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Clinical Use of Dexmedetomidine. Charles E. Smith, MD Professor of Anesthesia Director, Cardiothoracic Anesthesia MetroHealth Medical Center Case Western Reserve University Cleveland, Ohio, USA October 7, 2003. Objectives. Pharmacology of dex alpha 2 agonist

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clinical use of dexmedetomidine
Clinical Use of Dexmedetomidine

Charles E. Smith, MD

Professor of Anesthesia

Director, Cardiothoracic Anesthesia

MetroHealth Medical Center

Case Western Reserve University

Cleveland, Ohio, USA

October 7, 2003

objectives
Objectives
  • Pharmacology of dex
    • alpha 2 agonist
  • Molecular targets + neural substrates
    • locus caeruleus
    • natural sleep pathways
  • Clinical paradigms for use of dex in anesthesia
    • sedation + analgesia w/o resp depression
    • attenuation of tachycardia
    • smooth emergence + weaning from mech vent
pharmacology
Pharmacology
  • Establish and maintain adequate drug concentration at effector site to produce desired effect
    • sedation
    • hypnosis
    • analgesia
    • paralysis
  • Predict the time course of drug onset + offset
pharmacodynamics
Pharmacodynamics
  • Relationship between drug conc + effect
  • Interaction of drug with receptor
  • Receptor
    • cell component
    • interacts with drug
    • biochemical change
  • Examples of receptors:
    • AchR, GABA, opioid,  +  adrenergic
receptors
Receptors
  • Coupled to ion channels
    • neural signaling, 2nd messenger effects
  • Drug effects at receptor
    • agonist, antagonist or mixed effects
    • stereospecificity, racemic mixture of isomers
  • Receptor alterations
    • upregulated or downregulated (e.g., CHF)
    •  or  number (e.g., burns, myasthenia gravis)
pharmacodynamics6
Pharmacodynamics
  • Sedation/hypnosis
  • Anxiolysis
  • Analgesia
  • Sympatholysis (BP/HR, NE)
  • Reduces shivering
  • Neuroprotective effects
  • No effect on ICP
  • No respiratory depression
pharmacokinetics
Pharmacokinetics
  • Rapid redistribution: 6 min
  • Elimination half-life: 2 h
  • Vd steady state: 118 L
  • Clearance: 39 L/h
  • Protein binding: 94%
  • Metabolism: biotransformation in liver to inactive metabolites + excreted in urine
  • No accumulation after infusions 12-24 h
  • Pharmacokinetics similar in young adults + elderly
2 agonists
Clonidine

Selectivity: 2:1 200:1

t1/2  8 hrs1

PO, patch, epidural

Antihypertensive

Analgesic adjunct

IV formulation not available in US

Dexmedetomidine

Selectivity: 2:1 1620:1

t1/2  2 hrs

Intravenous

Sedative-analgesic

Primary sedative

Only IV 2 available for use in the US

2 Agonists
mechanism for the hypnotic effect
Mechanism for the Hypnotic Effect
  • Hyperpolarization of locus ceruleus neurons

–2A-Adrenoreceptor subtype

    • Activation of K+ channels
    • Inhibition of Ca++ channels
    • Inhibition of adenylyl cyclase
  •  Firing rate of locus caeruleus neurons
  •  Activity in ascending noradrenergic pathway
restorative properties of sleep
Restorative Properties of Sleep
  • Activates natural sleep pathways
  • Increased rate of healing
    • Promotes anabolism
      • Facilitates growth hormone release
    • Counteracts catabolism
      • Inhibits cortisol release
      • Inhibits catecholamine release
harmful effects of sleep deprivation
Harmful Effects of Sleep Deprivation
  •  pressor response to sympathetic stimulation
  • Impaired CV response to positioning change
  •  BP, HR + urine norepinephrine
  • Immune dysfunction
    •  ability of lymphocytes to synthesize DNA
    •  leukocyte phagocytic activity
    •  interferon production by lymphocytes
  • Cognitive dysfunction
    • Impaired memory, communication skills
    • Impaired decision-making
    • Confusional state [ICU]: apathy, delirium
mechanisms for analgesic effect
Mechanisms for Analgesic Effect

Opioids

2 Agonists

Peripheral nociceptors

 inflammation [e.g., bradykinin, other kinins]

