clinical update: dexmedetomidine and its use in neuroanesthesia · 2018-03-31 · αand βreceptor...

Clinical Update: Clinical Update:

Dexmedetomidine and its Dexmedetomidine and its

Use in NeuroanesthesiaUse in NeuroanesthesiaJason Ambrose, SRNA

Kathryn Williamson, SRNAGeisinger Medical Center/Bloomsburg University

Nurse Anesthesia ProgramApril 28, 2011

Learner ObjectivesLearner Objectives

Following this presentation, the learner should be able to:

� Describe the pharmacologic properties of dexmedetomidine

� Explain α2 receptor physiology and its contribution to

dexmedetomidine’s unique clinical effects

� List the clinical indications for use in the operative setting

� Discuss the unique properties of dexmedetomidine that allows

its use in neurosurgery

� Detail current trends for use in anesthetic practice

� Explain limitations of and alternatives to dexmedetomidine use

HistoryHistory11, 2211, 22

� Precedex (DEX) approved by the FDA in 1999

� DEX is the d-enantiomer of medetomidine, a medication that has historically been used for sedation in analgesia for veterinary medicine

� Fastest-growing IV sedative in 2009 and 2010

IndicationsIndications11, 2211, 22

� DEX initially approved for sedation of intubated and mechanically ventilated patients in the intensive care setting for up to 24 hours

� In 2008, DEX was approved for use in non-intubated patients requiring sedation prior to and/or during surgical and other procedures, allowing its use by anesthesia providers for awake intubations and for MAC sedation

� Hospira is also seeking supplemental New Drug Application for long term use in the intensive care setting

DosageDosage1111

� Initial bolus dose of 1.0 mcg/kg administered over 10 minutes

� The approved maintenance dosages are 0.2 to 0.7 mcg/kg/hr for ICU sedation and 0.2 to 1 mcg/kg/hr for procedural sedation

PhPharmacokineticsarmacokinetics1111

Distribution� DEX has a rapid redistribution half life (6 mins) and quickly disperses; becomes highly protein bound (94%)

� Exerts sedative effects 15 mins after loading dose; peak effects in 25 mins

� Does not accumulate (in healthy patients) in the first 24 hours

Metabolism� Extensively metabolized in the liver (glucuronidation and cytochrome-P450 metabolism); doses should be reduced in patients with hepatic failure; renal impairment does not significantly effect the pharmacokinetics of DEX

Elimination� Inactive metabolites are renally (95%) excreted

� Elimination half life approx 2 hrs.

αα and and ββ Receptor ReviewReceptor Review77

α1 Arteriole constriction in skin, mucous membranes, and viscera, causing an increase in peripheral resistance, dilated pupils, and contracted bladder

α2 Reduced sympathetic outflow resulting in peripheral vasodilation

β 1 Elevated chronotropy, dromotropy and intropy (HR, speed of conduction and force of contraction)

β 2 Bronchodilation, dilation of arterioles in skeletal muscles resulting in decreased peripheral resistance, increased glycogenolysis and gluconeogenesis in the liver and bladder, relaxation resulting in decreased urine output

Nine AdrenoreceptorsNine Adrenoreceptors1414

Actually, there are 9� α1a, α1b, α1d� β 1, β 2, β 3� α2a, α2b, α2c◦Central vs peripheral

◦Presynaptic vs postsynaptic

◦Extrasynaptic

�DEX acts primarily at the α2a receptor

αα2 2 SelectivitySelectivity1414

α1

Norepinephrine

Epinephrine

Dopamine

Clonidine

GuanabenzMedetomidine

Dexmedetomidine

α2

Selectivity: Clonidine α2: α1 250:1DEX α2: α1 1,620:1

Selectivity: Clonidine α2: α1 250:1DEX α2: α1 1,620:1

αα2 2 Receptor SubtypesReceptor Subtypes1414

α2A Locus ceruleusα2A Locus ceruleus

Vagomimetic actionVagomimetic action

Blocks T1-T4 (cardioaccelerator fibers)

Blocks T1-T4 (cardioaccelerator fibers)

α2B Thermoregulatory

inhibition in CNS

α2B Thermoregulatory

inhibition in CNS

α2C Brainstem vasomotor

center

α2C Brainstem vasomotor

center

Anxiolysis

α2B Cerebral vessels

and peripheral vasculature

α2B Cerebral vessels

and peripheral vasculature

α2A Peripheral smooth-muscle cells

α2A Peripheral smooth-muscle cells

α2A Dorsal horn of spinal cord

α2A Dorsal horn of spinal cord

α2Bα2B

Density of Density of αα2 2 ReceptorsReceptors77 Physiology of SleepPhysiology of Sleep88

Normal Sleep:Normal Sleep:� While awake, the locus ceruleus provides NE-mediated inhibition of the ventrolateral preoptic nucleus in the hypothalamus.

� Adenosine, one of the brain’s principal somnogens, accumulates from degradation of ATP during periods of prolonged wakefulness. Binding of adenosine in the ventrolateral preoptic nucleus is associated with increased activity (and therefore increased sleep).

� Adenosine binding and inhibition of the locus ceruleus lead to activation of the ventrolateral preoptic nucleus, which inhibitsthe ascending arousal circuits and promotes non-REM sleep.

Physiology of SleepPhysiology of Sleep88

DEXDEX--Induced Sleep:Induced Sleep:� DEX hyperpolarizes the locus ceruleus, inhibiting the release of norepinephrine

� Decreased firing by locus ceruleus allows the ventrolateral preoptic nucleus to reduce arousal by inhibiting the ascending noradrenergic pathway

� Summary: The EEG patterns of DEX-induced sedation closely resemble those of non-REM sleep

DEX PhysiologyDEX Physiology88

Clinical Effects of DEXClinical Effects of DEX18,2118,21

Agonism of α2 receptor causes:

� Dose dependent sedation and anxiolysis

� Analgesia (supraspinal & spinal sites)

� Decreased plasma catecholamines

� Centrally-mediated bradycardia and hypotension

� Diuresis due to inhibition of ADH release and

antagonism of ADH tubular effects

� Decongestant and antisialogogue effects

Adverse EffectsAdverse Effects1111

The MOST COMMON adverse events with DEX are

Hypotension and Bradycardia

which can be treated with standard medical intervention such as IV fluids, positioning, or administration of vasopressors such as epi, atropine or glycopyrrolate

*Proceed with caution with elderly, hypovolemia and chronic hypertensives

CNS EffectsCNS Effects55

Locus ceruleus

� Reduces neuronal firing, leading to sedative and hypnotic

response

Medullary dorsal motor nucleus of the vagus

� Bradycardic and hypotensive effects

Intermediolateral cell column and substantia gelatinosa of the

spinal cord

� Inhibits release of the nociceptive mediator substance P and

mediates the analgesic effect

Cerebral vasculature

� Cerebral vasoconstrictor

� Decreases cerebral blood flow

Respiratory EffectsRespiratory Effects5, 95, 9

Does not significantly alter:

� pH

� PaO2

� PaCO2

� Respiratory Rate

�Oxygen Saturation

Cardiovascular EffectsCardiovascular Effects5, 215, 21

Increasing

Concentrations

� Sedation

� Analgesia

� Heart rate

� Cardiac output

� Memory

Biphasic response (low, then high)

� Mean arterial pressure

� Pulmonary artery pressure

� Vascular resistance

Cardiovascular EffectsCardiovascular Effects10, 2110, 21

SafetySafety1313

Reported overdoses� 3 Adult patients◦ 2.6x dose for 20 minutes preoperatively for skin grafting

� BIS 22-30

◦ 10x dose post CABG for over 7 hours� Unarousable

◦ 60x dose for 15 minutes post debridement � Unarousable

� All patients maintained hemodynamic stability� After discontinuation of infusion all patients returned to baseline

� Unremarkable recoveries

SafetySafety1717

Pediatric overdose� 21 mo for MRI of brain� Ordered bolus 2 mcg/kg over 10minutes� Ordered infusion 1 mcg/kg/hr� Actual infusion 1 mcg/kg/min◦ 60 x intended dose

� 20 minutes to reach Aldrete score 9� 2 hours to reach baseline neuro status� Vital signs stable during procedure and recovery period

