The Effects of Different Vasopressors on the Innate Immune Response During Experimental Human Endotoxemia, a Pilot Proof-of-principle Study
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- concentration plasma TNFalpha (pg/ml) following endotoxemia between the noradrenaline and the placebo groups
研究概览
简要总结
Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. Catecholamines exert profound immunomodulatory effects. Noradrenaline in vitro inhibits LPS-induced pro-inflammatory cytokine production, however, the actions on immune function in vivo have not been assessed. Furthermore, effects on the immune system of viable vasopressor alternatives for the treatment of septic patients, namely phenylephrine and vasopressin, need to be established in humans in vivo.
详细描述
Rationale:
Septic shock is a major medical challenge associated with a high mortality rate and increasing incidence. It has become clear that the majority of septic patients do not succumb to an initial pro-inflammatory "hit", but at a later time-point in a pronounced immunosuppressive state, so called 'immunoparalysis'. Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. However, catecholamines exert profound immunomodulatory effects which have mainly been studied for adrenaline. It profoundly inhibits LPS-induced production of TNF-α, and enhances production of anti-inflammatory IL-10 in vitro, as well as in animal and human models of inflammation. Although in vitro studies have shown that noradrenaline inhibits LPS-induced pro-inflammatory cytokine production as potently as adrenaline, the effects of noradrenaline on the immune system in vivo have not yet been studied. Furthermore, effects on the immune system of viable vasopressor alternatives for the treatment of septic patients, namely phenylephrine and vasopressin, need to be established in humans in vivo.
Objective: To investigate whether noradrenaline exerts immunomodulatory effects in humans in vivo and to compare noradrenaline to other vasopressors (phenylephrine and vasopressin).
Study design: A randomized double-blind placebo-controlled study in healthy human volunteers during experimental endotoxemia.
Study population: 40 healthy male volunteers, aged 18-35 yrs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Written informed consent
- •Age ≥18 and ≤35 yrs
排除标准
- •Use of any medication
- •Previous spontaneous vagal collapse
- •History of atrial or ventricular arrhythmia
- •(Family) history of myocardial infarction or stroke under the age of 65 years
- •Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
- •Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
- •Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
- •Renal impairment (defined as plasma creatinin >120 μmol/l)
- •Liver enzyme abnormalities
- •Medical history of any disease associated with immune deficiency
- •CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxin administration
- •Participation in a drug trial or donation of blood 3 months prior to the LPS challenge
- •Use of recreational drugs within 7 days prior to experiment day
- •Recent hospital admission or surgery with general anaesthesia (<3 months)
- •Known anaphylaxis or hypersensitivity to the study drugs or their excipients
- •Recent anaesthesia with halogenated agents
- •Known cardiovascular disease (coronary artery disease)
- •Known chronic nephritis
研究组 & 干预措施
Norepinephrine
The noradrenaline group: a group of 10 subjects that will receive noradrenaline 0.05 μg/kg/min infusion for 5 hours, starting 60 minutes before endotoxin administration.
干预措施: Norepinephrine (Drug)
Vasopressins
The vasopressin group: a group of 10 subjects that will receive vasopressin 0.04 IU/min infusion for 5 hours, starting 60 minutes before endotoxin administration.
干预措施: Vasopressins (Drug)
Phenylephrine
The phenylephrine group: a group of 10 subjects that will receive phenylephrine 0.5 μg/kg/min infusion for 5 hours, starting 60 minutes before endotoxin administration.
干预措施: Phenylephrine (Drug)
Placebo
The placebo group: a group of 10 subjects that will receive NaCl 0.9% infusion for 5 hours, starting 60 minutes before endotoxin administration.
干预措施: Placebo (Drug)
结局指标
主要结局
concentration plasma TNFalpha (pg/ml) following endotoxemia between the noradrenaline and the placebo groups
时间窗: 1 day
comparison of subjects treated with noradrenaline compared to subjects treated with placebo
次要结局
- Cerebral vascular resistance(1 day)
- Cerebral Critical closing pressure(1 day)
- concentration plasma IL-6 (pg/ml)(1 day)
- concentration plasma IL-8 (pg/ml)(1 day)
- Leucocyte counts and differentiation(1 day)
- -The phenotype of circulating leukocytes(1 day)
- concentration plasma IL-10 (pg/ml)(1 day)
- concentration plasma IL-1RA (pg/ml)(1 day)
- concentration plasma IL-1beta (pg/ml)(1 day)
- symptoms during endotoxin day(1 day)
- blood pressure(1 day)
- temperature(1 day)
- cytokine production after ex vivo stimulation of leukocytes(1 day)
- phenotype of circulating leucocytes(1 day)
- Heart rate variability(1 day)
- Breathing frequency (breaths/ min)(1 day)
- Mean flow velocity of the median cerebral artery(1 day)
- cerebral microcirculatory flow(1 day)
- Stress Levels (in percentage based on heart rate and heart rate variability)(1 day)
- Tranfer function analysis(1 day)
- Microvascular flow (microvascular flow index)(1 day)
- Pulsatility index of the median cerebral artery(1 day)
- Mean flow index(via 1 day)
- cerebral oxygenation(1 day)