APPLICATIONS OF DEXMEDETOMIDINE IN PEDIATRIC PROCEDURAL SEDATION

John Berkenbosch, MD Director, University Children’s Sedation Service Associate Professor Pediatrics/Pediatric Critical Care University of Louisville [email protected]

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



2

BACKGROUND RECPTOR AGONISTS

• Prototype agent is clonidine • More recent applications in clinical practice • Sedation • Behavior disorders (ADHD) • Drug withdrawal • Hypertension • Problem – hypotension, oral = slow • Solution – 2 nd generation   2 specificity

DEXMEDETOMIDINE

• Precedex ® , Hospira • Pharmacologically active D- isomer of medetomidine • 1 st 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 t 1/2 • Elimination t 1/2 = 6 minutes = 2 hrs • V DSS – 118 liters – 94% protein bound • Intramuscular (2 u g/kg): • Peak plasma conc 13±18 min (variable) •  70% bioavailability • Enteral: • Buccal • Gastric   80% bioavailability 16-20% bioavailability

PHARMACOKINETICS PEDIATRIC

• Healthy children: • Bolus (0.33, 0.6, 1.0 u g/kg) • No different than adult – t 1/2 1.8 hr, V d 1.0 L/kg • General post-op population (3 mo-8 yr): • 8-24 hr infusions – 0.2-0.7 u g/kg/hr • Similar to adults – t 1/2 2.6 hr, V d 1.5 L/kg • Infants/toddlers post CV Sx (1-24 mo): • T 1/2 83 min • more rapid clearance than adults

METABOLISM

• Almost 100% biotransformation • Glucuronidation • Cytochrome P450 mediated • Metabolites all inactive – urinary elimination • Significant  t 1/2 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 substance P receptors  analgesia via  release of

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 G o - and G i - type G-proteins •  adenylate cyclase and cAMP formation • Hyperpolarization (K + -channels) •  Ca ++ conductance  NE release

CELLULAR MECHANISM

Ca ++ Ca ++ Ca ++

–

Decrease in action potential due to hyperpolarization



2 A Decrease in influx of Ca ++

–

G o



2 AR G k + 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 SaO 2 unaffected and PaCO 2 • Numerous reports during spontaneous ventilation

RESPIRATORY EFFECTS

Belleville JP et al, Anesthesiology 1992;77:1125 • 37 healthy, male volunteers - 0.25-1 u g/kg over 2 min • SaO 2 , PaCO 2 , ET CO2 , CO 2 response

Results:

• Irregular breathing/obstruction in 1.0, 2.0 u g/kg groups • Mild  SaO 2 , and V E ; mild  PaCO 2 ; blunted CO 2 response

PARAMETER

SpO2 (% saturation)

BASELINE

98.3 + 0.8

PaCO 2 (mmHg) Ventilation (l/min) 41.9 + 2.3

8.73 + 0.71

V E @ P ETCO2 55 mmHg 22.50 + 7.32

10 MIN

96.2 + 1.5

* 46.1 + 5.0

* 7.14 + 3.04

* 13.82 + 8.01

*

60 MIN

95.4 + 1.2

* 45.3 + 3.5

* 6.28 + 1.53

* 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 –

Tobias JD, Berkenbosch JW, South Med J

PICU

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

Morphine (mg/kg/24



) Midazolam (0.22 mg/kg/



)

0.74 + 0.5

Dexmedetomidine (0.25 µg/kg/



)

0.55 + 0.38

Dexmedetomidine (0.5 µg/kg/



)

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 –

Chrysostomou et al, Ped Crit Care Med

PICU

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 u g/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 –

Buck et al, Pharmacotherapy

PICU

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 u g/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 1 st 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 u g/kg) over 10 min, gtt 0.6

u g/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 u g/kg over 5 min • Maintenance: started at 0.5 u g/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) Overall (48) Primary (33) Rescue (15)

0.92

± 0.36

0.95

± 0.35

0.83

± 0.33

Ind Time (min) Maintenance (ug/kg/hr) Recovery (min)

10.3

± 4.7

0.69

± 0.32

84 ± 42 10.8

9.3

± ± 5.0

3.8

0.67

0.73

± ± 0.30

0.38

69 117 ± ± 34 41*

PROCEDURAL SEDATION

Berkenbosch JW, Pediatr Crit Care Med 2005;6:435

Group Overall (n=48) Primary (n=33) Rescue (n=15)



BP (mmHg)

19.0

± 18.4

(16.6

± 14.0) 15.5

± 14.6

(13.8

± 12.9) 31.1

± 29.4

(26.7

± 21.4) 

HR (BPM)

12.9

± 12.3

(12.4

± 12.6) 12.2

± 12.0

(12.0

± 14.0) 14.5

± 13.0

(13.0

± 9.4) 

RR (Br/min)

3.0

± 3.5

(13.4

± 16.1) 3.3

± 3.7

(14.8

± 17.3) 2.3

± 2.9

(10.4

± 12.8) • Modest  in HR, BP, RR - always normal for age • ET-CO 2 >50 in 1.7% (max 52 mmHg) • No recovery-related agitation 

SaO 2 (%)

2.6

± 2.0

(2.6

± 2.1) 2.1

± 2.0

(2.1

± 2.0) 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: 1 u g/kg bolus, then 0.5 u g/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: 1 u g/kg bolus, then 0.5 u g/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 u g/kg over 10 min or until RSS 4-5 • ± maintenance dose 1 u g/kg/hr as needed • N=250 pts, 2.9±1.9 yrs • Induction – 2.2 ±0.6 u g/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 u g/kg over 10 min • Maintenance: 1  2 u g/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

u g/kg, • Total - 2.7

 1.7

u g/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 u g/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 >30%  VS Respiratory desat obstruction Resp Assist Nausea/vomit Seizure

#

48 44 7 3 4 3 5 1

%

2.1

1.9

0.3

0.1

0.5

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±0.8

u g/kg (1-4.2 u g/kg) • Undiluted (100 u g/ml), slowly (buccal >> gastric) • Time to IV placement – 30-50 min • Success in all, minimal distress •  efficacy, efficiency with 3-4 u g/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 u g/kg 90 min preop (n=18) • Dex – 1 u g/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 u g/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 u g/kg dex, 1 mg/kg ketamine – 10 min • Maint – 0.7 u g/kg/hr dex/1 mg/kg/hr ketamine • Propofol/ketamine (n=22) • Induction - 1 mg/kg prop, 1 mg/kg ketamine (? time) • Maint – 100 u g/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 u g/kg dex, 2 mg/kg ketamine – 3 min • Maint: 2  1 u g/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 u g/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 u g/ml in 0.9% saline • Infusion usually req for lengthy procedures • Use pump for induction bolus – 12 u g/kg/hr = 1 u g/kg over 5 min • Coadmin with midazolam • Appears to  induction time, ?  rec time • Buccal/transmucosal • Use undiluted (100 u g/ml) drug • Slow drip into oral cavity   efficacy, efficiency by swallowing and, therefore, gastric absorption