dexmedetomidine for pediatric procedural sedation

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


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*


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


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%)


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%)


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


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

dexmedetomidine for pediatric procedural sedation

Education