What evidence supports transitioning from dexmedetomidine to clonidine for sedation management?
What evidence supports transitioning from dexmedetomidine to clonidine for sedation management?
Dexmedetomidine is a centrally acting α2 agonist that is approved by the Food and Drug Administration (FDA) in adults for procedural sedation and for sedation of intubated and mechanically ventilated patients in the intensive care unit (ICU) for up to 24 h.1,2 Although approved for up to 24 h, it is often used for longer durations. Discontinuation of dexmedetomidine has been associated with withdrawal symptoms (termed dexmedetomidine withdrawal syndrome) due to sympathetic hyperactivity.2 Although not well-defined, symptoms typically include tachycardia, hypertension, and agitation. Recently, clonidine has been studied to help wean from dexmedetomidine sedation. The purpose of this FAQ is to describe the literature on transitioning from dexmedetomidine infusions to clonidine to prevent symptoms of dexmedetomidine withdrawal.
Rationale for Clonidine Transition
Clonidine has been used to transition patients off dexmedetomidine due to its similar mechanism of action.2,3 Like dexmedetomidine, clonidine is a centrally acting α2 agonist; however, clonidine has lower α2 to α1 receptor specificity compared to dexmedetomidine (200:1 vs 1600:1), and has a longer half-life (8 to 12 h vs 2 h). During dexmedetomidine discontinuation, clonidine is hypothesized to attenuate the hyperactive effects of the central nervous system due to its α2 agonist effects and its lower affinity for the α2 receptors. Use of clonidine is advantageous as dexmedetomidine is only available intravenously, and often must be administered in the ICU. In contrast, clonidine is available for enteral and transdermal administration which may allow for transition out of the ICU and may result in cost savings. Another advantage of clonidine use includes its potential to reduce the symptoms of withdrawal of other ICU sedative agents such as opioids and benzodiazepines.
Guideline Recommendations
The 2018 Society of Critical Care Medicine (SCCM) Guideline for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU provides recommendations for preferred sedatives.4 The guideline conditionally recommends propofol or dexmedetomidine over benzodiazepines for sedation in critically ill, mechanically ventilated adults (excluding patients undergoing cardiac surgery) based on short- and long-term outcomes. Propofol is preferred when deep sedation is required. The appropriate duration of dexmedetomidine infusion is not defined by the guideline. In addition, using clonidine to discontinue the dexmedetomidine infusion is not mentioned in the guideline. Although not FDA-approved in pediatric patients, dexmedetomidine is commonly used for sedation in the pediatric population.1,5
Literature Summary
A literature search was conducted in MEDLINE to identify clinical studies evaluating the efficacy and safety of using clonidine to wean dexmedetomidine. Two studies were identified that evaluated transitioning from dexmedetomidine to clonidine in adult patients, and 5 studies were identified in pediatric patients (Table).6-12 Most of the studies were retrospective, single-center, with several limitations described in the Table. In addition, many patients were also on opioids and benzodiazepines which may have contributed to symptoms associated with dexmedetomidine or clonidine.
In the 2 adult studies, dexmedetomidine was discontinued in 65.4% of patients within 8 h of starting clonidine in the Terry et al (2015) study, while 50% and 75% of patients were successfully transitioned from dexmedetomidine within 24 h and 48 h of clonidine initiation in the Gagnon et al (2015) study.6,7 In pediatric patients, studies by Beitz et al (2019) and Haenecour et al (2017) did not find clonidine to affect withdrawal symptoms in patients weaned from dexmedetomidine.10,11 Use of clonidine resulted in numerically fewer elevated Withdrawal Assessment Tool-1 (WAT-1) scores in the study by Lardieri et al (2015), and use of clonidine resulted in a low rate of re-initiation of dexmedetomidine for withdrawal symptoms in the study by Liu et al (2020).9,12 Finally, a recent study by Lee et al (2020) found 37% of patients with elevated WAT-1 scores after transitioning with clonidine, and also found that higher doses and longer duration of dexmedetomidine are important to consider when choosing a starting clonidine dose.8
| Table. Studies evaluating transitioning from dexmedetomidine to clonidine.6-12 | ||||
|---|---|---|---|---|