� Kept overnight for observation◦ Uneventful stay

DEX and Volatile AgentsDEX and Volatile Agents1212

Patients for supratentorial craniotomy� Desflurane, Sevoflurane, and Isoflurane◦ No patient required administration of vasodilator

◦ No patient required administration of vasopressor

◦ Similar wake up times

� Desflurane had significantly shorter:◦ Time to eye opening following verbal command

◦ Time to orientation

Intubation and ExtubationIntubation and Extubation6, 266, 26

Fiber optic intubation � Calmer and more cooperative with FOI than with midazolam alone

� Greater patient satisfaction� No hemodynamic differences

Extubation after intracranial surgery� 0.5 µg/kg IV over 60 seconds 5 minutes prior to completion of surgery

� Decreased MAP� No difference in recovery time� Extubated without coughing

Neuroanesthesia Wish ListNeuroanesthesia Wish List

Desire a drug that can offer:� Ease of control (e.g. rapid onset/offset)

� Intracranial homeostasis

� Intraoperative hemodynamic stability

� Noninterference with neurophysiologic monitoring

� Neuroprotection

� Antinociception

Uses in NeuroanesthesiaUses in Neuroanesthesia

� Awake craniotomy

� Traditional craniotomy

� Carotid endartarectomy

� Deep brain stimulator

� Spinal surgery

� Aortic aneurysm repair

Options for NeuroanesthesiaOptions for Neuroanesthesia14, 1814, 18

DEX Benzos Propofol Opioids

Sedation X X X X

Anxiolysis X X

Analgesia X X

Arousability during sedation

X

Facilitate vent weaning

X

Lack of respiratory depression

X

Control delirium

X

Neurophysiological MonitoringNeurophysiological Monitoring1,31,3

Addition of DEX to TIVA regimen:� No clinically significant effect on SSEP monitoring◦ Within 50% baseline amplitude◦ Within 10% baseline latency

� No clinically significant effect on MEP monitoring

� Decreased Propofol requirements� Decreased narcotic requirements

Effect of DEX on SSEPsEffect of DEX on SSEPs1515 Awake CraniotomyAwake Craniotomy2, 20, 232, 20, 23

Asleep-Awake- Asleep� Motor and language mapping

� Deep brain stimulator placement

Role of DEX� Maintains respirations

� Allows for cooperative sedation

� Hemodynamic stability

� Safe in pediatric population

Video Clip: Speech MappingVideo Clip: Speech Mapping

http://www.youtube.com/watch?v=AFXJtOpV22s

Language testing performed during an awake craniotomy in a patient sedated with DEX

Neurovascular injuryNeurovascular injury99

DEX in neurovascular surgery patients:� Aneurysm clipping

� Excision of AVM

� Parenchymal brain tissue PO2 (PbrO2) monitoring◦ No significant reduction of PbrO2◦ Modest increase in PbrO2 with modest increase in MAP

� Did not cause reduce cerebral blood flow to injured area with already compromised oxygenation

NeuroprotectionNeuroprotection1515

DEX improved neuronal survival after transient global or focal ischemia in rats.

Several theories of mechanism:◦ Balance between apoptotic and antiapoptotic proteins

◦ Reduced glutamate release

◦ Enhanced glutamine disposal by oxidative metabolism in astrocytes

NeurostabilizationNeurostabilization21, 2421, 24

DEX after pituitary surgery did not have an effect on lumbar CSF pressure.

DEX in the presence of volatile anesthetics decreased CBF but oxygen consumption was maintained. There was no evidence of cerebral ischemia in this dog model.

DEX had no detrimental effect on local brain tissue oxygenation, suggesting maintenance of the cerebral oxygen supply-to-demand relationship.

