Dexmedetomidine For Pediatric Procedural Sedation

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  • 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.
  • Locus Ceruleus Activates transmembrane  2 -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.
  • VMC = vasomotor center
  • 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
  • Adult study - cardiorespiratory response to multiple, escalating doses. In highest dose group (2 u g/kg), saw small but statistically significant decreases in SpO 2 , PaCO 2 , 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
  • 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
  • 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 u g group) and fewer patients in dex groups had RSS scores of 1 (inadequate sedation) vs midazolam)
  • Most of the experience with dex in the ICU is also adult Has been described for use in both surgical and medical populations
  • 2 notes about these trials: Few centers would use midazolam only for MRI - ? Clinical relevance
  • RSS = Ramsay Sedation Score
  • 3 different protocolized dosing strategies (induction + maintenance infusion)
  • 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
  • Primary other sedatives inc chloral, ketamine, propofol, pentobarbital
  • 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 1 st degree ht block on EKG – briefly in PICU (4 hr) – 48 hr later readmitted with +ve monospot and recurrence of 1 st degree ht block
  • 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
  • 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 u g/kg vs midaz groups
  • 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
  • Initial maintenance dex at 2 u g/kg/hr, dec to 1 u g/kg/hr after 30 min
  • Dexmedetomidine For Pediatric Procedural Sedation

    1. 1. APPLICATIONS OF DEXMEDETOMIDINE IN PEDIATRIC PROCEDURAL SEDATION
    2. 2. GOALS <ul><li>Understand the pharmacology, physiology, and clinical properties of dexmedetomidine </li></ul><ul><li>Review clinical experience with dexmedetomidine for pediatric procedural sedation </li></ul><ul><ul><li>Adverse Events/Safety Profile </li></ul></ul><ul><ul><li>Coadministrations </li></ul></ul><ul><ul><li>Alternative administration methods </li></ul></ul><ul><li>Discuss practical issues related to use </li></ul>
    3. 3. BACKGROUND <ul><li>Despite recognition of sedation importance, few agent developments in recent past </li></ul><ul><li>Significant issues with some current agents </li></ul><ul><ul><li>Opiate/benzodiazepine – tolerance, efficacy </li></ul></ul><ul><ul><li>Chloral hydrate - predictability </li></ul></ul><ul><ul><li>Pentobarbital – agitation, duration </li></ul></ul><ul><ul><li>Propofol – limited access in some jurisdictions </li></ul></ul><ul><ul><li>Ketamine – emergence reactions, tolerance </li></ul></ul><ul><li> 2 -adrenoreceptor agonism </li></ul>
    4. 4. BACKGROUND  2 RECPTOR AGONISTS <ul><li>Prototype agent is clonidine </li></ul><ul><li>More recent applications in clinical practice </li></ul><ul><ul><ul><li>Sedation </li></ul></ul></ul><ul><ul><ul><li>Behavior disorders (ADHD) </li></ul></ul></ul><ul><ul><ul><li>Drug withdrawal </li></ul></ul></ul><ul><ul><ul><li>Hypertension </li></ul></ul></ul><ul><li>Problem – hypotension, oral = slow </li></ul><ul><li>Solution – 2 nd generation -   2 specificity </li></ul>
