Clonidine use during dexmedetomidine weaning: A systematic review

Table 1 Trial characteristics

Ref.	Type of study	Study dates	Total patients studied	ICU	Admitting diagnosis	Mechanical ventilation	Age (yr)	Sex	Weight (kg)	BMI (kg/m2)	APACHE score
Terry et al[24], 2015	Single-center, retrospective, observational study	February 1, 2013-February 28, 2014	26	Cardiac surgery 21 (80.7%), thoracic 3 (11.5%), neurology 1 (3.8%), surgical 1 (3.8%)	Respiratory 4 (15.4%), cardiac 20 (76.9%), trauma 1 (3.8%), substance abuse 1 (3.8%)	4 (14.8%)	54.4 ± 16.91	Male: 17 (63%), female: 9 (37%)	NR	32 ± 3.11	18 (14-22)2
Gagnon et al[23], 2015	Single-center prospective observational pilot study	January, 2014-March, 2014	20	Mixed medical, surgical, neuro ICU	Respiratory 12 (60%), neurologic 1 (5%), trauma 2 (10%), substance abuse 2 (10%), other 3 (15%)	13 (65%)	62 (54-73)2	Male: 13 (65%), female: 7 (35%)	NR	29.9 (26.5-33.1)2	62 (54-80)2
Bhatt et al[22], 2020	Single-center, prospective, double cohort observational study	November, 2017-December, 2018	42	Medical-surgical 10 (67%) vs 13 (48%), cardiothoracic 3 (20%) vs 8 (30%), neurosurgical 2 (13%) vs 6 (22%)	Respiratory 16 (38.1%), cardiac 12 (28.6%), gastroenterological 5 (11.9%), neurologic 2 (4.8%), trauma 1 (2.4%), sepsis/shock 6 (14.3%)	NR	Clonidine taper: 58 (43-662 vs no taper: 54 (45-66)2 (P = 0.93)	Male: 27 (64%), female: 15 (36%)	Clonidine taper: 86.9 (67.3-94.1)2 vs no taper 91.6 (78.9-101.1)2 (P = 0.19)	NR	NR

¹Data reported as mean ± SD.

²Data reported as median (interquartile range).

NR: Not reported; ICU: Intensive care unit; BMI: Body mass index, APACHE: Acute physiology and chronic health evaluation.

Table 2 Dosing schemes reported in study methods

Ref.	Formal protocol	Dexmedetomidine indication	Threshold for clonidine use	Initial clonidine dose	Dexmedetomidine wean	Clonidine taper
Terry et al[24], 2015	No	Primarily for sedation after cardiac surgery	No standard	No standard. 0.1 mg three times daily commonly used	No standard	No standard
Gagnon et al[23], 2015	Yes	Agitation: 12 (60%); Alcohol withdrawal: 3 (15%); Delirium: 2 (10%); Intolerance to other sedatives: 3 (15%)	Hemodynamically stable patients; Favorable response to DEX for 12-24 h	0.2-0.5 mg every 6 h; Start at 0.2 mg with DEX doses of < 0.7 µg/kg/h, weight < 100 kg or age > 65 yr; Start with 0.5 mg every 6 h for all other patients	Decrease DEX dose by 25% of baseline within 6 h of clonidine administration (as long as no rescue meds were needed for agitation)	Extend the dosing interval to every 8, 12 and 24 h every 1-2 d as tolerated until discontinuation
Bhatt et al[22], 2020	Yes	No clear selection criteria; patients with substance withdrawal were excluded	Variable; Clonidine taper and DEX wean started together	0.3 or 0.2 mg every 6 h; Start at 0.2 mg with DEX < 0.7 µg/kg/h, weight < 100 kg, age > 65 yr old; Start with 0.3 mg every 6 h for all other patients	Decrease DEX dose by 25% of baseline from 0 h to 6 h, and continue dose reduction by 25% every 6 h while on clonidine	Extend the dosing interval to every 8, 12 and 24 h every 1-2 d as tolerated until discontinuation

DEX: Dexmedetomidine.

Table 3 Outcomes data

Outcomes data	Terry etal[24], 2015	Gagnon etal[23], 2015	Bhatt etal[22], 2020
Breakthrough withdrawal	NR	11	Taper 11 (73%); No taper 16 (59%)2
Discharged on clonidine	Out of ICU: 14 (54%); Out of hospital: 6 (23%)	5 (25%)	NR
Use of other agents
Propofol	NR	No individual data	Taper: 5 (33%); No taper: 8 (30%)
Ketamine	NR	NR	Taper: 1 (6.7%); No taper: 6 (22.2%)
Benzodiazepines	Clonidine: 2 (22%); No clonidine: 5 (29%)	No individual data	Taper: 3 (20%); No taper: 3 (11%)
Antipsychotics	Clonidine: 4 (44%); No clonidine: 3 (18%)	DEX maintenance dose	Taper: 9 (60%); No taper: 10 (37%) (P = 0.2)
Opioids	Clonidine: 7 (78%); No clonidine: 13 (76%)	No individual data	No individual data
Hemodynamic changes
Tachycardia	NR	NR	Taper: 12 (80%); No taper: 20 (74%)
Hypertension	NR	DEX maintenance dose: 0; Transition: 0; Clonidine maintenance: 0; Clonidine taper final day: 0; Post clonidine: 1 (6%)	Taper: 6 (40%); No taper: 8 (30%)
Bradycardia	NR	DEX maintenance dose: 0; Transition: 0; Clonidine maintenance: 1 (5%); Clonidine taper final day: 1 (6%); Post clonidine: 0	0
Hypotension	Clonidine: 4 (44%); No clonidine: 6 (35%)	DEX maintenance dose: 8 (40%); Transition: 7 (35%); Clonidine maintenance: 4 (20%); Clonidine taper final day: 2 (12%); Post clonidine: 2 (25%)	0
Sedation assessment score	RASS; Clonidine: 0 (-2 to 2); No clonidine: 0 (0-2)	SAS Score outside the goal of 3-4; DEX maintenance: 10 (50%); Transition: 10 (50%); Clonidine maintenance: 9 (45%); Clonidine taper final day 13 (76%); Post clonidine: 2 (25%)	NR
CAM ICU	Clonidine: 4 (44%); No clonidine: 3 (18%), P = 0.036	DEX maintenance: 10 (50%); Transition: 11 (55%); Clonidine maintenance: 9 (45%); Clonidine taper final day: 13 (76%); Post clonidine: 3 (38%)	Taper: 11 (73%); No taper: 17 (63%)
Duration of mechanical ventilation (d), median (IQR)	NR	3.5 (0, 10.5)	NR
Hospital length of stay (d), median (IQR)	8 (4, 10.5)	16.5 (10.5, 29.5)	NR
ICU length of stay (d), median (IQR)	12.5 (7, 28)	9.5 (5, 16.5)	Taper: 22.7; No taper: 17
Mortality	0	2 (10%)	NR

¹Systolic blood pressure (SPB) > 180/120 after stopping despite 6-d taper, but was also tapering off methadone and clonazepam so causality if not clear.

²Significant withdrawal as defined by paper (≥ 2 heart rate > 90, Confusion Assessment Method positive, Richmond Agitation-Sedation Scale > 1, SBP > 140, Withdrawal Assessment Tool Version 1 > 2).

DEX: Dexmedetomidine; NR: Not reported; SAS: Sedation-Agitation scale.