Interview: Interview:

DEX in Awake CraniotomiesDEX in Awake Craniotomies2525

Dr. Steven Toms, Director of Neurosurgery, Geisinger Medical Center, Danville, PA, describes howDexmedetomidine facilitates an awake craniotomy

Case Report 1Case Report 11919

Planned Procedure: Posterior thoracolumbar fusion with SSEP & MEP monitoring

Patient: 15 year-old femaleHt: 1.625m Wt: 48 kgsAllergies: None knownRelevant Medical History: Idiopathic scoliosis, hypoplastic right lung disease, asthma, scarlet fever, and pneumonia

Current Medications: Daily MVI and Albuterol inhaler, used occasionally

Preop Assessment: Lungs clear to auscultation, regular heart rate & rhythm

Airway Assessment: Mallampati 2, thyromental distance 3 fingerbreadths

Preop Education: Prior to induction, the surgeon and the anesthesia team discussed the intraop wake-up test with the patient

Induction: Standard inhalational mask induction with Sevo, N2O and O2

After IV x 2 placed, pt given:

� Fentanyl 250 mcg

� Lorazepam 1 mg

� Rocuronium 30 mg

Direct laryngoscopy performed and atraumatic intubation with 7-mm

ETT, +ETCO2 & equal bilateral breath sounds noted

TIVA started following induction:

� DEX 0.9 mcg/kg/hr

� Ketamine 0.4 mg/kg/hr

� Fentanyl 1 mcg/kg/hr

Neurologic monitoring placed and pt positioned prone with meticulous attention to proper positioning and padding of pressure points


Maintenance Anesthesia:� N2O 60% + O2 40%� DEX 0.9-1.2 mcg/kg/hr� Ketamine 0.4-0.6 mg/kg/hr� Fentanyl 1-2 mcg/kg/hr� Pt recovered from induction dose of muscle relaxant with TOF 4/4

Prior to wake up test:� Fentanyl was turned off 30 minutes prior� DEX & Ketamine turned off 5-10 minutes prior� Pt awakened promptly, squeezed hands and moved feet on command as discussed preoperatively

Anesthesia resumed following testing with Propofol 50 mg bolus and Lorazepam 1 mg. DEX, Ketamine and Fentanyl infusions were resumed at previous rates.


Additional Intraoperative Information:

� Total surgical time was 9 hours

� EBL 1,100 mL

� Pt received 1,000 mL IV Hetastarch; 3,150 mL LR; 1 U autologous prbcs; and 502 mL autologous prbcs from Cell Saver

� Total of 250 mcg of Phenylephrine was administered in 50 mcg increments for BP support

� Results of SSEPs & MEPs remained satisfactory throughout the case

Postop:

� At the end of surgery, pt spontaneously breathing, opened eyes &followed commands. Extubated in OR and admitted to PICU.

� When interviewed, pt had no recollection of intraop wake-up test

� Pt did not require pain medication until 10 hrs postop

� Discharged to home 6 days postop



Planned Procedure: Left front awake craniotomy for resection of glioma

Patient: 66 year-old male

Ht: 1.855 m Wt: 116 kgs

Allergies: Sulfa, Oxycontin

Relevant Medical History: Complex partial seizures with suspected frontal lobe glioblastoma, TIAs, Depression, Sustained closed head injury from MVA in 1966

Preop Testing: Adenosine myocardial perfusion imaging with LVEF 57%, no WMA or inducible WMA; recent EKG- Sinus bradycardia with Mobitz II block

Current Medications: Keppra 500 mg po BID, Clonidine 0.05 mg po qhs, Metoprolol 25 mg po daily, Indomethacin 75 mg po daily, Clonazepam 0.25 mg po qhs, Allopurinol 300 mg po daily

Preop Assessment: Lungs clear to auscultation, sinus bradycardia rate 50s

Airway Assessment: Mallampati 2, thyromental distance 3 fingerbreadths

Preop Education: Prior to induction, the surgeon and the anesthesia team discussed the intraop wake-up test with the patient.

Premedication: Midazolam 2 mg

Induction: Placed on 4L oxygen via nasal cannula and given DEX bolus of 1 mcg/kg over 20 mins.

Prior to placement of Mayfield pins, localization of scalp per surgeon with mixture of Bupivicaine 0.5% + Lidocaine 1% + Epi 1:200,000 solution. Propofol bolus of 50 mg by CRNA.

Maintenance:

Primary - DEX infusion of 0.4 – 0.6 mcg/kg/hr

Adjuncts - Intermittent boluses of Propofol (20-40 mg) during periods of stimulation in addition to one-time doses of Ketamine 15 mg, Midazolam 2 mg (for total of 4 mg), and Fentanyl 25 mcg.

