Septic Shock
Conditions
Keywords
Sepsis
Brief summary
The investigators propose to conduct a multi-center randomized pilot feasibility trial comparing therapeutic plasma exchange to standard of care in patients diagnosed with septic shock.
Detailed description
The intervention arm consists of an exchange of one volume of plasma equivalent to the patient's total calculated blood volume (1.0 plasma volume exchange) performed daily until discontinuation of vasopressors, death or up to a maximum of 5 daily treatments. Solvent detergent plasma or frozen plasma (FP) depending on availability will be used as the replacement fluid. The control group will receive standard of care for the treatment of septic shock in accordance with local practice and informed by national and international guidelines. The management of septic shock, including but not limited to, antibiotic therapy, infection source control, therapy, fluid therapy, mechanical ventilation, and nutrition, will be at the discretion of the treating medical team, and will be recorded and reported. The investigators will monitor for development of coagulopathy by measure the INR and fibrinogen levels daily. These are expected to normalize with the use of plasma as replacement fluid. The investigators will monitor for adverse reactions related to central venous access devices (insertion related complications, infection, thrombosis) and/or TPE (including reaction to plasma, allergic reactions and hypotension). Venous access devices will be inserted by trained, experienced personnel using real-time ultrasound guidance. These data are routinely collected by apheresis programs across Canada as part of a data collection and reporting relationship with CAG. To further our understanding of the biologic impact of TPE in sepsis, plasma and whole blood samples will be collected at randomization (day 1), Pre-3rd TPE or Day 3 if in SOC group, pre-5th TPE or Day if SOC group, and 48 hours after completion of TPE or Day 7 if SOC group to evaluate markers of coagulation (ADAMTS-13 levels, DNase levels, histones).
Interventions
TPE procedures will be performed using a Spectra Optia ® apheresis machine (Terumo BCT, Lakewood, USA) according to usual-care procedures for apheresis. Venous access for the TPE procedures will be obtained through a double lumen dialysis catheter to provide adequate flow rates required for TPE. Regional citrate anticoagulation will be used for anticoagulation within the apheresis circuit. One to two grams of calcium chloride will be infused as per standard during TPE to prevent symptomatic hypocalcemia. Plasma volume will be calculated as per a standard formula whereby estimated plasma volume (in liters) = 0.07 x weight (kg) x (1 - hematocrit). In patients on dialysis, dialysis will be interrupted for the duration of the procedure. Antibiotics will be given after TPE to avoid clearance of the antibiotics. On the first day of TPE, a repeat dose of antibiotics will be administered after completion of TPE. Nurse clinicians trained in TPE will perform the TPE procedures.
Sponsors
Canadian Institutes of Health Research (CIHR)
Health Sciences Centre Foundation, Manitoba
McMaster University
University of Toronto
University of Manitoba
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
All investigators and research staff will be blinded to the allocation schedules. The PLEXSIS pilot trial is designed as a prospective randomized open, blinded endpoint (PROBE) trial. This pragmatic design is necessary given impractical nature of blinding the TPE intervention.
Intervention model description
A web-based randomization system maintained at the Center for Healthcare Innovation (CHI) (Winnipeg, Manitoba) will be used to allocate treatment assignments. The randomization process will consist of a computer-generated random listing of the treatment allocations in variable permuted blocks of 2 and 4. Participants will be randomized to Treatment (5 Therapeutic Plasma Exchanges) or Standard of Care.
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligible patients must be admitted to an ICU and must meet all of the following inclusion criteria: 1. ≥ 16 years of age 2. Refractory hypotension documented within 48 hours prior to enrollment requiring the institution and ongoing use of vasopressor agents (phenylephrine, norepinephrine, vasopressin, epinephrine, midodrine or dopamine \>5 mcg/kg/min) at enrollment. Refractory hypotension is defined as a systolic blood pressure (SBP) less than 90 mmHg, or SBP less than 30 mmHg below baseline, or a mean arterial blood pressure less than 65 mmHg, despite adequate fluid resuscitation 3. Capacity to initiate plasma exchange with 48 hours of vasopressor initiation. 4. At least 1 other new organ dysfunction (in addition to refractory hypotension), defined by the following at the time of enrollment: 1. Creatinine ≥1.5x the known baseline creatinine within 7 days, or ≥ 26.5 µmol/l increase in 48 hours, 2. Need for invasive mechanical ventilation or a P/F ratio \<250 3. Platelets \<100 x109/L, or a drop of 50 x109/L in the 3 days prior to enrollment 4. Arterial pH \< 7.30 or base deficit \> 5 mmol/L in association with a lactate \>/= to 3.0 mmol/L 45\. Known or suspected infection 2.4.3
Exclusion criteria
We will exclude patients who have any one of the following criteria at the time of enrollment: 1. Consent declined (refusal from patient, SDM, or physician) 2. Clinically apparent alternate causes for shock (cardiogenic, hemorrhagic, obstructive, neurogenic or anaphylactic) 3. Terminal illness with a life expectancy of less than 3 months 4. Are pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assess the feasibility of a large, multicenter trial of TPE in patients with septic shock | 18 months for enrollment | Assessing the feasibility of a large, multicenter trial of TPE in patients with septic shock will be the primary outcome. The primary measure of feasibility will be the ability to enroll an average of 2 patients per site per month. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess the rate of enrollment and adherence to the protocol of those enrolled | 18 months | The investigators will consider the consent rate to be adequate if 70% of SDM or patients when approached for consent are enrolled, an acceptable rate of protocol adherence to be 90% of all study participants; and the time from randomization to study treatment initiation to be satisfactory if this interval is less than 24 hours. |
| Number of participants that develop adverse reactions to TPE | Up to 8 days | The following will be recorded: a) major respiratory compromise; b) thrombotic events; c) major bleeding; d) anaphylaxis; e) central venous access insertion complications. |
| Further understand the biological impact of TPE in sepsis | up to 8 days | To further our understanding of the biologic impact of TPE in sepsis, sites will collect plasma and whole blood samples at randomization (day 1), pre-3rd TPE or day 3 if in SOC group, pre-5th TPE or day 5 if SOC group, and 48 hours after completion of last TPE or day 7 if SOC group to evaluate markers of coagulation (ADAMTS-13 levels, DNase levels, histones). Sites will collect whole blood samples on all randomized patients and profile DNA methylation on a random subset of 40 patients to determine changes in circulating immune cell remodeling. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mortality | up to day 60 | The pilot trial is not designed to detect differences in clinical outcomes. However, vital status will be accessed. |
| Organ failure | Up to day 21 | The pilot trial is not designed to detect differences in clinical outcomes. However, the investigators will measure and describe organ-support free-days to day 21, and change in SOFA score (multiple organ dysfunction score). |
Countries
Canada
Contacts
Primary ContactEmily Rimmer, MD, MSc
Backup ContactChantale Pineau, BA
Outcome results
None listed