Disclaimer: The aim of these rapid reviews is to retrieve, appraise, summarize and update the available evidence on COVID-related health technology. The reviews have not been externally peer- reviewed; they should not replace individual clinical judgement and the sources cited should be checked. The views expressed represent the views of the authors and not necessarily those of their host institutions. The views are not a substitute for professional medical advice.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

Patients with COVID-19 in severe respiratory distress necessitate mechanical ventilation. Adequate sedation is important among ventilated patients. Dexmedetomidine is an alpha2-adrenergic receptor agonist that produces sedation, analgesia and anxiolysis. It preserves respiratory function even when given in high doses; thus, it is commonly used for COVID-19 patients. Adverse effects with the use of dexmedetomidine include hypotension, bradycardia, nausea, vomiting, dry mouth, atrial fibrillation, pyrexia, chills, atelectasis, pleural effusion, pulmonary edema, hyperglcemia, hypocalcemia and acidosis.1,2

Due to the high cost of dexmedetomidine, a common clinical practice is to use dexmedetomidine in combination with other sedatives such as propofol, midazolam or

fentanyl. Co-administration of dexmedetomidine with other anesthetics, sedatives, and opioids may have additive effects. The use of dexmedetomidine reduces requirements for opioids and other anesthetics.3,4

This rapid review summarizes the available evidence on the efficacy and safety of a second sedative agent to be added to dexmedetomidine for sedation of patients with COVID-19.

METHODS

See General Methods Section.

Articles were selected based on the following inclusion criteria:

•Population: COVID-19 patients of any age, with any co-morbidities, any severity

•Intervention: sedative, any dose, any duration with dexmedetomidine

•Comparator: other sedatives, any dose, any duration with dexmedetomidine

•Outcomes: sedation, time to extubation, adverse events

•Study designs: randomized controlled trials (RCTs), non-randomized studies, observational studies (e.g. cohort, case-control, cross-sectional, case report, case series)

RESULTS

Characteristics of Included Studies

There are no completed or ongoing clinical trials that evaluate the efficacy or safety of dexmedetomidine with another sedative agent among COVID-19 patients.

There is a clinical trial to be conducted in China that evaluates the protective effect of dexmedetomidine among adult patients with severe COVID-19. The comparator was not stated in the registration. The outcomes include CKMB, Troponin I, neuron-specific enolase, BUN, creatinine, and lactic acid.The details of this trial are found in the Appendix.5

Recommendations from Other Guidelines

Currently, there are no guidelines that specifically mention the recommended add-on sedative agent to dexmedetomidine for sedation of COVID-19 patients.

	The	current consensus statements from	Safe Airway
Society		and Difficult Airway Society, the	Association
of	Anaesthetists the Intensive Care Society,		the Faculty
of	Intensive Care Medicine and the Royal		College of

Anaesthetists recommend using dexmedetomidine, lidocaine or opioids during extubation to minimize coughing among mechanically ventilated COVID-19.6,7 The World Health Organization recommends providing light sedation and minimizing continuous or intermittent sedation among patients with severe acute respiratory infection who are suspected to have COVID-19.8

The 2018 clinical practice guidelines for management of sedation among critically ill, mechanically ventilated adult patients recommend using light sedation. The use of propofol or dexmedetomidine over benzodiazepines was conditionally recommended based on low quality of evidence. Propofol, when compared to benzodiazepine, resulted in shorter time to light sedation (mean difference -7.2 hours, 95% confidence interval -8.9 to -5.5), and shorter time to extubation (mean difference -11.6 hours, 95% CI -15.6 to -7.6).9 There was no significant difference between dexmedetomidine and benzodiazepine in terms of time to extubation and length of stay in the intensive care unit. However, the panel issued a conditional recommendation favoring dexmedetomidine over benzodiazepine due to the desirable effects of dexmedetomidine.9

Similarly, the 2013 English-Spanish clinical practice guidelines for critically ill, mechanically ventilated patients strongly recommend conscious or cooperative sedation with propofol or dexmedetomidine based on moderate level of evidence that this approach decreases time to extubation, duration of stay in the intensive care unit, and incidence of delirium. Benzodiazepines were associated with increased incidence of coma and delirium resulting in higher morbidity and mortality.10

DISCUSSION

There are currently no studies that provide evidence on the most recommended add-on sedative agent to dexmedetomidine among COVID-19 patients in terms of efficacy and safety. The possible adverse effects of co- administration of dexmedetomidine with other sedatives have been reported in previous studies. These studies were conducted on various populations such as surgical intensive care unit patients and patients undergoing imaging procedures.

