APPLICATIONS OF DEXMEDETOMIDINE IN
PEDIATRIC PROCEDURAL SEDATION
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
BACKGROUND2 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
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
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
Dexmedetomidine
• Sedation – central, G-proteins (inhibition)• Analgesia – spinal cord, Substance P
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++
Ca++
–
– +
Decrease in influx of Ca++
Decrease in actionpotential due to
hyperpolarization
2A
2AR
Go Gk K+
K+
K+
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 EFFECTSBelleville 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(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**
*: 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 155 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 3221 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 (0.80.4 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(ug/kg)
Ind Time(min)
Maintenance(ug/kg/hr)
Recovery(min)
Overall (48)
0.92±0.36 10.3±4.7 0.69±0.32 84±42
Primary (33)
0.95±0.35 10.8±5.0 0.67±0.30 69±34
Rescue (15)
0.83±0.33 9.3±3.8 0.73±0.38 117±41*
PROCEDURAL SEDATION Berkenbosch JW, Pediatr Crit Care Med
2005;6:435
• Modest in HR, BP, RR - always normal for age• ET-CO2 >50 in 1.7% (max 52 mmHg)• No recovery-related agitation
Group BP(mmHg)
HR (BPM)
RR (Br/min)
SaO2
(%)
Overall(n=48)
19.0±18.4(16.6±14.0)
12.9±12.3(12.4±12.6)
3.0±3.5(13.4±16.1)
2.6±2.0(2.6±2.1)
Primary(n=33)
15.5±14.6(13.8±12.9)
12.2±12.0(12.0±14.0)
3.3±3.7(14.8±17.3)
2.1±2.0(2.1±2.0)
Rescue(n=15)
31.1±29.4(26.7±21.4)
14.5±13.0(13.0±9.4)
2.3±2.9(10.4±12.8)
3.2±1.6(3.3±1.6)
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: 23 ug/kg over 10 min• Maintenance: 12 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 - 1.40.6 ug/kg, • Total - 2.71.7 ug/kg
• Efficiency: Ind - 8.24.7 min, rec - 4727 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: 5747 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 – 3.12.1 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:• Ideal (2212, 95.7%)• Suboptimal (80,
3.4%)
Failures (n=17, 0.7%)• Inadequate (n=8)• Complications (n=3)• Unrelated (n=6)
Level of Care (n=2, 0.1%)• PICU (n=2)• Underlying Dx (n=2)
Complication
# %
Inad/agitation 48 2.1
>30% VS 44 1.9
Respiratory desat obstruction
734
0.3
Resp Assist 3 0.1
Nausea/vomit 5 0.5
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 – ORALZub 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 – ORALSchmidt 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: 21 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