    5. 5. DEXMEDETOMIDINE <ul><li>Precedex ® , Hospira </li></ul><ul><li>Pharmacologically active D- isomer of medetomidine </li></ul><ul><li>1 st synthesized in late 1980’s, Phase 1 studies in early 1990’s, clinical trials late 1990’s </li></ul><ul><li>~ 8-fold g reater  2:  1 selectivity than clonidine </li></ul><ul><ul><li>1620:1 vs 200:1 </li></ul></ul><ul><li>Shorter elimination half-life than clonidine </li></ul><ul><ul><li>2-3 vs 8-12 hr </li></ul></ul><ul><li>FDA approved for ICU sedation in adults </li></ul><ul><li>Hopefully pediatric clinical trials soon </li></ul>
    6. 6. PHARMACOKINETICS <ul><li>Intravenous: </li></ul><ul><ul><li>Distribution t 1/2 = 6 minutes </li></ul></ul><ul><ul><li>Elimination t 1/2 = 2 hrs </li></ul></ul><ul><ul><li>V DSS – 118 liters – 94% protein bound </li></ul></ul><ul><li>Intramuscular (2 u g/kg): </li></ul><ul><ul><li>Peak plasma conc 13 ±18 min (variable) </li></ul></ul><ul><ul><li> 70% bioavailability </li></ul></ul><ul><li>Enteral: </li></ul><ul><ul><li>Buccal -  80% bioavailability </li></ul></ul><ul><ul><li>Gastric -  16-20% bioavailability </li></ul></ul>
    7. 7. PHARMACOKINETICS PEDIATRIC <ul><li>Healthy children: </li></ul><ul><ul><li>Bolus (0.33, 0.6, 1.0 u g/kg) </li></ul></ul><ul><ul><li>No different than adult – t 1/2 1.8 hr, V d 1.0 L/kg </li></ul></ul><ul><li>General post-op population (3 mo-8 yr): </li></ul><ul><ul><li>8-24 hr infusions – 0.2-0.7 u g/kg/hr </li></ul></ul><ul><ul><li>Similar to adults – t 1/2 2.6 hr, V d 1.5 L/kg </li></ul></ul><ul><li>Infants/toddlers post CV Sx (1-24 mo): </li></ul><ul><ul><li>T 1/2 83 min </li></ul></ul><ul><ul><ul><li>more rapid clearance than adults </li></ul></ul></ul>
    8. 8. METABOLISM <ul><li>Almost 100% biotransformation </li></ul><ul><ul><li>Glucuronidation </li></ul></ul><ul><ul><li>Cytochrome P450 mediated </li></ul></ul><ul><ul><li>Metabolites all inactive – urinary elimination </li></ul></ul><ul><li>Significant  t 1/2 in hepatic failure (7.5 hr) </li></ul><ul><li><1% excreted as unchanged </li></ul><ul><li>No significant effect of renal impairment </li></ul>
    9. 9. MECHANISM CLINICAL CNS EFFECTS <ul><li>Locus ceruleus : </li></ul><ul><ul><li>Brainstem center - modulates wakefulness </li></ul></ul><ul><ul><li>Major site for hypnotic actions ( sedation, anxiolysis ) </li></ul></ul><ul><ul><li>Mediated via various efferent pathways: </li></ul></ul><ul><ul><ul><li>Thalamus and subthalamus  cortex </li></ul></ul></ul><ul><ul><ul><li>Nociceptive transmission via descending spinal tracts </li></ul></ul></ul><ul><ul><ul><li>Vasomotor center and reticular formation </li></ul></ul></ul><ul><li>Spinal cord: </li></ul><ul><ul><li>Binding to  2 receptors  analgesia via  release of substance P </li></ul></ul>
    10. 10. CNS ACTIONS <ul><li>Sedation – central, G-proteins (inhibition) </li></ul><ul><li>Analgesia – spinal cord, Substance P </li></ul>Dexmedetomidine
