Triple Therapy in Septic Shock Patients

A Prospective, Randomized Clinical Study Comparing Triple Therapy Regimen to Hydrocortisone Monotherapy in Reducing Mortality in Septic Shock Patients

this study is conducted to evaluate the role of the novel triple therapy combination in reducing the mortality rate, reducing the shock time, and reversal of organ damage.

the study includes two arms, the first arm is the control which received hydrocortisone monotherapy and the second arm is the intervention arm which received the triple therapy regimen.

calculation of 28 days in-hospital mortality is the primary outcome. shock time, vasopressor doses, infection markers, and organ function tests are the secondary outcomes.

the data will be analyzed by student t-test or Mann Whitney test, Fischer exact or chi-square test for numbers, repeated measures ANOVA will be used to consider confounders and other parameters, mortality will be expressed by Kaplan Meier and ROC curve.

For Multivariate analysis of repeated quantitative outcomes, linear mixed models were used to quantify the relationship between one dependent variable (SOFA, SCr, doses of vasopressors) and many independent variables including group type and sepsis phenotype adjusted to other clinical and demographic factors.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock; Organ Dysfunction Syndrome Sepsis
• Intervention / Treatment: Drug: vitamin c - thiamine- hydrocortisone

Detailed Description

Background:

"Sepsis" is a life-threatening organ dysfunction caused by the dysregulated host response to infection. Septic Shock: Subset of sepsis with circulatory and cellular/metabolic dysfunction associated with a higher risk of mortality. Organ dysfunction can be identified by acute change in the total Sequential Organ Failure Assessment (SOFA) score of 2 points or higher consequent to the infection.

Septic shock patients can be identified by developing sepsis with persistent arterial hypotension requiring vasopressors to keep mean arterial pressure (MAP) above 65 mm Hg and having serum lactate above 2 mmol/L. In hospitals, the mortality of septic shock according to retrospective studies is around 35%-54%. Pneumonia is the most common site of infection (about 50%) of cases, followed by intra-abdominal infection and urinary tract infection.

The (1-hr Bundle) is the cornerstone of the management, it encourages clinicians to act as quickly as possible to obtain blood cultures, administer broad-spectrum antibiotics, start appropriate fluid resuscitation, measure lactate, and begin vasopressors if clinically indicated. Ideally, these interventions would all begin in the first hour from sepsis recognition but may not necessarily be completed in the first hour. However, over the last few years, there have been interesting investigational novel therapeutic approaches. One of them is the use of high dose vitamin C. A small retrospective study demonstrated a mortality benefit by using high dose vitamin C, thiamine (vitamin B1), and hydrocortisone (Triple therapy) for treatment of septic shock in the adult population.

The normal plasma vitamin C level is ≥ 23 µmol/l. A recent study found that 88% of septic shock patients have hypovitaminosis C (<23 µmol/l), while 38% have a scurvy level (<11 µmol/l). The acute deficiency of vitamin C in this category of patients may be caused by the increased metabolic consumption due to critical illness such (trauma, burn, septic shock, etc.).

Vitamin C has pleiotropic effects such as antioxidant (direct radical scavenger- reduction of reactive oxygen species (ROS) production-regeneration of antioxidants), anti-inflammatory, and immune-supporting, cofactor/co-substrate biosynthesis, increasing catecholamine sensitivity and protection of microcirculation. Vitamin C enteral intake is insufficient in critically ill patients due to saturable mucosal sodium-dependent vitamin C transporter 1 (SCVC1). So, supplementation of high doses of vitamin C by intravenous route can restore normal plasma concentration and reverse the stress and its sequences (reduce the incidence of organ failure, reduce vasopressor support, and may reduce the overall mortality).

