The Effect of Vitamin C, Thiamine and Hydrocortisone on Clinical Course and Outcome in Patients With Severe Sepsis and Septic Shock

A Randomized, Double Blind, Placebo-Controlled Study to Investigate the Effects of Vitamin C, Hydrocortisone and Thiamine on the Outcome of Patients With Severe Sepsis and Septic Shock

The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year; the vast majority of these cases occur in low income countries. New therapeutic approaches to sepsis are desperately required; considering the global burden of sepsis these interventions should be effective, cheap, safe and readily available. The aim is to study the synergistic effect of vitamin C, hydrocortisone and thiamine on survival in patients with severe sepsis and septic shock.

Study Overview

• Status: Terminated
• Conditions: Sepsis; Critical Illness; Septic Shock; Fluid Overload
• Intervention / Treatment: Drug: Vitamin C; Drug: Hydrocortisone; Drug: Thiamine; Drug: 0.9% Sodium Chloride Injection

Detailed Description

AIM OF THE STUDY:

The goal is to determine the effects on clinical course and outcome of patients with severe sepsis and septic shock treated with vitamin C, hydrocortisone and thiamine.

BACKGROUND:

This study will be conducted in the intensive care unit of Department of Gastroenterology, University Medical Center (UMC) Ljubljana. All of the patients with severe sepsis and septic shock admitted to the Intensive Care Unit (ICU) in the past 12 hours will be screened for possible inclusion in the study. The diagnosis of severe sepsis and septic shock will be based on the 1992 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions.

PLAN OF THE STUDY:

After determining the eligibility for inclusion in our study, the investigators will acquire the written consent from the patient or relatives. The investigators (doctor on call) will randomize the patient either in the treatment or placebo group. The randomization will be done before-hand with the online tool Research Randomizer. After acquiring the randomized numbers, they will be placed in sealed envelopes. These envelopes will be available to the on-call doctor. The envelopes will then be sent to our outpatient clinic, where the studied substances will be mixed by a nurse, that will have no contact with the patients or the ICU staff. The substances will be marked with Vitamin C, Thiamine and Hydrocortisone, regardless if normal saline or the actual substances are inside the vials. Only this nurse will have the data regarding the contents of the vials.

Based on literature the investigators expect that survival and clinical course in sepsis and septic shock is correlated with fluid resuscitation and vasopressor use. Because of this, all of the included patients will be monitored with invasive hemodynamic monitoring (All of the patients will be monitored with the Edwards EV 1000 monitors).

All of the patients will be treated the same as per internationally recognized guidelines for treatment of septic shock. While the use of corticosteroids in severe sepsis is off-label, the patients will be informed of possible side-effects. This fact will also be written in the consent.

Neither the patients or the relatives will receive no financial compensation for study inclusion. During the hospitalization, the patients will receive three different substances in dosages, that are non toxic. During the study, there will be intermittent statistical analysis, and if increased mortality or severe side effects will be found then the study will be terminated. The confidentiality of personal data will be protected accordingly with the rules and laws of patient's privacy. The identity of patients will not be disclosed. The data acquired during the study will be available to the study participant. The anticipated costs will be covered by the Department of Gastroenterology, UMC Ljubljana. No financial compensation will be given to researchers.

During the study the following data will be acquired from the patients:

1. Age,
2. Sex,
3. Body weight,
4. Admitting diagnosis and source of infection,
5. Isolated pathogens,
6. Comorbidities,
7. The need for mechanical ventilation,
8. The use of vasopressors (all doses will be converted to Norepinephrine equivalents),
9. The duration of vasoactive therapy,
10. Daily urine output,
11. Fluid balance after 24 and 72 hours,
12. The presence of acute kidney failure
13. Duration of ICU stay and hospital stay,
14. Survival in ICU, hospital, after 28 and 60 days
15. Routine blood test for the first 4 days, a. creatinine b. White Blood Cells (WBC) c. Platelets d. Bilirubin e. Partial Pressure of Oxygen in Arterial Blood/Fraction of Inspired Oxygen (PaO2/FiO2) ratio e. procalcitonin (PCT) and procalcitonin clearance f. lactate g. blood samples will be stored for possible additional analysis

The patients' admission Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE IV scores will be recorded. The APACHE IV score allows calculation of the predicted hospital mortality and predicted ICU length of stay (LOS). The daily Sepsis-related Organ Failure Assessment (SOFA) score will be recorded for the first 4 treatment days.

Data analysis:

Summary statistics will be used to describe the clinical data and presented as mean ± standard deviation (SD), median with interquartile range (IQR) or percentages as appropriate. Chi squared analysis with Fisher's exact test (when appropriate) and Student's t test (Mann Whitney U test for non-normal distributions) were used to compare data between the active treatment group and the placebo group with statistical significance declared for probability values of 0.05 or less.

Data Safety & storage:

The main risk to subjects is the accidental release of Protected Health Information (PHI). Careful record management methods will be in place to ensure this type of privacy breach does not occur. The data set will be kept in a password-protected file and stored separately from the subject identification (ID) key in the locked office of the principal investigator. Only the research team will have access to this information, and will not disclose this information to any other person or entity. Three years after the completion of the study, all collected data will be destroyed by permanently deleting electronic copies.

EXPECTED RESULTS:

The investigators expect a faster recovery, shorter hospitalization, shorter use of vasoactive drugs and better survival in treatment group versus (vs.) control group.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • Department of Gastroenterology, UMC Ljubljana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of severe sepsis or septic shock within 12 hours of admission in our Intensive Care Unit (ICU).
• Informed consent.