    11. 11. MECHANISM – CENTRAL  2 <ul><li>Presynaptic receptors: </li></ul><ul><ul><li>Location: </li></ul></ul><ul><ul><ul><li>Sympathetic nerve endings </li></ul></ul></ul><ul><ul><ul><li>Noradrenergic CNS neurons </li></ul></ul></ul><ul><ul><li>Mechanism/action: </li></ul></ul><ul><ul><ul><li>Transmembrane receptors </li></ul></ul></ul><ul><ul><ul><li>Coupled to G o - and G i - type G-proteins </li></ul></ul></ul><ul><ul><ul><ul><li> adenylate cyclase and cAMP formation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hyperpolarization (K + -channels) </li></ul></ul></ul></ul><ul><ul><ul><ul><li> Ca ++ conductance  NE release </li></ul></ul></ul></ul>
    12. 12. CELLULAR MECHANISM Ca ++ Ca ++ Ca ++ – – + Decrease in influx of Ca ++ Decrease in action potential due to hyperpolarization  2 A  2 AR G o G k K + K + K +
    13. 13. NON-CNS EFFECTS <ul><li>Hypertension: </li></ul><ul><ul><li>peripheral  1 -agonism </li></ul></ul><ul><li>Bradycardia/hypotension: </li></ul><ul><ul><li>Sympathetic inhibition - medullary VMC </li></ul></ul><ul><li> shivering: </li></ul><ul><li>Diuresis: </li></ul><ul><ul><li> renin, vasopressin;  ANP </li></ul></ul>
    14. 15. RESPIRATORY EFFECTS <ul><li>Promoted as having minimal respiratory depressing effects </li></ul><ul><ul><li>0.17% incidence on monogram </li></ul></ul><ul><li>Most data suggests SaO 2 and PaCO 2 unaffected </li></ul><ul><li>Numerous reports during spontaneous ventilation </li></ul>
    15. 16. RESPIRATORY EFFECTS Belleville JP et al, Anesthesiology 1992;77:1125 <ul><li>37 healthy, male volunteers - 0.25-1 u g/kg over 2 min </li></ul><ul><li>SaO 2 , PaCO 2 , ET CO2 , CO 2 response </li></ul><ul><li>Results: </li></ul><ul><ul><li>Irregular breathing/obstruction in 1.0, 2.0 u g/kg groups </li></ul></ul><ul><ul><li>Mild  SaO 2 , and V E ; mild  PaCO 2 ; blunted CO 2 response </li></ul></ul><ul><li>PARAMETER BASELINE 10 MIN 60 MIN </li></ul><ul><li>SpO2 (% saturation) 98.3 + 0.8 96.2 + 1.5 * 95.4 + 1.2 * </li></ul><ul><li>PaCO 2 (mmHg) 41.9 + 2.3 46.1 + 5.0 * 45.3 + 3.5 * </li></ul><ul><li>Ventilation (l/min) 8.73 + 0.71 7.14 + 3.04 * 6.28 + 1.53 * </li></ul><ul><li>V E @ P ETCO2 55 mmHg 22.50 + 7.32 13.82 + 8.01 * 12.89 + 3.22 * </li></ul>
    16. 17. OR/PERIOPERATIVE OBSERVATIONS <ul><li> hypotension vs propofol </li></ul><ul><li>Blunted tachycardia during controlled hypotension </li></ul><ul><li>  PACU analgesia requirements </li></ul><ul><li>Blunted catecholamine response </li></ul><ul><ul><li>Potential importance with vascular procedures </li></ul></ul><ul><li>Respiratory - non-intubated </li></ul>
    17. 18. CLINICAL USE – PICU Tobias JD, Berkenbosch JW, South Med J 2004;97:451 <ul><li>PRT in 30 ventilated PICU patients </li></ul><ul><ul><li>Crossover (24 hr) comparison dex (0.25, 0.5 ug/kg/hr) vs midazolam (0.1 mg/kg/hr) </li></ul></ul><ul><ul><li>Morphine (0.1 mg/kg) prn agitation </li></ul></ul><ul><li>Outcomes: sedation quality, adjunct meds </li></ul>*: p<0.05 vs. midazolam group **: p=0.08 vs. midazolam group 5 & 2/10** 11 & 4/10 14 & 6/10 RSS = 1 (points, pts) 0.28 + 0.12* 0.55 + 0.38 0.74 + 0.5 Morphine (mg/kg/24  ) Dexmedetomidine (0.5 µg/kg/  ) Dexmedetomidine (0.25 µg/kg/  ) Midazolam (0.22 mg/kg/  )