| Study design | Subjects | Interventions | Results | Limitations |
| Adult patients | ||||
| Gagnon 20156 Prospective, single-center, pilot study | N=20 adult patients (median age, 62 years) in the ICU (medical, surgical, neurologic) Mean DEX duration prior to starting clonidine: 33 h Median DEX infusion rate: 1.0 mcg/kg/h | Clonidine 0.2 to 0.5 mg orally or sublingually every 6 h depending on factors below Start with 0.2 mg if DEX dose < 0.7 mcg/kg/h, body weight < 100 kg, or elderly Start with 0.3 to 0.5 mg if DEX dose ≥ 0.7 mcg/kg/h, body weight ≥ 100 kg, or young patients The DEX dose was reduced by 25% from baseline within 6 h after clonidine dose if no agitation requiring rescue medications occurred. Clonidine was adjusted for SAS goal of 3 to 4, agitation, hypotension, or bradycardia. DEX was adjusted for agitation or AEs. Clonidine was tapered by increasing the dosing interval every 24 to 48 h. | 50% and 75% of patients were successfully transitioned from DEX within 24 h and 48 h of clonidine initiation Daily fentanyl requirements were lower with clonidine than DEX (p=0.03) Hypotension occurred in 40% with DEX vs 20% with clonidine; one patient experienced bradycardia with clonidine One patient experienced clonidine withdrawal syndrome (BP > 180/120 mmHg) Pain scores were elevated with clonidine use alone | Small, single-center, observational study with no comparator group Documentation of efficacy and safety parameters varied |
| Terry 20157 Retrospective, single-center study | N=26 adults (mean age, 54.4 years) primarily in the cardiac ICU Median duration of DEX infusion prior to starting clonidine: 24 h in the 8 h group DEX infusion rate: ≤ 0.4 mcg/kg/h in most patients in the < 8 h group | Patients who discontinued DEX within 8 h after starting clonidine Patients who discontinued DEX > 8 h after starting clonidine Clonidine was initially administered 0.1 mg by mouth or enterally every 6 to 8 h | 65.4% of patients discontinued DEX within 8 h of starting clonidine No patients required re-initiation of DEX within 24 h Mean time to transition was 1 h (< 8 h group) vs 28 h (> 8 h group) RASS and CAM-ICU scores and rescue medication use were similar between the 2 groups Hypotension occurred in 35.5% and 44.4% of the 8 h group | Small, single-center, retrospective study without a non-clonidine comparator group The process of transitioning from DEX to clonidine was not standardized (eg, patient selection, dosing) |
| Pediatric patients | ||||
| Lee 20208 Retrospective, single-center study | N=38 pediatric patients (39 total DEX courses) (median age, 4.3 years) in the PICU who received DEX infusion ≥ 72 h and clonidine ≥ 48 h Mean dose: 1 mcg/kg/h Median duration of DEX infusion: 7.6 days (IQR, 5 to 11.5) | Median clonidine dose at initiation: 8.3 mcg/kg/day (< 50 kg) and 4.1 mcg/kg/day (≥ 50 kg) administered every 8 h (most commonly) Transition to clonidine occurred over a median of 0.8 days | 37% of patients had a WAT-1 scorea ≥ 3 when transitioning from DEX to clonidine 18% had elevated WAT-1 scores which required an increase in sedation (increase in DEX, clonidine, or a rescue dose of clonidine) Higher mean DEX dose in 24 h prior to starting clonidine correlated significantly with higher starting clonidine dose (p=0.04) 2 hypotensive events were possibly related to DEX and 2 to clonidine 1 bradycardic event was possibly related to DEX and 1 to clonidine | Small, single-center, retrospective study without a non-clonidine comparator group The process of transitioning from DEX to clonidine was not standardized (eg, patient selection, dosing) WAT-1 is not validated for assessing α-agonist withdrawal |
| Liu 20209 Retrospective, single-center study | N=22 pediatric patients (24 total DEX courses) (median age, 3.5 months) in the PICU who received DEX ≥ 48 h Median hourly DEX dose: 1.2 mcg/kg/h Median DEX treatment duration: 3.8 days Median DEX wean duration: 7 h | Clonidine enterally started at 2 mcg/kg every 6 h for age < 6 months old and 4 mcg/kg every 6 h for age ≥ 6 months old DEX was reduced by 50%, 30 min after the second dose of clonidine; DEX was discontinued 30 min after the third dose of clonidine Clonidine weaning procedure: 4 mcg/kg every 6 h for 4 doses; 4 mcg/kg every 8 h for 3 doses; 4 mcg/kg every 12 h for 2 doses; 4 mcg/kg at 24 h for 1 dose | Restarting a DEX infusion (ie, clinically significant withdrawal) occurred in 8.3% Patients in whom DEX was restarted had longer duration of DEX (19 days vs 3.6 days) (p=0.04) and numerically higher cumulative DEX dose (253 mcg/kg vs 117 mcg/kg) 6 courses required increased clonidine dose without restarting DEX infusion; 5 of 6 patients experienced improved WAT-1 scores Bradycardia or hypotension (requiring interventions) occurred in 2 encounters (8%) (one patient experienced septic shock requiring albumin bolus; one patient had prior bradycardia) | Small, single-center, retrospective study with no comparator group WAT-1 is not validated for assessing α-agonist withdrawal |
