Clinical trial NCT05093075: Therapeutic Plasma Exchange in Septic Shock: a Pilot Study
Official title: Therapeutic Plasma Exchange in Septic Shock: a Pilot Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Septic Shock
Keywords: Sepsis
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Health Sciences Centre Foundation, Manitoba
name: McMaster University
name: University of Toronto
First posted: 2021-10-26
Enrollment: 80
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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).

Eligibility 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 24 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. At least 1 other new organ dysfunction (in addition to refractory hypotension), defined by the following at the time of enrollment:

   a.) Creatinine ≥1.5x the known baseline creatinine, or ≥ 26.5 µmol/l increase, b.) Need for invasive mechanical ventilation or a P/F ratio \<250 c.) Platelets \<100 x109/L, or a drop of 50 x109/L in the 3 days prior to enrollment d.) Arterial pH \< 7.30 or base deficit \> 5 mmol/L in association with a lactate \>/= to 3.0 mmol/L
4. Known or suspected infection

Exclusion Criteria:

Patients who have any one of the following criteria at the time of enrollment will be excluded:

1. Consent declined (refusal from patient, SDM, or physician)
2. Clinically apparent alternate causes for shock (cardiogenic, hemorrhagic, obstructive, neurogenic or anaphylactic)
3. Received vasopressor therapy for greater than 24 hours prior to enrollment
4. Terminal illness with a life expectancy of less than 3 months
5. Are pregnant

Primary outcomes:
measure: Assess the feasibility of a large, multicenter trial of TPE in patients with septic shock
timeFrame: 18 months for enrollment
Secondary outcomes:
measure: Assess the rate of enrollment and adherence to the protocol of those enrolled
timeFrame: 18 months
measure: Number of participants that develop adverse reactions to TPE
timeFrame: Up to 8 days
measure: Further understand the biological impact of TPE in sepsis
timeFrame: up to 8 days
Other outcomes:
measure: Mortality
timeFrame: up to day 60
measure: Organ failure
timeFrame: Up to day 21
measure: Organ failure
timeFrame: Up to day 8
Locations:
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Calgary
country: Canada
facility: Southern Health Campus
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Hamilton
country: Canada
facility: Hamilton Health Sciences - Juravinski
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Quebec City
country: Canada
facility: Universite Laval
state: Quebec
Study officials:
affiliation: University of Manitoba
name: Ryan Zarychanski, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manitoba
name: Emily Rimmer, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L, Delaney M, Dunbar NM, Witt V, Wu Y, Shaz BH. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher. 2016 Jun;31(3):149-62. doi: 10.1002/jca.21470.
citation: Rimmer E, Houston BL, Kumar A, Abou-Setta AM, Friesen C, Marshall JC, Rock G, Turgeon AF, Cook DJ, Houston DS, Zarychanski R. The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis. Crit Care. 2014 Dec 20;18(6):699. doi: 10.1186/s13054-014-0699-2.
citation: Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med. 2002 Oct;28(10):1434-9. doi: 10.1007/s00134-002-1410-7. Epub 2002 Jul 23.
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citation: Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan;36(1):296-327. doi: 10.1097/01.CCM.0000298158.12101.41.
citation: Lega JC, Mismetti P, Cucherat M, Fassier T, Bertoletti L, Chapelle C, Laporte S. Impact of double-blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta-analysis. J Thromb Haemost. 2013 Jul;11(7):1240-50. doi: 10.1111/jth.12294.
citation: Binnie A, Walsh CJ, Hu P, Dwivedi DJ, Fox-Robichaud A, Liaw PC, Tsang JLY, Batt J, Carrasqueiro G, Gupta S, Marshall JC, Castelo-Branco P, Dos Santos CC; Epigenetic Profiling in Severe Sepsis (EPSIS) Study of the Canadian Critical Care Translational Biology Group (CCCTBG). Epigenetic Profiling in Severe Sepsis: A Pilot Study of DNA Methylation Profiles in Critical Illness. Crit Care Med. 2020 Feb;48(2):142-150. doi: 10.1097/CCM.0000000000004097.