    18. 19. CLINICAL USE – PICU Chrysostomou et al, Ped Crit Care Med 2006:7:126 <ul><li>Retrospective description of dex use in 38 post-cardiac surgical patients </li></ul><ul><ul><li>5 intubated, 33 spontaneously ventilating </li></ul></ul><ul><li>Used as primary sedative/analgesic agent </li></ul><ul><ul><li>No defined rescue regimen </li></ul></ul><ul><li>Mean infusion rate 0.3 u g/kg/  (0.1-0.75) x 15  5 hrs </li></ul><ul><ul><li>No loading dose </li></ul></ul><ul><li>Sedation and analgesia adequate 93% and 83% of the time </li></ul><ul><ul><li>1.3 rescue boluses/pt, increased in <1 yr (3.2 boluses/pt) </li></ul></ul><ul><li>Hypotension in 6 pts (16%), easily managed </li></ul><ul><li>No respiratory events </li></ul>
    19. 20. CLINICAL USE – PICU Buck et al, Pharmacotherapy 2008:7:51 <ul><li>Prospective, observational series of dex in 17 PICU patients (20 courses) </li></ul><ul><ul><li>cardiac surgical (13), medical (3), other surg (1) </li></ul></ul><ul><li>Dose range 0.2-0.7 u g/kg/  x 32  21 hr </li></ul><ul><ul><li>No loading dose </li></ul></ul><ul><li>Primary agent in 15, adjunct in 5 (failed conv) </li></ul><ul><ul><li>periextubation agent in 13 - all successful </li></ul></ul><ul><li>No reported significant cardiovascular events </li></ul>
    20. 21. ICU OBSERVATIONS <ul><li>Limited available data </li></ul><ul><li>Peds doses may be slightly higher, esp infants </li></ul><ul><li>Parent satisfaction high </li></ul><ul><ul><li>Lighter but less agitated </li></ul></ul><ul><ul><li> sedation/recovery-related “wooziness” </li></ul></ul><ul><li>Appears useful in non-intubated pts </li></ul><ul><ul><li>Effective bridge through extubation </li></ul></ul><ul><li>Not necessarily 1 st line </li></ul><ul><ul><li>reserve for difficult, long-term </li></ul></ul><ul><li>Analgesic effects probably not insignificant </li></ul>
    21. 22. PROCEDURAL SEDATION <ul><li>Most recently reported application but more published information compared with ICU </li></ul><ul><li>Expansion developed based on confirmation of limited resp depression </li></ul><ul><li>Nichols DP, et al Pediatr Anaesth 2005;15:199 </li></ul><ul><ul><li>Sedation of 5 children failing chloral hydrate/midazolam </li></ul></ul><ul><ul><li>Dex bolus (0.8  0.4 u g/kg) over 10 min, gtt 0.6 u g/kg/hr </li></ul></ul><ul><ul><li>Procedures completed </li></ul></ul><ul><ul><li>Modest  HR, BP; no significant respiratory effects </li></ul></ul>
    22. 23. PROCEDURAL SEDATION Berkenbosch JW, Pediatr Crit Care Med 2005;6:435 <ul><li>First reported prospective series </li></ul><ul><ul><li>non-invasive procedures </li></ul></ul><ul><li>Candidates: </li></ul><ul><ul><li>>4 y.o. </li></ul></ul><ul><ul><li>Previous chloral hydrate failure/poor candidate </li></ul></ul><ul><ul><li>Rescue from failed sedation </li></ul></ul><ul><li>Induction bolus: 0.5 u g/kg over 5 min </li></ul><ul><li>Maintenance: started at 0.5 u g/kg/hr - titrate </li></ul><ul><li>Monitor - Physiologic </li></ul><ul><li>- Effectiveness </li></ul><ul><li>- Recovery-related behavior </li></ul>
