Background

Centrifugation-based autotransfusion devices only salvage red blood cells while platelets are removed. The same™ device (Smart Autotransfusion for ME; i-SEP, France) is an innovative filtration-based autotransfusion device able to salvage both red blood cells and platelets. The authors tested the hypothesis that this new device could allow a red blood cell recovery exceeding 80% with a posttreatment hematocrit exceeding 40%, and would remove more than 90% of heparin and 75% of free hemoglobin.

Methods

Adults undergoing on-pump elective cardiac surgery were included in a noncomparative multicenter trial. The device was used intraoperatively to treat shed and residual cardiopulmonary bypass blood. The primary outcome was a composite of cell recovery performance, assessed in the device by red blood cell recovery and posttreatment hematocrit, and of biologic safety assessed in the device by the washout of heparin and free hemoglobin expressed as removal ratios. Secondary outcomes included platelet recovery and function and adverse events (clinical and device-related adverse events) up to 30 days after surgery.

Results

The study included 50 patients, of whom 18 (35%) underwent isolated coronary artery bypass graft, 26 (52%) valve surgery, and 6 (12%) aortic root surgery. The median red blood cell recovery per cycle was 86.1% (25th percentile to 75th percentile interquartile range, 80.8 to 91.6) with posttreatment hematocrit of 41.8% (39.7 to 44.2). Removal ratios for heparin and free hemoglobin were 98.9% (98.2 to 99.7) and 94.6% (92.7 to 96.6), respectively. No adverse device effect was reported. Median platelet recovery was 52.4% (44.2 to 60.1), with a posttreatment concentration of 116 (93 to 146) · 109/l. Platelet activation state and function, evaluated by flow cytometry, were found to be unaltered by the device.

Conclusions

In this first-in-human study, the same™ device was able to simultaneously recover and wash both platelets and red blood cells. Compared with preclinical evaluations, the device achieved a higher platelet recovery of 52% with minimal platelet activation while maintaining platelet ability to be activated in vitro.

Editor’s Perspective
What We Already Know about This Topic
  • Current centrifugation-based autotransfusion devices only salvage red blood cells and remove platelets. The ability to also salvage platelets would be important for clinical management.

What This Article Tells Us That Is New
  • This study evaluated a novel filtration-based cell salvaging autotransfusion device (i-SEP) capable of recovering red blood cells and platelets in cardiac surgical patients. The i-SEP system achieved platelet recovery of 52% from shed and residual cardiopulmonary bypass blood that maintained functional activity based on in vitro platelet testing.

Intraoperative cell salvage, or autotransfusion, allows the recovery of blood shed from the surgical field.1–3  It ensures both washing and concentration of red blood cells and finally their transfusion back to the patient. Autotransfusion has proven to be a cost-effective technique, associated with a reduction in the need for perioperative allogeneic blood transfusion during high bleeding risk surgical procedures, including cardiac surgery.1,4  Intraoperative cell salvage is therefore recommended by international guidelines as part of patient blood management strategies.1,5  Commercially available autotransfusion devices are based on a centrifugation process that allows only red blood cell recovery, while blood platelets are almost totally removed.1,2,6  Hence, large amounts of intraoperative cell salvage blood transfusion have been associated with thrombocytopenia and increased allogeneic platelet transfusion.7  Indeed, platelet function defects and thrombocytopenia are known conditions associated with perioperative bleeding.8–10  In addition, allogeneic platelet transfusion, while recommended to treat thrombocytopenia-induced bleeding, may also be associated with postoperative and intensive care unit complications.5,11–14  Further, allogeneic platelet concentrates are short shelf-life products that are prone to production shortages.15 

To overcome current limitations of both intraoperative cell salvage and allogeneic platelet transfusion, a new autotransfusion device was recently developed. The same™ by i-SEP (France) device is an innovative autotransfusion device based on a polyethersulfone hollow-fiber filtration technology. Preclinical studies recently demonstrated a high performance in both red blood cell recovery and plasma proteins and heparin washing.16,17  Further, the i-SEP device achieved a significant platelet recovery with minimal platelet activation while maintaining platelet ability to be activated in vitro.16  Our objective was to evaluate in a first-in-human study the cell recovery performance and the biologic safety of the i-SEP device during on-pump cardiac surgery. We tested the hypothesis that this new device could allow a red blood cell recovery exceeding 80% with a posttreatment hematocrit greater than 40%, and could remove more than 90% of heparin and 75% of free hemoglobin.