| Beitz 201910 Retrospective, single-center study | N=115 pediatric patients (median age, 36 months in DEX group) who received DEX ≥ 48 h Median duration of DEX: 13.5 days (clonidine group) vs 5.0 days (no-clonidine group) (p<0.001) Median maximum DEX dose: 0.9 mcg/kg/h (clonidine group) vs 0.8 (no-clonidine group) | Clonidine (n=27) (median dose, [route not defined] 4.5 mcg/kg/day; range, 1.4 to 18.8 mcg/kg/day) No clonidine (n=88) | Withdrawal symptoms occurred in 71.6% of patients who received clonidine and 63% of patients who did not (p=NS) There were no differences in tachycardia, hypertension, or agitation between groups | Small, retrospective, single-center study The process of transitioning from DEX to clonidine was not standardized Baseline DEX duration different between groups Minimal information provided (written as a letter to the editor) |
| Haenecour 201711 Retrospective, single-center, study | N=52 pediatric patients (68 total DEX courses) (median age, 5 months) in the PICU and CCCU who received DEX ≥ 48 h Total DEX duration: 127.7 h and 187.9 h in patients with no withdrawal and withdrawal Total DEX dose (cumulative): 103.4 mcg/kg and 193.8 mcg/kg in patients with no withdrawal and withdrawal | Clonidine was prescribed in 37 encounters (54.4%) Median total oral clonidine daily dose: 16 mcg/kg Median overlap time of clonidine and DEX was 30 h | Clonidine administration did not affect occurrence of withdrawal; withdrawal occurred in 13 of 37 encounters taking clonidine (p=NS) | The purpose of the study was to evaluate risk factors for DEX withdrawal, not to evaluate clonidine primarily Small, single-center, retrospective study The process of transitioning from DEX to clonidine was not standardized WAT-1 is not validated for assessing α-agonist withdrawal |
| Lardieri 201512 Retrospective, single-center study | N=19 patients (20 total DEX courses) (median age, 1.5 years) in the PICU who were being weaned from DEX ≥ 5 days Median DEX infusion duration prior to starting clonidine: 241.8 h (clonidine group) vs 134.0 h (no-clonidine group) (p=0.003) Mean DEX infusion rate prior to weaning: 1.0 mcg/kg/h in both groups | Clonidine transdermal patch (mostly 100 mcg/24 h) applied ≥ 48 h prior to stopping DEX (mean, 5.6 days before stopping DEX) (n=12) No clonidine (n=8) | In 24 h after DEX discontinuation, elevated WAT-1 scores ≥ 3 occurred in 36.4% and 66.7% in the clonidine and non-clonidine groups (mean number of elevated scores, 0.8 vs 3.2) (p=NS) Rebound systolic and diastolic hypertension occurred in 16.7% and 33.3% of patients in the clonidine group and 0 and 12.5% patients in the no clonidine group Mean heart rate was lower in the clonidine group (112 bpm) compared to no clonidine (138.4 bpm) (p=0.003) Rebound tachycardia occurred in 25% vs 50% of patients in the clonidine and no-clonidine groups (p=NS) | Small, single-center, retrospective study The process of transitioning from DEX to clonidine was not standardized WAT-1 is not validated for assessing α-agonist withdrawal |
| aWAT-1 scores range from 0 to 12; scores ≥ 3 indicate clinically significant withdrawal. Abbreviations: AEs=adverse events; BP=blood pressure; bpm=beats per minute; CAM-ICU=Confusion Assessment Method for the ICU; CCCU=cardiac critical care unit; DEX=dexmedetomidine; ICU=intensive care unit; IQR=interquartile range; NS=non-significant; PICU=pediatric intensive care unit; RASS=Richmond Agitation Sedation Scale; SAS=Sedation-Agitation Scale; WAT-1=Withdrawal Assessment Tool-1. |
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Use in Practice
According to a survey of American Academy of Pediatrics Section on Critical Care members, 87.8% of members were concerned regarding dexmedetomidine withdrawal.5 In addition, 81% of respondents reported managing dexmedetomidine withdrawal by weaning dexmedetomidine and starting clonidine. Most respondents used enteral clonidine (71%) and some also used transdermal clonidine (29%). Although the enteral clonidine dosing varied, the most common dosing strategy was to initiate enteral clonidine 1 mcg/kg every 6 h. The majority of respondents (74%) indicated monitoring for withdrawal symptoms using the WAT-1 scores.
