Sepsis, Sepsis Syndrome, Septic Shock, Severe Sepsis
Conditions
Brief summary
Nociceptin is a protein found in the body, with a number of functions in the central nervous system, blood vessels and the gut. There is evidence that it may have a role in controlling the immune response to infection, and may act as a link between the brain and immune system. In infection, or after surgery, there is an increase in nociceptin, and subjects greater elevations of nociceptin have a poorer outcome. There is evidence that cells of the immune system may produce nociceptin, although it is not yet known which cells are capable of producing it, and what switches on production. This study aims to determine 1. Which cells of the immune system can produce nociceptin 2. If there is a difference in the ability to produce nociceptin between healthy volunteers and patients with severe infections
Interventions
DIAGNOSTIC_TESTSeptic
30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.
Sponsors
The Royal College of Anaesthetists
University Hospitals, Leicester
University of Leicester
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* For septic patients; 1. Participant is willing and able to give informed consent for participation in the study, or if lacking capacity, a next of kin or advocate is willing and able to give assent for participation in the study. Must be able to read and understand English. 2. Male or Female, aged 18 years or above. 3. Diagnosed with sepsis and admitted to the intensive care unit. 4. Able (in the Investigators opinion) and willing to comply with all study requirements. 5. Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study. Healthy Volunteers; 1. Participant is willing and able to give informed consent for participation in the study. Must be able to read and understand English. 2. Male or Female, aged 18 years or above and be 3. In good health. 4. Have had no course of medication, whether prescribed or over-the-counter, in the four weeks before first study dose and no individual doses in the final two weeks other than mild analgesia, vitamins and mineral supplements or, for females, oral contraceptives 5. Able (in the Investigators opinion) and willing to comply with all study requirements. 6. Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study.
Exclusion criteria
* 1\. Conditions which may make phlebotomy hazardous to the participant (such as significant bleeding disorders or anaemia, or allergy), or to the investigator (blood viral infection). 2\. Any significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study. 3\. Participants who have participated in another research study involving an investigational product in the past 12 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Day 1 | Measure of N/OFQ presence in granulocytes and associated supernatant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality In-hospital, at 30 Days | 30 days | All cause mortality at 30 days |
| Time to ICU Discharge (or Death if on ICU) | Time to ICU discharge (or death if on ICU) | — |
| Granulocyte Count | Day 1 | Count of the number of neutrophils in the original sample |
| Acute Physiology and Chronic Health Evaluation (APACHE-2) Score | Day 1 | The Acute Physiology and Chronic Health Evaluation (APACHE-2) score for the patient. APACHE 2 is an international standard,12 variable score from 0-71 reflecting disease severity in the critically unwell during the first 24 hours of illness. The score is a combined measure of illness severity (acute physiology), and background chronic health factors. Increased score represents increased predicted mortality. Variables recorded include AaDO2 or PaO2 (depending on FiO2), temperature, mean arterial pressure, blood pH, heart rate, respiratory rate, serum sodium, serum potassium, creatinine, hematocrit, white blood cell count, Glasgow Coma Scale Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). APACHE II: a severity of disease classification system. Critical Care Medicine. 13 (10): 818-29 |
| Sequential Organ Failure Assessment (SOFA) Score | Day 1 | The Sequential Organ Failure Assessment (SOFA) score for the patient, a score predictive of mortality in sepsis for intensive care patients based on respiratory, cardiovascular, hepatic, coagulation, renal and neurological function (each scored 0-4, with a maximum overall score of 24). The worst (most deranged) physiological values for the first 24 hours are used. A higher score predicts increased mortality. The mortality breakdown for each sofa score range is - SOFA 0-6 (\<10% mortality), 7-9 (15-20%), 10-12 (40-50%), 13-14 (50 - 60%), 15 (\> 80%), 16 to 24 (\> 90%) |
| Time to Death or Discharge | Number of days between admission and death or discharge from hospital | Time to death or discharge (days) |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Septic Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse \>90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately. | 6 |
| Healthy Volunteers Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately. | 8 |
| Total | 14 |
Baseline characteristics
| Characteristic | Healthy Volunteers | Total | Septic |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 13 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Continuous | 34.5 years | 52 years | 75.5 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United Kingdom | 8 participants | 14 participants | 6 participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 6 | 0 / 8 |
