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APPLICATIONS OF DEXMEDETOMIDINE IN PEDIATRIC PROCEDURAL SEDATION John Berkenbosch, MD Director, University Children’s Sedation Service Associate Professor.

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Presentation on theme: "APPLICATIONS OF DEXMEDETOMIDINE IN PEDIATRIC PROCEDURAL SEDATION John Berkenbosch, MD Director, University Children’s Sedation Service Associate Professor."— Presentation transcript:

1 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 john.berkenbosch@louisville.edu

2 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

3 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

4 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 – 2 nd generation -   2 specificity

5 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

6 PHARMACOKINETICS Intravenous: Distribution t 1/2 = 6 minutes Elimination t 1/2 = 2 hrs V DSS – 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

7 PHARMACOKINETICS PEDIATRIC Healthy children: Bolus (0.33, 0.6, 1.0 ug/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 ug/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

8 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

9 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

10 CNS ACTIONS Dexmedetomidine Sedation – central, G-proteins (inhibition) Analgesia – spinal cord, Substance P

11 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

12 CELLULAR MECHANISM Ca ++ – – + Decrease in influx of Ca ++ Decrease in action potential due to hyperpolarization 2A2A  2 AR GoGo GkGk K+K+ K+K+ K+K+

13 NON-CNS EFFECTS Hypertension: peripheral  1 -agonism Bradycardia/hypotension: Sympathetic inhibition - medullary VMC  shivering: Diuresis:  renin, vasopressin;  ANP

14

15 RESPIRATORY EFFECTS Promoted as having minimal respiratory depressing effects 0.17% incidence on monogram Most data suggests SaO 2 and PaCO 2 unaffected Numerous reports during spontaneous ventilation

16 RESPIRATORY EFFECTS Belleville JP et al, Anesthesiology 1992;77:1125 37 healthy, male volunteers - 0.25-1 ug/kg over 2 min SaO 2, PaCO 2, ET CO2, CO 2 response Results: Irregular breathing/obstruction in 1.0, 2.0 ug/kg groups Mild  SaO 2, and V E ; mild  PaCO 2 ; blunted CO 2 response PARAMETER BASELINE 10 MIN 60 MIN SpO2 (% saturation)98.3 + 0.896.2 + 1.5 * 95.4 + 1.2 * PaCO 2 (mmHg)41.9 + 2.346.1 + 5.0 * 45.3 + 3.5 * Ventilation (l/min)8.73 + 0.717.14 + 3.04 * 6.28 + 1.53 * V E @ P ETCO2 55 mmHg22.50 + 7.3213.82 + 8.01 * 12.89 + 3.22 *

17 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

18 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 + 0.50.55 + 0.380.28 + 0.12* RSS = 1 (points, pts) 14 & 6/1011 & 4/105 & 2/10** *: p<0.05 vs. midazolam group **: p=0.08 vs. midazolam group

19 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 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

20 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 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

21 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

22 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 ug/kg) over 10 min, gtt 0.6ug/kg/hr Procedures completed Modest  HR, BP; no significant respiratory effects

23 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

24 PROCEDURAL SEDATION Berkenbosch JW, Pediatr Crit Care Med 2005;6:435 48 patients, 6.9±3.7 yrs - 15 “rescues” GroupInduction (ug/kg) Ind Time (min) Maintenance (ug/kg/hr) Recovery (min) Overall (48) 0.92±0.3610.3±4.70.69±0.3284±42 Primary (33) 0.95±0.3510.8±5.00.67±0.3069±34 Rescue (15) 0.83±0.339.3±3.80.73±0.38117±41*

25 PROCEDURAL SEDATION Berkenbosch JW, Pediatr Crit Care Med 2005;6:435 Modest  in HR, BP, RR - always normal for age ET-CO 2 >50 in 1.7% (max 52 mmHg) No recovery-related agitation Group  BP (mmHg)  HR (BPM)  RR (Br/min)  SaO 2 (%) 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)

26 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

27 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

28 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

29 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 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 (n=120) >20 below NL in 28 (3.7%) – no intervention Mean rec time ~34 min vs 72 min with pentobarb

30 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%)

31 CLINICAL EXPERIENCE Lubisch N, Berkenbosch JW, (submitted, 2008) Sedation: Dex alone (n= 32), dex + midaz (n=283) 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: >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%)

32 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

33 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%)

34 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 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%)

35 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/agitation482.1 >30%  VS441.9 Respiratory desat obstruction 734734 0.3 Resp Assist30.1 Nausea/vomit50.5 Seizure10.1

36 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

37 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±0.8ug/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

38 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 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

39 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

40 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

41 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)

42 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

43 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


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