Pharmacokinetics and Clinical Effects of Escalating Doses of Clonidine in ICU Patients
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- clonidine plasma concentrations
研究概览
简要总结
This study is developed for assessing the pharmacodynamic and pharmacokinetic properties of intravenous (IV) clonidine in critically ill patients on the ICU, and to estimate the optimal dosing strategy for IV clonidine.
详细描述
Many patients in intensive care units (ICU's) require sedation and analgesia to tolerate mechanical ventilation and other ICU procedures. Commonly used GABA-ergic anaesthetics like propofol, midazolam and morphine have potential adverse effects that may increase morbidity, prolong ICU stay and provoke delirium. Recent studies have shown that sedation with alpha-2-adrenergic agonists may lead to a reduction of the total amount of gamma-aminobutyric acid (GABA) -ergic anaesthetics and reduction of delirium1In clinical practice the alpha-2-adrenergic agent clonidine is widely used off label as an add-on sedative in mechanically ventilated patients who suffer from delirium, but there are no large studies proving that this therapy is effective and safe. Limited information exists on the pharmacokinetics of iv clonidine, especially in ICU patients. Besides, dosing regimens of clonidine differ widely among ICU's in the Netherlands, and in the literature.
The sample size required for pharmacokinetic modelling with an acceptable level of precision is inversely related to the number of blood samplings taken from each individual. Population pharmacokinetic experiments that have been published have generally used 50 or more subjects. However, in the investigators study a relatively large number of blood samples are taken (>10 per subject when the protocol is completed, see section 6.3). THe investigators estimate that sufficient precision can be obtained with a sample size of 24 subjects, generating an estimated 240 to 360 blood samples.
In a recent publication of a computer simulated population pharmacokinetics of an absorption model using a design that involved 6 samplings per subject, it was estimated that a two-compartment first-order model would need 50 subjects (i.e. 300 blood samplings) to obtain a model with 50% precision and a power of 0.8.
The investigators 24 subjects will be treated with 3 different doses of clonidine (600, 1200 and 1800 µg/day), that is 8 per treatment arm.
On top of this, 8 patients receiving no clonidine will serve as a reference group, in order to interpret hemodynamic and safety data, and to illustrate dose-response relationships.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •In order to be eligible to participate in this study, a subject must be:
- •at least 18 years of age
- •intubated
- •sedated at the start of the study. Because of the high incidence of delirium on the ICU in all age categories, all age groups > 18 years will be included
排除标准
- •Severe neurotrauma,
- •Severe dementia (living in a nursing home)
- •Inability to speak Dutch or English, which is one of the causes of not being able to use the CAM-ICU.
- •The use of clonidine during the 96 hours before the start of the study.
- •Bradycardia (<50/min)
- •Severe hypotension (MAP < 65 after volume resuscitation and vasopressors)
- •Pregnancy and lactation (pregnancy test are routinely performed in premenopausal women on the ICU).
- •Known clonidine intolerance
- •Liver cirrhosis (Child Pugh class C)
- •Recent and acute myocardial infarction
- •Severe heart failure (LVEF < 30%)
- •Second or third degree atrioventricular (AV)-block without a permanent pacemaker
- •Expected transfer to another hospital.
研究组 & 干预措施
Clonidine 600mcg
4 patients receive 600 µg/day of clonidine without loading schedule. 4 patients receive 600 µg/day of clonidine with a loading schedule of 300 µg in 4 h.
干预措施: Clonidine (Catapresan®) 0,150 mg/ml, ampoule 1 ml (Drug)
Clonidine 1200mcg
- 4 patients receive 1200 µg/day of clonidine without loading schedule.
- 4 patients receive 1200 µg/day of clonidine with a loading schedule of 600 µg in 4 h.
干预措施: Clonidine (Catapresan®) 0,150 mg/ml, ampoule 1 ml (Drug)
Clonidine 1800mcg
- 4 patients receive 1800 µg/day of clonidine without loading schedule.
- 4 patients receive 1800 µg/day of clonidine with a loading schedule of 900 µg in 4 h.
干预措施: Clonidine (Catapresan®) 0,150 mg/ml, ampoule 1 ml (Drug)
结局指标
主要结局
clonidine plasma concentrations
时间窗: up to 7 days
pharmacokinetic and pharmacodynamic properties of intravenous clonidine in ICU patients Clonidine plasma concentration at start of infusion at t=2, t=4, t=8 and t=12 h Clonidine plasma concentration during study, once daily Clonidine plasma concentration after stopping infusion at t=ω+8, t=ω+16, t=ω+24 h, and t=ω+48 h (ω= end of infusion).
次要结局
- heart rate(up to 7 days)
- blood pressure(up to 7 days)
- delirium(up to 7 days)
- use of antipsychotics(up to 7 days)
研究者
M. Zeeman
drs M. Zeeman
Deventer Ziekenhuis