Exclusion Criteria:

• Age < 18 years
• Pregnancy
• Do Not Resuscitate (DNR/DNI) with limitations of care
• Patients with fatal underlying disease who are unlikely to survive to hospital discharge (e.g.: disseminated malignant disease)
• Patients primarily admitted for acute coronary syndromes, acute cerebrovascular incidents or active gastrointestinal (GI) bleeds
• Patients that need immediate surgical treatment
• Patients with HIV and a cell count of cluster of differentiation 4 (CD4) cells < 50 mm2,
• Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency.
• Patients with severe sepsis/septic shock transferred from another hospital
• Patients with features of sepsis/septic shock > 24 hours
• Patients who require treatment with corticosteroids for an indication other than sepsis (chronic corticosteroid use, known Addison's Disease, Ulcerative colitis, Crohn's disease...)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active substances; Vitamin C: Vitamin C will be mixed as 1500 mg vitamin C in 50ml container, which will then be infused over 30 minutes to 1 hour. The bag will be labeled by the pharmacy as Vitamin C. The dosing schedule is 1500mg every 6 hours for 4 days or until discharge from the ICU. Hydrocortisone: Hydrocortisone will be mixed as 50 mg of Hydrocortisone in 50 ml of 0.9 % Sodium Chloride. Patients will be treated with hydrocortisone 50mg IV q 6 hourly for 4 days or until ICU discharge. Thiamine: Intravenous thiamine will be given in a dose of 200mg q 12 hourly for 4 days or until ICU discharge.	Drug: Vitamin C; Vitamin C: Vitamin C will be applied as per instructions described in arm/group descriptions.; Other Names: Ascorbic Acid; Drug: Hydrocortisone; Hydrocortisone: Hydrocortisone will be applied as per instructions described in arm/group descriptions.; Other Names: Corticosteroids; Drug: Thiamine; Intravenous thiamine will be applied as per instructions described in arm/group descriptions.; Other Names: B1 Vitamin
Placebo Comparator: Control; Vitamin C placebo will consist of an identical container of 50cc normal saline (0.9% Sodium Chloride Injection) (but with no vitamin C) and will be labelled vitamin C. Placebo will be infused over 30-60 minutes as per the infusion instructions of the active vitamin. Hydrocortisone placebo will be provided in an identical 50 ml bag of 0.9% Sodium Chloride Injection. Placebo patients will receive a matching vial of 0.9% Sodium Chloride Injection.	Drug: 0.9% Sodium Chloride Injection; 0.9 % Sodium Chloride will be applied as placebo as per instructions described in arm/group descriptions.; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital mortality	We will compare mortality between the treatment and placebo groups during the hospitalization	From date of randomization till time of discharge, assessed up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
60 day mortality	We will compare mortality between the treatment and placebo groups after 60 days after inclusion in the study	60 days from inclusion in the study
28 day mortality	We will compare mortality between the treatment and placebo groups after 28 days after inclusion in the study	28 days from inclusion in the study
Time to vasopressor independence	Defined as the time from starting the active treatment/placebo to discontinuation of all pressors	Defined as the time from starting the active treatment/placebo to discontinuation of all pressors, till discharged from ICU, assessed in the first month
PCT clearance	Clearance of calculated procalcitonin using the following formula: initial PCT minus PCT at 96 hours, divided by the initial PCT multiplied by 100.	The first 4 days in Intensive Care Unit
Delta SOFA score	Delta Systemic Organ Failure Assesment score, defined as the initial SOFA score minus the day 4 SOFA score. The Sequential Organ Failure Assessment (SOFA) is a morbidity severity score and mortality estimation tool developed from a large sample of ICU patients throughout the world. The higher the value, the higher the mortality. The maximum score is 24, the lowest 0.	The first 4 days in Intensive Care Unit
ICU length of stay (LOS) and ICU free days.	ICU free days is calculated as the number of days alive and out of the ICU to day 28	ICU free days is calculated as the number of days alive and out of the ICU to day 28
Hospital Length of Stay	The length of stay in the hospital	Hospital Length of Stay through the study completion, assessed up to 12 months

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Investigators: Principal Investigator: Sebastian Stefanovic, MD, University Medical Center Ljubljana, Department of Gastroenterology

Publications and helpful links

General Publications

• Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036. Epub 2016 Dec 6.
• Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, Wolfe R, Moskowitz A, Smithline H, Ngo L, Cocchi MN; Center for Resuscitation Science Research Group. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016 Feb;44(2):360-7. doi: 10.1097/CCM.0000000000001572.
• Artenstein AW, Higgins TL, Opal SM. Sepsis and scientific revolutions. Crit Care Med. 2013 Dec;41(12):2770-2. doi: 10.1097/CCM.0b013e31829eb98f.
• Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga G, Bokhari F, Vogeser M; American College of Critical Care Medicine. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008 Jun;36(6):1937-49. doi: 10.1097/CCM.0b013e31817603ba.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2017
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: October 25, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 7, 2017

Study Record Updates

• Last Update Posted (Actual): February 19, 2019
• Last Update Submitted That Met QC Criteria: February 17, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Sepsis; Critical Illness; Vitamin C; Hemodynamics; Hydrocortisone; Thiamine; Fluid Responsiveness
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Sepsis; Toxemia; Shock, Septic; Shock; Critical Illness; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Protective Agents; Micronutrients; Antioxidants; Vitamin B Complex; Vitamins; Hydrocortisone; Ascorbic Acid; Thiamine
• Other Study ID Numbers: CSEPSIS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected IPD
• IPD Sharing Time Frame: For a year after the completion of the study
• IPD Sharing Access Criteria: Contributing authors that will sign the declaration of patient data confidentiality.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No