Neurologic monitoring performed after bone flap excised and dura opened per surgeon. Pt allowed to fully awaken and speech and motor testing performed successfully.


For patient wake up testing:� DEX infusion decreased from 0.6 to 0.4 mcg/kg/hr� Pt awakened and was able squeezed hands, moved feet and verballyresponded on command as discussed preoperatively.

� Following testing, pt was given Propofol bolus 20 mg x 2 and Ketamine 15 mg for resedation.

Intraoperative:Approximately 4 hours into the case and during completion of the resection, the patient became very agitated and jerked his head out of the Mayfield pins. The patient grabbed the drapes and begin trying to move off of the OR table.

The decision was made to more deeply sedate the patient to maintain safety. The pt was given a Propofol bolus of 100 mg and an LMA #5 was inserted. Maintenance anesthesia was adjusted accordingly:◦ DEX 0.6 mcg/kg/hr◦ Propofol 25 mcg/kg/min◦ Phenlyephrine 50 mcg/min


Additional Intraoperative Information:

� Total surgical time was 6 hours

� EBL 200 mL

� Pt received 2,600 mL IV Plasmalyte; UOP was 1,175 mL

� Mannitol 50 grams and Decadron 10 mg were given as requested by surgeon for visualization soon after induction. In addition, Zofran 4 mg was given for prophylactic PONV treatment.

� Results of SSEPs remained satisfactory throughout the case; direct cortical stimulation failed to reveal motor response. Stereotactics were lost after patient agitation and self removal of Mayfield pins.

Postop:

� At the end of surgery, pt spontaneously breathing, opened eyes & followed commands. LMA removed in OR and taken to PACU.

� In PACU, pt found to be aphasic and had a R hemiplegia

� CT & MRI did not immediately show signs of ICH or stroke

� Discharged to rehabilitation facility 3 days postop and then to home


Case DiscussionCase Discussion

� DEX and Ketamine – potential for balanced anesthetic

� Patient selection – importance of preanesthetic evaluation

� Timing of bolus dosing

SummarySummary

� DEX has various niche indications for use as an anesthesia adjunct or primary agent

� Patient selection important – personality and health status

� Patient preparation extremely important if wake up testing used

� Look for R&D on products that are α2 subtype specific

ReferencesReferences

1. Anschel, D., Aherne, A., Soto, R., Carrion, W., Hoegerl, C., Nori, P., et al. (2008). Successful intraoperativespinal cord monitoring during scoliosis surgery using a total intravenous anesthetic regimen including dexmedetomidine. Journal of Clinical Neurophysiology, 25 (1), 56-61.

2. Ard, J., Doyle, W., & Bekker, A. (2003). Awake craniotomy with dexmedetomidine in pediatric patients. Journal of Neurosurgical Anesthesiology, 15 (3), 263-266.

3. Bala, E., Sessler, D., Nair, D., McLain, R., Dalton, J., & Farag, E. (2008). Motor and somatosensory evoked potentials are well maintained in patients given dexmedetomidine during spinal surgery. Anesthesiology, 109 (3), 417-425.

4. Baucom, D. (2010, December 15). Morbidity and mortality conference. GeisingerMedical Center Anesthesia Department.

5. Bekker, A., & Sturaitis, M. (2005). Dexmedetomidine for neurological surgery. Operative Neurosurgery, 57, 1-10.

6. Berges, S., Bender, S., McSweeny, T., Fernandez, S., Dzwonczyk, R., & Sage, K. (2010). A comparative study of dexmedetomidine with midazolam and midazolam alone for sedation during elective awake fiberoptic intubation. Journal of Clinical Anesthesia, 22, 35-40.

7. Boyer, J. (2009). Treating agitation with dexmedetomidine in the ICU. Dimensions of Critical Care Nursing, 28 (3), 102-109.


8. Brown, E., Lydic, R., & Schiff, N. (2010). General anesthesia, sleep, and coma. (R. Schwartz, Ed.) The New England Journal of Medicine, 362 (27), 2638-2650.