Trial Design

The i-TRANSEP study (Prospective, Multicenter, Single-arm Clinical Investigation Evaluating the Safety, Performance and Clinical Benefit of a New Autotransfusion Device in Cardiac Surgery; NCT04588350) was designed as a first-in-human, interventional, open-label, noncomparative, multicenter trial of the i-SEP autotransfusion device during on-pump cardiac surgery. It was conducted at four high-volume tertiary referral hospitals in France. The study was approved by the French National Agency for Medicines and Health Products Safety (Agence Nationale de Sécurité du Médicament et des Produits de Santé, Saint-Denis, France; IDRCB 2019-A00392-55-A) and by the Ethics Committee (Comité de Protection des Personnes Sud-Ouest et Outre-mer II, Toulouse, France; 2-19-060 ID4420). Written informed consent was obtained from all subjects during preoperative anesthesia assessment. The analysis followed the Transparent Reporting of Evaluations with Nonrandomized Design guidelines (Supplementary Table S1, https://links.lww.com/ALN/D167).

Participants

Patients were eligible if they were older than 18 yr; planned for a first-time elective noncomplex cardiac surgery under cardiopulmonary bypass including isolated coronary artery bypass graft surgery, isolated single valve repair or replacement surgery or aortic root surgery; and had neither anemia (preoperative hemoglobin less than 13 g/dl for a man and less than 12 g/dl for a woman) nor thrombocytopenia (preoperative platelets count less than 150 · 109/l). Preoperative exclusion criteria included emergency surgery, active endocarditis, redo surgery, combined surgery, heart transplantation or mechanical circulatory support surgery, expected circulatory arrest, uninterrupted oral anticoagulation or antiplatelet agent (except aspirin) according to European Association of Cardiothoracic Anaesthesiology and Intensive Care guidelines, active malignancy, systemic or local bacterial infections, proof or suspicion of a congenital or acquired coagulation disorder, intention to refuse any blood transfusion, and absolute contraindications to heparin. Intraoperative exclusion criteria were a salvaged blood volume less than 500 ml or the use of i-SEP device emergency mode.

Intervention

The same™ by i-SEP autotransfusion device is a medical device consisting of reusable equipment and disposable consumables (Supplementary Figure S1, https://links.lww.com/ALN/D167). The device has received the CE marking according to Medical Device Regulation, MDR 2017/745 (certificate No. MDR 750385), and is now commercially available in Europe. The blood processing by the device has been extensively described in published preclinical reports.16,17  Briefly, shed blood is collected and heparinized through a dual-lumen suction line in a sterile blood collection reservoir (including a 40-μm filter) previously primed with 200 ml of the heparinized 0.9% NaCl solution (heparinized saline drip 25,000 U/l). The salvaged blood is then treated by the device with both filtration and washing with 0.9% NaCl solution. After an initial filtration phase (of short duration, dependent on the initial hematocrit) to obtain a hematocrit of around 45% in the circuit, the recovered blood undergoes two successive fixed phases of dilution and filtration to obtain a posttreatment volume with a hematocrit around 45% in the reinfusion bag. This process results in platelet recovery that is largely independent of the concentration process of red blood cells.

For the current study, the i-SEP device was used intraoperatively to treat both shed blood from the surgical field and residual cardiopulmonary bypass circuit blood, from sternotomy to surgical wound closure, under controlled depression level using the suction line, with a vacuum level of –150 mbar. The standard program used during the study allowed a first treatment cycle of 700 ml and further treatment cycles of 500 ml of collected blood. Processed blood was collected in a separate reinfusion bag for each treatment cycle to allow posttreatment blood analysis and transfused to the patients intraoperatively, before or after effective weaning from cardiopulmonary bypass. The processed blood was transfused to the patient using a transfusion line according to each center’s practice.