    23. 24. PROCEDURAL SEDATION Berkenbosch JW, Pediatr Crit Care Med 2005;6:435 <ul><li>48 patients, 6.9 ±3.7 yrs - 15 “rescues” </li></ul>0.73 ±0.38 0.67 ±0.30 0.69 ±0.32 Maintenance ( u g/kg/hr) 117±41* 69 ±34 84 ±42 Recovery (min) 9.3±3.8 10.8 ±5.0 10.3 ±4.7 Ind Time (min) 0.83 ±0.33 Rescue (15) 0.95 ±0.35 Primary (33) 0.92 ±0.36 Overall (48) Induction (u g/kg) Group
    24. 25. PROCEDURAL SEDATION Berkenbosch JW, Pediatr Crit Care Med 2005;6:435 <ul><li>Modest  in HR, BP, RR - always normal for age </li></ul><ul><li>ET-CO 2 >50 in 1.7% (max 52 mmHg) </li></ul><ul><li>No recovery-related agitation </li></ul>3.2±1.6 (3.3±1.6) 2.3±2.9 (10.4±12.8) 14.5±13.0 (13.0±9.4) 31.1±29.4 (26.7±21.4) Rescue (n=15) 2.1±2.0 (2.1±2.0) 3.3±3.7 (14.8±17.3) 12.2±12.0 (12.0±14.0) 15.5±14.6 (13.8±12.9) Primary (n=33) 2.6±2.0 (2.6±2.1) 3.0±3.5 (13.4±16.1) 12.9±12.3 (12.4±12.6) 19.0±18.4 (16.6±14.0) Overall (n=48)  SaO 2 (%)  RR (Br/min)  HR (BPM)  BP (mmHg) Group
    25. 26. PROCEDURAL SEDATION <ul><li>Only 2 comparative trials to date: </li></ul><ul><li>Koroglu A, Br J Anaesth 2005;94:821 </li></ul><ul><ul><li>Dex vs midazolam for MRI sedation </li></ul></ul><ul><ul><li>80 patients, 1-7 yrs </li></ul></ul><ul><ul><li>Dex: 1 u g/kg bolus, then 0.5 u g/kg/hr </li></ul></ul><ul><ul><li>Midazolam: 0.2 mg/kg, then 0.36 mg/kg/hr </li></ul></ul><ul><ul><li>Efficacy: 32/40 (dex) vs 8/40 (midazolam) </li></ul></ul><ul><ul><li>Onset: 19 min (dex) vs 35 min (midazolam) </li></ul></ul><ul><ul><li>Similar CV effects - nothing significant </li></ul></ul><ul><li>Concl: dex > efficacy vs midazolam </li></ul><ul><li>Problem – midaz rarely sole agent for MRI </li></ul>
    26. 27. PROCEDURAL SEDATION <ul><li>Koroglu A, Anesth Analg 2006;103:63 </li></ul><ul><ul><li>Dex vs propofol for MRI sedation </li></ul></ul><ul><ul><li>60 patients aged 1-7 yrs </li></ul></ul><ul><ul><li>Dex: 1 u g/kg bolus, then 0.5 u g/kg/hr </li></ul></ul><ul><ul><li>Propofol: 3 mg/kg bolus, then 6 mg/kg/min </li></ul></ul><ul><ul><li>Efficacy similar: 83% (dex) vs 90% (propofol) </li></ul></ul><ul><ul><li>Onset – 11 min (dex) vs 4 min (propofol) </li></ul></ul><ul><ul><li> rec time with dex (27 vs 18 min) </li></ul></ul><ul><ul><li> hypoxia with dex (0% vs 13%) </li></ul></ul><ul><li>Concl: Consider as alternative to propofol </li></ul>
    27. 28. PROCEDURAL SEDATION <ul><li>Preceding series with limited power – small n </li></ul><ul><li>Mason K, Pediatr Anaesth 2008;18;393 </li></ul><ul><ul><li>Dex for CT scan sedation – protocolized </li></ul></ul><ul><ul><li>Bolus 2 u g/kg over 10 min or until RSS 4-5 </li></ul></ul><ul><ul><ul><li>± maintenance dose 1 u g/kg/hr as needed </li></ul></ul></ul><ul><ul><li>N=250 pts, 2.9±1.9 yrs </li></ul></ul><ul><ul><li>Induction – 2.2 ±0.6 u g/kg over 10.5±4.2 min </li></ul></ul><ul><ul><li>Recovery - 27±16 min </li></ul></ul><ul><ul><li>Modest dec HR (15-30% in 54%, >30% in 20%) and BP (15-30% in 24%, >30% in 7%) </li></ul></ul><ul><ul><ul><li>No information on interventions </li></ul></ul></ul><ul><ul><ul><li>Most pronounced toward procedure conclusion </li></ul></ul></ul>
