Continuing Education Activity

The FDA-approved indications for dexmedetomidine are sedation of intubated and mechanically ventilated patients in the intensive care unit (ICU) and peri-procedural (or peri-operative) sedation of non-intubated patients. Over time, usage has expanded to off-label uses, including treatment and prevention of delirium, adjunctive analgesia, therapy for insomnia in the ICU, and treatment of alcohol withdrawal. Dexmedetomidine has also been used in peripheral nerve blocks to prolong the duration of analgesia. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of dexmedetomidine, pertinent for members of the interprofessional team in treating patients where anesthesia is appropriate.

Objectives:

• Identify the mechanism of action of dexmedetomidine.
• Summarize the indicated uses for dexmedetomidine.
• Review the adverse effect profile and contraindications of dexmedetomidine.
• Explain the importance of improving care coordination among the interprofessional team to enhance care delivery for patients when using dexmedetomidine as an anesthesia agent.

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Indications

The FDA-approved indications for dexmedetomidine are sedation of intubated and mechanically ventilated patients in the intensive care unit (ICU) and peri-procedural (or peri-operative) sedation of non-intubated patients. Over time, usage has expanded to off-label uses, including treatment and prevention of delirium, adjunctive analgesia, therapy for insomnia in the ICU, and treatment of alcohol withdrawal. This expanded list of indications is because it commonly produces a sedated state, allowing patients to be comfortable and cooperative during mechanical ventilation. Additionally, it does not require stoppage to accomplish extubation and is safe to use in non-intubated patients because it does not produce significant respiratory depression. Given THAT inherent analgesic properties are rare with most sedatives, dexmedetomidine produces an opioid-sparing effect.[1] Dexmedetomidine is used to treat episodes of agitation associated with schizophrenia or bipolar disorder.[2]

ICU sedation with dexmedetomidine has been demonstrated to decrease the incidence and duration of delirium and delay the onset of delirium compared with other sedatives.[3] Evidence also exists that there is a reduction in both the time to extubation and the number of ventilator-dependent hours in patients with delirium.[4] These reductions may be related to the ability of dexmedetomidine to reduce the need for other medications (for example, propofol, benzodiazepines, and opioids) to promote a comfortable/cooperative patient. This effect has been particularly useful in the treatment of elderly post-cardiac surgery patients.[5] The beneficial effects in this particular patient population extend into longer outcomes, including survival at two years and improved cognitive function and quality of life. It has also become common to treat poor sleep in the ICU with dexmedetomidine infusions at doses as high as 1.5 mcg/kg per hr. This practice is supported by research showing dexmedetomidine often yields sleep quality closely related to stage 2 non-REM sleep.[6] However, it is also important to note that there is data showing alteration of normal sleep patterns, and subjects achieve no restorative rapid-eye-movement or slow-wave sleep. Additionally, studies demonstrating the benefit in clinical outcomes related to improved sleep generated by dexmedetomidine are sparse.[7]

Dexmedetomidine is commonly used in anesthesia practice as well. It is used for procedural sedation for a variety of operations. It is also used frequently for sedation during the performance of awake intubation. It is ideally suited for this indication for the reasons stated above. Dexmedetomidine is also an adjunct infusion during general anesthesia. There is evidence that dexmedetomidine decreases postoperative pain, postoperative opioid usage, and nausea.[8] This effect has also been shown to be present when using dexmedetomidine for sedation during procedures performed under spinal anesthesia.[9] However, at least one recent study has been called into question this opioid-sparing effect for a cohort of patients undergoing major spine surgery.[10] There has been some interest in using dexmedetomidine as an adjunct to prevent emergence agitation, postoperative delirium, and postoperative cognitive dysfunction. There is evidence for the prevention of emergence agitation in both children and adults.[11] [12]Because of enthusiasm over apparent prevention/treatment of delirium with dexmedetomidine when used for ICU sedation, it was hoped this benefit would be reproduced for postoperative delirium when using an intraoperative infusion of dexmedetomidine; however, a recent randomized trial did not show a statistically significant benefit in this postoperative population.[13] Dexmedetomidine has also been used in peripheral nerve blocks to prolong the duration of analgesia. Research suggests that dexmedetomidine may extend the duration of a peripheral nerve block for approximately 3 hours.[14]

