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

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

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

5 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

6 PHARMACOKINETICS Intravenous: Intramuscular (2ug/kg): Enteral:
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

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 – 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

8 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

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 Sedation – central, G-proteins (inhibition)
Analgesia – spinal cord, Substance P Dexmedetomidine High concentrations of 2 adrenergic receptors in the brain (locus ceruleus), brain stem, and spinal cord. The locus ceruleus is primarily responsible for regulating stress/anxiety and consciousness. Therefore, activation of these receptors produces sedation and anxiolysis and general decrease in CNS sympathetic discharge. Activation in the spinal cord produces analgesic effect mediated by Substance P.

11 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

12 CELLULAR MECHANISM Ca++ – + a2A a2AR Go Gk K+
Decrease in influx of Ca++ Decrease in action potential due to hyperpolarization a2A a2AR Go Gk K+ Locus Ceruleus Activates transmembrane a2-adrenergic receptor of the noradrenergic neuron, dexmedetomidine. Via subsequent G-protein coupling, one of two effects observed – either inhibition of Ca++ influx (voltage-sensitive calcium channels) or promotion of K+ efflux (potassium channels). The net effect is cell membrane hyperpolarization, making it less likely to fire, thereby decreasing norepinephrine release. Result is an inhibition of histamine release and hypnotoc response in a pattern that resembles the natural sleep pathway.

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

14 Summary of actions: CNS – sedation/anxiolysis (locus ceruleus) CNS – analgesia (spinal, substance P) Cardiovascular – bradycardia (sympathetic inhibition) Cardiovascular – hypertension (early, peripheral 1 agonism) Cardiovascular – hypotension (later, sympathetic inhibition  vasodilation) Renal – diuresis (ANP/renin/vasopressin

15 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

16 RESPIRATORY EFFECTS Belleville JP et al, Anesthesiology 1992;77:1125
37 healthy, male volunteers 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) * * PaCO2 (mmHg) * * Ventilation (l/min) * * PETCO2 55 mmHg * * Adult study - cardiorespiratory response to multiple, escalating doses. In highest dose group (2 ug/kg), saw small but statistically significant decreases in SpO2, PaCO2, minute ventilation, and an altered ventilatory response to hypercarbia. While not likely of great clinical importance, and of smaller magnitude than with other commonly used sedatives (at equi-sedating doses), the data DO suggest some small respiratory depressing effects of dexmedetomidine

 hypotension vs propofol Blunted tachycardia during controlled hypotension   PACU analgesia requirements Blunted catecholamine response Potential importance with vascular procedures Respiratory - non-intubated Primary source of experience is adult literature Compared to propofol, dex use in the OR was associated with less significant hypotension though it persisted longer in the PACU, as well as an inconsistent decrease in immediate post-op analgesic (opioid) requirements. During procedures employing controlled hypotension, the degree of tachycardia response during hypotension is blunted Following vascular procedures, post-op dex use up to 48 hours was associated with less hypertension and decreased serum catecholamine levels, especially norepeniphrine Several operative studies now have described ongoing post-extubation sedation with dex with limited if any significant respiratory effects

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) * RSS = 1 (points, pts) 14 & 6/10 11 & 4/10 5 & 2/10** Crossover study of midazolam vs low-dose (0.25) or higher dose (0.5) dex in 30 ventilated PICU pts – n=10 per group Morphine 0.1 mg/kg prn for agitation/pain Pts crossed over dex to/from midazolam at 24 hrs if still ventilated (no crossover between dex groups) Evaluation of sedation quality (Ramsay Sedation Score) and amount of adjunct morphine use Less morphine use in both dex groups (significant in 0.5 ug group) and fewer patients in dex groups had RSS scores of 1 (inadequate sedation) vs midazolam) *: 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/ ( ) 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 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 1st line reserve for difficult, long-term Analgesic effects probably not insignificant Most of the experience with dex in the ICU is also adult Has been described for use in both surgical and medical populations

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” Group Induction (ug/kg) Ind Time (min) Maintenance (ug/kg/hr) Recovery 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*

25 PROCEDURAL SEDATION Berkenbosch JW, Pediatr Crit Care Med 2005;6:435
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) Modest  in HR, BP, RR - always normal for age ET-CO2 >50 in 1.7% (max 52 mmHg) No recovery-related agitation

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 2 notes about these trials: Few centers would use midazolam only for MRI - ? Clinical relevance

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 RSS = Ramsay Sedation Score

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 3 different protocolized dosing strategies (induction + maintenance infusion)

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%) Sedation options especially limited for EEG exams due to EEG/seizure altering effects of most sedatives KCH = Kosair Children’s Hospital; Louisville, KY CECH = Chris Evert Children’s Hospital; Ft. Lauderdale, FL

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%) Primary other sedatives inc chloral, ketamine, propofol, pentobarbital

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/agitation 48 2.1 >30%  VS 44 1.9 Respiratory desat obstruction 7 3 4 0.3 Resp Assist 0.1 Nausea/vomit 5 0.5 Seizure 1 Database does not enable us to differentiate inadequate sedation from agitation Failures uncommon, rarely related to complications Respiratory events extremely uncommon compared to being most common event with other sedatives Pts requiring increased level of care: Pt wheezed during nuc med study – sent to PICU – subsequently Dx aspiration pneumonia and UTI/sepsis Pt with 1st degree ht block on EKG – briefly in PICU (4 hr) – 48 hr later readmitted with +ve monospot and recurrence of 1st degree ht block

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 – 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 Dex administered transmucosally (slow drip into buccal cavity, not swallowed) Dose of dex relatively low Unclear what effects of altered timing schedule is on post-op effects While no difference in post-op anxiety, found decreased pain scores and signs of decreased sympathetic tone (dec HR, BP) on arrival to PACU in pts receiving either dex or clonidine

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 mg/kg IN dex 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 All premeds given with 20 mg/kg acetaminophen and given 60 min prior to anesthesia induction Rationale – circumvent taste, paradoxical agitation issues with po midaz Dex diluted in 0.9% saline to make final administered volume of 0.4 mL in all pts Benefits of dex in sedation, parental separation were also dose dependent * = sig diff comparing dex 1 ug/kg vs midaz groups

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 Increasing interest in co-administration with ketamine to blunt sympathetic effects of ketamine and still maintain respiratory benefits of both. Rescue anesthetic if needed with 1 mg/kg ketamine Due to increased ketamine boluses, authors concluded that dex/ketamine was feasible but not superior to propofol/ketamine

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) Initial maintenance dex at 2 ug/kg/hr, dec to 1 ug/kg/hr after 30 min

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: Buccal/transmucosal
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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