Therapeutic Plasma Exchange in Septic Shock: A Pilot Study

Overview

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

• 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 hypo

Primary outcome measures

• Assess the feasibility of a large, multicenter trial of TPE in patients with septic shock [Time frame: 18 months for enrollment]

Secondary outcome measures (3)

• Assess the rate of enrollment and adherence to the protocol of those enrolled [Time frame: 18 months]
• Number of participants that develop adverse reactions to TPE [Time frame: Up to 8 days]
• Further understand the biological impact of TPE in sepsis [Time frame: up to 8 days]

Eligibility criteria

Eligible patients must be admitted to an ICU and must meet all of the following inclusion criteria:

• ≥ 16 years of age
• 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
• Capacity to initiate plasma exchange with 48 hours of vasopressor initiation.
• 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 within 7 days, or ≥ 26.5 µmol/l increase in 48 hours,
• 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 enrollment
• 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:

• Consent declined (refusal from patient, SDM, or physician)
• Clinically apparent alternate causes for shock (cardiogenic, hemorrhagic, obstructive, neurogenic or anaphylactic)
• Terminal illness with a life expectancy of less than 3 months
• Are pregnant

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Canada · 11 centers

• Foothills Medical Centre — Calgary
• Southern Health Campus — Calgary
• University of Alberta — Edmonton
• University of Manitoba — Winnipeg
• Hamilton Health Sciences - Juravinski — Hamilton
• St. Joseph's Hospital — Hamilton
• Queen's University at Kingston — Kingston
• Ottawa Hospital — Ottawa
• … and 3 more centers

Publications

• 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. PMID 27322218
• 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. PMID 25527094
• 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. PMID 12373468
• 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. PMID 30515242
• 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 Colleg PMID 18158437
• 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. PMID 23659614
• 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; PMID 31939781

Identifiers

NCT: NCT05093075 · HS23165 (B2019:093)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