In this trial involving elective surgery patients planned to be admitted to an HDU for postoperative monitoring, clonidine increased the time spent asleep on the first postoperative night by approximately 100 minutes. Patients who received clonidine reported having had a better night’s sleep, and were observed by their bedside nurse to return to sleep more quickly after awakenings. No effect on delirium was able to be observed in this low-risk patient cohort. The only reported adverse effects from clonidine were bradycardia and hypotension, which were uncommon and required only cessation of the study medication.
The results of this study are consistent with several trials of dexmedetomidine following surgery. In a similar design to our trial aside from choice of medication, a study of low-dose (0·1 µg/kg/hr), non-titrated dexmedetomidine in 700 elective surgical patients ≥ 65 years admitted to a Beijing ICU [13] found a reduction in postoperative delirium incidence from 23–9%. While the mean APACHE II score on admission, 10.2–10.6, was similar to our study, just over 50% of those patients were intubated at study enrolment, and approximately 75% used patient-controlled opioids, perhaps explaining the higher incidence of delirium. Duration of sleep was not measured, but subjective sleep quality was significantly better in the dexmedetomidine group on postoperative days 1–3, consistent with our more detailed sleep results. In a similar study design, of 61 extubated ICU postoperative patients, those randomised to 0·1 µg/kg/hr dexmedetomidine (compared to placebo) on the first postoperative night had longer deep sleep, increased sleep efficiency, and better subjective sleep quality.[12] Others have found a nocturnal postoperative dexmedetomidine bolus [20] or infusion [21] compared to placebo reduced delirium [20] [21] following cardiac surgery, but neither of these trials assessed sleep as an outcome. No trial has assessed clonidine as we have done in this study.
In this study, clonidine had no observable analgesic effect. Clonidine is well-recognised as an effective analgesic adjunct for postoperative pain, with dose-dependent opioid sparing effects optimal at 3µg/kg bolus followed by 3µg/kg/hr infusion.[22] Our infusion of 0.3 µg/kg/hr without a preceding bolus is therefore likely to have been insufficient to produce maximal analgesia, but avoided the hypotension of higher doses.[22]
The dose selected for our study was based on both safety and extrapolation of likely effectiveness. Australian guidelines for clonidine as an anaesthesia adjunct that were in place when the study was designed [23] recommended intravenous loading with 1.5-5.0 µg/kg (maximum 600 µg) followed by infusion at 0.3 µg/kg/hr. This appears based on a 32-patient study of clonidine vs. placebo,[24] in which a postoperative infusion of 0.3 µg/kg/hr for six hours produced a mean reduction in blood pressure of 13 mmHg and heart rate 2 bpm. In a 70-patient comparison of intravenous clonidine and dexmedetomidine for sedation in predominantly surgical ICU patients,[25] median equi-sedative infusion doses required for a RASS of -3 or -4 were 0.4 µg/kg/hr for dexmedetomidine and 1.4 µg/kg/hr for clonidine. Assuming a linear conversion, scaling the 0.4 µg/kg/hr dexmedetomidine dose down to 0.1 µg/kg/hr (as used in [13]) would result in an equivalent clonidine infusion rate of 0.35 µg/kg/hr. Loading doses of intravenous clonidine cause bradycardia and hypotension.[22, 26] Consequently, we avoided using a loading dose.
We used of a consumer-targeted wrist sleep tracking device to assess the study primary outcome. Polysomnography is the gold standard for sleep measurement, but this is intrusive, labour intensive, costly, and is impractical in large numbers of patients.[27] Bispectral index (BIS) monitoring is also intrusive and prone to patient dislodgement. Wrist actigraphy is less intrusive and expensive, but although it detects sleep with good sensitivity, it overestimates sleep in immobile ICU patients.[28] Actigraphy is also unable to distinguish sleep stages. Consumer-targeted sleep tracking devices, such as the FitBit Alta HR, combine wrist actigraphy with reflective photoplethysmography to measure heart rate. Using the two modalities, these devices report time spent in each sleep stage (wake, N1 and N2, N3, and REM) and sleep statistics such as total sleep time and number of awakenings with moderate-to-good reliability in healthy volunteers when compared to polysomnography.[18] In a 507-patient study, a FitBit device accurately measured total sleep time in non-intubated ICU patients.[29]
Subjective sleep quality can also be assessed using questionnaires. At least 13 questionnaires have been used in ICU research,[30] but the RCSQ is the only scale validated in an ICU population.[31] The self-reported RCSQ correlated closely with polysomnography in 70 ICU patients.[31] It is unclear whether nurses’ assessment of sleep quality using the RCSQ is a reliable substitute for patient self-assessment.[32, 33] Our study found a clearer effect of clonidine in patient-reported scores, with the exception of the nurses’ observation of the time taken to fall asleep sleep – perhaps the most difficult element for a patient to assess.