    28. 29. PROCEDURAL SEDATION Mason K et al, Pediatr Anaesth 2008;18;403 <ul><li>High dose dex as sole agent for MRI sedation </li></ul><ul><li>Bolus + infusion, rescue with pentobarb </li></ul><ul><li>747 patients over 2 year period </li></ul><ul><li>Progressive increase in doses over time (n=3) </li></ul><ul><ul><li>Induction: 2  3 u g/kg over 10 min </li></ul></ul><ul><ul><li>Maintenance: 1  2 u g/kg/hr </li></ul></ul><ul><li>Success: 91.8% (dose 1) vs 97.6% (dose 3) </li></ul><ul><li>Dec pentobarb use: 8.2 vs 10.4% vs 2.4% </li></ul><ul><li>Modest bradycardia (n=120) </li></ul><ul><ul><li>>20 below NL in 28 (3.7%) – no intervention </li></ul></ul><ul><li>Mean rec time ~34 min vs 72 min with pentobarb </li></ul>
    29. 30. CLINICAL EXPERIENCE Lubisch N, Berkenbosch JW (submitted, 2008) <ul><li>Dex in patients with neurobehavioral disease </li></ul><ul><ul><li>Many need EEG, MRI but sedation options limited </li></ul></ul><ul><li>Combined databases from 2 Institutions </li></ul><ul><ul><li>Demographics, adjuncts, procedures, efficacy </li></ul></ul><ul><ul><li>Limited by differences between databases </li></ul></ul><ul><li>315 pts, KCH (n=74), CECH (n=241) </li></ul><ul><ul><li>Age: 6.8 ± 3.9 yrs (8 mo-24 yr) </li></ul></ul><ul><ul><li>1° Dx = autism (83.1%) </li></ul></ul><ul><ul><li>1° procedure = MRI (78%) </li></ul></ul>
    30. 31. CLINICAL EXPERIENCE Lubisch N, Berkenbosch JW, (submitted, 2008) <ul><li>Sedation: </li></ul><ul><ul><li>Dex alone (n= 32), dex + midaz (n=283) </li></ul></ul><ul><ul><li>Induction - 1.4  0.6 u g/kg, </li></ul></ul><ul><ul><li>Total - 2.7  1.7 u g/kg </li></ul></ul><ul><li>Efficiency: Ind - 8.2  4.7 min, rec - 47  27 min </li></ul><ul><li>Adverse: </li></ul><ul><ul><li>>30%  SBP (n=30, 9.6%), HR (n=64, 20.3%) </li></ul></ul><ul><ul><ul><li>Glycopyrollate x4, NS bolus x1 </li></ul></ul></ul><ul><ul><li>UAObstr in 1 - nasal trumpet </li></ul></ul><ul><ul><li>Sedation failures (n=4, 1.3%) </li></ul></ul><ul><ul><li>Recovery-related agitation – severe: n=2 (0.6%) </li></ul></ul>
    31. 32. PSRC EXPERIENCE Berkenbosch JW, Lubisch N, PSRC (in preparation) <ul><li>Major limitation of single Institution studies is sample size and power. </li></ul><ul><li>Pediatric Sedation Research Consortium – 37 institution collaborative </li></ul><ul><li>July 1, 2004 – Data collection begun </li></ul><ul><li>Through 9/2007 – 90,000+ sedation entries </li></ul><ul><li>Database queried from 7/1/2004 – 9/1/2007 for all sedations using dexmedetomidine </li></ul>
    32. 33. PSRC EXPERIENCE Berkenbosch JW, Lubisch N, PSRC (in preparation) <ul><li>2309 sedations , 7 Institutions </li></ul><ul><li>Age: 57  47 mos (median 36 mos) </li></ul><ul><ul><li>221 (9.6%)  12 mos, 96 (4.2%)  6 mos </li></ul></ul><ul><li>ASA I=618, ASA II=738, ASA III=431 (n=1803) </li></ul><ul><ul><li>Co-morbidities in 1038 (47%) </li></ul></ul><ul><li>1  diagnoses: </li></ul><ul><ul><li>Neurologic (n=1389, 60%), Hem-Onc (n=328, 14%) </li></ul></ul><ul><li>1  procedures = radiology (n=2026, 88%) </li></ul><ul><ul><li>MRI (1469, 64%), CT (460, 20%), NM (133, 6%) </li></ul></ul>
