Zinc and Inflammation in Sepsis

July 4, 2013 updated by: University of Aberdeen

The purpose of the proposed project is to investigate measures of zinc status in relation to oxidative stress and inflammation in patients with sepsis. We hypothesise that zinc depletion can modulate inflammatory responses, leading to increased oxidative stress and mitochondrial dysfunction.

Sepsis is a severe infection is the leading cause of death in critically ill patients [1]. Zinc deficiency impairs overall immune function and resistance to infection [2]. In vitro exposure of monocytes to lipopolysaccharide (LPS) leads to decreased cellular zinc content [3] and zinc redistribution has been shown in human volunteers in response to LPS [4]. Zinc depletion occurs in hospitalized patients including those with infections, the elderly, alcoholics, trauma or burns [5-8], conditions which are common among critically ill patients with sepsis. In a mouse model of sepsis, zinc depletion prior to sepsis resulted in more inflammation and more severe organ injury and increased mortality [9]. In patients with sepsis, early feeding with zinc resulted in faster recovery of organ function compared with control [10]. Zinc status is likely to be compromised in the critically ill and that zinc depletion may affect inflammatory responses and recovery.

Although zinc is not an antioxidant itself, it binds to metallothionein [11] and zinc supplementation decreases oxidative stress [12]. Oxidative stress has been consistently reported in patients with sepsis [13-15]. We have recently shown that protection of mitochondrial function with antioxidants can reduce organ damage in rats [16]. Pentraxin-3 is an inflammatory marker which is regulated in part by antioxidants and plays a key role in innate immunity [17].

The consequences of zinc deficiency may relate, in part, to its effects on nuclear factor NFκB, a transcription factor crucial to the signalling networks involved in sepsis [18]. Higher NFκB activity is associated with increased mortality in patients with sepsis [19,20]. It is likely that compromised antioxidant defences and inflammation occurs as a consequence of zinc deficiency.

We propose to measure plasma zinc and metallothionein mRNA status in relation to inflammatory markers including key cytokines, pentraxin-3, markers of oxidative stress and antioxidant status in patients with sepsis.

Study Overview

Status

Completed

Conditions

Detailed Description

Following ethical approval consent will be sought from either the patient, or assent from a near relative. Successive patients admitted to the Intensive Care Unit at Aberdeen Royal Infirmary who fulfil the following criteria for sepsis, given below, within a 24h time window, will be included.

  • Clinical suspicion or evidence of acute infection

  • SIRS defined by two or more of the following:

    1. Core temperature <36 degrees C or >38 degrees C
    2. Tachycardia; heart rate > 90 beats/min.
    3. Tachypnoea; respiratory rate > 20 breaths/min or mechanical ventilation
    4. White blood count >12 x 109/l or <4 x 109/l

In this pilot study we will recruit 20 patients with sepsis and 20 critically ill patients with no clinical suspicion of sepsis. Patients will be excluded if they are <16 years, pregnant or lactating, HIV positive, receiving corticosteroids or other known immuno-modulatory drugs (including statins), have cancer or autoimmune disorders or if consent/assent is refused.

Blood samples will be obtained on Days 1,2, 5, 10 and 14 of the ICU stay. Peripheral whole blood will be sampled from an indwelling arterial line and plasma will be separated for analysis of plasma zinc using atomic absorption spectroscopy. Plasma interleukin-6 (IL-6) and pentraxin-3 (PTX3) will be measured using enzyme immunoassay and total antioxidant capacity and lipid hydroperoxides will be measured colourimetrically [17]. Peripheral blood mononuclear cells (MNC) will be separated using single density gradient centrifugation, RNA extracted and metallothionein mRNA measured using qPCR [21]. Nuclear extracts of MNC will be prepared and nuclear factor kappa B (NFκB)activation measured using an enzyme immunoassay [17].

Study Type

Observational

Enrollment (Actual)

39

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Scotland
      • Aberdeen, Scotland, United Kingdom, AB41 8TK
        • Aberdeen Royal Infirmary

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Successive patients admitted to the Intensive Care Unit at Aberdeen Royal Infirmary who fulfil the following criteria for sepsis, given below, within a 24h time window.

• .

Description

Patients with sepsis

Inclusion Criteria:

  • admitted to ICU with clinical suspicion or evidence of acute infection PLUS two or more of the following:

    1. Core temperature <36 degrees C or >38 degrees C
    2. Tachycardia; heart rate > 90 beats/min.
    3. Tachypnoea; respiratory rate > 20 breaths/min or mechanical ventilation

    4. White blood count >12 x 10 9/l or <4 x 10 9/l

      Control patients

  • admitted to ICU with no clinical evidence or suspicion of infection

Exclusion Criteria:

  • under 16 years old
  • pregnant or lactating
  • HIV positive
  • receiving corticosteroids or other known immuno-modulatory drugs
  • treated with statins in the last month
  • have cancer
  • have autoimmune disorders
  • consent/assent is refused

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Sepsis
Patients with sepsis
Control
Patients with no clinical evidence of sepsis, but who are critically ill

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma zinc concentration
Time Frame: 14 days
Plasma zinc will be measured in patients with sepsis and non-spetic critically ill control patients.
14 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Interleukin-6
Time Frame: 14 days
The relationship between IL-6 and plasma zinc
14 days
Pentraxin-3
Time Frame: 14 days
The relationship between PTX-3 and plasma zinc
14 days
Plasma lipid peroxide
Time Frame: 14 days
The relationship between LPO and plasma zinc
14 days
Plasma total antioxidant capacity
Time Frame: 14 days
The relationship between TAC and plasma zinc
14 days
Metallothionein mRNA
Time Frame: 14 days
Change in MTmRNA in mononuclear leucocytes in relation to plasma zinc and inflammatory markers
14 days
Nuclear factor kappa B
Time Frame: 14 days
Change in NFkB in nuclear extracts from mononuclear cells in relation to plasma zinc
14 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Aberdeen

Collaborators

UK Intensive Care Society

Investigators

  • Principal Investigator: Helen Galley, PhD, University of Aberdeen
  • Principal Investigator: Nigel Webster, PhD, University of Aberdeen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2012

Primary Completion (Actual)

May 1, 2013

Study Completion (Actual)

May 1, 2013

Study Registration Dates

First Submitted

March 31, 2011

First Submitted That Met QC Criteria

March 31, 2011

First Posted (Estimate)

April 4, 2011

Study Record Updates

Last Update Posted (Estimate)

July 8, 2013

Last Update Submitted That Met QC Criteria

July 4, 2013

Last Verified

July 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11/AL/0137

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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