Perioperative Management

Participants received usual anesthetic and surgical management, according to each center’s protocol. Cardiopulmonary bypass was conducted only using roller pumps. Heparin and protamine dosing were based either on the HMS Plus device (Medtronic, USA) or weight-based protocol and conventional activated clotting time. Tranexamic acid was used for all patients according to current guidelines. All patients were admitted to the cardiothoracic intensive care unit immediately after surgery. Perioperative administration of blood products followed current international guidelines and was based on either conventional or viscoelastic coagulation tests.

Study Outcomes

The primary outcome was a composite, assessed by sampling blood in the device, of cell recovery performance, by the red blood cell recovery and the posttreatment hematocrit with targets of 80% and 40%, respectively; and of biologic safety by the washing performance for heparin and free hemoglobin expressed as removal ratios (washout) with targets of 90% and 75%, respectively. Secondary safety and performance outcomes on the patient included perioperative blood product use up to 30 days after the intervention, postoperative blood loss up to 48 h or drainage removal, reintervention for bleeding from surgery to discharge, adverse events incidence through a 1-month follow-up period, and complete blood count evolution up to 48 h after surgery. Perioperative bleeding was quantified using the universal definition for perioperative bleeding score.18  Secondary outcomes on the device before and after each treatment cycle included major plasma proteins removal, triglyceride removal, platelet and leukocyte recovery, and platelet function assessed by flow cytometry (only for the first two treatment cycles). An independent data safety monitoring board, comprising two physicians and a statistician, reviewed all biologic and clinical data.

Blood Sample Collection and Laboratory Analyses

Complete blood counts were performed from the patient’s blood at anesthesia induction, at intensive care unit admission (immediate postoperative evaluation), and at day 1 and day 2 after surgery.

Blood cell recovery and washing performance were assessed for each treatment cycle by sampling pretreatment blood in the collection reservoir and posttreatment blood in the reinfusion bag. The sampling procedure was identical for all tests. A new reinfusion bag was used for each cycle to facilitate the posttreatment sampling. Blood was gently homogenized in both the collection reservoir and the transfusion bag before taking samples to ensure homogeneous sampling. The following laboratory analyses were performed for all patients and all cycles: complete blood count (including red blood cell count, leukocyte count, platelet count, hematocrit, and total hemoglobin level), plasma free hemoglobin, total proteins, albumin, potassium, and triglyceride concentrations. Plasma was obtained from citrate tubes and frozen (–80°C) before performing centralized measurement of anti-Xa value STA-Liquid-anti-Xa on a STA R Max coagulometer (Stago, France) in samples diluted to 1:20 or 1:2 in normal pool plasma to allow measurement of high heparin concentration. Blood cell recovery was calculated using the following formula: cell recovery = [(posttreatment blood volume × posttreatment cell concentration) / (pretreatment blood volume × pretreatment cell concentration)] × 100. Washing performance of plasma components was measured using removal ratios as follows: (initial quantity of component – final quantity of component) / initial quantity of component. Cell recovery and removal ratios were expressed for each patient by pooling cells or plasma component quantities for all cycles. Due to hemolysis occurring during and/or after treatment and washing process, free hemoglobin removal ratio was calculated using the following formula: [1 – QfHbp / (QHbi – QHbp + QfHbi)] × 100, where QHbi and QHbp are the quantities of hemoglobin in pre- and posttreatment blood, respectively, and QfHbi and QfHbp are the quantities of pre- and posttreatment free hemoglobin. The hemolysis index was further evaluated using free hemoglobin measured as follows: (100 − hematocrit) × free hemoglobin [g/dl] / total hemoglobin [g/dl].