Mechanism of Action

Dexmedetomidine is an alpha agonist having sedative, anxiolytic, hypnotic, analgesic, and sympatholytic properties. It produces these effects by inhibiting central sympathetic outflow by blocking the alpha receptors in the brainstem, thereby inhibiting the release of norepinephrine. It has a selectivity of 1600 to 1 for the alpha2 receptor as compared to alpha1. This selectivity is especially significant compared to another alpha agonist, clonidine, with a selectivity of 220 to 1. The mechanism by which dexmedetomidine may increase the duration of a peripheral nerve block is not fully understood but is believed to most likely be a perineural mechanism rather than a systemic or central mechanism, which appears to prolong the duration by blocking the cation current.[15]

Administration

For ICU sedation, the typical dosage range is 0.2 to 0.7 mcg/kg per hour. However, the dose can increase to 1.5 mcg/kg per hour to achieve the desired sedation level. Doses as high as 2.5 mcg/kg per hour have been described, but it is unlikely that doses higher than 1.5 mcg/kg per hour achieve any further therapeutic benefit in the absence of increased side effects. Dosage adjustments for renal or hepatic impairment are not required but should be considered, especially for hepatic impairment. The manufacturer does not recommend durations longer than 24 hours; however, longer durations have been demonstrated as safe and effective. Clinicians can administer a loading dose of 0.5 to 1.0 mcg/kg; this is usually avoidable if the medication is for labile, critically ill patients or those with tenuous hemodynamics.

When used in anesthesia, the typical dosing is a loading dose of 0.5 to 1.0 mcg/kg, usually followed by a continuous infusion of 0.2 to 0.7 mcg/kg per hour titrated to desired sedation goals. As mentioned, higher infusion doses can help achieve the desired effect.

When used as an adjunct for peripheral nerve block, the dose of dexmedetomidine is usually 1 mcg/kg to achieve the desired prolongation.[16]

When used for treatment of mild agitation, it is dosed as 120 mcg administered sublingually or buccally. For severe agitation, the initial dose is 180 mcg, administered sublingually or buccally.

Adverse Effects

The most common adverse effects of dexmedetomidine are hypotension, bradycardia, and hypertension. Hypertension can result from the stimulation of alpha subtypes of receptors in vascular smooth muscles. Hypertension usually does not require treatment and can be avoided by the slow administration or omission of the loading dose. Hypotension and bradycardia are the results of the stimulation of presynaptic alpha receptors, which leads to a decreased release of norepinephrine; this is in addition to the decrease in the central sympathetic outflow. These are concerns regardless of the route of administration.[17]

Contraindications

There are no absolute contraindications to the use of dexmedetomidine. However, it should be used cautiously in patients with bradycardia and hypotension, as the medication may exacerbate these findings. Additionally, it should be used cautiously in patients with known heart failure as there is level B evidence showing dexmedetomidine can potentially exacerbate myocardial dysfunction.

Monitoring

There are no specific drug monitoring requirements. The level of sedation, heart rate/rhythm, blood pressure, and pulse oximetry require close monitoring.

Toxicity

At present, there is no chemical reversal or antidote for dexmedetomidine. Supportive care and close monitoring are the staples of treatment for overdose.

Enhancing Healthcare Team Outcomes

Dexmedetomidine is a useful non-opioid drug used to manage pain and sedation in the ICU and operating room. The drug is effective, but its use does require monitoring of vital signs. Both the pharmacist and clinician should ensure the administration of the right dose to prevent adverse effects. ICU nurses should know that the drug requires caution in patients with heart failure. All these disciplines working collaboratively as an interprofessional healthcare team will optimize outcomes when using dexmedetomidine. [Level 5] The primary downside to dexmedetomidine is its cost.

Review Questions

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References

1.

McLaughlin M, Marik PE. Dexmedetomidine and delirium in the ICU. Ann Transl Med. 2016 Jun;4(11):224. [PMC free article: PMC4916356] [PubMed: 27385042]

2.

Smith CM, Santalucia M, Bunn H, Muzyk A. Sublingual Dexmedetomidine for the Treatment of Agitation in Patients with Schizophrenia and Bipolar Disorder. Clin Psychopharmacol Neurosci. 2023 May 30;21(2):215-221. [PMC free article: PMC10157019] [PubMed: 37119214]

3.

Djaiani G, Silverton N, Fedorko L, Carroll J, Styra R, Rao V, Katznelson R. Dexmedetomidine versus Propofol Sedation Reduces Delirium after Cardiac Surgery: A Randomized Controlled Trial. Anesthesiology. 2016 Feb;124(2):362-8. [PubMed: 26575144]

4.

