Study design and population
This pilot single-center open-label randomized controlled trial was conducted in the Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. We considered for inclusion all adult patients admitted to our institution’s intensive care unit (ICU) following in- or out-of-hospital cardiac arrest. Those who presented one of the following criteria within 24 h of admission were eligible: time-to-ROSC > 25 min and/or serum lactate level > 6 mmol/l and/or need for norepinephrine > 0.2 µg/kg/min for ≥ 1 h to maintain mean arterial pressure (MAP) > 60–70 mmHg. In the absence of a consensual definition for PCAS, these criteria were chosen based on their association with IL-6 plasma levels or post-cardiac arrest shock, a major feature of PCAS accounting for most deaths within the first 3 days [15, 16]. Exclusion criteria included evidence of the patient’s refusal to participate in clinical trials, imminent withdrawal of care, pregnancy, refractory CA with ECMO implantation, need for RRT at the time of randomization, active bleeding or high risk of bleeding.
Since eligible patients were expected to be unable to provide informed consent prior to randomization and since the intervention could not be delayed, an emergency consent procedure was performed. According to this procedure, patients without documented refusal to participate in clinical trials could be included pending the approval of a physician independent from the trial. Consent from a proxy was sought as soon as possible as well as from the patient himself once able to provide informed consent. The study protocol was approved by the Ethics Committee of Vaud (2018-00421) and registered at ClinicalTrials.gov (NCT03523039).
Intervention
Patients were randomized on a 1:1 basis to receive either standard of care (SOC) or standard of care plus hemoadsorption (HA). Randomization sequence was generated using the Excel (Microsoft, Redmond, USA) Rand () function with a 1:1 ratio and permuted blocks of variable sizes. The allocation group was stored within numbered sealed envelopes.
All patients were managed according to local protocol and international guidelines. This included 24 h of targeted temperature management with a central temperature target at 35–36 °C, hemodynamic management targeting a mean arterial pressure > 70 mmHg, glycemic control, avoidance of hyperoxia (PaO2 target 70–100 mmHg), and sedation.
For patients allocated to the intervention group, HA was performed as a stand-alone therapy, using a CytoSorb® cartridge (CytoSorbents Corporation, Monmouth Junction, NJ, USA) and a multiFiltrate® monitor (Fresenius Medical Care, Bad Homburg, Germany) in hemoperfusion mode. Blood flow was maintained > 200 ml/min, and ideally between 250 and 400 ml/min. In order to minimize the risk of bleeding, regional circuit anticoagulation was achieved with a heparin–protamine regimen (see Additional file 1) [17]. After the insertion of a dialysis catheter in a femoral vein, the therapy was initiated within 6 h of randomization and maintained for a minimum of 12 h and up to 24 h. Patients with early (< 12 h) circuit failure, were not included in the efficacy analysis. At the end of the intervention, the dialysis catheter was removed and sent to the laboratory for microbiological analysis.
Endpoints
Since this was a pilot study, we assessed the procedure’s feasibility, safety and efficacy.
Feasibility was assessed by the ratio of included/screened patients, the time to therapy initiation and the percentage of patients who actually received > 12 h of HA in the intervention group.
Safety endpoints included anaphylactoid reactions, bronchospasm, bleeding complications, need for red blood cells transfusion, coagulation abnormalities (defined as a systemic aPTT ≥ 1.5 times baseline value), catheter-related complications (thrombosis, hematoma at insertion site, infections) and new-onset thrombopenia (thrombocytes < 150 G/l) within one and 2 days after randomization. Any other untoward event was recorded and reported.
Efficacy was assessed by the trend in cytokines’ plasma levels within 72 h of randomization and their absolute and relative reduction at 48 h compared to the baseline value (randomization). A large panel of cytokines was assessed including pro-inflammatory (IL-1β, IL-2, IL-6, IL-8, IL-5, interferon (IFN)-γ, GM-CSF, TNF-α) and anti-inflammatory (IL-4, IL-10) mediators. The relative reduction was calculated using the following formula:
$$\begin{aligned} {\text{Relative}}\, {\text{reduction}}\, {\text{at}} 48\,{\text{hours}}\, = & \,\frac{{{\text{absolute}} \,{\text{reduction}} \,{\text{at}} \,48 \,{\text{hours}}}}{{{\text{value}} \,{\text{at}} \,{\text{randomization}} }} \\ \, = & \, \frac{{{\text{value}} \,{\text{at}} \,{\text{randomization}} - {\text{value}}\,{\text{at}}\,48\, {\text{hours}}}}{{{\text{value}} \,{\text{at}} \,{\text{randomization}} }} \\ \end{aligned}$$
Blood samples for cytokines analysis were drawn from the arterial line or the central venous catheter at six time points (randomization, 6, 12, 24, 48 and 72 h post-randomization) into ethylenediaminetetraacetic acid tubes. They were centrifuged at 1500 RPM at 4 °C for 10 min. Three aliquots of 100 μl plasma were prepared and stored at − 80 °C. Cytokines analyses were performed using a Human Cytokine Magnetic 10-Plex Panel on the Luminex® Platform (Thermo Fischer Scientific®, Waltham, USA). For IL-6, an enzyme-linked immunosorbent assay (ELISA) analysis was also performed. All analyses were conducted according to the manufacturer’s protocol and results are reported in pg/mL.
Secondary endpoints included serum levels of C-reactive protein at day 2, acute kidney injury (AKI) during ICU stay (as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines 2012 [18]), change in SOFA score at day 1 and 2, all-cause mortality at day-14 and day-28, ICU length of stay (LOS), 50% decrease in vasopressors dose within 24 and 48 h and shock reversal within 24 h. Shock reversal was defined as a sustained decrease in norepinephrine requirement to < 10 µg/min and a sustained normalization of serum lactate level (< 2 mmol/l).
Statistical analyses
For this pilot study, a convenience sample of 20 patients per arm was arbitrarily decided. The protocol allowed to decrease this sample size to 10 patients per arm for either safety reasons or slow recruitment. Patients with an intervention duration < 12 h were excluded from the efficacy analysis.
All data were collected and stored within a secured database. Qualitative variables are expressed as numbers (percentages) and continuous variables as median (interquartile range—IQR). Due to the exploratory character of the study and the small number of patients, we only performed descriptive analyses with simple comparison tests between groups. Comparisons of secondary outcomes were made using Fisher’s exact test or Wilcoxon rank-sum test, as appropriate, and were exploratory. In the efficacy analysis, we considered only cytokines with > 50% of values above detection thresholds at randomization and at 48 h. A two-tailed p value < 0.05 was considered statistically significant. Analyses were performed with STATA version 17.0 (StataCorp LP, College Station, Texas) and figures created with GraphPad Prism 7 (GraphPad Software, USA).