    33. 34. PSRC EXPERIENCE Berkenbosch JW, Lubisch N, PSRC (in preparation) <ul><li>Administration: Bolus alone: n=164 (7.1%) </li></ul><ul><li>Infusion alone: n=360 (15.6%) </li></ul><ul><li>PO alone: n=215 (9.3%) </li></ul><ul><li>Bolus+infusion: n=1566 (68%) </li></ul><ul><li>Total dose – 3.1  2.1 u g/kg </li></ul><ul><li>Adjunct midazolam in 1535 (66.4%) </li></ul><ul><ul><li>Analgesic (n=42), Sedatives (n=107) </li></ul></ul><ul><li>Administration: Physician: n=112 (4.8%) </li></ul><ul><li>APRN: n=1485 (64.3%) </li></ul><ul><li>RN: n=1347 (58.3%) </li></ul>
    34. 35. PSRC EXPERIENCE Berkenbosch JW, Lubisch N, PSRC (in preparation) <ul><li>Conditions produced : </li></ul><ul><ul><li>Ideal (2212, 95.7%) </li></ul></ul><ul><ul><li>Suboptimal (80, 3.4%) </li></ul></ul><ul><li>Failures (n=17, 0.7%) </li></ul><ul><ul><li>Inadequate (n=8) </li></ul></ul><ul><ul><li>Complications (n=3) </li></ul></ul><ul><ul><li>Unrelated (n=6) </li></ul></ul><ul><li> Level of Care (n=2, 0.1%) </li></ul><ul><ul><li>PICU (n=2) </li></ul></ul><ul><ul><li>Underlying Dx (n=2) </li></ul></ul>0.1 3 Resp Assist 0.1 1 Seizure 0.5 5 Nausea/vomit 0.3 7 3 4 Respiratory desat obstruction 1.9 44 >30%  VS 2.1 48 Inad/agitation % # Complication
    35. 36. PSRC EXPERIENCE Berkenbosch JW, Lubisch N, PSRC (in preparation) <ul><li>Highly effective </li></ul><ul><ul><li>Dex alone – 724/729 (99.3%) </li></ul></ul><ul><ul><li>Dex + Midazolam – 1334/1440 (99.6%) </li></ul></ul><ul><ul><li>Dex + any adjunct – 2298/2309 (99.5%) </li></ul></ul><ul><li>Adverse events favorable compared to PSRC </li></ul><ul><ul><li>Respiratory – 1:329 vs 1:49 </li></ul></ul><ul><ul><li>Airway Intervention – 1:770 vs 1:89 </li></ul></ul><ul><ul><li>Failed sedation – 1:210 vs 1:338 </li></ul></ul><ul><li>Availability to/administration by non-physicians </li></ul>
    36. 37. NON-IV USE – ORAL Zub et al, Pediatr Anesth 2005;932 <ul><li>Dex (vs of midaz) as premed for OR/IV </li></ul><ul><ul><li>Planned IV dex d/t EEG in 9, OR premed in 4 </li></ul></ul><ul><ul><li>7/9 - prior failed attempts with other po </li></ul></ul><ul><li>13 pts, 8.3 ±3 yrs (4-14) </li></ul><ul><li>po dose - 2.6±0.8 u g/kg (1-4.2 u g/kg) </li></ul><ul><ul><li>Undiluted (100 u g/ml), slowly (buccal >> gastric) </li></ul></ul><ul><li>Time to IV placement – 30-50 min </li></ul><ul><ul><li>Success in all, minimal distress </li></ul></ul><ul><li> efficacy, efficiency with 3-4 u g/kg </li></ul>
    37. 38. NON-IV USE – ORAL Schmidt et al, Pediatr Anesth 2007;667 <ul><li>Pre-op po midaz vs po clonidine vs TM dex on post-op pain/anxiety </li></ul><ul><ul><li>Midaz – 0.5 mg/kg 30 min preop (n=22) </li></ul></ul><ul><ul><li>Clonidine – 4 u g/kg 90 min preop (n=18) </li></ul></ul><ul><ul><li>Dex – 1 u g/kg 45 min preop (n=20) </li></ul></ul><ul><li>Various elective, ambulatory surgeries </li></ul><ul><ul><li>Anesthetic time – 116 min, surgical time 83 min </li></ul></ul><ul><li>Similar recovery/discharge times </li></ul><ul><li>Similar anxiety but  pain, htn in  2 agonist grp </li></ul>
