HIGH-dose Intravenous VItamin C in Patients With Septic Shock: HIGH-VIS Trial
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Time to cessation of vasopressor support
研究概览
简要总结
Despite promising observational and phase 1 data, the therapeutic potential of vitamin C for the management of septic shock has not borne out in recent large multi-centre randomized controlled trials. There is biological plausibility for benefit with intravenous vitamin C, and the investigators hypothesize that the doses used in these trials were insufficient to demonstrate an effect. High-dose vitamin C has been trialed in patients with cancer and burns and proven to be safe. The investigators have recently demonstrated a dramatic benefit of high-dose intravenous vitamin C in reversing organ dysfunction in a large mammalian model of sepsis. The proposed prospective interventional study will be the first to administer high-dose intravenous vitamin C in critically ill patients with sepsis. The objectives of this study will be to determine whether high-dose intravenous vitamin C (i) reduces vasopressor requirement in critically ill patients with septic shock (ii) reverses organ dysfunction and (iii) is well tolerated.
详细描述
The investigators plan to conduct a phase 1, feasibility, prospective, two-centre, randomised, open-label, trial in 30 ICU patients with septic shock to test whether the intravenous administration of two stepped doses of high-dose intravenous vitamin C for 48 hours leads to a reduction in duration of vasopressor requirement and an improvement in organ failure scores and blood biomarkers of sepsis compared to standard care.
Patients will be randomized 1:1:1 to receive either 30 g of vitamin C twice daily for 48 hours (+ 30 g load) (n=10), 60 g of vitamin C twice daily for 48 hours (+ 30 g load) (n=10) or usual care (no vitamin C) (n=10).
Vitamin C is provided by the manufacturer (Orthomolecular Medisearch Laboratory P/L, Braeside, Victoria, Australia) as 30 grams in 100 ml. At study commencement (T = 0) patients randomized to either vitamin C arm will receive a loading dose of 30 grams of vitamin C infused through central venous access via a dedicated line over 2 hours (50 ml/hr =15 g/hr). In patients randomized to 60 g/day, this will be immediately followed by an infusion of 30 grams of vitamin C (100 ml) over 6 hours which will then be repeated at 14, 26 and 38 hours (i.e., 2 days of treatment). In patients randomized to the higher dose, two vials (200 ml = 60 grams) will be infused through a central venous catheter over 6 hours immediately following the 30 gram loading dose. This dose will be repeated at 14, 26 and 38 hours (i.e., 2 days of treatment). Patients in the control arm will receive usual care.
The investigators also plan to describe the pharmacokinetic parameters of high-dose intravenous vitamin C in critically ill patients with septic shock. These results will inform a subsequent multi-centre, blinded, parallel group randomized controlled trial to determine the efficacy of high-dose intravenous vitamin C for the reversal of septic shock and potentially improved survival.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of septic shock within 24 hours of admission to the ICU
- •Age 18 - 80 years
- •Presence of a central venous catheter for vasopressor infusion
- •Presence of an arterial line to monitor blood pressure
- •Definition of sepsis Suspected or documented infection and an increase of ≥ 2 SOFA points consequent to the infection.
- •Definition of septic shock Sepsis AND an arterial lactate >2 mmol/L AND need for vasopressor therapy to keep MAP >65 mmHg for > 2 hours despite fluid resuscitation therapy.
排除标准
- •Age <18 or > 80 years
- •DNI (do not intubate) orders i.e., Goals of Care other than A
- •Patients with a primary admission diagnosis of a traumatic brain injury
- •Patients with features of septic shock admitted in the ICU > 24 hours
- •Patients with a known history of glucose-6 phosphate dehydrogenase (G-6PD) deficiency
- •Patients with a history of renal stones
- •Patients with known or suspected scurvy
- •Patients previously enrolled in this study
- •Plasma sodium >150 mmol/L
- •Plasma sodium < 130 mmol/L
- •Haemoglobin < 90 g/L
- •Jehova's witness
- •Receiving isoprenaline
研究组 & 干预措施
Intermediate dose
Sodium ascorbate (vitamin C) is provided by the manufacturer (Orthomolecular Medisearch Laboratory P/L, Braeside, Victoria, Australia) as 30 grams in 100 ml.
- 30 gram load over 2 hours (T = 0 - 2 hours)
- 30 gram infusion over 6 hours (T = 2-8 hours) which will be repeated at 14, 26 and 38 hours
干预措施: Sodium Ascorbate (Drug)
High dose
Sodium ascorbate (vitamin C) is provided by the manufacturer (Orthomolecular Medisearch Laboratory P/L, Braeside, Victoria, Australia) as 30 grams in 100 ml.
- 30 gram load over 2 hours (T = 0 - 2 hours)
- 60 gram infusion over 6 hours (T = 2-8 hours) which will be repeated at 14, 26 and 38 hours
干预措施: Sodium Ascorbate (Drug)
结局指标
主要结局
Time to cessation of vasopressor support
时间窗: 7 days
Time to cessation of vasopressor support (up to day 14). This will be defined as per the VITAMINS trial, as the patient being alive at discontinuation of all vasopressors for at least 4 hours in the presence of MAP \>65 mmHg for the same 4 hour period as reported in the ICU charts. Use of vasopressor will be defined as any use of noradrenaline, adrenaline, vasopressin, metaraminol, dopamine or phenylephrine. Data on doses will be obtained hourly and the doses summed for each study day. Vasopressor dose will be calculated as the sum of norepinephrine and 'norepinephrine equivalent' doses.
次要结局
- Inflammatory markers(24, 48 and 72 hours)
- Respiratory Sequential organ failure assessment score(7 days)
- Randomised to screened patient ratio(Duration of study: 12 months)
- Plasma C-reactive protein(24, 48 and 72 hours)
- Body temperature(24, 48 and 72 hours)
- Cardiovascular Sequential organ failure assessment score(7 days)
- Area under the vitamin C plasma concentration versus time curve(72 hours)
- Percentage of randomized patients compliant with study protocol(Duration of study: 12 months)
- Sequential Organ Failure Assessment score(7 days)
- Haematological Sequential organ failure assessment score(7 days)
- Liver Sequential organ failure assessment score(7 days)
- Renal Sequential organ failure assessment score(7 days)
- Neurological Sequential organ failure assessment score(7 days)
- Vitamin C plasma elimination half-life(72 hours)
- Maximum plasma concentration of vitamin C (cMax)(72 hours)
- Urinary markers of renal injury(72 hours)
- Number of patients screened(Duration of study: 12 months)
- Plasma procalcitonin(24, 48 and 72 hours)
- Plasma thrombomodulin(24, 48 and 72 hours)
- Plasma proteomics(72 hours)
- Plasma cystatin C(72 hours)