Study the Impact of Statins in Septic Shock

Prospective Randomized Study to Assess Impact of Statins in Septic Shock

Sepsis is a common, expensive, frequently fatal and highly complex inflammatory syndrome wherein multiple cellular and humoral pathways are involved. Since it's a multifactorial syndrome merely blocking one of the various inflammatory pathways may not suffice to provide effective treatment and this may partly explain why most of the adjunctive therapies developed for severe sepsis have yielded disappointing results in rigorous clinical trials. Statins have varied pleiotropic effects on the inflammatory mediators and there addition to the current adjuvant therapies in septic shock may help in reduction of mortality. The present trial aims to study survival benefit and changes in bio-marker levels in septic shock.

Adult patients (>=18 years) in septic shock and admitted to ICU will be included in the study. Patients will be randomized as per computer generated random number into the Drug (Atorvastatin, 40 mg) or matched placebo group. Drug or placebo will be given to selected patient via nasogastric tube for 7 days. Bio markers (Il-6, TNF-alpha) estimated during the trial week (Days 1, 4, and 7). All clinical and study personnel and patients remained blinded to the study group assignment throughout the trial.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Atorvastatin; Drug: Placebo

Detailed Description

Objectives:

• Study impact of statins on levels of biomarkers (IL-6 and TNF-α) of sepsis.
• Study survival benefit of statins in septic shock.

Introduction:

Sepsis is the leading cause of mortality in non-coronary ICUs. Mortality associated with sepsis is still considerably high. Rising economic burden of managing sepsis is a major concern. Statin is an anti-hyperlipidemic drug with pleiotropic effects. It has properties like anti-inflammatory/oxidative, immunomodulatory effects, enhances endothelial function, reduction in blood thrombogenicity, and increased nitric oxide (NO) bioavailability. Available evidence suggests that statins may play a positive role in reduction of mortality in sepsis. However, the multidimensional heterogeneous character of the available studies does not allow drawing firm conclusions about its usefulness in sepsis and septic shock. This randomized, double blinded, placebo controlled trial is an attempt to study the impact of statins on mortality and biomarker levels in septic shock.

Details of material and methods:

Patients >= age 18 yrs meeting the American European consensus conference definition of septic shock will be enrolled into the study. After the written informed consent from the primary decision maker the patients will be randomized into either the drug or placebo group. Each group will either receive Atorvastatin 40mg or a matched placebo for 7 days. IL-6 and TNF alpha levels will be estimated on D1, D4 and D7 of the trial week. Relevant clinical and laboratory (clinical biochemistry, hematological, coagulation parameters, LFT and renal function tests) will be recorded simultaneously. Severity scores, event free days (vasopressor, ventilation, dialysis, transfusion, parenteral nutrition), and mortality after 28 days of inclusion in study will be recorded.

Ethical Issues:

Written informed consent will be taken from either the patient (if possible) or from the primary decision maker related to the patient.

Study population:

A total of 80 patients of septic shock admitted in ICU will be enrolled into this study. Patients either admitted with septic shock or who develop septic shock during their stay in ICU will be eligible for inclusion into the study. The statin and placebo group will have 40 patients each.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • UP
    • Lucknow, UP, India, 226014
      • Department of Immunology, SGPGIMS
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226014
      • Department of Critical Care Medicine

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:

• Clinical disease of septic shock
• Aged eighteen years and above
• Admitted to ICU

Exclusion Criteria:

• Previous statin induced myopathy or hypersensitivity reaction
• Greater than two and half times elevated liver transaminases
• Chronic liver disease
• Pregnant or lactating mothers

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Statin; Atorvastatin, 40 mg for 7 days in patients of septic shock admitted to ICU	Drug: Atorvastatin; Atorvastatin or placebo given for 7 days to patients of septic shock admitted to ICU
PLACEBO_COMPARATOR: Placebo; Matched placebo, 40 mg for 7 days in patients of septic shock admitted to ICU	Drug: Placebo; Equally matched placebo for 7 days to patients of septic shock admitted to ICU

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	28 day mortality after inclusion in study.	28 day of ICU stay

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytokines in septic shock	IL-6, TNF-α levels on Day 1, 4 and 7.	Day 1, 4 and 7 of commencement of trial drug.
Vasopressor free days.	Vasopressor free days during septic shock.	28 days after commencement of trial drug.
Ventilation free days.	Ventilation free days during septic shock.	28 days after commencement of trial drug.
Renal replacement free days.	Renal replacement free days during septic shock.	28 days after commencement of trial drug.
Transfusion free days.	Transfusion free days during septic shock.	28 days after commencement of trial drug.
Total parenteral nutrition free days.	Total parenteral nutrition free days during septic shock.	28 days after commencement of trial drug.

Collaborators and Investigators

• Sponsor: Sanjay Gandhi Postgraduate Institute of Medical Sciences
• Investigators: Principal Investigator: Ratender K Singh, MD., Sanjay Gandhi Post Graduate Institute of Medical Sciences

Publications and helpful links

General Publications

• Singh RK, Agarwal V, Baronia AK, Kumar S, Poddar B, Azim A. The Effects of Atorvastatin on Inflammatory Responses and Mortality in Septic Shock: A Single-center, Randomized Controlled Trial. Indian J Crit Care Med. 2017 Oct;21(10):646-654. doi: 10.4103/ijccm.IJCCM_474_16.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (ACTUAL): October 1, 2014
• Study Completion (ACTUAL): January 1, 2015

Study Registration Dates

• First Submitted: September 15, 2015
• First Submitted That Met QC Criteria: February 11, 2016
• First Posted (ESTIMATE): February 12, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): February 12, 2016
• Last Update Submitted That Met QC Criteria: February 11, 2016
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Septic Shock; Statins
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: PGI/IMP/IEC/56/19.08.2011