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.

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).

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

The investigators do not plan to make individual participant data available to other researchers.

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.