• Failures (n17, 0.7)
• Inadequate (n8)
• Complications (n3)
• Unrelated (n6)
• ? Level of Care (n2, 0.1)
• PICU (n2)
• Underlying Dx (n2)

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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 1329 vs 149
• Airway Intervention 1770 vs 189
• Failed sedation 1210 vs 1338
• Availability to/administration by non-physicians

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NON-IV USE ORALZub et al, Pediatr Anesth
2005932

• 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, 8.33 yrs (4-14)
• po dose - 2.60.8ug/kg (1-4.2 ug/kg)
• Undiluted (100 ug/ml), slowly (buccal gtgt gastric)
• Time to IV placement 30-50 min
• Success in all, minimal distress
• ? efficacy, efficiency with 3-4 ug/kg

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NON-IV USE ORALSchmidt et al, Pediatr Anesth
2007667

• Pre-op po midaz vs po clonidine vs TM dex on
  post-op pain/anxiety
• Midaz 0.5 mg/kg 30 min preop (n22)
• Clonidine 4 ug/kg 90 min preop (n18)
• Dex 1 ug/kg 45 min preop (n20)
• 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

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NON-IV USE INTRANASALYuen et al, Anesth Analg
20081715

• 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 n9 with midaz, 0 with dex

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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 (n22)
• 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 (n22)
• 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

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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)

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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

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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