We studied clonidine as an alternative to dexmedetomidine for several reasons. Clonidine is cheaper than dexmedetomidine in our hospital. At study commencement, an ampoule (200 µg / 2 mL) of dexmedetomidine was A$52.00, compared to A$5.70 for 150 µg / 1 mL of intravenous clonidine. Oral formulations are even cheaper: a 150 µg clonidine tablet costs only A$0.39. Dexmedetomidine is only available in intravenous form, requiring intravenous access, an infusion pump, and monitoring by nursing staff. If an equivalent dose of clonidine could be administered enterally or transcutaneously, discomfort and cost would be reduced. Dexmedetomidine’s potential cardiovascular side effects require monitored critical-care environments, while enteral or transcutaneous clonidine could be administered in surgical wards. Dexmedetomidine’s short elimination half-life (two hours) allows for easy titration when used as a sedative,[9] but if used for low-dose prophylaxis, titratability is less useful. Clonidine’s longer elimination half-life (12–16 hours) means any protective effects against postoperative delirium or improvement in sleep – if they exist – might last longer.
These results have potentially important implications for practice in the ward context as well as the HDU. Clonidine is used safely on hospital wards for hypertension, opioid withdrawal, as an analgesic adjunct.[34] Formulation as a transcutaneous patch [35] potentially expands postoperative utility in patients unable to swallow. In patients > 65 years, 75µg clonidine orally every 3 hours produced plasma concentrations at the high end of the therapeutic range. No safety concerns were identified.[36] The oral bioavailability of clonidine approaches 100%.[37] In an 80kg adult, a dose of 75µg PO q3hr is therefore approximately comparable to the 0.3 µg/kg/hr IV used in our trial. For an average 80 kg adult, a 300mg clonidine patch would equate to an infusion of 0.16 µg/kg/hr.[38]
We recognise several limitations to our study. Only 83 of the planned 120 patients (69%) were randomised. Unplanned early termination of clinical trials has been argued to exaggerate effect size, although in reality this effect is very small.[39] Adjustment for the two major potential confounders identified prior to study commencement had no effect on the results. Our study has many of the characteristics of single-centre trials we have previously identified as potentially misleading [40]: intercurrent care in our HDU might interact with clonidine and so limit external validity; our results might be specific to patients with this low baseline risk; knowledge that a patient was enrolled might have led clinicians to pay them more attention; and more subtle clonidine cardiovascular effects than could be recorded in our monitoring might nonetheless have unblinded treating clinicians. Although there was a difference in the primary outcome and several congruent secondary outcomes, the study was underpowered to detect differences in important end points including ICU length of stay, and the patients’ baseline risk of delirium was too low for this outcome to be affected.
Nonetheless, our study has many strengths. Its double-blinded design reduced bias. Patients were treated in an HDU that paid good attention to non-pharmacological aspects of sleep optimisation, so the medication effect was in addition to, not instead of, good clinical care. The magnitude of effect on the primary outcome is biologically plausible and consistent with earlier trials of a2 agonists in similar contexts. The outcome differences are patient-centred, especially the superiority in patient-reported sleep scores. The trial’s broad eligibility criteria suggest this intervention might safely translate to postoperative patients in less intensely monitored environments. That we had to screen 1169 patients to randomise 83 was primarily due to trial resource limitations, not patient ineligibility.