The pre-symptomatic detection of early extreme response to an infection (sepsis)
| ISRCTN | ISRCTN17375399 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17375399 |
| Secondary identifying numbers | S167-01 |
- Submission date
- 26/10/2020
- Registration date
- 28/10/2020
- Last edited
- 14/07/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
We are trying to develop a blood test which would allow us to predict whether (and when) patients will go on to develop the severe complications of infection. We call severe infection “sepsis”, which can cause people to become very ill and need intensive care.
Who can participate?
Adults aged between 18 and 80 who are undergoing elective surgery.
What does the study involve?
- Taking blood samples (15 ml) and urine samples from participants before their operation and each day afterwards for a week or until they leave hospital or develop an infection.
· Noting details of medical background
· Noting details such as pulse and blood pressure, each day
- Use of blood and urine to measure various things including which genes are activated in any response to infection
- Collection of some follow up details from hospital records
- Use of these data in this study and possibly use of the data and samples in future studies
What are the benefits and risks of participating?
Developing a blood test to predict the onset of these problems would allow us to start treatment very early and early treatment is more effective and saves lives. The study may have major implications for patients in the future, though it will not be of immediate benefit to the participant. There are no risks involved in the study. The only inconvenience is that of having a daily blood test over and above the normal blood tests normally needed. We will try to ensure these samples are taken together to minimize the inconvenience to the participant.
Where is the study run from?
1. Defence Science and Technology Laboratory (Dstl) Porton Down (UK)
2. Centre for Intensive Care Medicine, Department of Medicine & Wolfson Institute for Biomedical Research, University College London (UK)
When is the study starting and how long is it expected to run for?
Who Is funding the study?
1. Ministry of Defence (UK)
2. Defense Threat Reduction Agency (USA)
Who is the main contact?
Prof. Mervin Singer, m.singer@ucl.ac.uk
Contact information
Scientific
University College London
Cruciform Building
Gower St
London
WC1E 6BT
United Kingdom
| Phone | +44 (0)207 6796714 |
|---|---|
| m.singer@ucl.ac.uk |
Public
DSTL
Porton Down
Salisbury
SP4 0JQ
United Kingdom
 ORCID ID |
0000-0003-1774-5335 |
|---|---|
| Phone | +44 (0)1980 957424 |
| ralukaszewski@dstl.gov.uk |
Study information
| Study design | Observational case control |
|---|---|
| Primary study design | Observational |
| Secondary study design | Case-control study |
| Study setting(s) | Hospital |
| Study type | Diagnostic |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | A multi-centre study to investigate immune modulators for the early diagnosis of sepsis in patients undergoing major elective surgery |
| Study acronym | MASH |
| Study objectives | Patterns of host biomarker expression in the blood of patients undergoing high-risk elective surgery predict which patients will and will not go onto develop sepsis before the onset of clinical symptoms of infection. |
| Ethics approval(s) | Approved 22/02/2007, Southampton & South West Hampshire Research Ethics Committee (A) (1st Floor Regents Park Surgery, Park Street, Shirley, Southampton, Hampshire, SO16 4RJ, UK; +44 203 8036 2466; hampshirea.rec@hra.nhs.uk), ref: 06/Q1702/152 |
| Health condition(s) or problem(s) studied | Prediction of sepsis in elective surgery patents |
| Intervention | Demographic and clinical data will be gathered daily along with blood samples for immune modulators and urine samples. Some patients will have a straightforward perioperative course (non-septic group) and some will develop sepsis (sepsis group). Blood and urine samples will be taken daily for up to 7 days in all patients (or until discharge for the non-sepsis group and until the time of development of sepsis in the sepsis group). Standard blood biochemistry and haematology assays will be run. Appropriate microbiological analysis of a variety of clinical matrices (e.g. blood, urine, swab and sputum) will be undertaken when there is a clinical suspicion of infection. Expression of host genes in the transcriptomes of patients that go on to develop sepsis that differentiates patient groups who do and do not go onto develop sepsis. Gene expression will be measured using microarray and reverse transcriptase quantitative polymerase chain. Gene expression (RT-qPCR) will be analysed in blood samples taken before surgery and then on each day following surgery for 7 days or until the patient developed sepsis, or until the patient is discharged earlier than 7 days post-surgery. |
| Intervention type | Other |