9. Drummond, J., & Sturaitis, M. (2010). Brain tissue oxygenation during dexmedetomidine administration in surgical patients with neurovascular injuries. Journal of Neurosurgical Anesthesiology, 22 (4), 336-341.

10. Ebert, T., Hall, J., Barney, J., Uhrich, T., & Colinco, M. (2000). The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology, 93 (2), 382-394.

11. Full Prescribing Information. (2010, October 1). Retrieved March 15, 2011, from http://www.precedex.com/wp-content/uploads/2010/01/Precedex_Full_PI.pdf.

12. Gunes, Y., Turktan, M., Erman, T., Ozbek, H., & Isik, G. (2009). Anesthesia for craniotomy: Comparison of sevoflurane, desflurane, or isoflurane anesthesia supplemented with and infusion of dexmedetomidine during supratentorial craniotomy. Neurosurgery Quarterly, 19 (2), 110-115.

13. Jorden, V., Pousman, R., Sanford, M., & Thorborg, P. H. (2004). Dexmedetomidine overdose in the perioperative setting. The Annals of Pharmacotherapy, 38, 803-807.


14. Kamibayashi, T., Maze, M. (2000). Clinical uses of alpha-2 adrenergic agonists. Anesthesiology, 93: 1345-1349.

15. Li, B. H., Lohmann, J. S., Schuler, H. G., & Cronin, A. J. (2003). Preservation of the cortical somatosensory-evoked potential during dexmedetomidine infusion in rats. Anesthesia & Analgesia, 96, 1155-1160.

16. Mack, F., Perrine, K., Kobylarz, E., Schwartz, T., & Lien, C. (2004).Dexmedetomidine and neurocognitive testing in an awake craniotomy. Journal of Neurosurgical Anesthesiology, 16 (1), 20-25.

17. Max, B., & Mason, K. (2010). Extended infusion of dexmedetomidine toan infant at sixty times the intended rate. International Journal of Pediatrics, 2010, 1-6.

18. Maze, M., & Fujinaga, M. (2000). Adrenoreceptors in pain modulation: Which subtype should be targeted to produce analgesia. Anesthesiology, 92, 934-936.

19. Penney, R. (2010). Use of dexmedetomidine and ketamine infusions during scoliosis repair surgery with somatosensory and motor-evoked potential monitoring: A case report. AANA Journal, 78(6), 446-450.

20. Piccioni, F., & Fanzio, M. (2008). Management of anesthesia in awake craniotomy. Minerva Anestesiologica, 74 (7), 393-408.


21. Reves, J., Glass, P., Lubarsky, D., McEvoy, M., & Martinez-Ruiz, R. (2010). Intravenous Anesthetics. In R. Miller, L. Eriksson, L. Fleisher, J. Wiener-Kronish, & W. Young, Miller's Anesthesia (7th ed., pp. 719-768). Philadelphia, PA: Churchill Livingstone.

22. Rosenberg, D. (2008, October 30). FDA approves new indication for Hospira's Precedex (dexmedetomidine HCL) injection. Retrieved fromhttp://phx.corporate-ir.net/phoenix.zhtml?c=175550&p=irol-newsArticle&ID=1219872&highlight=precedex on March 15, 2011.

23. Sebeo, J., Deiner, S., Alterman, R., & Osborn, I. (2010). Anesthesia for pediatric deep brain stimulation. Anesthesiology Research and Practice, 1-4.

24. Talke, P., Tong, C., Lee, H. W., Caldwell, J. Eisenach, & Richardson, C. A. (1997). Effect of dexmedetomidine on lumbar cerebrospinal fluid pressure in humans. Anesthesia & Analgesia, 85, 358-364.

25. Toms, S. (2011, April 1). Personal interview with J. Ambrose & K. Williamson.

26. Turan, G., Ozgultekin, A., Turan, C., Dincer, E., & Yuksel, G. (2008). Advantageous effects of dexmedetomidine on haemodynamic and recovery responses during extubation for intracranial surgery. European Journal of Anesthesiology, 25, 816-820.

clinical update: dexmedetomidine and its use in neuroanesthesia · 2018-03-31 · αand βreceptor...

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