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!
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?
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
Romagnoli et al – Sleep duration and architecture in non-intubated intensive care unit patients: an observational study
Further gripes
- Not powered for secondary outcome measures, including important safety outcomes
- 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.
- Questionable generalisability given single centre and inclusion/exclusion criteria. Local practice and protocols regarding sleep may affect generalizability.
- No recording of the use of non-pharmacological (sleep mask, earplugs) for each group.
- 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.
- 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?
- 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.
- 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.
- 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.
- 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?
- RCSQ is validated for self-use; here, it was used by bedside nurses.
- 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