Platelet activation was evaluated in vitro by measuring surface expression of platelet activation markers using flow cytometry. Platelet activation was assessed at rest and before and after blood treatment by the device to evaluate the potential impact of processing on platelets. Stimulation by thrombin receptor PAR1-activating peptide 6 (TRAP6) was used as a surrogate to determine whether posttreatment platelets can be activated after being processed by the i-SEP device. P-selectin (CD62P), CD63, glycoprotein Ib, and glycoprotein IIb were assessed using the PLT glycoprotein or receptors kit from Biocytex (Stago, France) and expressed as number of receptors according to the manufacturer’s instructions. Active glycoprotein IIbIIIa was assessed using PAC-1 antibody binding (Becton Dickinson, USA) and expressed as mean fluorescence intensity, as previously described.19  Upon activation, surface expression of P-selectin, CD63, glycoprotein IIb, and active glycoprotein IIbIIIa is increased, whereas glycoprotein Ib surface exposure is reduced. Due to the technical difficulty of these ex vivo analyses performed on fresh blood and requiring extensive logistics to process these samples in a timely manner, flow-cytometric analyses were planned only for the first two cycles and could not be carried out for all patients. Specialized analysis of active glycoprotein IIbIIIa expression was only planned in one center (University Hospital of Bordeaux, Bordeaux, France) as an exploratory additional analysis.

Sample Size Calculation and Statistical Analysis

No a priori statistical power calculation was conducted. A sample size of 50 participants was chosen to provide sufficiently precise primary endpoint estimates and to have at least 90% probability of observing perioperative clinical events with an incidence of 5% or greater. Patient characteristics were expressed as number (percentage) for categorical variables and median with interquartile range for continuous variables. A statistical analysis plan was made before accessing the data. For heparin and triglyceride measurements, values inferior to the limit of quantification, respectively 0.1 U/ml and 0.1 mmol/l, were substituted with limit of quantification / 2 (0.05 U/ml and 0.05 mmol/l, respectively). Statistical analyses were performed using SAS version 9.4 or later (SAS Institute Inc., USA) and Prism 8 (GraphPad Software, USA). The data were tested for normality using the D’Agostino and Pearson normality test. Outliers were not excluded from the analyses. The differences between two conditions are reported as actual differences between medians with Hodges–Lehman computed 95% CI. Because the treated blood is different across treatment cycles (e.g., shed blood vs. residual cardiopulmonary bypass blood) and also because the filtration and washing process uncouples pre- and posttreated blood, we considered each sample (e.g., cycle 1 pretreatment) as independent. Consequently, Kruskal–Wallis with post hoc Dunn’s correction test were used for multiple comparisons between treatment phases, cycles, and TRAP6 stimulation in the flow-cytometric analysis of platelet activation markers. All tests used a two-tailed hypothesis. Statistical significance was achieved for P < 0.05.

During the study period from September 2020 to April 2021, 53 adult patients undergoing elective on-pump cardiac surgery were included (fig. 1). Three patients were excluded before surgery: two patients for surgery being postponed and one patient for a technical device deficiency before the start of the surgery (electric clamp malfunction; maintenance was performed by the manufacturer). Fifty patients underwent cardiac surgery and autotransfusion with the i-SEP device, of whom one patient was mistakenly included due to undiagnosed metastatic cancer at the time of surgery (eligibility deviation). The results are reported for all 50 patients.

Fig. 1.

Flow chart of the i-TRANSEP study (same™ by i-SEP device; Nantes, France).

Fig. 1.

Flow chart of the i-TRANSEP study (same™ by i-SEP device; Nantes, France).

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Baseline Characteristics

Baseline patient, hematologic, and surgery characteristics are summarized in table 1. Preoperative characteristics were consistent with the inclusion of low-risk patients with a European System for Cardiac Operative Risk Evaluation II predicted mortality of 1.0% (1.0 to 1.6; interquartile range). Out of 50 patients, 26 patients (52%) underwent isolated single valve repair or replacement surgery, 18 patients (36%) isolated coronary artery bypass graft surgery, and 6 patients (12%) aortic root surgery without circulatory arrest.

Table 1.