Reade MC, Eastwood GM, Bellomo R, Bailey M, Bersten A, Cheung B, Davies A, Delaney A, Ghosh A, van Haren F, Harley N, Knight D, McGuiness S, Mulder J, O'Donoghue S, Simpson N, Young P., DahLIA Investigators. Australian and New Zealand Intensive Care Society Clinical Trials Group. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. JAMA. 2016 Apr 12;315(14):1460-8. [PubMed: 26975647]

5.

Zhang DF, Su X, Meng ZT, Li HL, Wang DX, Xue-Ying Li, Maze M, Ma D. Impact of Dexmedetomidine on Long-term Outcomes After Noncardiac Surgery in Elderly: 3-Year Follow-up of a Randomized Controlled Trial. Ann Surg. 2019 Aug;270(2):356-363. [PubMed: 29742525]

6.

Alexopoulou C, Kondili E, Diamantaki E, Psarologakis C, Kokkini S, Bolaki M, Georgopoulos D. Effects of dexmedetomidine on sleep quality in critically ill patients: a pilot study. Anesthesiology. 2014 Oct;121(4):801-7. [PubMed: 24988068]

7.

Goucher Miranda H, Krystal AD, Fierro MA. Nocturnal Dexmedetomidine in Nonintubated, Critically Ill Patients: Sleep or Sedation? Anesthesiology. 2017 Aug;127(2):397-398. [PubMed: 28719531]

8.

Blaudszun G, Lysakowski C, Elia N, Tramèr MR. Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2012 Jun;116(6):1312-22. [PubMed: 22546966]

9.

Chan IA, Maslany JG, Gorman KJ, O'Brien JM, McKay WP. Dexmedetomidine during total knee arthroplasty performed under spinal anesthesia decreases opioid use: a randomized-controlled trial. Can J Anaesth. 2016 May;63(5):569-76. [PubMed: 26830642]

10.

Naik BI, Nemergut EC, Kazemi A, Fernández L, Cederholm SK, McMurry TL, Durieux ME. The Effect of Dexmedetomidine on Postoperative Opioid Consumption and Pain After Major Spine Surgery. Anesth Analg. 2016 May;122(5):1646-53. [PubMed: 27003917]

11.

Kim SY, Kim JM, Lee JH, Song BM, Koo BN. Efficacy of intraoperative dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery. Br J Anaesth. 2013 Aug;111(2):222-8. [PubMed: 23524149]

12.

Patel A, Davidson M, Tran MC, Quraishi H, Schoenberg C, Sant M, Lin A, Sun X. Dexmedetomidine infusion for analgesia and prevention of emergence agitation in children with obstructive sleep apnea syndrome undergoing tonsillectomy and adenoidectomy. Anesth Analg. 2010 Oct;111(4):1004-10. [PubMed: 20705788]

13.

Deiner S, Luo X, Lin HM, Sessler DI, Saager L, Sieber FE, Lee HB, Sano M, and the Dexlirium Writing Group. Jankowski C, Bergese SD, Candiotti K, Flaherty JH, Arora H, Shander A, Rock P. Intraoperative Infusion of Dexmedetomidine for Prevention of Postoperative Delirium and Cognitive Dysfunction in Elderly Patients Undergoing Major Elective Noncardiac Surgery: A Randomized Clinical Trial. JAMA Surg. 2017 Aug 16;152(8):e171505. [PMC free article: PMC5831461] [PubMed: 28593326]

14.

Kirksey MA, Haskins SC, Cheng J, Liu SS. Local Anesthetic Peripheral Nerve Block Adjuvants for Prolongation of Analgesia: A Systematic Qualitative Review. PLoS One. 2015;10(9):e0137312. [PMC free article: PMC4565585] [PubMed: 26355598]

15.

Andersen JH, Grevstad U, Siegel H, Dahl JB, Mathiesen O, Jæger P. Does Dexmedetomidine Have a Perineural Mechanism of Action When Used as an Adjuvant to Ropivacaine?: A Paired, Blinded, Randomized Trial in Healthy Volunteers. Anesthesiology. 2017 Jan;126(1):66-73. [PubMed: 27792047]

16.

Koyyalamudi V, Sen S, Patil S, Creel JB, Cornett EM, Fox CJ, Kaye AD. Adjuvant Agents in Regional Anesthesia in the Ambulatory Setting. Curr Pain Headache Rep. 2017 Jan;21(1):6. [PubMed: 28210917]

17.

Correction to: Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016 Sep 20;134(12):e261. [PubMed: 27647303]

Disclosure: Bradley Reel declares no relevant financial relationships with ineligible companies.

Disclosure: Christopher Maani declares no relevant financial relationships with ineligible companies.