Recent small controlled studies suggested the dosing range of vitamin C is from 6-16 gm/day. Also, a dose-response relationship in patients who received high doses of vitamin C was proven. Vitamin C is actively transported in tissue cells by (SCVC2), leading to achieving a high intracellular level than the plasma especially in leukocytes and neurons protecting them against ROS. While high doses of vitamin C given were not associated with any harms related to the drug, there is a theoretical concern regarding the use of high doses related to the potential risk for developing oxalate crystals in the urinary tract, For this reason, co-administration of thiamine with these high doses of vitamin C acts as a co-enzyme for the function of glyoxalate-amino transferase which catalyzes the degradation of glyoxalate to carbon dioxide instead of the oxalate. Another note is a short course of high doses vitamin C has not been found to increase the risk of renal calculi in the previous studies. Also, patients with glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency are at risk of hemolysis with high doses of vitamin C.

Thiamine has a crucial role in cellular metabolic processes. Thiamine deficiency is common in critically ill patients when becomes insufficient pyruvate not converted to acetyl coenzyme A resulting in impaired aerobic respiration and switch to anaerobic respiration leading to elevate of lactate level. Previous studies showed improvement in lactate level and in organ dysfunction with supplementation of thiamine for critically ill patients, thiamine dose is 200mg every 12 hours.

Hydrocortisone is another major component of the recommended triple therapy, the dose of hydrocortisone in septic shock is 200 mg/day, The rationale for its use is that, in septic shock, the released component of the cell membrane of gram-negative and gram-positive bacteria and endotoxins induce nitric oxide synthase which promotes the relaxation of vascular beds in addition to releasing of inflammatory cytokines such tumor necrosis factor (TNF-alpha) and interleukins (IL-1). These cytokines suppress the action of Adreno-Cortico Trophic Hormone (ACTH) on the adrenal gland and decrease the endogenous cortisol and compete with cortisol on receptor sites and diminish its effect, By supplying hydrocortisone, reversing of these mechanisms occurs which improves response to vasopressors, blocks phospholipase A2 then reduces prostacyclins and prostaglandins (vasodilators), reducing the diminished steroid action at receptor sites. Synergism appears between hydrocortisone and vitamin C based on two roles, one of them is glucocorticoid binding to glucocorticoid receptors is negatively affected by oxidizing molecules and this can be reversed by administration of high doses of vitamin C which restores the glucocorticoid receptor functions.

Also, it was found that the transcellular transportation of vitamin C via SVCT2 is impaired due to the downregulation of this transporter during septic shock, hydrocortisone has been shown increasing the expression of this transporter and then increases the cellular uptake.

Aim of the study To determine the effectiveness of triple therapy regimen (vitamin C, vitamin B1, and Hydrocortisone) in the reduction of mortality of septic shock patients.

Methodology Study subjects and designs This is an interventional, controlled, single-blind prospective parallel study to be conducted in the (ICUs) at the Air Force Specialized Hospital (AFSH), Cairo, Egypt.

Subjects will be selected according to the following inclusion and exclusion criteria:

Sample size Sample size will be calculated based on this equation

assuming the following parameters: Anticipated Incidence of mortality: GP1 (hydrocortisone arm) = 40.4%, in GP 2 (triple therapy arm) = 8.5%.

Alpha = 0.05, power = 95%, enrollment ratio = 1 So each group will consist of 44 patients (total = 88).

• By considering dropout rate = 20%, So each group will consist of 53 patients and the total sample size =106 patients.
• The first arm will take the triple therapy regimen (vitamin C, vitamin B1, and Hydrocortisone), the Second arm will take Hydrocortisone as the standard of care.

Data collection:

From each patient the following data will be collected:

• Age, gender, height and weight, and any allergies (on admission)
• Causes of ICU admission (on admission).
• Patient's past medical history (PMH) (on admission)
• SOFA score to be assessed on admission and daily (primary outcome) [28] and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE ӏӏ) [29] score (on admission only).
• Hemodynamic data (blood pressure, pulse, central venous pressure (CVP), respiratory rate, O2 saturation) on admission, and daily.
• Infection markers (total leukocytic count, CRP), lactate level, serum creatinine, Aspartate Aminotransferase (AST), Alanine aminotransferase (ALT). on admission and for follow- up daily (secondary outcome).