Dexmedetomidine-propofol

A retrospective cohort study evaluated the duration of mechanical ventilation among surgical intensive care patients given dexmedetomidine and propofol compared to propofol alone. The median dose of dexmedetomidine was 0.32 mcg/kg/hour with propofol at 14.08 mcg/kg/min, while the median dose of propofol alone was 11.03 mcg/kg/ min. Those who received combination dexmedetomidine- propofol had significantly higher rates of hypotension and use of antipsychotic medication for delirium, while those who received propofol alone had significantly increased rates of bradycardia. There was no significant difference in the duration of mechanical ventilation, length of stay in the intensive care unit, and mortality rate.11

Another retrospective cohort study compared adverse hemodynamic event rates among patients given combination dexmedetomidine and propofol, dexmedetomidine alone, and propofol alone. Propofol was infused at a starting

rate of 5 ug/kg/min and titrated by 5 ug/kg/min every 5 minutes, while dexmedetomidine was started at a dose of 0.2 ug/kg/hour and titrated by 0.1 ug/kg/hour every 30 minutes to obtain target sedation. Those who received combination dexmedetomidine-propofol had significantly increased incidence of hypotension. Those given combination dexmedetomidine-propofol and propofol alone had significantly longer duration of mechanical ventilation, length of stay in the intensive care unit. There was no significant difference in mortality rates among the 3 groups.12

Dexmedetomidine-midazolam

An open-label randomized controlled trial evaluated the duration of mechanical ventilation among pediatric patients undergoing cardiac surgery given low-dose dexmedetomidine at 0.5 mcg/kg/hour with midazolam (0.05 mg/kg/hour) and morphine (10 mcg/kg/hour). The control group received midazolam (0.1 mg/kg/hour) and morphine (20 mcg/kg/hour). There was no clinically significant difference in the development of hypotension and bradycardia between the 2 groups. There was no significant difference in the duration of mechanical ventilation.13

Dexmedetomidine-ketamine

A quasi-experimental study compared dexmedetomidine- ketamine combination and midazolam for sedation among patients undergoing MRI in terms of efficacy of sedation and safety. The study reported lower complication rates (e.g. oxygen desaturation, hypotension, and aspiration pneumonia) in the dexmedetomidine-ketamine group. The doses used were 35 mcg dexmedetomidine, 35 mg ketamine, and 2-3 mg midazolam (up to 10 mg midazolam if insufficiently sedated). The efficacy of sedation was comparable between the 2 groups.14

Arandomized study on ventilated post-coronary artery bypass graft surgical patients compared dexmedetomidine- ketamine (dexmedetomidine 1 ug/kg then 0.2-0.7 ug/ kg/hour, ketamine 1 mg/kg then 0.25 mg/kg/hour) and propofol-ketamine (propofol 1 mg/kg then 25-50 ug/ kg/min, ketamine 1 mg/kg then 0.25 mg/kg/hour) in terms of safety and efficacy. There was no significant difference in hemodynamic stability and length of stay in the intensive care unit between the 2 groups. Patients given dexmedetomidine-ketamine had significantly shorter duration of mechanical ventilation.15

CONCLUSION

At present, there are no studies that evaluate the efficacy or safety of dexmedetomidine with another sedative agent among COVID-19 patients.

Clinical practice guidelines for management of sedation among critically ill, mechanically ventilated adult patients recommend the use of propofol or dexmedetomidine over benzodiazepines due to decreased time to sedation

and duration, decreased stay in the ICU, and decreased incidence of delirium.

The use of dexmedetomidine reduces requirements for opioids and other anesthetics. Possible adverse events, such as hypotension or bradycardia, should be carefully considered in the choice of add-on sedative agent.

Declaration of Conflict of Interest

No conflict of interest.

REFERENCES

1.Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: a novel sedative-analgesic agent. Proc (Bayl Univ Med Cent). 2001; 14(1):13-21. doi: 10.1080/08998280.2001.11927725

2.Kaur M, Singh PM. Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesth Essays Res. 2011; 5(2):128-33. doi: 10.4103/0259-1162.94750.