Baseline Patient, Hematologic, and Surgery Characteristics

Baseline Patient, Hematologic, and Surgery Characteristics
Baseline Patient, Hematologic, and Surgery Characteristics

Blood Processing by the Device

Overall, 168 treatment cycles were performed with 3 (2 to 4; minimum, 1; maximum, 9) treatment cycles per patient (table 2). The median volume of salvaged blood (blood lost and heparinized saline drip) was 1,994 (1,665 to 2,607) ml, of which 1,755 (1,245 to 2,290) ml was processed by the device, with a pretreatment hematocrit of 17.0% (13.8 to 18.4). The median cumulated treated blood volume for reinfusion was 527 (372 to 684) ml. Nineteen patients (38%) underwent more than three treatment cycles, corresponding to a processed volume of 2,808 (2,287 to 3,136) ml and a reinfused volume of 721 (631 to 830) ml. The median treatment duration per cycle was 5.6 (5.0 to 6.2) min. Wash solution volume was 4 (3 to 4) l, and the waste bag (3-l capacity) had to be changed every two cycles.

Table 2.

Perioperative Outcomes

Perioperative Outcomes
Perioperative Outcomes

Primary Outcome

Median red blood cell recovery was 86.1% (80.8 to 91.6) with a posttreatment hematocrit of 41.8% (39.7 to 44.2) (table 3). Overall, 39 of 50 patients (78%) had a global red blood cell recovery 80% or greater, while 37 of 50 patients (74%) reached a mean posttreatment hematocrit 40% or greater. Median heparin removal ratio was 98.9% (98.2 to 99.7) with a posttreatment heparin concentration of 0.3 (0.1 to 0.5) U/ml corresponding to 80 (19 to 213) units (table 4). Median free hemoglobin removal ratio was 94.6% (92.7 to 96.6) with a posttreatment concentration of 284 (222 to 376) mg/dl and posttreatment hemolysis index of 1.2% (0.9 to 1.6). Global heparin and free hemoglobin removal ratios were respectively greater than 90% and 75% for all patients.

Table 3.

Cell Recovery Performance

Cell Recovery Performance
Cell Recovery Performance
Table 4.

Washing Performance

Washing Performance
Washing Performance

Secondary Outcomes

Cell Recovery Performance

Cell recovery performance is reported in table 3. Besides red blood cells, the device exhibited a high platelet recovery of 52.4% (44.2 to 60.1), with a posttreatment concentration of 116 (93 to 146) 109/l. The global quantity of salvaged platelets in patients with more than three treatment cycles was 0.9 × 1011 (0.7 × 1011 to 1.2 × 1011) platelets. The device produced a global leukocyte recovery rate of 90.0% (83.4 to 97.4) with leukocyte counts in the posttreated blood of 10.2 (7.4 to 14.0) · 109/l. The cell recovery performance remained unchanged through all successive cycles (Supplementary Table S2, https://links.lww.com/ALN/D167).

Platelet Function Analysis

Flow-cytometric analysis of platelet activation was performed in 44 patients and demonstrated a nonsignificant trend for higher surface expression of P-selectin (fig. 2A), CD63 (fig. 2B), and active glycoprotein IIbIIIa (Supplementary Figure S2, https://links.lww.com/ALN/D167) between pretreated and posttreated blood for both the first and second cycles, and a small significant increase in glycoprotein IIb expression during the first cycle (5,478 [2,551 to 8,047; 95% CI] receptors; P = 0.038; fig. 2C). Blood processing by the device was not associated with a reduction in glycoprotein Ib surface expression (fig. 2D).

Fig. 2.

Effect of i-SEP device (France) processing on P-selectin, CD63, glycoprotein IIb, and glycoprotein Ib platelet expression and evaluation of platelet activation potential by thrombin receptor pathway stimulation using thrombin receptor-activating peptide 6 (TRAP6). P-selectin (A), CD63 (B), glycoprotein IIb (C), and glycoprotein Ib (D) expression were reported as the number of receptors per platelet and measured between pretreatment (Pre) and posttreatment (Post; concentrated) blood for first and second each cycle (n = 42 to 44 for first cycle and n = 39 to 41 for second cycle 2). *P < 0.05; ****P < 0.001. Measurements were performed before (−) or after TRAP6-induced platelet activation (+).