Statistical analysis

Different statistical tests selection will be based on the type of data and the calculated outcome:

• Mortality (primary outcome) calculation will be evaluated by the chi-square test.
• Reversal of organs failure, weaning from the mechanical ventilator, and vasopressors will be evaluated using the Mann-Whitney test.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt, 4260010
    • Air Force Specialized Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age >18 years.
• Diagnosis of septic shock has been established (need vasopressors to maintain MAP ≥ 65, lactate ≥ 2mmol/L and SOFA score ≥2) [25,26].

Exclusion Criteria:

• Pregnancy and lactation.
• Refusal of attending staff or patient family.
• Contraindication to any of the components of the triple therapy regimen such as (hypersensitivity to vitamin C and Patients with G6PD deficiency).
• Patients on immunosuppressive medications and oncology patients. Do not resuscitate/do not intubate (DNR, DNI) patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydrocortisone Monotherapy	Drug: vitamin c - thiamine- hydrocortisone; Triple therapy regimen (vitamin c - thiamine- hydrocortisone); Other Names: Triple therapy
Experimental: triple therapy regimen (vitamin c - thiamine- hydrocortisone)	Drug: vitamin c - thiamine- hydrocortisone; Triple therapy regimen (vitamin c - thiamine- hydrocortisone); Other Names: Triple therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of patients who died within 28 days.	patients were followed up daily for 28 days, this is the number of patients who died within 28 days.	28 days
ICU Mortality	The number of patients who died during ICU stay	Within 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the number of days that are needed to off the patients from vasopressors.	average number of days that are needed to off the patients from vasopressors.	28 Days
the number of days that are needed to off the patients from mechanical ventilation.	average number of days that are needed to off the patients from mechanical ventilation.	28 days
Change in organ's functions test such as (serum creatinine, Alanine Aminotransferase (ALT)	change was calculated as the values at ICU stay and specific cut off points (after 48 hr, after 96 hr).	28 days

Collaborators and Investigators

• Sponsor: Air Force Specialized Hospital, Cairo, Egypt
• Investigators: Principal Investigator: Abdelrhman Hussein, Air Force Specialized Hospital

Publications and helpful links

General Publications

• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af.
• Plevin R, Callcut R. Update in sepsis guidelines: what is really new? Trauma Surg Acute Care Open. 2017 Sep 7;2(1):e000088. doi: 10.1136/tsaco-2017-000088. eCollection 2017.
• Korosec Jagodic H, Jagodic K, Podbregar M. Long-term outcome and quality of life of patients treated in surgical intensive care: a comparison between sepsis and trauma. Crit Care. 2006;10(5):R134. doi: 10.1186/cc5047.
• Zahar JR, Timsit JF, Garrouste-Orgeas M, Francais A, Vesin A, Descorps-Declere A, Dubois Y, Souweine B, Haouache H, Goldgran-Toledano D, Allaouchiche B, Azoulay E, Adrie C. Outcomes in severe sepsis and patients with septic shock: pathogen species and infection sites are not associated with mortality. Crit Care Med. 2011 Aug;39(8):1886-95. doi: 10.1097/CCM.0b013e31821b827c. Erratum In: Crit Care Med. 2011 Oct;39(10):2392. Vesim, Aurelien [corrected to Vesin, Aurelien].
• Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. No abstract available. Erratum In: N Engl J Med. 2013 Nov 21;369(21):2069.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2019
• Primary Completion (Actual): November 9, 2020
• Study Completion (Actual): November 9, 2020

Study Registration Dates

• First Submitted: August 8, 2020
• First Submitted That Met QC Criteria: August 8, 2020
• First Posted (Actual): August 11, 2020

Study Record Updates

• Last Update Posted (Actual): January 26, 2021
• Last Update Submitted That Met QC Criteria: January 22, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Septic shock; sepsis; Vitamin C; Hydrocortisone; Thiamine
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock; Systemic Inflammatory Response Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin B Complex; Hydrocortisone; Ascorbic Acid; Thiamine
• Other Study ID Numbers: 2019/11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No