Inhibit sympathetic- mediated pain

Primary afferent neurons

Inhibit release of SP and glutamate

Inhibit release of SP and glutamate

Second order neurons

Inhibit firing

Inhibit firing

Subcortical + cortex

Decrease emotive aspects

Decrease emotive aspects

Descending inhibitory pathways

Activate PAG; activate noradrenergic pathways

Disinhibit A5/A7 noradrenergic pathways

dex package insert info
Dex: Package Insert Info
  • Indications
    • Sedation of intubated and ventilated patients during treatment in an ICU setting x 24 h
  • Contraindications
    • Caution in patients with advanced heart block, severe ventricular dysfunction, shock
  • Drug interactions
    • Vagal effects can be counteracted by atropine / glyco
  • Clearance is lower w hepatic impairment
  • Withdrawal sx after discontinuation: not seen after 24 h use
  • Adrenal insufficiency: no effect on cortisol response to ACTH
clinical uses of dex in anesthesia
Bariatric surgery

Sleep apnea patients

Craniotomy: aneurysm, AVM [hypothermia]

Cervical spine surgery

Off-pump CABG

Vascular surgery

Thoracic surgery

Conventional CABG

Back surgery, evoked potentials

Head injury

Burn

Trauma

Alcohol withdrawal

Awake intubation

Clinical Uses of Dex in Anesthesia
sleep apnea patients
Sleep Apnea Patients

Anesthesia considerations

  • Morbid obesity, at risk for aspiration
  • Difficult IV access
  • Systemic + pulm HTN, cor pulmonale
  • Postop airway obstruction + ventilatory arrest with anesthetic drugs
    •  upper airway muscle activity
    • inhibition of normal arousal patterns
    • upper airway swelling from laryngoscopy, surgery, intubation

Dexmedetomodine

  • Anesthetic adjunct to minimize opioid + sedative use

Ogan OU, Plevak DJ: Mayo Clinic; www.sleepapnea.org

gastric bypass surgery patients
Gastric Bypass Surgery Patients

Morbidly obese patients

  • Prone to hypoxemia
  • Sleep apnea is common
  • Respiratory depression w opioids

Dexmedetomidine, 0.1 to 0.7 ug/kg/hr, prospectively studied in 32 pts

  •  opioid use in dex group
  • 1 pt in control gp needed reintubation
  • Dex pts more likely to be normotensive w  HR

Craig MG et al: IARS abstract, 2002. Baylor

dex improves postop pain mgt after bariatric surgery
Dex Improves Postop Pain Mgt after Bariatric Surgery

RCT, n= 25. Dex started at 0.5 to 0.7 ug/kg/hr 1 hr prior to end of surgery [vs.saline]. Double- blind

  • Infusion adjusted according to need
  • Dex continued in PACU
  • PACU pain control with PCA

Dexmedetomidine

  • Morphine use  in dex gp (P < 0.03)
  • Pain score better in dex gp: 1.8 vs 3.4 (P < 0.01)
  • % time pain free in PACU  in dex gp:
    • 44% vs 0 (P < 0.002)
  • Better control of HR in dex gp

Ramsay MA, et al: Anesthesiology, 2002: A-910 and A-165. Baylor

craniotomy for aneurysm avm
Craniotomy for Aneurysm / AVM

Anesthesia considerations

  • Smooth induction + emergence
  • Prevent rupture
  • Avoid cerebral ischemia
  • Hypothermia (33 oC)  CMRO2, CBF, CBV, CSF, ICP

Dexmedetomodine

  •  sympathetic stimulation
  •  or no change in ICP
  •  shivering w/o resp depression
  • Preserved cognitive fct
    • reliable serial neuro exams

Doufas AG et al: Stroke 2003;34. Louisville, KY

coronary artery surgery patients
Coronary Artery Surgery Patients

Herr study, n=300: Dex vs. controls [propofol]

  • RCT, dex started at sternal closure, 0.4 ug/kg/hr after loading dose, and 0.2 to 0.7 ug/kg/hr for 6- 24 hrs after extubation
  • Ramsay > 3 before extub, Ramsay 2 after extub

Dexmedetomidine

  • Faster time to extub in dex gp
    • by 1 hr
  • 94% did not require propofol
  • 70% did not require morphine
    • (vs. 34% controls)
  • Dex pts had less Afib (7 vs 12 pts)

Herr DL: Crit Care Med 2000;28:M248. Washington Hospital

cabg and lung disease
CABG and Lung Disease

Lung Disease

  • Often delays tracheal extubation
  • RCT, n= 20. Dex started at end of surgery, 0.2 to 0.7 ug/kg/hr, + continued 6 hr after extubation vs. controls (propofol)
  • Ramsay > 3 before extub, Ramsay 2 after extub

Dexmedetomidine

  • Faster time to extub:
    • 7.8 + 4.6 h v. 16.5 + 11.8 h
  • No difference in PaCO2 between gps 30 min after extub: 37.9 v. 34.9 mmHg