A review by Gagnon et al (2017) recommends an adult dosing strategy for dexmedetomidine and clonidine, which is similar to the dosing used in the Gagnon et al (2015) study.6,13 The authors suggest the following dosing of enteral clonidine: 0.1 to 0.3 mg every 6 to 8 h and titrated to 0.4 mg every 6 h based on clinical features.13 Reduce the dexmedetomidine infusion by 25% with each clonidine dose. A lower initial dose of clonidine (eg, 0.2 mg enterally every 6 to 8 h) can be considered in the following patients: body weight less than 100 kg, age greater than 70 years, or sedated at dexmedetomidine dose < 0.7 mcg/kg/h. The authors do not recommend using transdermal patches because of the time to reach steady state (3 to 4 days) and potentially impaired absorption in critically ill patients. Patients in whom clonidine should not be used include the following: heart rate < 50 beats/minute, mean arterial blood pressure < 65 mm Hg, systolic blood pressure < 90 mm Hg, need for vascular support, or atrioventricular conduction defects greater than first-degree block. Hypotension is a common adverse event associated with clonidine. In addition, clonidine discontinuation has been associated with withdrawal symptoms such as rebound hypertension; therefore, tapering clonidine by increasing the dosing interval every 24 to 48 h is advised. The following clonidine tapering example is provided: 0.3 mg enterally every 6 h for 4 doses; then 0.3 mg enterally every 8 h for 3 doses; then 0.3 mg enterally every 12 h for 2 doses; then 0.3 mg per day for 1 dose, then discontinue.
Conclusion
Overall, clonidine is a promising agent for preventing dexmedetomidine withdrawal symptoms when dexmedetomidine is discontinued. However, data supporting the use of clonidine are limited and primarily based on small, single-center, retrospective studies. Therefore, further studies are required to define the role of clonidine for weaning dexmedetomidine, determine appropriate patients for use of clonidine, and to establish optimal dosing strategies.
References
- Precedex. Package Insert. Hospira, Inc; 2020.
- Glaess SS, Attridge RL, Christina Gutierrez G. Clonidine as a strategy for discontinuing dexmedetomidine sedation in critically ill patients: A narrative review. Am J Health Syst Pharm. 2020;77(7):515-522. doi:10.1093/ajhp/zxaa013
- Kamat PP, Kudchadkar SR. IV clonidine in the PICU: Time for dexmedetomidine to share the limelight?. Pediatr Crit Care Med. 2018;19(8):792-794. doi:10.1097/PCC.0000000000001649
- Devlin JW, Skrobik Y, Gélinas C, 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
- Thompson RZ, Gardner BM, Autry EB, Day SB, Krishna AS. Survey of the current use of dexmedetomidine and management of withdrawal symptoms in critically ill children. J Pediatr Pharmacol Ther. 2019;24(1):16-21. doi:10.5863/1551-6776-24.1.16
- Gagnon DJ, Riker RR, Glisic EK, Kelner A, Perrey HM, Fraser GL. Transition from dexmedetomidine to enteral clonidine for ICU sedation: an observational pilot study. Pharmacotherapy. 2015;35(3):251-259. doi:10.1002/phar.1559
- Terry K, Blum R, Szumita P. Evaluating the transition from dexmedetomidine to clonidine for agitation management in the intensive care unit. SAGE Open Med. 2015;3:2050312115621767. doi:10.1177/2050312115621767
- Lee MM, Caylor K, Gockenbach N. Evaluating the transition from dexmedetomidine to clonidine for the prevention of withdrawal in critically ill pediatric patients. J Pediatr Pharmacol Ther. 2020;25(2):104-110. doi:10.5863/1551-6776-25.2.104
- Liu J, Miller J, Ferguson M, Bagwell S, Bourque J. The impact of a clonidine transition protocol on dexmedetomidine withdrawal in critically ill pediatric patients. J Pediatr Pharmacol Ther. 2020;25(4):278-287. doi:10.5863/1551-6776-25.4.278
- Beitz ER, Seabury R, Miller CD, Darko WQ, Probst LA, Steidl KE. Clonidine for dexmedetomidine withdrawal in pediatric patients: A single center’s experience. J Pediatr Pharmacol Ther. 2019;24(6):542-543. doi:10.5863/1551-6776-24.6.542
- Haenecour AS, Seto W, Urbain CM, Stephens D, Laussen PC, Balit CR. Prolonged dexmedetomidine infusion and drug withdrawal in critically ill children. J Pediatr Pharmacol Ther. 2017;22(6):453-460. doi:10.5863/1551-6776-22.6.453
- Lardieri AB, Fusco NM, Simone S, Walker LK, Morgan JA, Parbuoni KA. Effects of clonidine on withdrawal from long-term dexmedetomidine in the pediatric patient. J Pediatr Pharmacol Ther. 2015;20(1):45-53. doi:10.5863/1551-6776-20.1.45
- Gagnon DJ, Fontaine GV, Riker RR, Fraser GL. Repurposing valproate, enteral clonidine, and phenobarbital for comfort in adult ICU patients: A literature review with practical considerations. Pharmacotherapy. 2017;37(10):1309-1321. doi:10.1002/phar.2017
Prepared by:
Patricia Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
August 2020
The information presented is current as July 17, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.