Fig. 2.

Effect of i-SEP device (France) processing on P-selectin, CD63, glycoprotein IIb, and glycoprotein Ib platelet expression and evaluation of platelet activation potential by thrombin receptor pathway stimulation using thrombin receptor-activating peptide 6 (TRAP6). P-selectin (A), CD63 (B), glycoprotein IIb (C), and glycoprotein Ib (D) expression were reported as the number of receptors per platelet and measured between pretreatment (Pre) and posttreatment (Post; concentrated) blood for first and second each cycle (n = 42 to 44 for first cycle and n = 39 to 41 for second cycle 2). *P < 0.05; ****P < 0.001. Measurements were performed before (−) or after TRAP6-induced platelet activation (+).

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TRAP6 stimulation of posttreated blood induced significant changes in platelet activation markers surface expression, with increased expression of P-selectin (fig. 2A), CD63 (fig. 2B), glycoprotein IIb (fig. 2C), and active glycoprotein IIbIIIa (Supplementary Figure S2, https://links.lww.com/ALN/D167) and decreased glycoprotein Ib surface expression (fig. 2D), compared to unstimulated posttreated blood for both first and second cycles. These results demonstrate that recovered platelets retain a potential of in vitro activation after being processed by the device.

Washing Performance

Washing performance is reported in table 4. Besides heparin and free hemoglobin, the i-SEP device exhibited high washing performance with total protein and triglyceride removal ratios of 94.5% (92.2 to 95.3) and 94.0% (90.8 to 95.9), respectively. Potassium removal ratio was 89.1% (87.7 to 91.7) with a posttreatment potassium concentration of 2.3 (2.0 to 2.8) mmol/l. The plasma components removal performance remained unchanged through all successive cycles (Supplementary Table S2, https://links.lww.com/ALN/D167).

Postoperative Outcomes

Postoperative outcomes are reported in table 2. Perioperative use of blood product up to 24 h after surgery was low, with an incidence of packed red blood cell transfusion of 2 of 50 (4%), fresh frozen plasma of 1 of 50 (2%), fibrinogen concentrate of 4 of 50 (8%), and no platelet concentrate transfusion. Consistent with inclusion criteria, 41 of 50 patients (82%) presented insignificant to moderate perioperative bleeding according to universal definition for perioperative bleeding score (class 0 to 2). Postoperative complete blood counts evolution demonstrated a mild anemia and thrombocytopenia, expected for cardiac surgery (Supplementary Table S3, https://links.lww.com/ALN/D167). Median platelet count was 195 (169 to 231) · 109/l at anesthesia induction and 158 (136 to 199) · 109/l immediately after surgery upon arrival in the intensive care unit, corresponding to a median decrease of 39 (17 to 61) · 109/l.

Overall, 245 adverse events were reported in 42 of 50 patients (84%) (Supplementary Table S4, https://links.lww.com/ALN/D167). None was considered related to the device by either the investigator or the data safety monitoring board, and thus no adverse device effect was reported. Serious adverse events occurred in 15 patients (16 events; Supplementary Table S5, https://links.lww.com/ALN/D167). Three patients experienced fatal adverse events in the postoperative period. One patient suffered cardiorespiratory arrest due to pericardial tamponade 10 days after the surgery, while another patient developed refractory cardiogenic shock 6 days after the procedure and subsequently passed away. The third patient died 23 days after the surgery due to metastatic cancer that had not been diagnosed at the time of inclusion. A data and safety monitoring board thoroughly reviewed all these events and concluded that none of them was potentially related to the device. Reintervention for bleeding accounted for 50% of serious adverse events (8 of 16 events), of which only 1 occurred during the first 48 h after surgery (reintervention for left internal mammary artery bleeding).

