The use of clonidine in elderly patients with delirium; pharmacokinetics and hemodynamic responses

Background The Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is an RCT investigating the effect of clonidine in medical patients > 65 years with delirium. To assess the dosage regimen and safety measures of this study protocol, we measured the plasma concentrations and hemodynamic effects of clonidine in the first 20 patients. Methods Patients were randomised to clonidine (n = 10) or placebo (n = 10). The treatment group was given a loading dose (75μg every 3rd hour up to a maximum of 4 doses) to reach steady state, and further 75μg twice daily until delirium free for 2 days, discharge or a maximum of 7 days. Blood pressure (BP) and heart rate (HR) were measured just before every dose. If the systolic BP was < 100 mmHg or HR < 50 beats per minute the next dose was omitted. Plasma concentrations of clonidine were measured 3 h after each drug intake on day 1, just before intake (day 2 and at steady state day 4–6) and 3 h after intake at steady state (Cmax). Our estimated pre-specified plasma concentration target range was 0.3–0.7μg/L. Results 3 h after the first dose of 75μg clonidine, plasma concentration levels rose to median 0.35 (range 0.24–0.40)μg/L. Median trough concentration (C0) at day 2 was 0.70 (0.47–0.96)μg/L. At steady state, median C0 was 0.47 (0.36–0.76)μg/L, rising to Cmax 0.74 (0.56–0.95)μg/L 3 h post dose. A significant haemodynamic change from baseline was only found at a few time-points during the loading doses within the clonidine group. There was however extensive individual BP and HR variation in both the clonidine and placebo groups, and when comparing the change scores (delta values) between the clonidine and the placebo groups, there were no significant differences. Conclusions The plasma concentration of clonidine was at the higher end of the estimated therapeutic range. Hemodynamic changes during clonidine treatment were as expected, with trends towards lower blood pressure and heart rate in patients treated with clonidine, but with dose adjustments based on SBP this protocol appears safe. Trial registration ClinicalTrials.gov NCT01956604, 09.25.2013. EudraCT Number: 2013–000815-26, 03.18.2013. Enrolment of first participant: 04.24.2014

The protocol of the Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID:a randomised placebo-controlled trial

Background Delirium affects 15% of hospitalised patients and is linked with poor outcomes, yet few pharmacological treatment options exist. One hypothesis is that delirium may in part result from exaggerated and/or prolonged stress responses. Dexmedetomidine, a parenterally-administered alpha2-adrenergic receptor agonist which attenuates sympathetic nervous system activity, shows promise as treatment in ICU delirium. Clonidine exhibits similar pharmacodynamic properties and can be administered orally. We therefore wish to explore possible effects of clonidine upon the duration and severity of delirium in general medical inpatients. Methods/Design The Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is a randomised, placebo-controlled, double-blinded, parallel group study with 4-month prospective follow-up. We will recruit 100 older medical inpatients with delirium or subsyndromal delirium in the acute geriatric ward. Participants will be randomised to oral clonidine or placebo until delirium free for 2 days (Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria), or after a maximum of 7 days treatment. Assessment of haemodynamics (blood pressure, heart rate and electrocardiogram) and delirium will be performed daily until discharge or a maximum of 7 days after end of treatment. The primary endpoint is the trajectory of delirium over time (measured by Memorial Delirium Assessment Scale). Secondary endpoints include the duration of delirium, use of rescue medication for delirium, pharmacokinetics and pharmacodynamics of clonidine, cognitive function after 4 months, length of hospital stay and need for institutionalisation. Discussion LUCID will explore the efficacy and safety of clonidine for delirium in older medical inpatients. Trial registration ClinicalTrials.gov NCT01956604 . EudraCT Number: 2013-000815-2

The Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo-controlled trial

Objectives The aim of this double‐blinded randomised placebo‐controlled trial was to investigate the efficacy of clonidine for delirium in medical inpatients greater than 65 years. Methods Acutely admitted medical patients greater than 65 years with delirium or subsyndromal delirium were eligible for inclusion. Included patients were given a loading dose of either placebo or clonidine; 75 μg every third hour up to a maximum of four doses to reach steady state and further 75 μg twice daily until delirium free for 2 days, discharge or a maximum of 7 days of treatment. The primary endpoint was the trajectory of the Memorial Delirium Assessment Scale (MDAS) for the 7 days of treatment. Presence of delirium according to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) criteria and severity measured by MDAS were assessed daily until discharge or a maximum of 7 days after end of treatment. Results Because of slower enrolment than anticipated, the study was halted early. Ten patients in each group were studied. The low recruitment rate was mainly due to the presence of multiple patient exclusion criteria for patient safety. There was no significant difference between the treatment group in the primary endpoint comparing the trajectory of MDAS for the 7 days of treatment using mixed linear models with log transformation, (P = .60). The treatment group did not have increased adverse effects. Conclusions No effect of clonidine for delirium was found, although the study was under powered. Further studies in less frail populations are now required

The Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo-controlled trial

Objectives The aim of this double‐blinded randomised placebo‐controlled trial was to investigate the efficacy of clonidine for delirium in medical inpatients greater than 65 years. Methods Acutely admitted medical patients greater than 65 years with delirium or subsyndromal delirium were eligible for inclusion. Included patients were given a loading dose of either placebo or clonidine; 75 μg every third hour up to a maximum of four doses to reach steady state and further 75 μg twice daily until delirium free for 2 days, discharge or a maximum of 7 days of treatment. The primary endpoint was the trajectory of the Memorial Delirium Assessment Scale (MDAS) for the 7 days of treatment. Presence of delirium according to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) criteria and severity measured by MDAS were assessed daily until discharge or a maximum of 7 days after end of treatment. Results Because of slower enrolment than anticipated, the study was halted early. Ten patients in each group were studied. The low recruitment rate was mainly due to the presence of multiple patient exclusion criteria for patient safety. There was no significant difference between the treatment group in the primary endpoint comparing the trajectory of MDAS for the 7 days of treatment using mixed linear models with log transformation, (P = .60). The treatment group did not have increased adverse effects. Conclusions No effect of clonidine for delirium was found, although the study was under powered. Further studies in less frail populations are now required

Cerebrospinal Fluid S100B and Alzheimer's Disease Biomarkers in Hip Fracture Patients with Delirium

Objectives: This study aimed to investigate the relationship between cerebrospinal fluid (CSF) S100B astrocyte-derived protein and delirium and to perform stratified analyses according to clinical and CSF markers of dementia. Methods: We performed a prospective cohort study in a university hospital setting. The participants were patients admitted for hip fracture (n = 98) or for elective surgery (n = 50). Delirium was assessed daily perioperatively in hip fracture patients using the Confusion Assessment Method. A consensus-based diagnosis of prefracture dementia was made using all available information. CSF was drawn at the onset of spinal anesthesia. S100B and phosphorylated tau (P-tau) concentrations were measured using electrochemiluminescence immunoassay and enzyme-linked immunosorbent assays, respectively. Results: In the hip fracture population (n = 98) there was no significant difference in CSF S100B concentrations between patients with ongoing preoperative (i.e., prevalent) delirium (n = 36, median [interquartile range] 1.11 μg/L [0.91–1.29]) and patients who never developed delirium (n = 46, 1.08 μg/L [0.92–1.28], p = 0.92). In patients without preoperative delirium, those who developed delirium postoperatively (i.e., incident delirium) (n = 16, 1.38 μg/L [1.08–1.62]) had higher concentrations of S100B than the 46 who never did (p = 0.013). This difference was confined to patients with pathological concentrations of P-tau (≥60 ng/L, n = 38). We also found that P-tau and S100B were correlated in CSF in the elective surgery patients. Conclusions: CSF S100B was elevated in patients with incident delirium who also had pathological levels of the Alzheimer disease biomarker P-tau, suggesting vulnerability caused by a preexisting process of astrocytic activation and tau pathology

The use of clonidine in elderly patients with delirium; pharmacokinetics and hemodynamic responses

Background The Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is an RCT investigating the effect of clonidine in medical patients > 65 years with delirium. To assess the dosage regimen and safety measures of this study protocol, we measured the plasma concentrations and hemodynamic effects of clonidine in the first 20 patients. Methods Patients were randomised to clonidine (n = 10) or placebo (n = 10). The treatment group was given a loading dose (75μg every 3rd hour up to a maximum of 4 doses) to reach steady state, and further 75μg twice daily until delirium free for 2 days, discharge or a maximum of 7 days. Blood pressure (BP) and heart rate (HR) were measured just before every dose. If the systolic BP was < 100 mmHg or HR < 50 beats per minute the next dose was omitted. Plasma concentrations of clonidine were measured 3 h after each drug intake on day 1, just before intake (day 2 and at steady state day 4–6) and 3 h after intake at steady state (Cmax). Our estimated pre-specified plasma concentration target range was 0.3–0.7μg/L. Results 3 h after the first dose of 75μg clonidine, plasma concentration levels rose to median 0.35 (range 0.24–0.40)μg/L. Median trough concentration (C0) at day 2 was 0.70 (0.47–0.96)μg/L. At steady state, median C0 was 0.47 (0.36–0.76)μg/L, rising to Cmax 0.74 (0.56–0.95)μg/L 3 h post dose. A significant haemodynamic change from baseline was only found at a few time-points during the loading doses within the clonidine group. There was however extensive individual BP and HR variation in both the clonidine and placebo groups, and when comparing the change scores (delta values) between the clonidine and the placebo groups, there were no significant differences. Conclusions The plasma concentration of clonidine was at the higher end of the estimated therapeutic range. Hemodynamic changes during clonidine treatment were as expected, with trends towards lower blood pressure and heart rate in patients treated with clonidine, but with dose adjustments based on SBP this protocol appears safe