| Primary outcome measure | Original primary outcome: 1. Development of sepsis, measured using the “sepsis 2” criteria which is a Systemic Inflammatory Response Syndrome (SIRS) characterised by 2 of the following (measured daily for 7 days after surgery): 1.1. Temperature >38 or <36°C measured by clinical observation 1.2. Respiratory rate >20/min or PCO2 <4.3 or the need for ventilation measured by clinical observation 1.3. Tachycardia >90/min after fluid resuscitation measured by clinical observation 1.4. White cell count >10 or < 4 x10(9)/l, or >10% immature forms measured by blood test A clinical adjudication panel sifted blinded patient data (including all relevant patient observations and clinical data) to determine which patients adhered to this criteria and which did not. The definition of the study’s primary outcome (SEPSIS) was later changed to be defined as organ dysfunction (characterised by an increase in daily Sequential Organ Failure Assessment (SOFA) score of 2 or more from one day to the next) caused by an infectious agent. Sufficient clinical data was collected during the study to enable identification of patients who achieved the new “sepsis 3” criteria. The parameters for SOFA score include (measured using standard clinical biochemistry and haematology assays, daily for up to 7 days after surgery): 1.1. Respiratory system function (PO2/FiO2 mmHg/kPa >400 to <100) 1.2. Coagulation (Platelets x 10³ >150 to <20) 1.3. Liver function (Bilirubin levels <1.2 to >12.0 mg/dl) 1.4. Cardiovascular system function (MAP or medication to maintain MAP) 1.5. Central nervous system function (Glasgow Coma Score) 1.6. Renal system function (Creatinine levels <1.2 to >5.0 mg/dl) 2. Biomarkers in whole blood samples (collected daily for 7 days) of patients who go on to develop sepsis, assessed using gene expression measured using microarray and RT-qPCR |
| Secondary outcome measures | 1. The time point at which sepsis occurred judged by a clinical advisory panel using the information collected for the primary outcome measures 2. Identification of alternative biomarkers such as proteins and metabolomic by-products was enabled through the collection of patient sera at the same time points as whole blood. Secondary analysis of protein expression by immunoassay in serial serum samples will enable identification of biomarker signatures that do not rely on RT-qPCR |
| Overall study start date | 01/06/2006 |
| Completion date | 28/02/2017 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 4,385 |
| Total final enrolment | 4385 |
| Key inclusion criteria | 1. Patients aged between 18 and 80 years 2. Ability to give written informed consent prior to study participation 3. Patients undergoing elective high-risk surgery (e.g. aortic vascular surgery, cardio-thoracic surgery, colonic surgery, gastrectomy, oesophago-gastrectomy, Whipple’s procedure, biliary or urological procedures) 4. ASA grades 1, 2, 3 |
| Key exclusion criteria | 1. Pregnant patients 2. Immunosuppressed patients (e.g. HIV disease, anti-rejection medication) |
| Date of first enrolment | 01/11/2007 |
| Date of final enrolment | 20/02/2017 |
Locations
Countries of recruitment
- England
- Germany
- United Kingdom
Study participating centres
Birmingham
B9 5SS
United Kingdom
235 Euston Road
Bloomsbury
London
NW1 2BU
United Kingdom
Prescot Street
Liverpool
L7 8XP
United Kingdom
Harehills
Leeds
LS9 7TF
United Kingdom
Upper Maudlin Street
Bristol
BS2 8HW
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2TH
United Kingdom
Westminster Bridge Road
London
SE1 7EH
United Kingdom
Frankfurt am Main
60590
Germany
Sponsor information
Government
Porton Down
Salisbury
SP4 0JQ
United Kingdom
| Phone | +44 (0)1980 957424 |
|---|---|
| ralukaszewski@dstl.gov.uk | |
| Website | https://www.gov.uk/government/organisations/defence-science-and-technology-laboratory |
"ROR" |
https://ror.org/04jswqb94 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- MOD
- Location
- United Kingdom
Government organisation / National government
- Alternative name(s)
- U.S. Defense Threat Reduction Agency, DOD Defense Threat Reduction Agency, United States Defense Threat Reduction Agency, US DoD Defense Threat Reduction Agency, Defense Special Weapons Agency, Defense Nuclear Agency, Defense Atomic Support Agency, DTRA, US DTRA
- Location
- United States of America
Results and Publications
| Intention to publish date | 01/01/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a publically available repository. All raw data is derived following the anonymisation of participating patients. Transcriptomic data will be uploaded to a publicly available GEO database. Individual patient metadata will not be publicly available but will be available to individual patients on a case by case basis. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | 13/07/2022 | 14/07/2022 | Yes | No |
Editorial Notes
14/07/2022: Publication reference added.
02/11/2020: Internal review.
27/10/2020: Trial’s existence confirmed by Southampton & South West Hampshire Research Ethics Committee (A)