| other Total, other adverse events | 0 / 6 | 0 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 8 |
Outcome results
Primary
Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist
Measure of N/OFQ presence in granulocytes and associated supernatant
Time frame: Day 1
Population: Biosensor cells
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Septic | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Eosinophils | 34.25907426 mean % responsive biosensor cells | Standard Deviation 26.36477836 |
| Septic | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Neutrophils | 25.73232323 mean % responsive biosensor cells | Standard Deviation 25.95276607 |
| Septic (+NOP Antagonist SB612111) | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Eosinophils | 5.882352941 mean % responsive biosensor cells | — |
| Septic (+NOP Antagonist SB612111) | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Neutrophils | 8.712121212 mean % responsive biosensor cells | Standard Deviation 0.535686955 |
| Septic (N/OFQ Control) | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Eosinophils | 44.17193917 mean % responsive biosensor cells | Standard Deviation 30.09734468 |
| Septic (N/OFQ Control) | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Neutrophils | 48.66792929 mean % responsive biosensor cells | Standard Deviation 37.86453531 |
| Healthy Volunteers | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Eosinophils | 25.13095238 mean % responsive biosensor cells | Standard Deviation 31.52494693 |
| Healthy Volunteers | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Neutrophils | 32.34442641 mean % responsive biosensor cells | Standard Deviation 22.5667298 |
| Healthy Volunteers (+NOP Antagonist SB612111) | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Eosinophils | 17.86976912 mean % responsive biosensor cells | Standard Deviation 14.33561565 |
| Healthy Volunteers (+NOP Antagonist SB612111) | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Neutrophils | 12.87518038 mean % responsive biosensor cells | Standard Deviation 20.00326171 |
| Healthy Volunteers (N/OFQ Control) | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Eosinophils | 39.97303622 mean % responsive biosensor cells | Standard Deviation 32.13672569 |
| Healthy Volunteers (N/OFQ Control) | Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist | Neutrophils | 17.06777597 mean % responsive biosensor cells | Standard Deviation 15.88672067 |
Secondary
Acute Physiology and Chronic Health Evaluation (APACHE-2) Score
The Acute Physiology and Chronic Health Evaluation (APACHE-2) score for the patient. APACHE 2 is an international standard,12 variable score from 0-71 reflecting disease severity in the critically unwell during the first 24 hours of illness. The score is a combined measure of illness severity (acute physiology), and background chronic health factors. Increased score represents increased predicted mortality. Variables recorded include AaDO2 or PaO2 (depending on FiO2), temperature, mean arterial pressure, blood pH, heart rate, respiratory rate, serum sodium, serum potassium, creatinine, hematocrit, white blood cell count, Glasgow Coma Scale Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). APACHE II: a severity of disease classification system. Critical Care Medicine. 13 (10): 818-29
Time frame: Day 1
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Septic | Acute Physiology and Chronic Health Evaluation (APACHE-2) Score | 19.8 score on a scale |
Secondary
Granulocyte Count
Count of the number of neutrophils in the original sample
Time frame: Day 1
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Septic | Granulocyte Count | Neutrophils | 5.07 x10^7 cells ml-1 |
| Septic | Granulocyte Count | Eosinophils | 0.98 x10^7 cells ml-1 |
| Septic (+NOP Antagonist SB612111) | Granulocyte Count | Neutrophils | 2.05 x10^7 cells ml-1 |
| Septic (+NOP Antagonist SB612111) | Granulocyte Count | Eosinophils | 1.61 x10^7 cells ml-1 |
Secondary
Mortality In-hospital, at 30 Days
All cause mortality at 30 days
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Septic | Mortality In-hospital, at 30 Days | 3 Participants |
| Septic (+NOP Antagonist SB612111) | Mortality In-hospital, at 30 Days | 0 Participants |
Secondary
Sequential Organ Failure Assessment (SOFA) Score
The Sequential Organ Failure Assessment (SOFA) score for the patient, a score predictive of mortality in sepsis for intensive care patients based on respiratory, cardiovascular, hepatic, coagulation, renal and neurological function (each scored 0-4, with a maximum overall score of 24). The worst (most deranged) physiological values for the first 24 hours are used. A higher score predicts increased mortality. The mortality breakdown for each sofa score range is - SOFA 0-6 (\<10% mortality), 7-9 (15-20%), 10-12 (40-50%), 13-14 (50 - 60%), 15 (\> 80%), 16 to 24 (\> 90%)
Time frame: Day 1
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Septic | Sequential Organ Failure Assessment (SOFA) Score | 9.33 score on a scale |
Secondary
Time to Death or Discharge
Time to death or discharge (days)
Time frame: Number of days between admission and death or discharge from hospital
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Septic | Time to Death or Discharge | 17.5 days |
Secondary
Time to ICU Discharge (or Death if on ICU)
Time frame: Time to ICU discharge (or death if on ICU)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Septic | Time to ICU Discharge (or Death if on ICU) | 7.5 days |