3.Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet. 2017; 56(8):893-913. doi: 10.1007/s40262-017-0507-7.

4.Haselman MA. Dexmedetomidine: a useful adjunct to consider in some high-risk situations. AANA J. 2008;76(5):335-9.

5.Evaluation of the protective effect of dexmedetomidine on patients with severe novel coronavirus pneumonia (COVID-19) [Internet]. [cited 2020 Apr 9]. Available from: http://www.chictr.org.cn/ showprojen.aspx?proj=51081

6.Brewster DJ, Chrimes N, Do TB, Fraser K, Groombridge CJ, Higgs A, et al. Consensus statement: Safe Airway Society principles of airway management and tracheal intubation specific to the COVID-19 adult patient group. Med J Aust. 2020. doi: 10.5694/mja2.50598.

7.Cook TM, El-Boghdadly K, McGuire B, McNarry AF, Patel A, Higgs A. Consensus guidelines for managing the airway in patients with COVID-19: Guidelines from the Difficult Airway Society, the Association of Anaesthetists the Intensive Care Society, the Faculty of Intensive Care Medicine and the Royal College of Anaesthetists. Anaesthesia. 2020; 75(6):785-99. doi: 10.1111/anae.15054. [Epub ahead of print]

8.World Health Organization. Clinical management of severe acute respiratory infection when COVID-19 is suspected [Internet]. 2020 [cited 2020 Apr 13]. Available from: https://www.who.int/ publications-detail/clinical-management-of-severe-acute-respiratory- infection-when-novel-coronavirus-(ncov)-infection-is-suspected.

9.Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, Pandharipande PP, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. doi: 10.1097/CCM.0000000000003299.

10.Celis-Rodríguez E, Birchenall C, de la Cal MÁ, Castorena Arellano G, Hernández A, Ceraso D, et al. Clinical practice guidelines for evidence-based management of sedoanalgesia in critically ill adult patients. Med Intensiva. 2013; 37(8):519-74. doi: 10.1016/j. medin.2013.04.001.

11.Louie JM, Lonardo NW, Mone MC, Stevens VW, Deka R, Shipley W, et al. Outcomes when using adjunct dexmedetomidine with propofol sedation in mechanically ventilated surgical intensive care patients. Pharmacy (Basel). 2018; 6(3):93. doi: 10.3390/pharmacy6030093.

12.Buckley MS, Agarwal SK, MacLaren R, Kane-Gill SL. Adverse hemodynamic events associated with concomitant dexmedetomidine and propofol for sedation in mechanically ventilated ICU patients. J Intensive Care Med. 2019; 885066619884548. doi: 10.1177/0885066619884548.

13.Garisto C, Ricci Z, Tofani L, Benegni S, Pezzella C, Cogo P. Use of low-dose dexmedetomidine in combination with opioids and midazolam in pediatric cardiac surgical patients: randomized controlled

trial. Minerva Anestesiol. 2018; 84(9):1053-62. doi: 10.23736/S0375- 9393.18.12213-9.

14.Kim JG, Lee HB, Jeon SB. Combination of dexmedetomidine and ketamine for magnetic resonance imaging sedation. Front Neurol. 2019; 10:416. doi: 10.3389/fneur.2019.00416.

15.Mogahd MM, Mahran MS, Elbaradi GF. Safety and efficacy of ketamine-dexmedetomidine versus ketamine-propofol combinations for sedation in patients after coronary artery bypass graft surgery. Ann Card Anaesth.2017; 20(2):182-7.doi: 10.4103/aca.ACA_254_16.

Appendix. Characteristics of clinical trials

			Start and
			estimated
No. Clinical Trial ID / Title		Status	primary	Study design	Country
			completion
			date
1	Evaluation of the	Not yet	Not stated	Interventional	China
	protective effect of	recruiting		study
	dexmedetomidine on
	patients with severe

novel coronavirus pneumonia (COVID-19)

ChiCTR2000030853

Population	Intervention	Comparison	Outcomes
	Group(s)	Group(s)
Adults with	Dexmedetomidine	Not stated	CKMB,
symptomatic			Troponin
COVID-19			I, neuron-
infection			specific
			enolase,
			BUN,
			creatinine,
			lactic acid