    38. 39. NON-IV USE – INTRANASAL Yuen et al, Anesth Analg 2008;1715 <ul><li>DBRCT IN dex vs po midaz for OR premed </li></ul><ul><li>96 pts, 2-12 yrs old – elective minor surgery </li></ul><ul><ul><li>po midaz - 0.5 mg/kg </li></ul></ul><ul><ul><li>IN dex - 0.5 or 1.0 u g/kg (diluted to 0.4 ml/pt) </li></ul></ul><ul><li>Modest resistance to IN admin (5.2%) </li></ul><ul><ul><li>No c/o pain/burning with IN </li></ul></ul><ul><li> sedation in dex at separation (22/59/75%*) </li></ul><ul><ul><li>No diff in separation ease, induction behavior </li></ul></ul><ul><li>Trend to dec HR, BP with dex – sig in D1 grp </li></ul><ul><li>Paradoxical rxn – n=9 with midaz, 0 with dex </li></ul>
    39. 40. COADMINISTRATIONS Tosun et al, J Cardiovasc Vasc Anesth, 2006 <ul><li>Dex or propofol + ketamine in CHD cath lab </li></ul><ul><li>44 children with acyanotic CHD – 4 mo-16 yr </li></ul><ul><ul><li>Dex/ketamine (n=22) </li></ul></ul><ul><ul><ul><li>Induction - 1 u g/kg dex, 1 mg/kg ketamine – 10 min </li></ul></ul></ul><ul><ul><ul><li>Maint – 0.7 u g/kg/hr dex/1 mg/kg/hr ketamine </li></ul></ul></ul><ul><ul><li>Propofol/ketamine (n=22) </li></ul></ul><ul><ul><ul><li>Induction - 1 mg/kg prop, 1 mg/kg ketamine (? time) </li></ul></ul></ul><ul><ul><ul><li>Maint – 100 u g/kg/min prop/1 mg/kg/hr ketamine </li></ul></ul></ul><ul><li> ketamine (2.0 vs 1.3 mg/kg/hr) and rec time (45 vs 20 min) in dex group </li></ul><ul><li>Similar changes in HR/BP, minimal resp effects </li></ul>
    40. 41. COADMINISTRATIONS Mester et al, Am J Therap , 2008 <ul><li>Dex/ketamine in cath lab – case series </li></ul><ul><li>16 pts with acyanotic CHD </li></ul><ul><ul><li>Ind: 1 u g/kg dex, 2 mg/kg ketamine – 3 min </li></ul></ul><ul><ul><li>Maint: 2  1 u g/kg/hr dex, ketamine 1 mg/kg prn </li></ul></ul><ul><li>No response to cannulation </li></ul><ul><li>Early  dex dose in 2 d/t HR </li></ul><ul><ul><li>No clinically sig HR/BP changes, no tachycardia </li></ul></ul><ul><li>Mild UAO in 2 – reposition; no hypercarbia </li></ul><ul><li>Concl – good analgesia, minimal CV-resp </li></ul><ul><ul><li>Likely 2 ° inc dex dose vs prior study (Tosun) </li></ul></ul>
    41. 42. CONCLUSIONS <ul><li>Effective for non-invasive procedures </li></ul><ul><ul><li>Coadmin with analgesics for invasive?? </li></ul></ul><ul><li>Dose moderately higher than for ICU sedation </li></ul><ul><ul><li>2-3 u g/kg/hr well tolerated medium-term </li></ul></ul><ul><li>Lack of recovery-related agitation significant </li></ul><ul><ul><li>Minimal compared to chloral, barbiturates </li></ul></ul><ul><li>Role of adjunct benzodiazepines unclear </li></ul><ul><li>Similar CV,  resp vs propofol </li></ul><ul><ul><li> availability vs propofol in many venues </li></ul></ul><ul><li>Ongoing paucity of comparative reports/trials </li></ul>
    42. 43. PRACTICAL POINTS <ul><li>IV use: </li></ul><ul><ul><li>Dilute to 4 u g/ml in 0.9% saline </li></ul></ul><ul><ul><li>Infusion usually req for lengthy procedures </li></ul></ul><ul><ul><ul><li>Use pump for induction bolus – 12 u g/kg/hr = 1 u g/kg over 5 min </li></ul></ul></ul><ul><ul><li>Coadmin with midazolam </li></ul></ul><ul><ul><ul><li>Appears to  induction time, ?  rec time </li></ul></ul></ul><ul><li>Buccal/transmucosal </li></ul><ul><ul><li>Use undiluted (100 u g/ml) drug </li></ul></ul><ul><ul><li>Slow drip into oral cavity  efficacy, efficiency by  swallowing and, therefore, gastric absorption </li></ul></ul>

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