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Sepsis has been characterised as a dysregulated host response to infection. Adjunctive therapies targeting the inflammatory cascade are being increasingly explored, although to date, have failed to demonstrate consistent benefit, and sepsis continues to manifest poor outcomes. Hospital mortality in patients with septic shock remains as high as 22% in Australia and New Zealand. From a global perspective, 31 million sepsis and 19 million severe sepsis cases are expected to be treated in hospitals all over the world per year.
To date, experimental data have reported that both high dose intravenous vitamin C and corticosteroids attenuate the acceleration of the inflammatory cascade and possibly reduce the endothelial injury characteristic of sepsis, enhance the release of endogenous catecholamines and improve vasopressor responsiveness.
Therefore, the investigators plan to conduct a feasibility pilot prospective, multi-centre, randomised, open-label, trial in ICU patients with septic shock to test whether the intravenous administration of high dose Vitamin C (6g/d), Thiamine (400mg/d) and Hydrocortisone (200mg/d) leads to a more rapid resolution shock and vasopressor dependence.
Full description
The investigators plan to conduct a feasibility pilot prospective, multi-centre, randomised, open-label, trial in ICU patients with septic shock to test whether the intravenous administration of high dose Vitamin C (6g/d), Thiamine (400mg/d) and Hydrocortisone (200mg/d) for a maximum of ten days leads to a more rapid resolution shock and vasopressor dependence.
Hypothesis:
Treatment with a combination of intravenous Vitamin C, Thiamine and Hydrocortisone reduces duration of vasopressor (measured by hours alive and vasopressor free) use censored at 7 days compared to standard care with Hydrocortisone alone.
This is a prospective, feasibility, pilot, multi-centre, randomised, open-label controlled trial. This study will be performed in seven Victorian ICUs in Australia. Patients admitted to an ICU of the participating hospitals with the primary diagnosis of septic shock will be screened for inclusion into this study.
Rationale:
Experimental data have demonstrated that both corticosteroids and intravenous vitamin C attenuate the release of pro-inflammatory mediators, reduce the endothelial injury characteristic of sepsis (thereby reducing endothelial permeability and improving microcirculatory flow), augment the release of endogenous catecholamines and enhance vasopressor responsiveness. In animal models, these effects have resulted in reduced organ injury and increased survival. However, their effect in critically ill humans is unknown.
Previous research suggests that vitamin C and glucocorticoids may act synergistically and improve vasopressor responsiveness in patients with sepsis and septic shock.
Randomisation:
ICU patients will be enrolled as soon as possible but no later than 24 hours after fulfilling the criteria for septic shock. Patients will be allocated in a 1:1 ratio to either the treatment group, receiving intravenous Vitamin C (1.5g every 6 hours), Thiamine (200mg every 12 hours) and Hydrocortisone (50mg every 6 hours), or to the control group, receiving Hydrocortisone (50mg every 6 hours) alone.
Treatment allocation will occur using a computerized system and concealed allocation. The clinical staff involved in patient care will administer the additional drugs to those allocated to the treatment arm of the trial as soon as possible after the identification of septic shock and randomization.
Patients readmitted to ICU during the same hospital stay will not receive any further doses of study drugs.
Study Treatment will continue until:
Study Drugs
This study will be an open label study:
Intervention group:
In both groups (treatment and control), patients will be treated with hydrocortisone 50mg IV q 6 hourly for the duration of study treatment. After shock resolution and/or a maximum fo 7 days Hydrocortisone will be tapered off or stopped.
Statistical analysis:
Originally, the investigators assumed a mean (SD) duration of vasopressor dependency of 50 (28) hours and estimated a required sample size of 120 patients (60 per group) to identify a clinically relevant decrease of vasopressor dependency and an increase in days alive and vasopressor free at 7 days of 25% (20 hours) (i.e. increase from 41 to 55 hours of days alive and vasopressor free at day 7) with a power of 90% at an alpha level of 0.05.
The investigators have recalculated the sample size based on the pooled standard deviation of hours alive and vasopressor free of the first 59 participants. The pooled standard deviation of hours alive and vasopressor free at 7 days for the 59 patients is 51.6 hours.
To have a 90% power (2 sided p-value of 0.05) to detect a 25-hour difference based on a standard deviation of 51.6, the trial will require 180 patients (90 per group). Allowing for a 20% inflation for non-normality and dropout/withdrawal, the required total sample size is 216 (108 per group). The robustness of the sample size estimate will be further assessed after recruitment of 108 patients (50% of the sample size).
Consent: The major ethical issues associated with this study relate involve the recruitment of participants who are dependent on medical care and in need of immediate intervention for the management of life-threatening haemodynamic instability.
Once subjects are recovered and are able to consider the information sheet, they will be offered the opportunity to withdraw from study follow-up. If a participant dies due to the nature of their critical illness before consent was able to be obtained from the person responsible/medical treatment decision maker, then consent will not be sought and data collected will be used. This is in line with the process followed by other similar intensive care studies conducted previously and approved by the relevant HRECs all where consent to continue has been utilised.
Enrollment
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Inclusion criteria
Patient in the intensive care unit (ICU) with septic shock:
Exclusion criteria
Age < 18 years
Pregnancy
DNR (do not resuscitate)/DNI (do not intubate) orders
Death is deemed to be imminent or inevitable during this admission, and either the attending physician, patient or substitute decision-maker is not committed to active treatment
Patients with known HIV infection
Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency
Patients transferred from another ICU or hospital with a diagnosis of a septic shock for > 24 hours
Patients with a diagnosis of a septic shock for > 24 hours
Patients with known or suspected
Clinician expects to prescribe systemic glucocorticoids for an indication other than septic shock (not including nebulised or inhaled corticosteroid)
Patient is receiving treatment for systemic fungal infection or has documented Strongyloides infection at the time of randomisation
Patient with known chronic iron overload due to iron storage and other diseases
Patient previously enrolled in this study
Clinician expects to prescribe high dose vitamin C for another indication
Primary purpose
Allocation
Interventional model
Masking
216 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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