Our study reports the first-in-human evaluation of the same™ by i-SEP filtration-based autotransfusion device in 50 patients undergoing on-pump cardiac surgery. The main findings were as follows. First, red blood cells were efficiently recovered and concentrated with a fast-processing time under 6 min per cycle. Second, the device achieved a high washing performance regarding heparin and plasma proteins. Third, 52% of platelets were recovered with minimal platelet activation while maintaining platelet ability to be activated in vitro. Fourth, the performance of the device was sustained along multiple successive treatment cycles. Finally, no adverse device effect was reported.

Red Blood Cell Recovery

While efficiently recovering red blood cells, the standard mode of the i-SEP device achieved a targeted posttreatment hematocrit of 40%, which stood in the lower range compared to a commercially available centrifugation-based autotransfusion device.20–23  However, current evidence is highly heterogeneous, and comparative well-conducted studies are missing to compare the i-SEP device to centrifugation-based devices. Further, posttreatment hematocrits obtained with the i-SEP device remain above observed hematocrit values during cardiopulmonary bypass and immediately after cardiac surgery.24–26  Therefore, it is highly unlikely that the intraoperative use of the i-SEP device will induce hemodilution. Finally, the i-SEP innovative process should be seen as a trade-off between high red blood cell concentration and platelet recovery. The commercial version of the device includes a high-hematocrit mode aiming for a hematocrit of 55 to 60%, in case of perioperative fluid restrictive strategy.

Washing Performance

In line with preclinical data, the i-SEP device demonstrated high heparin and plasma proteins removal ratios, comparable with current centrifugation-based devices.16,20,23,27–29  Further, we demonstrated a high removal of triglyceride with the standard program, in line with data obtained using centrifugation.30,31  Free hemoglobin removal, while difficult to evaluate because hemolysis might occur after processing the blood, was high and comparable to centrifugation-based devices.20,21  Even though posttreatment free hemoglobin concentration was higher than previously reported in the preclinical study,16  it remained below the recommended threshold of 500 to 1,000 mg/dl according to the Association for the Advancement of Blood & Biotherapies (Bethesda, Maryland) guidelines.32 

Platelet Recovery and Function

The current study confirmed a high platelet recovery of more than 50%, which represents a 6- to 10-fold increase compared to centrifugation-based devices.20,29,33  This level of platelet recovery is a major innovative feature of the i-SEP device. Moreover, in vitro assessment of platelet activation markers using flow cytometry demonstrated that blood processing only induced a limited platelet activation. Further, recovered platelets exhibited a consistent response to thrombin receptor pathway in vitro, which indicates that they might retain their hemostatic function.34  This platelet recovery performance was sustained along multiple successive treatment cycles, allowing the device to produce clinically relevant platelet quantities when large amounts of shed blood were processed. Bleeding patients with more than three treatment cycles received 721 (631 to 830) ml of processed blood (equivalent to three packed red blood cells) containing around 0.9 × 1011 platelets, which is approximately the equivalent of two units of whole blood–derived platelets (one third of a single donor apheresis platelet concentrate). This result is consistent with massive transfusion protocols using plasma, platelets, and red blood cells in a 1:1:1 to 1:1:2 ratio.35  By offering the opportunity to reinfuse to the patients their own platelets in addition to their red blood cells, this new device might significantly improve perioperative hemostasis. This hypothesis remains valid during cardiac surgery, as there is limited evidence linking cardiopulmonary bypass–induced platelet dysfunction, which is poorly characterized, to increased bleeding risk.36  To the best of our knowledge, the i-SEP device is the only autotransfusion device able to simultaneously recover and wash human platelets and red blood cells in a fast-processing time. Indeed, recently developed filtration-based devices (HemoBag, Global Blood Resources, USA; HemoSep, Brightwake, United Kingdom; HemoClear, HemoClear BV, The Netherlands) greatly differ from the i-SEP device by producing blood cell filtration, without washing and/or using long processing times.37–39 

Strengths and Limitations

The i-TRANSEP study is the first clinical evaluation of the same™ autotransfusion device in cardiac surgery, with a multicenter and pragmatic design ensuring generalizability. First, the device performance was extensively analyzed for a high number of cycles. Besides cell recovery and washing performance, its main strength lies in the detailed evaluation of platelet recovery and cytometric analysis of the platelet activation state. Further, safety evaluation of the device was ensured by an independent data safety monitoring board. Finally, it provides valuable clinical data that will help setting up prospective interventional studies.

