Therapeutic Plasma Exchange in Septic Shock: A Pilot Study

Septic Shock Clinical Trial

— PLEXSIS  

Official title:

Therapeutic Plasma Exchange in Septic Shock: A Pilot Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05093075
• Other study ID #: HS23165 (B2019:093)
• Status: Recruiting
• Phase: Phase 2
• Start date: June 1, 2023
• Est. completion date: December 2026

Study information

• Verified date: December 2023
• Source: University of Manitoba
• Contact: Emily Rimmer, MD, MSc
• Phone: 204-787-2128
• Email: erimmer[@]cancercare.mb.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: December 2026
• Est. primary completion date: March 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

Intervention

Other:
• Therapeutic Plasma Exchange
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.

Locations

Country	Name	City	State
Canada	University of Alberta	Edmonton	Alberta
Canada	Hamilton Health Sciences - Juravinski	Hamilton	Ontario
Canada	St. Joseph's Hospital	Hamilton	Ontario
Canada	Ottawa Hospital	Ottawa	Ontario
Canada	Universite Laval	Quebec City	Quebec
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	University of Manitoba	Winnipeg	Manitoba

Sponsors (5)

Lead Sponsor	Collaborator
University of Manitoba	Canadian Institutes of Health Research (CIHR), Health Sciences Centre Foundation, Manitoba, McMaster University, University of Toronto

Country where clinical trial is conducted

Canada, 

References & Publications (7)

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. — View 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. — View Citation

Davies R, O'Dea K, Gordon A. Immune therapy in sepsis: Are we ready to try again? J Intensive Care Soc. 2018 Nov;19(4):326-344. doi: 10.1177/1751143718765407. Epub 2018 Apr 4. — View 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. Erratum In: Crit Care Med. 2008 Apr;36(4):1394-6. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mortality	The pilot trial is not designed to detect differences in clinical outcomes. However, vital status will be accessed.	up to day 60
Other	Organ failure	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).	Up to day 21
Other	Organ failure	The pilot trial is not designed to detect differences in clinical outcomes. However, the investigators will measure change in SOFA score (multiple organ dysfunction score).	Up to day 8
Primary	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. The primary measure of feasibility will be the ability to enroll an average of 2 patients per site per month.	18 months for enrollment
Secondary	Assess the rate of enrollment and adherence to the protocol of those enrolled	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.	18 months
Secondary	Number of participants that develop adverse reactions to TPE	The following will be recorded: a) major respiratory compromise; b) thrombotic events; c) major bleeding; d) anaphylaxis; e) central venous access insertion complications.	Up to 8 days
Secondary	Further understand the biological impact of TPE in sepsis	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.	up to 8 days