Low-dose clonidine infusion to improve sleep in postoperative patients in the high-dependency unit. A randomised placebo-controlled single-centre trial

SFY – Low-dose clonidine infusion to improve sleep in postoperative patients in the high-dependency unit. A randomised placebo-controlled single-centre trial

What was it?

Single-center, double-blind, placebo-controlled pilot trial (CLONES study) evaluating low-dose intravenous clonidine (0.3 μg/kg/h), versus saline placebo, to improve sleep in postoperative patients in a high-dependency unit (HDU).

The Devil in the Details!

• 80 patients analyzed (39 clonidine, 41 placebo), in 1 academic hospital in China
• Clonidine infusion vs. placebo on the first postoperative night
• Adult patients post-elective non-cardiac surgery.
• Primary outcome: Total sleep time (objective, via consumer-grade wearable device), 20:00-06:00.
• Secondary outcomes: Subjective sleep quality (patient and nurse reports), safety events (e.g., hypotension, bradycardia).

The Results!

• Patients receiving a low-dose clonidine infusion slept a mean difference of 100.8 ([CI 38.2,163.4] p=0.002) minutes longer than those receiving a saline infusion.
• Improved subjective sleep quality: Patients and nurses reported faster sleep onset and better rest.
• They spent more time in light sleep (mean difference 87.7 [CI 28.7, 146.7] p=0.005) minutes, though they had more awakenings (mean 4.5 [CI 0.5, 8.5], p=0.027).
• Whilst not significantly different, the median fentanyl equivalent dose of analgesia was less in the clonidine group (median 75mcg vs 160mcg [CI -296, 126] p=0.59).
• Safety profile: 4 patients stopped clonidine due to bradycardia or hypotension; no serious adverse events requiring treatment.

They concluded

The authors concluded that among postoperative elective surgical patients admitted to HDU, a low-dose non-titrated clonidine infusion, compared to placebo, was associated with longer and subjectively better-quality sleep.

Gripe Point Summary!

Detailed gripes here

It provides promising evidence for clonidine as a sleep aid, but:

• Single-center design limits generalizability.
• Not powered for secondary outcome measures, including important safety outcomes
• Consumer-grade sleep device raises accuracy concerns.
• Impact of clonidine on heart rate and the device algorithm for determining sleep status, bradycardia in 10%
• Only assessed one night, missing long-term effects.
• Questionable use of mean difference and t-test on primary outcome measure, given skewed distribution of placebo data
• Excluded high-risk patients, narrowing applicability.
• Small sample size (absolute and relative to the total possible eligible participants)

Our Summary

In postoperative HDU patients, low-dose clonidine infusion (0.3 μg/kg/h) increased sleep time by ~100 minutes and improved subjective sleep quality compared to placebo, with minor safety concerns. This pilot study suggests clonidine’s potential as a cost-effective sleep aid, but larger, multicenter trials are needed.

Who’s worked on this before?

Liu et al – Low-dose clonidine infusion to improve sleep in postoperative patients in the high-dependency unit. A randomised placebo-controlled single-centre trial

Beswick et al – The effectiveness of non-pharmacological sleep interventions for improving inpatient sleep in hospital: A systematic review and meta-analysis

Maldonado et al. – Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery

Kamdar et al. 2020 – Perceptions and Practices Regarding Sleep in the Intensive Care Unit. A Survey of 1,223 Critical Care Providers

Heavner et al – A Rapid Systematic Review of Pharmacologic Sleep Promotion Modalities in the Intensive Care Unit

Wu et al – Low-dose Dexmedetomidine Improves Sleep Quality Pattern in Elderly Patients after Noncardiac Surgery in the Intensive Care Unit: A Pilot Randomized Controlled Trial

Romagnoli et al – Sleep duration and architecture in non-intubated intensive care unit patients: an observational study

Further gripes

1. Not powered for secondary outcome measures, including important safety outcomes
2. Possible impact of clonidine on heart rate and the device algorithm for determining sleep status. Actigraphy alone is known to overestimate sleep in immobile ICU patients.
3. Questionable generalisability given single centre and inclusion/exclusion criteria. Local practice and protocols regarding sleep may affect generalizability.
4. No recording of the use of non-pharmacological (sleep mask, earplugs) for each group.
5. The sample had low APACHE-II scores – there is likely local variation in eligibility for HDU vs what can be managed in a level 1 setting.
6. There was a low prevalence of PCA use (<10%). There was a high proportion of patients receiving clonidine intra-operatively compared to our local site. Was this centre’s HDU population representative of your centre’s?
7. Questionable use of mean difference and t-test on primary outcome measure, given skewed distribution of placebo data. The histogram of the saline group was positively skewed, with low total sleep time outliers. This may mean a parametric t-test was inappropriate for comparison of mean differences.
8. Small sample size (absolute and relative to the total possible eligible participants, 83/1169). Stopped early due to covid/exhaustion of funding. Planned n of 120, from sample size calculation. Exclusion criteria included bradyarrhythmia, chronic alpha-2 agonist use, advanced dementia, previous ADR to alpha-2 agonists, ESRD, non-cardiac surgery, non-intubated, comorbidities that would interfere with sleep measurement (not specified), and patients planned for discharge directly from HDU. 
9. High proportion of clonidine infusions stopped due to hypotension/bradycardia (10%). This perhaps challenges the authors’ suggestion of suitability for use in a less monitored environment, given the high rate of cessation.
10. The choice of a sleep window of 8pm-6am – many may choose to sleep later into the morning following a surgery – the chosen time window may exclude a significant period of time for sleep (6-9am for example). Would the results have differed if this period had been included? 
11. RCSQ is validated for self-use; here, it was used by bedside nurses.
12. Use of other pharmacological sleep interventions, eg zoplicone / melatonin, not recorded for either group, could confound the results. 

CCN’s Reflection

This pilot trial offers a compelling case for low-dose clonidine as a practical, low-cost sleep aid in postoperative care, with a solid double-blind design and clear results. However, its single-centre scope, reliance on potentially flawed sleep measurement, and lack of long-term or high-risk patient data temper enthusiasm. It’s a strong first step, but we need bigger, broader trials to confirm clonidine’s role in the HDU—and to ensure we’re not just sedating patients into a false sense of rest. Stay tuned for the multicenter sequel!

Written by Dr Connor Putnam

Peer Reviewed by Dr Jonny Wilkinson