Our study has several limitations. First, it was a noncomparative study and therefore was not designed to evaluate clinical benefit of the device. Second, functional analysis of platelets using aggregometry, although considered as the reference test, was impossible given the nature of posttreatment blood. Hence, we used in vitro thrombin-receptor signaling and flow cytometry as a surrogate for the platelet function test. Third, due to the processed blood being potentially retransfused at different times during cardiac surgery (during and/or after cardiopulmonary bypass), platelet counts and platelet function testing could not be performed in the patient’s blood immediately before and after retransfusion. Finally, the small sample size of this pilot study precludes firm conclusions to be drawn regarding clinical safety of the device.

Future Studies

Given the performance of the device and its ability to recover platelets, we can now hypothesize, in addition to conventional intraoperative cell salvage abilities, (1) that the device might decrease perioperative bleeding and (2) that the processing of shed blood by the i-SEP device might be sufficient to decrease or overcome the need for platelet transfusion in the setting of massive surgical bleeding. An upcoming prospective randomized controlled trial comparing the i-SEP device to conventional centrifugation-based autotransfusion devices during high bleeding risk cardiac surgery will evaluate the potential benefit and cost-effectiveness of combined platelet and red blood cell autotransfusion. In addition, postmarket clinical follow-up studies will provide real-world evaluation of the device in both cardiac and high bleeding risk noncardiac surgeries.

Conclusions

In a first-in-human noncomparative study during adult on-pump cardiac surgery, the same™ by i-SEP device was able to efficiently recover and wash red blood cells with a fast processing time. Further, the device achieved a high platelet recovery of 52% with minimal platelet activation while maintaining platelet ability to be activated in vitro. This study supports the upcoming large-scale comparative trial to assess the clinical benefit and safety of the device in terms of perioperative bleeding and allogeneic blood product use.

Acknowledgments

The authors thank Amélie Martin, M.Sc. (University Hospital of Rennes, Rennes, France), Isabelle Gouin-Thibault, Pharm.D., Ph.D. (University Hospital of Rennes, Rennes, France), Christine Mouton, M.D. (University Hospital of Bordeaux, Bordeaux, France), Cécile Degryse, M.D. (University Hospital of Bordeaux, Bordeaux, France), and Bernard Cholley, M.D., Ph.D. (European Hospital Georges Pompidou, Paris, France) for assistance during data collection and analysis.

Research Support

This study was supported by i-SEP (Nantes, France).

Competing Interests

Dr. Mansour received payments made to his institution from i-SEP (Nantes, France) for consulting fees, and French Fractionating and Biotechnologies Laboratory (Les Ulis, France), Aguettant (Lyon, France), and Pfizer (Paris, France) for lecture fees. Dr. Godier reports personal fees from Aguettant, Bayer (La Garenne-Colombes, France), Boehringer Ingelheim (Paris, France), Bristol Myers Squibb/Pfizer (Paris, France), French Fractionating and Biotechnologies Laboratory, Sanofi (Paris, France), Alexion (Levallois-Perret, France), CSL Behring (Paris, France), Octapharma (Boulogne-Billancourt, France), Viatris (Lyon, France), and Stago (Asnières-sur-Seine, France) outside the submitted work. Dr. Rozec reports personal fees from French Fractionating and Biotechnologies Laboratory, NordicPharma (Paris, France), Aguettant, Medtronic (Paris, France), and Baxter (Guyancourt, France) outside the submitted work. Dr. Zlotnik reports personal fees from i-SEP. Dr. Gaussem reports personal fees from Elsevier (Issy-les-Moulineaux, France). Dr. Ouattara received expertise fees from i-SEP. The other authors declare no competing interests.

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