Sumping ST: CCM 2000;28:M249. Duke

thoracotomy thoracoscopy
Thoracotomy + Thoracoscopy

Thoracotomy + thoracoscopy patients

  • COPD, pleural effusion, marginal pulmonary fct
  •  pCO2 +  pO2 with opioids for analgesia
  • Thoracic epidural: mainly for thoracotomy
  • Dex: mainly for thoracoscopy

Dexmedetomidine

  • Patients are arousable, but sedated
  • Does not  ventilatory drive
  • Greatly  need for opioids
  • Alternative to thoracic epidural
  • Continue after extubation
vascular surgery
Vascular Surgery

Vascular surgery patients

  • Usually at risk for CAD, ischemia, HTN, tachycardia
  • Dex attenuates periop stress response
  • Dex attenuates  BP w AXC, especially thoracic aorta

Dexmedetomidine

  • RCT, n=41. Dex continued 48 hr postop
  • HR  in dex gp at emergence
    • 73 + 11 v. 83 + 20 bpm
  • Better control of HR in dex gp
  • Plasma NE levels  in dex gp

Talke et al: Anesth Analg 2000;90:834. Multicenter

meta analysis of alpha 2 agonists
Meta- Analysis of Alpha-2 Agonists

23 trials, n=3395.

  • All surgeries:  mortality + ischemia
  • Vascular:  MI + mortality
  • Cardiac:  ischemia
  • Cardiac:  BP (more hypotension)

Conclusions:

  • Not class 1 evidence yet, but trials look promising
    • Especially vascular surgery

Wijeysundera, Am J Med 2003;114:742. Univ of Toronto

other surgical procedures
Other Surgical Procedures
  • Neck + back surgery
    • Dex causes minimal effect on SSEP monitoring
    • Smooth emergence, especially cervical spine
    • Easy to evalute neuro fct prior to + after extub
  • Abdominal surgery
    • Dexmedetomidine provides analgesia without respiratory depression
    • Especially useful in elderly undergoing colon resections, TAH, + other stressful procedures
perioperative dex infusion protocol
Perioperative Dex Infusion Protocol

Example: 70 kg patient. Assess BP, HR, volume status

Hypovolemic

Normovolemic

Monitor BP/HR

throughout

If bradycardia, infusion

Volume preload500 to 1000 cc LR

2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml

Start at 40 mL/hr

Usual load: 25 to 35 ug or 6 to 9 mL over 10-15 min

Stop load if  HR

Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr]

Dex=dexmedetomidine.

considerations with anesthesia use of dexmedetomidine
Considerations With AnesthesiaUse of Dexmedetomidine
  • Dilute in 0.9% saline: 4 mcg/mL
  • Requires infusion pump: mcg/kg/h
  • Transient HTN: with rapid bolus
  • Hypotension may occur, especially if hypovolemia
  •  HR (attenuation of tachycardia): usually desirable
  •  conc of inhaled agents: BIS monitoring
  • Continue infusion after extubation for 30 min [PACU]
  • L + D: not studied
  • Pediatrics: abstracts + case reports [Lerman, Toronto]
  • Geriatrics: more hypotension + bradycardia:  dose
use of dexmedetomidine in the burn unit
Use of Dexmedetomidine in the Burn Unit
  • 2 agonist effect assists in the management of burn patients; blunts catecholamine surge
  • Use in intubated and non-intubated burn patients
  • Administer as a standard load once patient is normovolemic (range: 0.4 to 0.7 mcg/kg/hr)
  •  dose for less severe burns and non-intubated patients
    • 0.2 to 0.4 mcg/kg/hr for routine burn care
    • outpatient dressing changes, instead of ketamine
alcohol withdrawal and trauma
Alcohol Withdrawal and Trauma
  • Trauma often occurs in males who are intoxicated
  • Trauma pt may experience agitation and is at risk for exacerbating underlying injuries (e.g., SCI)
  • Benzodiazepines typically used
    • Intubation and ventilation often required if extreme agitation
  • Dexmedetomidine is an alternative
    • Spontaneous breathing
    • Hemodynamic stability
    • Adequate sedation
    • Prevention of autonomic effects of withdrawal
    • Pain control
summary
Summary
  • Goal is to establish + maintain adequate drug conc at effector site to produce desired effect
  • Dex can help optimize anesthesia via:
    • Sedation, analgesia +  sympathetic activity
    • Attenuation of stress response +  HR
    • Smooth emergence + tracheal extubation
  • Unique mechanism of action on natural sleep pathway permits sedation + analgesia w/o respiratory depression
  • Adjunct agent of choice for many surgeries