APPLICATIONS%20OF%20DEXMEDETOMIDINE%20IN%20PEDIATRIC%20PROCEDURAL%20SEDATION

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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

Midazolam (0.22 mg/kg/?) Dexmedetomidine (0.25 µg/kg/?) Dexmedetomidine (0.5 µg/kg/?)
Morphine (mg/kg/24?) 0.74 0.5 0.55 0.38 0.28 0.12
RSS 1 (points, pts) 14 6/10 11 4/10 5 2/10
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

Group Induction (ug/kg) Ind Time (min) Maintenance (ug/kg/hr) Recovery (min)
Overall (48) 0.920.36 10.34.7 0.690.32 8442
Primary (33) 0.950.35 10.85.0 0.670.30 6934
Rescue (15) 0.830.33 9.33.8 0.730.38 11741
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PROCEDURAL SEDATION Berkenbosch JW, Pediatr
Crit Care Med 20056435
Group ? BP (mmHg) ? HR (BPM) ? RR (Br/min) ? SaO2 ()
Overall (n48) 19.018.4 (16.614.0) 12.912.3 (12.412.6) 3.03.5 (13.416.1) 2.62.0 (2.62.1)
Primary (n33) 15.514.6 (13.812.9) 12.212.0 (12.014.0) 3.33.7 (14.817.3) 2.12.0 (2.12.0)
Rescue (n15) 31.129.4 (26.721.4) 14.513.0 (13.09.4) 2.32.9 (10.412.8) 3.21.6 (3.31.6)

• 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)

Complication
Inad/agitation 48 2.1
gt30 ? VS 44 1.9
Respiratory desat obstruction 7 3 4 0.3
Resp Assist 3 0.1
Nausea/vomit 5 0.5
Seizure 1 0.1
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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