Therapeutic Plasma Exchange in Septic Shock: A Pilot Study

Study Overview
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Brief Summary
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At the Health Sciences Centre and St. Boniface Hospital in Winnipeg, Manitoba, the investigators propose to conduct a two-center randomized trial comparing therapeutic plasma exchange to standard of care in patients diagnosed with septic shock.

Detailed Description
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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 plasma exchange) performed daily until discontinuation of vasopressors, death or up to a maximum of 5 days. Frozen plasma (FP) 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, fluid therapy, mechanical ventilation, and nutrition, will be at the discretion of the treating PLEXSIS 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), TPE (including reaction to plasma, allergic reactions and hypotension). Venous access devices will be inserted by trained, experienced personnel using real-time ultrasound guidance. To further our understanding of the biologic impact of TPE in sepsis, the investigators will collect plasma and whole blood samples at randomization (day 1), post TPE on day 1, prior to TPE treatment on day 3, and 48 hours after completion of TPE to evaluate markers of coagulation (D-dimer, thrombin-antithrombin (TAT) complexes, protein C levels, plasminogen-activator inhibitor 1) and ADAMTS13.

Official Title
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Therapeutic Plasma Exchange in Septic Shock: A Pilot Study

Conditions
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Septic Shock

Intervention / Treatment
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* Other: Therapeutic Plasma Exchange


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible patients must be admitted to an ICU and must meet all of the following inclusion criteria: ≥ 18 years of age Refractory hypotension documented within 18 hours prior to enrolment requiring the institution and ongoing use of vasopressor agents (phenylephrine, norepinephrine, vasopressin, epinephrine, midodrine or dopamine >5 mcg/kg/min) at enrolment. Refractory hypotension is defined as a systolic blood pressure (SBP) less than 90 mmHg, or a SBP more than 30 mmHg below baseline, or a mean arterial blood pressure less than 65 mmHg, plus the receipt of ≥ 2 litres of intravenous fluid for the treatment of hypotension. At least 1 other new organ dysfunction (in addition to refractory hypotension), defined by the following at the time of enrollment: Creatinine ≥1.5x the known baseline creatinine, or ≥ 26.5 μmol/l increase or <0.5 ml/kg of urine output for 6-12 hours according to the KDIGO (Kidney Disease improving Global Outcomes) guideline definition of acute kidney injury. Need for invasive mechanical ventilation or a P/F ratio <250 Platelets <100 x109/L, or a drop of 50 x109/L in the 3 days prior to enrolment Arterial pH < 7.30 or base deficit > 5 mmol/L in association with a lactate >/= to 4.0 mmol/L Exclusion Criteria: We will exclude patients who have any one of the following criteria at the time of enrolment: Consent declined (refusal from patient, SDM, or physician) Clinically apparent other forms of shock including cardiogenic, obstructive (e.g. massive pulmonary embolism, cardiac tamponade, tension pneumothorax), hemorrhagic, neurogenic, or anaphylactic Received vasopressor therapy for greater than 24 hours prior to enrolment Are currently enrolled in related trial Terminal illness with a life expectancy of less than 3 months Are pregnant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Participants randomized to treatment will received 1.0 plasma volume exchanges daily until discontinuation of vasopressors, death or to a maximum of 5 treatments. The management of septic shock, including but not limited to, antibiotic therapy, infection source control, fluid therapy, mechanical ventilation, and nutrition, will be at the discretion of the treating medical team, and will be recorded and reported. | Other: Therapeutic Plasma Exchange<br>* 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.<br>|
| No Intervention: Standard of Care Arm<br>Participants randomized to Standard-of-Care will be treated at the discretion of the treating medical team. The management of septic shock, including but not limited to, antibiotic therapy, infection source control, fluid therapy, mechanical ventilation, and nutrition, will be at the discretion of the treating medical team, and will be recorded and reported. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the feasibility of a large, multicenter trial of TPE in patients with septic shock | Assessing the feasibility of a large, multicenter trial of TPE in patients with septic shock will be the primary outcome. Our primary measure of feasibility will be the ability to enroll an average of 2 patients per site per month. | 18 months for enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the rate of enrollment and adherence to the protocol of those enrolled | We will consider the consent rate to be adequate if 30% of eligible patients are enrolled, an acceptable rate of protocol adherence to be 90% of all study participants; and we will consider the time from randomization to study treatment initiation to be satisfactory if this interval is less than 6 hours. | 18 months | 
| Number of participants that develop adverse reactions to TPE | The following will be recorded: a) plasma transfusion reactions b) occurrence of transfusion related acute lung injury (TRALI) c) development of coagulopathy (INR >1.4) d) complications related to central venous access devices including bleeding or pneumothorax post-insertion, thrombosis, and line infection. | 18 months | 
| Further understand the biological impact of TPE in sepsis | To further our understanding of the biologic impact of TPE in sepsis, we will collect plasma samples at randomization (day 1), and prior to TPE treatments on days 2, 3 and 5 to evaluate coagulation markers, and ADAMTS13. We will perform activity-based protein profiling of serine hydrolases on patients treated with TPE compared to controls. We will observe changes in the protein profile over time in the same patients to determine associated with septic shock(controls) and compare to those who are treated with TPE. We will attempt to identify key enzymes that may be affected by TPE in septic shock. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis