Novel heat exchanger in extracorporeal circuit: technical and biological feasibility

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Using a pig model, we assess its technical feasibility, biocompatibility, and safety.16 pigs were randomly assigned to either the ‘cooled’ or ‘control’ group and underwent midline laparotomy to establish extracorporeal circulation (blood flow 500 ml/min) via the caudal vena cava for up to four hours. During the experiment, blood samples were collected at four time points at the baseline and at the 15th, 60th, and 240th minute of the experiment. In the ‘cooled’ group, blood was cooled to 20°C and rewarmed to 37°C, while in the control group, blood was maintained at 37°C. A total of 6 ‘cooled’ and 4 ‘control’ pigs survived the experiment. Our findings confirm the technical feasibility of the proposed device, which effectively maintained the required temperature differentials and kept the pressure differentials in the circuit within 150 mmHg. No issues with circuit patency were observed. Additionally, no adverse effects were detected on renal, liver, cardiac, or erythrocyte function. On the contrary, our data suggests that local hypothermia in the extracorporeal circuit reduces blood coagulation and may mitigate surgery induced inflammation or stress. Biological sciences/Biotechnology Health sciences/Medical research/Pre clinical studies Biological sciences/Physiology/Circulation Extracorporeal circuit hypothermia biocompatibility coagulation inflammation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Techniques involving the extracorporeal (EC) circuit, such as continuous renal replacement techniques (CRRT) and extracorporeal membrane oxygenation (ECMO), have become essential in intensive care medicine, witnessing a swift expansion in worldwide adoption [ 1 , 2 ]. These methods are built upon the traditional extracorporeal circulation circuit (ECC) and subsequently evolved into a more compact form known as the minimized ECC. When blood meets various materials in ECC, the coagulation process is promptly activated. Consequently, anticoagulants are a standard requirement in all EC techniques. In CRRT, regional citrate anticoagulation is the first-line choice, whereas heparin is commonly used in ECMO. However, these techniques carry certain risks for patients with specific comorbidities [ 3 , 4 ]. Blood coagulation relies on various factors, including (i) the action of enzymes in the coagulation cascade, such as thrombin, (ii) the aggregation of thrombocytes, and (iii) the counteractive role of fibrinolytic enzymes, which work against the formation of blood clots. Importantly, these processes are influenced by temperature [ 5 , 6 ]. Notably, both enzymatic activities (in the coagulation cascade and fibrinolytic enzymes) are immediately hindered as the temperature drops below 37°C, and this inhibition intensifies with further decreases in temperature. However, thrombus formation exhibits a nonlinear response: platelet formation remains constant or is slightly stimulated within the 34–37°C range but sharply declines below 32°C [ 7 ]. Consequently, temperatures below 32°C demonstrate a relatively strong anticoagulant effect, presenting potential therapeutic applications [ 8 ]. Building on this, we posit the existence of a potential alternative for anticoagulation that may be more suitable for specific applications within the ECC spectrum. To test this hypothesis, we previously conducted a 6-hour pig experimental study, demonstrating that the cooling method effectively preserves circuit patency through anticoagulation [ 9 ]. We then extended our research with a 24-hour animal experiment to evaluate clinical feasibility, which revealed challenges related to circuit lifespan [ 10 ]. In this study, we propose a similar in-circuit cooling anticoagulation approach using an innovative heat exchanger constructed from medically approved materials. Using a preclinical pig model, we assess its technical feasibility and investigate the limits of blood flow that can be cooled and subsequently reheated to a target temperature. As a secondary objective, we evaluate whether the device affects renal, hepatic, cardiac, or erythrocyte function, as well as coagulation and inflammatory parameters. Methods Approval for animal experiments Animal handling was in accordance with the European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (86/609/EU). The study protocol was approved by the University Animal Care Committee. Experiments were performed at the animal laboratory of the Biomedical center at Charles University Medical School. The study was carried out in compliance with the ARRIVE guidelines [11]. Animal selection and instrumentation One pig was used for a pilot experiment, and an additional 16 pigs of either sex, with an average body mass of 41.1 kg, were included in the study and subsequently randomized into COOL and CTRL groups. All animals were premedicated with an intramuscular injection of 10 mg/kg ketamine (Narkamon; Spofa, a.s., Prague, Czech Republic), 5 mg/kg azaperone (Stresnil, Janssen Pharmaceutica, Belgium), and 0.5 mg atropine (Atropin Biotika, Hoechst Biotika, Slovak Republic). General anesthesia was induced and maintained with intravenous propofol (1% solution, 5–10 mg/kg/h; Propofol, Fresenius Kabi, Norway). Continuous analgesia was provided throughout the procedure via intravenous administration of fentanyl (1–2 μg/kg/h; Fentanyl Torrex, Chiesi cz, Czech Republic). Under sonographic guidance, the jugular vein and femoral artery were cannulated, and arterial and central venous pressures were measured. The temperature was monitored using a catheter in the bladder. Animals were mechanically ventilated (FiO 2 0.3, PEEP 3 cm H2O, tidal volume 8 ml/kg, respiratory rate adjusted to maintain end-tidal PCO 2 between 4.0 and 5.0 kPa). Balanced crystalloids and norepinephrine were administered in case of hypotension (see Supplementary Table S8 online for details). Midline laparotomy was performed to enter the abdominal cavity and the infrahepatic part of caudal vena cava was then dissected. All the lumbar veins on the posterior side of vena cava at the level between confluence of iliac veins and inflow of renal veins were transected for safer manipulation with caval vein. Two plastic cannulas of ¼ inch diameter (19 French scale) were used for connection of the pig circulatory system to the extracorporeal circuit (see Fig.1). The suction cannula was inserted in caudal vena cava through venotomy around 4 cm above confluence of iliac veins and secured with two purse-string sutures. A similar technique was used to insert the outflow cannula into the caudal vena cava at the level of the renal vein inflow. The shape and placement of the cannulas prevent their suction on the vessel wall. To prevent blood clotting in the extracorporeal shunt, 100 IU of heparin (Zentiva, Czech Republic) per kilogram of body weight was administered 5 minutes before cannula insertion, followed by 1000 IU of heparin every 60 minutes during the experiment At the end of the experiment, the pig was euthanized under general anaesthesia by potassium chloride. Extracorporeal circuit design Our group designed a heat exchanger (HE) comprising 216 parallel tubes, which was manufactured by a certified medical device producer under our guidance to meet both technical and biological compatibility requirements. The HE features a special pair of discs called a laminarizer, which homogenizes the flow of heating/cooling liquid to maximize the efficiency of heat exchange [12]. The design of our experimental system is illustrated in Fig. 1. Two HEs were connected in series to form a closed circuit, allowing blood to be drawn through the system via a suction cannula and then returned to the animal. The system includes two bubble traps placed after each HE, with a common centrifugal ECMO pump (550 BIO-CONSOLE, Medtronic, USA) controlling blood flow up to 2000 ml/min. This circuit design is based on the standard ECMO circuits used in the author's clinical practice. Additionally, the system is equipped with four temperature and pressure sensors (Omega Engineering, USA) located before and after each HE. The cooling and rewarming of blood in the HEs are achieved by circulating distilled water through two other devices, developed by our group and controlled by a computer system (Texas Instruments, CA, USA). The entire system was assembled under sterile conditions and filled with a crystalloid solution before connecting to the animal. Pilot animal and blood flow adjustment To evaluate the system's feasibility, circuit patency, and proper blood flow adjustment, a pilot pig was used in a preliminary experiment following established protocols for animal instrumentation and circuit design. After the operation, the animal was connected to our system with blood cooling set to 20 °C. Pressure and temperature differentials were monitored for 2 hours before and after each HE using our sensors. During the experiment, while maintaining a blood flow rate of 500 ml/min, the system effectively sustained the required temperature differentials (37/20 °C) with a pump pressure difference of up to 100 mmHg. A further increase in pump speed primarily led to higher pump pressures and was not accompanied by the expected increase in flow rate. A pilot experiment indicated that a flow rate of 500 ml/min is the limiting factor for the specific design of our two HEs connected in series in the ECC. Theoretically, under these conditions—500 ml/min blood flow, a 40 kg animal, absence of recirculation in the system, physiological intravascular and extravascular conditions, and a 4-hour duration—the system cools and reheats a single erythrocyte approximately 100 times. Protocol and measured parameters After anesthesia, blood samples were collected, and the pigs underwent surgery. The experiment then commenced according to the protocol outlined in Fig. 2. Eight pigs in the cooled group underwent a 4-hour procedure where their blood was cooled to 20 ºC and then rewarmed to 37 ºC. In contrast, eight pigs in the control group experienced the same procedure, except their blood was continuously maintained at 37 ºC. Blood samples were collected from the circuit port near the suction cannula (see Fig. 1, A) at the following time points: preoperative (TP-PC), baseline (TP-0), 15 minutes (TP-15), 60 minutes (TP-60), and 4 hours (TP-240) after the start of the experiment. To assess system functionality, body core temperature and hemodynamic parameters (mean arterial pressure, central venous pressure and heart rate) were monitored. A comprehensive biochemical and hematological evaluation was performed as detailed in Supplementary Table S7 online. Briefly, this included testing liver and kidney parameters, metabolic functions, ions, complete blood count including differential, RBC membrane stability, platelet function, coagulation status, and inflammation induction. Selection and categorization of blood markers for analysis The complete set of measured biochemical and hematological data is available online, in the Supplementary Results file (see link at the end of this paper). Out of 53 blood parameters, we selected 32 for analysis, focusing on those that were consistently measurable within range. These were divided into five clusters based on functional relevance. Three additional markers, indicative of diverse health issues, were analyzed separately. Cluster A Liver: This includes albumin (ALB) and liver enzymes (AST, ALT, GGT, ALP), all indicators of liver function. Lactate dehydrogenase (LD) was excluded due to its broader role across systems. Cluster B, Erythrocytes: Comprising 9 markers related to erythrocyte function and oxidative stress, this includes Hemoglobin (HGB), Hematocrit (HCT), Erythrocyte count (Ery), Red cell distribution width (RDW), Mean corpuscular haemoglobin concentration (MCHC), Mean cell haemoglobin (MCH), Mean corpuscular volume (MCV), and two Free hemoglobin indicators (FHb, FHb2). Schistocyte count and Polychromasia were not available. Cluster C, Hemostasis: Focused on coagulation, this includes Prothrombin time (PT.R), Thrombocytes (TRB), Plateletcrit (PCT), Platelet distribution width (PDW), and Fibrinogen (FB). aPTT, Thrombin time and platelet aggregation were excluded due to measurement issues. Cluster D, Inflammation and Immunity: This includes six leukocyte-related markers: Leukocytes (Leu), Segmented neutrophils (NeuM), Band neutrophils (NeuI), Monocytes (Mono), PMN elastase (PMN), and Lymphocytes (Lym). Cluster E, Kidney-Related: Encompasses Urea (UREA), Sodium (Na), and Chlorine (Cl), indicating kidney function and ion balance. Potassium (K) was analyzed separately due to its involvement in multiple systems. Unclustered Outcomes: Troponin T (TnT), Lactate dehydrogenase (LD), and Potassium (K) were analyzed independently due to their broad relevance across multiple health conditions. Statistical modelling Data analysis was performed in ‘R’ 1 within ‘R-studio’ 2 environment using Bayesian hierarchical regression models via the ‘brms’ 4,5 R package [13, 14]. Bayesian approach was chosen since it does not rely on large-sample approximations and is thus more suitable for small sample size 3 . Models were run with 4 chains, each with 6,000 iterations (including 2,000 warmups), to estimate parameter distributions. Outcome transformations were applied to reduce heteroscedasticity: square-root (for Band neutrophils and PMN elastase) and Log2 (for Troponin T and free hemoglobin measures). All outcomes were Z-standardized before analysis. Models included animal identity as a random intercept and three fixed effects: time (0–4 hours post-initiation), cooling (control vs. cooled), and their interaction (time:cooling), allowing us to assess whether time trends differed between cooled and control animals. Predictor time describes the time development of all parameters within each group separately, while predictor cooling compares the parameters between the two groups in time 0. The predictor time*cooled expresses the interaction of our method and demonstrates its effect. Autoregression correlation structures or random slopes were included when leave-one-out cross-validation and posterior predictive checks indicated improved model fit. Priors for fixed effects were set as normal distribution with mean = 0 and sigma of 0.5 (for cooling) or 1 (for time and interaction). This conservative setup shrinks estimates toward null effect to reduce overfitting. Given the small sample size and potential intercorrelation among blood markers, we used Principal Component Analysis (PCA) for dimensionality reduction. The first principal component (PC) for each marker cluster was extracted. For clusters where the first PC explained less than 50% of variance, a second PC was also extracted. These PCs served as outcome variables in the multivariate Bayesian models. Thus, the final primary model included 8 PCs plus the 3 unclustered outcomes. In addition, each original outcome was also analyzed individually using the same Bayesian framework as secondary analysis. Uncertainty is reported with 95% credible intervals. We also report a transformation of the Probability of Direction (PD), an index (ranging from 0.5 to 1) that represents the certainty that the effect is in a particular direction. For interpretative clarity, we show its transformation ( p ) as 2×(1−PD), which serves as a Bayesian analog to the frequentist p-value, quantifying the effect’s clarity in a similar manner as P-value ([15]. We primarily focused on the interaction between time and cooling to assess whether cooling influenced the time course of each outcome. This effect is reported as the '1-hour change difference between groups, representing the difference in average outcome slopes between cooled and control animals. Results In course of the experiments, 2 COOL (25%) and 4 CTRL (50%) pigs died; these animals were excluded from the study. The cause of death was the development of refractory circulatory failure. The pigs died within a time interval of 60 to 200 minutes during the experiment. Available data show no differences between groups (COOL vs. CTRL) at the accessible time points (TP-0, TP-15, TP-60). Results are presented with 6 and 4 pigs in the COOL and CTRL groups, respectively. Technical feasibility of the circuit During all experiments, the system maintained the set temperatures in both the CTRL and COOL groups. Pump pressures remained stable with the difference never exceeded 150 mmHg, we observed no issues regarding circuit patency. Temperatures measured between the HEs in the COOL group were also stable, and the blood temperature upon return to the animal was 37°C. Pressure and temperature data for one pig from the CTRL group and one from the COOL group are shown in Figs. 3 and 4. Hemodynamic status and temperature of the animals Mean arterial pressure (MAP) at the beginning of the experiment (TP-PC) was 52 mmHg in both groups (average across all animals). The time course of MAP during the experiments is shown in Fig. 5. MAP did not differ significantly between groups or over the duration of the experiment. The time course of heart rate during the experiments is shown in Fig. 6. Similarly, heart rate did not differ significantly between groups or over time. The average central venous pressure (CVP) was 6 mmHg (min 3, max 9 mmHg) in the CTRL group and 4 mmHg (min 2, max 8 mmHg) in the COOL group. The average SpO 2 was 97% (min 94, max 98%) in the CTRL group and 97% (min 96, max 98%) in the CTRL group. The average pH was 7.38 (min 7.34, max 7.43) in the CTRL group and 7.39 (min 7.29, max 7.44) in the CTRL group. The average temperature of animals was 37.7°C (min 36.7°C, max 38.5°C) in the CTRL group and 37.7°C (min 36.7°C, max 37.7°C) in the CTRL group. To summarize, SpO₂, pH, and temperature were maintained within physiological ranges during the experiments. Complete data on hemodynamic monitoring, temperature, and pH are available in the Supplementary Results file (online; see link at the end of this paper). Principal component analysis The 32 blood parameters were often intercorrelated (see Supplementary Figs. S1 and S2). For liver markers (Cluster A), the 1st PC (liverPC1) explained 60% of variance, correlating with all six liver outcomes (r ≥ 0.68). In erythrocytes (Cluster B), the 1st PC (erythPC1, 42% variance) increased with HGB, HCT, and ERY (r ≥ 0.80) and decreased with MCV and MCH (r ≤ -0.63), while erythPC2 (26%) related to FHb measures (r ≥ 0.84). For coagulation markers (Cluster C), coagPC1 (46%) aligned with TRB and PCT (r ≥ 0.92) and negatively with PDW (r = -0.64); coagPC2 (29%) aligned with FB (r = 0.82) and negatively with PT.R (r = -0.68). Inflammation markers (Cluster D) had inflaPC1 (50%) linked to Leu, NeuI, and NeuM (r ≥ 0.69), negatively with Lym (r = -0.98), while inflaPC2 correlated with Mono (r = 0.83) and NeuI/NeuM (r ≈ ±0.5).For kidney-ions (Cluster E), kidneyPC1 (58%) increased with UREA (r = 0.53) and decreased with Natrium and Chlorine (r ≤ -0.81). Bayesian regression on principal components No clear initial differences were found between control and cooled animals at time 0 (see the row 'cooled' in Table 1). Coagulation Markers (CoagPC1 and CoagPC2): CoagPC1 showed a decline over time, more pronounced in cooled animals (1-hour change difference between groups = -0.14, 95% CI: -0.26 to -0.01). CoagPC2 clearly increased in controls but there was not consistent increase in cooled animals, indicating cooling reduced the rate of increase (difference = -0.20, CI: -0.36 to -0.03; Fig. 7). Inflammation Markers (InflaPC1): InflaPC1, linked to high leukocyte counts and low lymphocyte proportion, increased over time in both groups, with a milder increase in the cooled group (difference = -0.23, CI: -0.42 to -0.04, Fig. 8). For all other parameters, including renal, liver and erythrocyte markers, changes over time were not clearly different between groups, with detailed results available in Table 1. Individual outcome-specific models At time 0, only PMN elastase showed an initial difference between control and cooled animals (see rows 'Cooled' in Supplementary Tables S2-S6). Coagulation Markers: Only fibrinogen showed a trend toward a reduced 1-hour change in the cooled group (1-hour difference = -0.10, CI: -0.22 to 0.01, Supplementary Table S4), but not other parameters. Inflammation Markers: In controls, leukocyte count, segmented neutrophils, and lymphocyte proportion shifted notably, with leukocyte count and segmented neutrophils increasing and lymphocytes decreasing. Cooling likely moderated these changes: leukocyte count may rose less in cooled animals (difference = -0.19, CI: -0.32 to -0.002), and lymphocyte decline slowed with cooling (difference = 0.24, CI: 0.034 to 0.48). Cooling also reduced the increase in PMN elastase (difference = -0.046, CI: -0.078 to -0.013), though baseline group differences may have influenced PMN results (see Supplementary Fig. S10). Non-Clustered Parameters (Troponin T, Lactate Dehydrogenase, and Potassium): Troponin T showed no notable change over time in either group, with no clear impact from cooling. Lactate dehydrogenase declined in cooled animals but remained stable in controls, though cooling only slightly accelerated the decline (difference = -0.18, CI: -0.36 to 0.017). Potassium levels rose significantly over time in both groups, without noticeable impact from cooling (Supplementary Fig. S6). For details on all other parameters, including those included in clusters where rate of change of PCs did not differ clearly between groups, please refer to Supplementary Tables S2-S6. Table 1 . Estimated effect of time (an hour) presence of cooling ( cooled ) and the time*cooled interaction [ time*cooled (int) ] on each of 11 outcomes (Z-standardized). Results are based on a multivariate Bayesian hierarchical model with weakly regularizing prior. For principal components in the ‘Outcome’ column, correlating parameters are shown (red shows positive and blue negative correlations). ‘β’: estimated effect. ‘Q2.5’ and ‘Q97.5’: bounds of 95% credible interval. ‘p’: 2*(1- probability of direction 12 ). See methods for details and abbreviations. Outcome Predictor β Q2.5 Q97.5 p liverPC1 + all liver markers time (ctrl) 0.007 -0.134 0.145 0.9266 time (cooled) -0.082 -0.195 0.032 0.1629 Cooled -0.206 -0.876 0.505 0.5504 time*cooled (int) -0.087 -0.261 0.087 0.3172 erythPC1 + HGB, HCT, PCT – MCV, MCH time (ctrl) -0.096 -0.243 0.051 0.1888 time (cooled) -0.197 -0.317 -0.074 0.0015 Cooled -0.209 -0.949 0.564 0.5831 time*cooled (int) -0.101 -0.281 0.082 0.2784 erythPC2 + FHb – RDW, MCH time (ctrl) -0.023 -0.168 0.122 0.742 time (cooled) 0.011 -0.109 0.127 0.8561 Cooled -0.453 -1.23 0.419 0.296 time*cooled (int) 0.034 -0.152 0.212 0.7032 coagPC1 + TRB, PCT – PDW time (ctrl) -0.083 -0.18 0.014 0.092 time (cooled) -0.22 -0.298 -0.143 <0.001 Cooled -0.315 -1.084 0.508 0.4384 time*cooled (int) -0.138 -0.258 -0.019 0.0251 coagPC2 + FB – PT.R time (ctrl) 0.162 0.03 0.295 0.0187 time (cooled) -0.034 -0.141 0.076 0.5276 Cooled 0.254 -0.59 1.022 0.5455 time*cooled (int) -0.196 -0.36 -0.029 0.0229 inflaPC1 + Leu, NeuI, NeuM – Lym time (ctrl) 0.484 0.331 0.638 <0.001 time (cooled) 0.251 0.129 0.377 <0.001 Cooled 0.264 -0.495 0.969 0.483 time*cooled (int) -0.233 -0.422 -0.042 0.0187 inflaPC2 + Mono, NeuI – NeuM time (ctrl) -0.22 -0.533 0.107 0.1742 time (cooled) 0.062 -0.208 0.327 0.6402 Cooled -0.329 -0.995 0.388 0.3584 time*cooled (int) 0.281 -0.112 0.668 0.1514 kidneyPC1 + UREA – Na, Cl time (ctrl) 0.248 0.056 0.437 0.0129 time (cooled) 0.121 -0.031 0.271 0.1175 Cooled -0.055 -0.851 0.737 0.8868 time*cooled (int) -0.126 -0.362 0.108 0.2848 Troponin T time (ctrl) -0.039 -0.239 0.144 0.6734 time (cooled) 0.101 -0.089 0.273 0.281 Cooled -0.081 -0.812 0.672 0.8282 time*cooled (int) 0.14 -0.081 0.355 0.2041 Lactate dehydrogenase time (ctrl) -0.002 -0.155 0.147 0.9846 time (cooled) -0.18 -0.302 -0.057 0.0054 Cooled 0.234 -0.532 0.946 0.5241 time*cooled (int) -0.179 -0.362 0.017 0.0695 Potassium time (ctrl) 0.442 0.304 0.577 <0.001 time (cooled) 0.499 0.388 0.611 <0.001 Cooled 0.315 -0.337 0.891 0.319 time*cooled (int) 0.058 -0.112 0.232 0.4924 Individual outcome-specific models At time 0, only PMN elastase showed an initial difference between control and cooled animals (see rows 'Cooled' in Supplementary Tables S2-S6). Coagulation Markers: Only fibrinogen showed a trend toward a reduced 1-hour change in the cooled group (1-hour difference = -0.10, CI: -0.22 to 0.01, Supplementary Table S4), but not other parameters. Inflammation Markers: In controls, leukocyte count, segmented neutrophils, and lymphocyte proportion shifted notably, with leukocyte count and segmented neutrophils increasing and lymphocytes decreasing. Cooling likely moderated these changes: leukocyte count may rose less in cooled animals (difference = -0.19, CI: -0.32 to -0.002), and lymphocyte decline slowed with cooling (difference = 0.24, CI: 0.034 to 0.48). Cooling also reduced the increase in PMN elastase (difference = -0.046, CI: -0.078 to -0.013), though baseline group differences may have influenced PMN results (see Supplementary Fig. S10). Non-Clustered Parameters (Troponin T, Lactate Dehydrogenase, and Potassium): Troponin T showed no notable change over time in either group, with no clear impact from cooling. Lactate dehydrogenase declined in cooled animals but remained stable in controls, though cooling only slightly accelerated the decline (difference = -0.18, CI: -0.36 to 0.017). Potassium levels rose significantly over time in both groups, without noticeable impact from cooling (Supplementary Fig. S6). For details on all other parameters, including those included in clusters where rate of change of PCs did not differ clearly between groups, please refer to Supplementary Tables S2-S6. Discussion As shown in our two previous studies, regional cooling may influence blood coagulation status in specific types of EC techniques [ 9 , 10 ]. A significant limitation of our most recent experiment was the restricted lifespan of the ECC when comparing the cooling method to the standard heparinization approach. This limitation prevented consideration for clinical use, which we attribute primarily to the construction of the used heat exchanger, particularly the aluminum layer in direct contact with blood. In the current study, we present an experiment featuring a novel heat exchanger (HE) design, where all components are made from polyethylene certified for use in blood transfusion sets. Both the development and production were entrusted to a company specializing in medical devices with EU certification. We believe this new HE design addresses the biological compatibility issues encountered with previous EC circuit setups in our experiments and meets all legal requirements defined by the EU Medical Devices Regulation [ 16 ]. Our main goal was to test its technical feasibility, which also required developing a prototype of the EC circuit. In general, EC circuits support or replace the function of vital organs such as the kidneys, heart, lungs, or liver. This broad range of applications requires a wide range of blood flow rates through the circuit — from as low as 100 ml/hour in CRRT to as high as 5,000 ml/hour in veno-arterial ECMO. Such a wide range places high demands on the design of both the blood pump and the circuit, which must preserve blood integrity and have sufficient biocompatibility. Therefore, among all possible pump types, only peristaltic and centrifugal pumps are currently used. To test our novel heat exchanger in a circuit prototype, where even two heat exchangers will be connected in series, choosing the appropriate blood pump is crucial. In theory, peristaltic and centrifugal pumps differ functionally: the former provides a constant flow, while the latter generates constant pressure. In a peristaltic pump, the tubing is cyclically compressed to expel a fixed volume of blood, producing pulsatile pressure peaks with each cycle. In contrast, a centrifugal pump uses a rotating disk to spin the blood, generating pressure via centrifugal force exerted on the pump walls. This pressure remains relatively constant over time, while the flow rate depends on the resistance within the circuit. Therefore, in the event of a circuit obstruction, a peristaltic pump attempts to maintain constant flow, leading to a significant rise in pressure peaks. Conversely, a centrifugal pump limits flow under increased resistance, while maintaining a steady pressure. Blood elements, especially erythrocytes, can be damaged by pumps due to changes in shear forces, leading to hemolysis. This theoretical understanding, supported by clinical findings [ 17 , 18 ] has led to our decision to use only a centrifugal pump in our experiments. This pump is considered to be more variable and to cause less hemolysis compared to peristaltic one. In addition to the pump, other components of the extracorporeal circuit can influence hemolysis. These include tubing kinks and cannulas that are too small, both of which can create localized high shear force [ 19 ]. To minimize this risk, we use the largest possible cannula size that can be safely inserted into the vena cava, along with tubing of similar diameter (19 French size). Although it is not entirely common in centrifugal pump-driven ECC, we decided to insert two gas bubble traps into our circuit. We aim to avoid unexpected gas bubble formation during sudden temperature changes in the blood, which could interfere with circuit patency (by obstructing HE tubes) or cause embolic complications in the animals [ 20 ]. In our study, Bayesian models did not reveal signs of erythrocyte deterioration in either the control or cooled groups, measured by blood count and free hemoglobin. This suggests that our HE design and cooling method may be without measurable negative effect on red blood cells and appear to be safe for cellular integrity. It is important to note that we encountered no technical issues with the circuit and its patency in any of the experiments. Our secondary aim was to observe the biological effects of in-circuit cooling on selected organ, coagulation, and inflammation parameters. When blood comes into contact with synthetic surfaces, it exposes the organism to significant mechanical and biological stress, leading to widespread activation of the innate immune system. This response shares characteristics with systemic inflammatory response syndrome [ 21 ] and also serves as a potent trigger for coagulation. Our data, analysed using Bayesian models, showed a clear increase in inflammatory markers in the CTRL animals, whereas the cooling intervention appeared to attenuate this response. Specifically, the CTRL group exhibited elevated leukocyte counts, segmented neutrophils, and PMN elastase levels, along with a reduced proportion of lymphocytes. These changes were less pronounced or negligible in the cooled animals, suggesting a trend toward anti-inflammatory effects associated with the cooling method. Our cooling method reduced the increase in coagulation parameters during the experiments, according to results from Bayesian model analysis. Furthermore, fibrinogen—a well-known marker of inflammation and pro-coagulation—tended to increase in the CTRL group but not in the cooled group. Similarly, we observed a reduction in lactate dehydrogenase (LD) levels in the cooled group. LD is an enzyme present in many organs, including erythrocytes, which contain up to 100 times more LD than plasma. Since our study did not reveal any significant haemolysis, we presume that the observed reduction in LD in the cooled pigs may reflect a protective effect of hypothermia. In summary, these non-specific indicators suggest potential anti-inflammatory and anti-coagulative properties of our cooling method. Finally, Bayesian models did not reveal any clear effect of cooling on liver or kidney function, although the observation period may have been too short to detect potential changes. Similarly, troponin T levels remained unchanged across all groups, suggesting that our experimental setup did not significantly impact cardiac function. Study limitations The most serious issue we encountered was extensive pig mortality, reaching up to 40%, despite the pilot experiment appearing uneventful. Circulatory failure followed by cardiac arrest was identified as the primary cause of death, likely due to the extensive nature of the surgery combined with significant interference in circulatory dynamics. Pigs are known for their high splanchnic blood flow, which supports their rapid growth [ 22 , 23 ]. Insertion of a 19 French cannula into the vena cava reduced the vessel diameter by approximately half (see Fig. 1 ), which likely causing a dramatic decrease in preload and leading to circulatory instability. The animals experienced persistent hypotension throughout the experiment; the average mean arterial pressure (MAP) at TP-PC was 52 mmHg. With one exception, we were unable to maintain normotension using either volume loading or norepinephrine administration (see Fig. 5 and Supplementary Table S8 for details). Serum potassium concentration increased significantly in both groups over the course of the experiment, likely due to a high surgical burden, potentially exacerbated by propofol infusion syndrome. We speculate that the increase in potassium levels cannot be attributed to acidosis, as blood pH remained within normal range in all animals. In further experiments, it is necessary to change the cannulation access technique to a less invasive, percutaneously advanced catheter approach, commonly used in humans, which cause no circulation instability. Therefore, we do not consider it reasonable to increase statistical significance by expanding the number of experimental animals. A further limitation of our study is the limited set of samples used to evaluate the immune response. The primary aim of our work was to demonstrate the technical and functional feasibility of the novel heat exchanger. Consequently, the promising findings related to immune response are based on non-specific results and were not investigated in detail. We suggest that future research should focus on a small, standardized animal model with controlled minimal stress, employing only the percutaneous puncture technique and mimicking sepsis. Conclusion The innovative heat exchanger used in the ECC demonstrates clinical feasibility. We did not observe any adverse effects on liver, kidney, or other metabolic functions, blood counts, or the stability of the erythrocyte membrane. We confirmed the anticoagulant effect of local hypothermia. Furthermore, we observed signs of an anti-inflammatory effect from the cooling method, which may contribute to organ protection. Declarations Funding: The work was supported from European Regional Development Fund - Project „Fighting Infectious Diseases” (No. CZ.02.1.01/0.0/0.0/16_019/0000787). Author Contribution R.J., T.F. and S.J. wrote the manuscript, T.F. conducted the statistical analysis, D.J., B.L., B.O., P.R., R.J., M.V. and M.M. performed the animal experiments, L.V. and K.J. supervised the project. All authors reviewed the manuscript. Data Availability Data are published in the files Supplementary_FIgs_Tabs and Suppl_Results. References Salathé, C. et al. Epidemiology and outcomes of elderly patients requiring renal replacement therapy in the intensive care unit: an observational study. BMC Nephrol 22 (2021). Karagiannidis, C. et al. Extracorporeal membrane oxygenation: evolving epidemiology and mortality. Intensive Care Med . 42, 889-896 (2016). Li, R. et al. Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: a meta‐analysis of randomized controlled trials. Therapeutic Apheresis and Dialysis , 26 , 1086-1097 (2022). Stammers, A. et al. Anticoagulant use during extracorporeal membrane oxygenation using heparin and direct thrombin inhibitors in covid-19 and ards patients. Journal of Extracorporeal Technology 54 , 223-234 (2022). Wolberg, A.S. et al. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma 56, 1221-28 (2004). Rohrer, M.J., Natale, A.M. Effect of hypothermia on the coagulation cascade. Crit Care Med. 20 , 1402-14 (1992). Kander T, Schött U. Effect of hypothermia on haemostasis and bleeding risk: a narrative review. J Int Med Res . 47 , 3559-3568 (1019). Martini, W.Z. The effects of hypothermia on fibrinogen metabolism and coagulation function in swine. Metabolism 56, 214-21 (2007). Kroužecký, A. et al. Regional cooling of the extracorporeal blood circuit: a novel anticoagulation approach for renal replacement therapy? Intensive Care Med . 35, 364-70 (2009). Kroužecký, A. et al. The safety and efficacy of a new anticoagulation strategy using selective in-circuit blood cooling during haemofiltration--an experimental study. Nephrol Dial Transplant . 26 , 1622-7 (2011). du Sert, N. P. et al. The arrive guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol. 18 , 1–12 (2020). Bolek, L., Dejmek, J., Růžička, J., Beneš, J, Petránková, Z. Heat exchanger with laminarizer. European patent EP 2 678 628 B1. Applied 10. 4. 2014, published 1. 2. 2017 (2017). R Core Team. R: A Language and Environment for Statistical Computing. Published online https://www.r-project.org (2022). Nalborczyk, L. et al. An Introduction to Bayesian Multilevel Models Using brms: A Case Study of Gender Effects on Vowel Variability in Standard Indonesian. J Speech Lang Hear Res . 62, 1225-1242 (2019). Makowski, D., Ben-Shachar, M.S., Chen, S.H.A., Lüdecke, D. Indices of Effect Existence and Significance in the Bayesian Framework. Front Psychol . 10, 2767 (2019). Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC. http://data.europa.eu/eli/reg/2017/745/2025-01-10 (2017). Poder, T.G. et al. Quantitative assessment of haemolysis secondary to modern infusion pumps. Vox Sang . 112 , 201-209 (2017). Valeri, C.R. et al. Effects of centrifugal and roller pumps on survival of autologous red cells in cardiopulmonary bypass surgery. Perfusion 21, 291-6 (2006). Greenberg, K.I., Choi, M.J. Hemodialysis Emergencies: Core Curriculum 2021. Am J Kidney Dis . 77, 796-809 (2021). Shekar, K. et al. (2014). Extracorporeal life support devices and strategies for management of acute cardiorespiratory failure in adult patients: a comprehensive review. Critical Care 18 https://doi.org/10.1186/cc13865 (2014). Millar, J.E. et al. The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology. Crit Care 20 , 387 (2016). Donaldson, R.I. et al. Efficacy of past, present, and future fluid strategies in an improved large animal model of non-compressible intra-abdominal hemorrhage. J Trauma Acute Care Surg . 91, S99-S106 (2021). Morgan, C.G.et al. Evaluation of prolonged 'Permissive Hypotension': results from a 6-hour hemorrhage protocol in swine. Trauma Surg Acute Care Open 4, doi: 10.1136/tsaco-2019-000369 (2019). Additional Declarations No competing interests reported. Supplementary Files SupplFigsTabs.pdf Cite Share Download PDF Status: Published Journal Publication published 22 Oct, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 30 Jun, 2025 Reviews received at journal 20 Jun, 2025 Reviews received at journal 13 Jun, 2025 Reviewers agreed at journal 10 Jun, 2025 Reviews received at journal 09 Jun, 2025 Reviewers agreed at journal 03 Jun, 2025 Reviewers agreed at journal 03 Jun, 2025 Reviewers invited by journal 03 Jun, 2025 Editor invited by journal 28 May, 2025 Editor assigned by journal 21 May, 2025 Submission checks completed at journal 20 May, 2025 First submitted to journal 16 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6680449","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":465983266,"identity":"d387def9-eaeb-490b-b716-14cc9664844f","order_by":0,"name":"jiri ruzicka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYBACxmYGhgMgBhsQMnwokIMIJxCrhXGGgTFhLUiAjYGZB6YFH2Bu5314gHHPYXs+9mOJn20MDPIY2M+YPXjAYGeP22HsBgcYnh1mZuNJOyydY2BQzMCTY26QwJDMjFsLG9AvBw6zsUmwNwC1/ElskOAxk0hgOMBGSAsPUEvzbwsDA7gWHkJaJNgk2I5JMyBpkcCrJeFAugHQL2mWPUC/ABllEgkGyQa4tBj2H2P+8OGAtb18+zHjGz8qDPL42Q9vk/xRgTvEDBsYUCMuAeJtnHYwMMijCyRgUTQKRsEoGAUjHAAAaytEuSnI8jcAAAAASUVORK5CYII=","orcid":"","institution":"Charles University","correspondingAuthor":true,"prefix":"","firstName":"jiri","middleName":"","lastName":"ruzicka","suffix":""},{"id":465983267,"identity":"a8290ebb-7a47-41e1-9368-777f84837a30","order_by":1,"name":"Tichanek Filip","email":"","orcid":"","institution":"Institute of Clinical and Experimental Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tichanek","middleName":"","lastName":"Filip","suffix":""},{"id":465983269,"identity":"81ab8e7d-e8fb-4beb-8beb-18539af8bfc2","order_by":2,"name":"Skorpil Jiri","email":"","orcid":"","institution":"Krajská Zdravotní","correspondingAuthor":false,"prefix":"","firstName":"Skorpil","middleName":"","lastName":"Jiri","suffix":""},{"id":465983272,"identity":"ecc1debd-00a1-4827-bc67-d0dab32959f3","order_by":3,"name":"Dejmek Jiri","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Dejmek","middleName":"","lastName":"Jiri","suffix":""},{"id":465983273,"identity":"dc5cbf20-bdc6-48bd-b931-ed3d364a0625","order_by":4,"name":"Bolek Lukas","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Bolek","middleName":"","lastName":"Lukas","suffix":""},{"id":465983274,"identity":"03f57f9e-98e3-44be-9af2-fb05ff5559bc","order_by":5,"name":"Brzon Ondrej","email":"","orcid":"","institution":"Likmed","correspondingAuthor":false,"prefix":"","firstName":"Brzon","middleName":"","lastName":"Ondrej","suffix":""},{"id":465983275,"identity":"036b88a2-b21a-4e82-94e1-1185b2761a1d","order_by":6,"name":"Palek Richard","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Palek","middleName":"","lastName":"Richard","suffix":""},{"id":465983276,"identity":"302158b5-9478-4b36-a6e4-c28629a7bafa","order_by":7,"name":"Rosendorf Jachym","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Rosendorf","middleName":"","lastName":"Jachym","suffix":""},{"id":465983277,"identity":"e6825ec6-413e-4513-a45a-7be3a54ffbcf","order_by":8,"name":"Moulisova Vladimira","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Moulisova","middleName":"","lastName":"Vladimira","suffix":""},{"id":465983278,"identity":"8273d413-8f99-45cd-b4f0-66d9716f98cf","order_by":9,"name":"Massaro Maria","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Massaro","middleName":"","lastName":"Maria","suffix":""},{"id":465983279,"identity":"06e1b5db-464b-468d-b16b-7215583adc44","order_by":10,"name":"Liska Vaclav","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Liska","middleName":"","lastName":"Vaclav","suffix":""},{"id":465983280,"identity":"ff5ae946-f8fb-4965-8e5c-7d242a4af0e3","order_by":11,"name":"Kuncova Jitka","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Kuncova","middleName":"","lastName":"Jitka","suffix":""}],"badges":[],"createdAt":"2025-05-16 11:38:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6680449/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6680449/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-20798-w","type":"published","date":"2025-10-22T16:17:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84203645,"identity":"1d392bdc-0817-4eb9-97c8-22ee9be7054b","added_by":"auto","created_at":"2025-06-09 08:44:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":99952,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExperimental Design\u003c/strong\u003e: A – Cannula placement in the caval vein. B – Bubble trap. S – Introduction site for balanced crystalloids. BS – Sampling port for blood collection. Q – Centrifugal pump. T1, T2 – Temperature sensors. P1, P2 – Pressure sensors.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/e9b35ad0cc7e416fef42af78.png"},{"id":84204438,"identity":"01c7264c-4b48-4598-a12d-c4c8895dc857","added_by":"auto","created_at":"2025-06-09 08:52:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":42769,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTimepoints of blood sample collection\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/5a16f52fec6a1c6b0df69ff4.png"},{"id":84201894,"identity":"3632a036-6983-489f-b17b-3f991eb5267e","added_by":"auto","created_at":"2025-06-09 08:36:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":134280,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime duration of temperatures and pressures in the CTRL group\u003c/strong\u003e. T1 and T2 refer to the temperature before the first HE and after the second HE, respectively. P1 and P2 represent the pressures before and after the pump. See Fig. 1 for further explanation\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/b9ba48ca10a8c70c99bcf63b.png"},{"id":84201895,"identity":"375bbb96-4a16-4412-a342-e20ca81702f8","added_by":"auto","created_at":"2025-06-09 08:36:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":145185,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime duration of temperatures and pressures in the CTRL group\u003c/strong\u003e. T1 and T2 refer to the temperature before the first HE and after the second HE, respectively. P1 and P2 represent the pressures before and after the pump. See Fig. 1 for further explanation\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/9c838007f0a09edc20fa89f8.png"},{"id":84203647,"identity":"b3a8621e-7aeb-4fb2-86aa-066ec3fd087e","added_by":"auto","created_at":"2025-06-09 08:44:32","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":79485,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime course of mean arterial pressure. \u003c/strong\u003ePC – beginning of experiment. 0 – TP-0, 15-TP-15, 60 – TP-60, 240 – TP-240.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/88598d526612688c31ac36c4.png"},{"id":84201897,"identity":"dcbbdd9d-0d1d-47eb-8714-b66a971295c3","added_by":"auto","created_at":"2025-06-09 08:36:31","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":79260,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime course of heart rate\u003c/strong\u003e. PC – beginning of experiment. 0 – TP-0, 15-TP-15, 60 – TP-60, 240 – TP-240.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/63b0a98e23399ca22dfa8822.png"},{"id":84201902,"identity":"606e74ba-fdae-446b-bc7f-475c0dfc4727","added_by":"auto","created_at":"2025-06-09 08:36:32","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":304348,"visible":true,"origin":"","legend":"\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e,\u003cstrong\u003eb\u003c/strong\u003e) Effect of the blood cooling on the 1\u003csup\u003est\u003c/sup\u003e (\u003cstrong\u003ea\u003c/strong\u003e) and 2\u003csup\u003end\u003c/sup\u003e (\u003cstrong\u003eb\u003c/strong\u003e) principal component (PC) extracted from a cluster of blood coagulation-related markers. \u003cstrong\u003eTop\u003c/strong\u003e: Time-course of PC during the time of the experiment, with thick lines implying model fit. \u003cstrong\u003eBottom\u003c/strong\u003e: posterior probability distribution for the effect of \u003cem\u003etime\u003c/em\u003e (left) and ‘\u003cem\u003etime*cooling’\u003c/em\u003e interaction (right) on the PC values, with dashed curves indicating prior probability distribution, and solid lines (under the curves) showing bounds of 95% (thick lines) and 99% (tiny lines) Bayesian credible intervals. (\u003cstrong\u003ec\u003c/strong\u003e) The posterior probability distribution for the effect of the \u003cem\u003etime\u003c/em\u003e (left) and ‘\u003cem\u003etime*cooling’\u003c/em\u003e interaction (right) on individual coagulation-related parameters. Lines under the posterior area indicate 95% CIs. ‘p’: 2*(1- \u003cem\u003eprobability of direction\u003c/em\u003e). See methods for details and abbreviations. (\u003cstrong\u003ed\u003c/strong\u003e) Pearson correlations between the 1st and the 2nd principal components and individual blood markers. See methods abbreviations.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/eae04eccb16ec570f2604a28.png"},{"id":84201903,"identity":"803b5d28-4a84-417b-ac67-4a302fbc32e4","added_by":"auto","created_at":"2025-06-09 08:36:32","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":334329,"visible":true,"origin":"","legend":"\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e,\u003cstrong\u003eb\u003c/strong\u003e) Effect of the blood cooling on the 1\u003csup\u003est\u003c/sup\u003e (\u003cstrong\u003ea\u003c/strong\u003e) and 2\u003csup\u003end\u003c/sup\u003e (\u003cstrong\u003eb\u003c/strong\u003e) principal component (PC) extracted from a cluster of inflammation/immunity-related blood markers. \u003cstrong\u003eTop\u003c/strong\u003e: Time-course of PC during the time of the experiment, with thick lines implying model fit. \u003cstrong\u003eBottom\u003c/strong\u003e: posterior probability distribution for the effect of \u003cem\u003etime\u003c/em\u003e (left) and ‘\u003cem\u003etime*cooling’\u003c/em\u003e interaction (right) on the PC values, with dashed curves indicating prior probability distribution, and solid lines (under the curves) showing bounds of 95% (thick lines) and 99% (tiny lines) Bayesian credible intervals. ‘p’: 2*(1- \u003cem\u003eprobability of direction\u003c/em\u003e\u003csup\u003e12\u003c/sup\u003e). See methods for details and abbreviations. (\u003cstrong\u003ec\u003c/strong\u003e) The posterior probability distribution for the effect of the \u003cem\u003etime\u003c/em\u003e (left) and ‘\u003cem\u003etime*cooling’\u003c/em\u003e interaction (right) on individual inflammation-related parameters. Lines under the posterior area indicate 95% CIs. (\u003cstrong\u003ed\u003c/strong\u003e) Pearson correlations between the 1st and the 2nd principal components and individual blood markers. See methods abbreviations.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/9a78cd6e492168394e09c465.png"},{"id":94490689,"identity":"957cff12-fa9d-4839-aafa-b26ac767352e","added_by":"auto","created_at":"2025-10-27 17:13:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2272567,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/e717a0e0-da9a-4feb-8057-0a36e6c3d63d.pdf"},{"id":84203649,"identity":"dff1a158-3fa2-4b3b-bc7b-dc603ffab502","added_by":"auto","created_at":"2025-06-09 08:44:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":5493498,"visible":true,"origin":"","legend":"","description":"","filename":"SupplFigsTabs.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6680449/v1/97d438e93908d14aebb20b92.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Novel heat exchanger in extracorporeal circuit: technical and biological feasibility","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTechniques involving the extracorporeal (EC) circuit, such as continuous renal replacement techniques (CRRT) and extracorporeal membrane oxygenation (ECMO), have become essential in intensive care medicine, witnessing a swift expansion in worldwide adoption [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. These methods are built upon the traditional extracorporeal circulation circuit (ECC) and subsequently evolved into a more compact form known as the minimized ECC.\u003c/p\u003e \u003cp\u003eWhen blood meets various materials in ECC, the coagulation process is promptly activated. Consequently, anticoagulants are a standard requirement in all EC techniques. In CRRT, regional citrate anticoagulation is the first-line choice, whereas heparin is commonly used in ECMO. However, these techniques carry certain risks for patients with specific comorbidities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBlood coagulation relies on various factors, including (i) the action of enzymes in the coagulation cascade, such as thrombin, (ii) the aggregation of thrombocytes, and (iii) the counteractive role of fibrinolytic enzymes, which work against the formation of blood clots. Importantly, these processes are influenced by temperature [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Notably, both enzymatic activities (in the coagulation cascade and fibrinolytic enzymes) are immediately hindered as the temperature drops below 37\u0026deg;C, and this inhibition intensifies with further decreases in temperature. However, thrombus formation exhibits a nonlinear response: platelet formation remains constant or is slightly stimulated within the 34\u0026ndash;37\u0026deg;C range but sharply declines below 32\u0026deg;C [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, temperatures below 32\u0026deg;C demonstrate a relatively strong anticoagulant effect, presenting potential therapeutic applications [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBuilding on this, we posit the existence of a potential alternative for anticoagulation that may be more suitable for specific applications within the ECC spectrum.\u003c/p\u003e \u003cp\u003eTo test this hypothesis, we previously conducted a 6-hour pig experimental study, demonstrating that the cooling method effectively preserves circuit patency through anticoagulation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. We then extended our research with a 24-hour animal experiment to evaluate clinical feasibility, which revealed challenges related to circuit lifespan [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we propose a similar in-circuit cooling anticoagulation approach using an innovative heat exchanger constructed from medically approved materials. Using a preclinical pig model, we assess its technical feasibility and investigate the limits of blood flow that can be cooled and subsequently reheated to a target temperature.\u003c/p\u003e \u003cp\u003eAs a secondary objective, we evaluate whether the device affects renal, hepatic, cardiac, or erythrocyte function, as well as coagulation and inflammatory parameters.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eApproval for animal experiments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnimal handling was in accordance with the European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (86/609/EU).\u0026nbsp;The study protocol was approved by the University Animal Care Committee. Experiments were performed at the animal laboratory of the Biomedical center at Charles University Medical School. The study was carried out in compliance with the ARRIVE guidelines [11].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnimal selection and instrumentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne pig was used for a pilot experiment, and an additional 16 pigs of either sex, with an average body mass of 41.1 kg, were included in the study and subsequently randomized into COOL and CTRL groups.\u003c/p\u003e\n\u003cp\u003eAll animals were premedicated with an intramuscular injection of 10 mg/kg ketamine (Narkamon; Spofa, a.s., Prague, Czech Republic), 5 mg/kg azaperone (Stresnil, Janssen Pharmaceutica, Belgium), and 0.5 mg atropine (Atropin Biotika, Hoechst Biotika, Slovak Republic). General anesthesia was induced and maintained with intravenous propofol (1% solution, 5\u0026ndash;10 mg/kg/h; Propofol, Fresenius Kabi, Norway). Continuous analgesia was provided throughout the procedure via intravenous administration of fentanyl (1\u0026ndash;2 \u0026mu;g/kg/h; Fentanyl Torrex, Chiesi cz, Czech Republic).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUnder sonographic guidance, the jugular vein and femoral artery were cannulated, and arterial and central venous pressures were measured. The temperature was monitored using a catheter in the bladder. Animals were mechanically ventilated (FiO\u003csub\u003e2\u003c/sub\u003e 0.3, PEEP 3 cm H2O, tidal volume 8 ml/kg, respiratory rate adjusted to maintain end-tidal PCO\u003csub\u003e2\u003c/sub\u003e between 4.0 and 5.0 kPa). Balanced crystalloids and norepinephrine were administered in case of hypotension (see Supplementary Table S8 online for details).\u003c/p\u003e\n\u003cp\u003eMidline laparotomy was performed to enter the abdominal cavity and the infrahepatic part of caudal vena cava was then dissected. All the lumbar veins on the posterior side of vena cava at the level between confluence of iliac veins and inflow of renal veins were transected for safer manipulation with caval vein. Two plastic cannulas of \u0026frac14; inch diameter (19 French scale) were used for connection of the pig circulatory system to the extracorporeal circuit (see Fig.1). The suction cannula was inserted in caudal vena cava through venotomy around 4 cm above confluence of iliac veins and secured with two purse-string sutures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA similar technique was used to insert the outflow cannula into the caudal vena cava at the level of the renal vein inflow. The shape and placement of the cannulas prevent their suction on the vessel wall. To prevent blood clotting in the extracorporeal shunt, 100 IU of heparin (Zentiva, Czech Republic) per kilogram of body weight was administered 5 minutes before cannula insertion, followed by 1000 IU of heparin every 60 minutes during the experiment\u003c/p\u003e\n\u003cp\u003eAt the end of the experiment, the pig was euthanized under general anaesthesia by potassium chloride.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtracorporeal circuit design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur group designed a heat exchanger (HE) comprising 216 parallel tubes, which was manufactured by a certified medical device producer under our guidance to meet both technical and biological compatibility requirements. The HE features a special pair of discs called a laminarizer, which homogenizes the flow of heating/cooling liquid to maximize the efficiency of heat exchange [12]. The design of our experimental system is illustrated in Fig. 1.\u003c/p\u003e\n\u003cp\u003eTwo HEs were connected in series to form a closed circuit, allowing blood to be drawn through the system via a suction cannula and then returned to the animal. The system includes two bubble traps placed after each HE, with a common centrifugal ECMO pump (550 BIO-CONSOLE, Medtronic, USA) controlling blood flow up to 2000 ml/min. This circuit design is based on the standard ECMO circuits used in the author\u0026apos;s clinical practice. Additionally, the system is equipped with four temperature and pressure sensors (Omega Engineering, USA) located before and after each HE. The cooling and rewarming of blood in the HEs are achieved by circulating distilled water through two other devices, developed by our group and controlled by a computer system (Texas Instruments, CA, USA). The entire system was assembled under sterile conditions and filled with a crystalloid solution before connecting to the animal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePilot animal and blood flow adjustment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the system\u0026apos;s feasibility, circuit patency, and proper blood flow adjustment, a pilot pig was used in a preliminary experiment following established protocols for animal instrumentation and circuit design. After the operation, the animal was connected to our system with blood cooling set to 20 \u0026deg;C. Pressure and temperature differentials were monitored for 2 hours before and after each HE using our sensors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the experiment, while maintaining a blood flow rate of 500 ml/min, the system effectively sustained the required temperature differentials (37/20 \u0026deg;C) with a pump pressure difference of up to 100 mmHg.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA further increase in pump speed primarily led to higher pump pressures and was not accompanied by the expected increase in flow rate. A pilot experiment indicated that a flow rate of 500 ml/min is the limiting factor for the specific design of our two HEs connected in series in the ECC.\u003c/p\u003e\n\u003cp\u003eTheoretically, under these conditions\u0026mdash;500 ml/min blood flow, a 40 kg animal, absence of recirculation in the system, physiological intravascular and extravascular conditions, and a 4-hour duration\u0026mdash;the system cools and reheats a single erythrocyte approximately 100 times.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol and measured parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter anesthesia, blood samples were collected, and the pigs underwent surgery. The experiment then commenced according to the protocol outlined in Fig. 2.\u003c/p\u003e\n\u003cp\u003eEight pigs in the cooled group underwent a 4-hour procedure where their blood was cooled to 20 \u0026ordm;C and then rewarmed to 37 \u0026ordm;C. In contrast, eight pigs in the control group experienced the same procedure, except their blood was continuously maintained at 37 \u0026ordm;C.\u003c/p\u003e\n\u003cp\u003eBlood samples were collected from the circuit port near the suction cannula (see Fig. 1, A) at the following time points: preoperative (TP-PC), baseline (TP-0), 15 minutes (TP-15), 60 minutes (TP-60), and 4 hours (TP-240) after the start of the experiment. To assess system functionality, body core temperature and hemodynamic parameters (mean arterial pressure, central venous pressure and heart rate) were monitored.\u003c/p\u003e\n\u003cp\u003eA comprehensive biochemical and hematological evaluation was performed as detailed in Supplementary Table S7 online. Briefly, this included testing liver and kidney parameters, metabolic functions, ions, complete blood count including differential, RBC membrane stability, platelet function, coagulation status, and inflammation induction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSelection and categorization of blood markers for analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe complete set of measured biochemical and hematological data is available online, in the Supplementary Results file (see link at the end of this paper).\u003c/p\u003e\n\u003cp\u003eOut of 53 blood parameters, we selected 32 for analysis, focusing on those that were consistently measurable within range. These were divided into five clusters based on functional relevance. Three additional markers, indicative of diverse health issues, were analyzed separately.\u003c/p\u003e\n\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003eCluster A Liver: This includes albumin (ALB) and liver enzymes (AST, ALT, GGT, ALP), all indicators of liver function. Lactate dehydrogenase (LD) was excluded due to its broader role across systems.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCluster B, Erythrocytes: Comprising 9 markers related to erythrocyte function and oxidative stress, this includes Hemoglobin (HGB), Hematocrit (HCT), Erythrocyte count (Ery),\u0026nbsp;Red cell distribution width\u0026nbsp;(RDW),\u0026nbsp;Mean corpuscular haemoglobin concentration\u0026nbsp;(MCHC),\u0026nbsp;Mean cell haemoglobin\u0026nbsp;(MCH),\u0026nbsp;Mean corpuscular volume\u0026nbsp;(MCV), and two Free hemoglobin indicators (FHb, FHb2). Schistocyte count and Polychromasia were not available.\u003c/li\u003e\n \u003cli\u003eCluster C, Hemostasis: Focused on coagulation, this includes Prothrombin time (PT.R), Thrombocytes (TRB), Plateletcrit (PCT),\u0026nbsp;Platelet distribution width\u0026nbsp;(PDW), and Fibrinogen (FB). aPTT, Thrombin time and platelet aggregation were excluded due to measurement issues.\u003c/li\u003e\n \u003cli\u003eCluster D, Inflammation and Immunity: This includes six leukocyte-related markers: Leukocytes (Leu), Segmented neutrophils (NeuM), Band neutrophils (NeuI), Monocytes (Mono), PMN elastase (PMN), and Lymphocytes (Lym).\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Cluster E, Kidney-Related: Encompasses Urea (UREA), Sodium (Na), and Chlorine (Cl), indicating kidney function and ion balance. Potassium (K) was analyzed separately due to its involvement in multiple systems.\u003c/li\u003e\n \u003cli\u003eUnclustered Outcomes: Troponin T (TnT), Lactate dehydrogenase (LD), and Potassium (K) were analyzed independently due to their broad relevance across multiple health conditions.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical modelling\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData analysis was performed in \u0026lsquo;R\u0026rsquo;\u003csup\u003e1\u003c/sup\u003e within \u0026lsquo;R-studio\u0026rsquo;\u003csup\u003e2\u003c/sup\u003e environment using Bayesian hierarchical regression models via the \u0026lsquo;brms\u0026rsquo;\u003csup\u003e4,5\u003c/sup\u003e R package [13, 14]. \u0026nbsp;Bayesian approach was chosen since it does not rely on large-sample approximations and is thus more suitable for small sample size\u003csup\u003e3\u003c/sup\u003e. Models were run with 4 chains, each with 6,000 iterations (including 2,000 warmups), to estimate parameter distributions. Outcome transformations were applied to reduce heteroscedasticity: square-root (for Band neutrophils and PMN elastase) and Log2 (for Troponin T and free hemoglobin measures). All outcomes were Z-standardized before analysis.\u003c/p\u003e\n\u003cp\u003eModels included animal identity as a random intercept and three fixed effects: time (0\u0026ndash;4 hours post-initiation), cooling (control vs. cooled), and their interaction (time:cooling), allowing us to assess whether time trends differed between cooled and control animals. Predictor time describes the time development of all parameters within each group separately, while predictor cooling compares the parameters between the two groups in time 0. The predictor time*cooled expresses the interaction of our method and demonstrates its effect.\u003c/p\u003e\n\u003cp\u003eAutoregression correlation structures or random slopes were included when leave-one-out cross-validation and posterior predictive checks indicated improved model fit. Priors for fixed effects were set as normal distribution with mean = 0 and sigma of 0.5 (for cooling) or 1 (for time and interaction). This conservative setup shrinks estimates toward null effect to reduce overfitting.\u003c/p\u003e\n\u003cp\u003eGiven the small sample size and potential intercorrelation among blood markers, we used Principal Component Analysis (PCA) for dimensionality reduction. The first principal component (PC) for each marker cluster was extracted. For clusters where the first PC explained less than 50% of variance, a second PC was also extracted. These PCs served as outcome variables in the multivariate Bayesian models. Thus, the final primary model included 8 PCs plus the 3 unclustered outcomes. In addition, each original outcome was also analyzed individually using the same Bayesian framework as secondary analysis.\u003c/p\u003e\n\u003cp\u003eUncertainty is reported with 95% credible intervals. We also report a transformation of the Probability of Direction (PD), an index (ranging from 0.5 to 1) that represents the certainty that the effect is in a particular direction. For interpretative clarity, we show its transformation (\u003cem\u003ep\u003c/em\u003e) as 2\u0026times;(1\u0026minus;PD), which serves as a Bayesian analog to the frequentist p-value, quantifying the effect\u0026rsquo;s clarity in a similar manner as P-value ([15]. We primarily focused on the interaction between time and cooling to assess whether cooling influenced the time course of each outcome. This effect is reported as the \u0026apos;1-hour change difference between groups, representing the difference in average outcome slopes between cooled and control animals.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn course of the experiments, 2 COOL (25%) and 4 CTRL (50%) pigs died; these animals were excluded from the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe cause of death was the development of refractory circulatory failure. The pigs died within a time interval of 60 to 200 minutes during the experiment. Available data show no differences between groups (COOL vs. CTRL) at the accessible time points (TP-0, TP-15, TP-60).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults are presented with 6 and 4 pigs in the COOL and CTRL groups, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTechnical feasibility of the circuit\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring all experiments, the system maintained the set temperatures in both the CTRL and COOL groups. Pump pressures remained stable with the difference never exceeded 150 mmHg, we observed no issues regarding circuit patency. Temperatures measured between the HEs in the COOL group were also stable, and the blood temperature upon return to the animal was 37\u0026deg;C. Pressure and temperature data for one pig from the CTRL group and one from the COOL group are shown in Figs. 3 and 4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHemodynamic status and temperature of the animals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean arterial pressure (MAP) at the beginning of the experiment (TP-PC) was 52 mmHg in both groups (average across all animals). The time course of MAP during the experiments is shown in Fig. 5. MAP did not differ significantly between groups or over the duration of the experiment.\u003c/p\u003e\n\u003cp\u003eThe time course of heart rate during the experiments is shown in Fig. 6. Similarly, heart rate did not differ significantly between groups or over time.\u003c/p\u003e\n\u003cp\u003eThe average central venous pressure (CVP) was 6 mmHg (min 3, max 9 mmHg) in the CTRL group and 4 mmHg (min 2, max 8 mmHg) in the COOL group.\u003c/p\u003e\n\u003cp\u003eThe average SpO\u003csub\u003e2\u003c/sub\u003e was 97% (min 94, max 98%) in the CTRL group and 97% (min 96, max 98%) in the CTRL group. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe average pH was 7.38 (min 7.34, max 7.43) in the CTRL group and 7.39 (min 7.29, max 7.44) in the CTRL group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe average temperature of animals was 37.7\u0026deg;C (min 36.7\u0026deg;C, max 38.5\u0026deg;C) in the CTRL group and 37.7\u0026deg;C (min 36.7\u0026deg;C, max 37.7\u0026deg;C) in the CTRL group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo summarize, SpO₂, pH, and temperature were maintained within physiological ranges during the experiments.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComplete data on hemodynamic monitoring, temperature, and pH are available in the Supplementary Results file (online; see link at the end of this paper).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrincipal component analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 32 blood parameters were often intercorrelated (see Supplementary Figs. S1 and S2). For liver markers (Cluster A), the 1st PC (liverPC1) explained 60% of variance, correlating with all six liver outcomes (r \u0026ge; 0.68). In erythrocytes (Cluster B), the 1st PC (erythPC1, 42% variance) increased with HGB, HCT, and ERY (r \u0026ge; 0.80) and decreased with MCV and MCH (r \u0026le; -0.63), while erythPC2 (26%) related to FHb measures (r \u0026ge; 0.84).\u003c/p\u003e\n\u003cp\u003eFor coagulation markers (Cluster C), coagPC1 (46%) aligned with TRB and PCT (r \u0026ge; 0.92) and negatively with PDW (r = -0.64); coagPC2 (29%) aligned with FB (r = 0.82) and negatively with PT.R (r = -0.68). Inflammation markers (Cluster D) had inflaPC1 (50%) linked to Leu, NeuI, and NeuM (r \u0026ge; 0.69), negatively with Lym (r = -0.98), while inflaPC2 correlated with Mono (r = 0.83) and NeuI/NeuM (r \u0026asymp; \u0026plusmn;0.5).For kidney-ions (Cluster E), kidneyPC1 (58%) increased with UREA (r = 0.53) and decreased with Natrium and Chlorine (r \u0026le; -0.81).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBayesian regression on principal components\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo clear initial differences were found between control and cooled animals at time 0 (see the row \u0026apos;cooled\u0026apos; in Table 1).\u003c/p\u003e\n\u003cp\u003eCoagulation Markers (CoagPC1 and CoagPC2): CoagPC1 showed a decline over time, more pronounced in cooled animals (1-hour change difference between groups = -0.14, 95% CI: -0.26 to -0.01). CoagPC2 clearly increased in controls but there was not consistent increase in cooled animals, indicating cooling reduced the rate of increase (difference = -0.20, CI: -0.36 to -0.03; Fig. 7).\u003c/p\u003e\n\u003cp\u003eInflammation Markers (InflaPC1): InflaPC1, linked to high leukocyte counts and low lymphocyte proportion, increased over time in both groups, with a milder increase in the cooled group\u0026nbsp;(difference = -0.23, CI: -0.42 to -0.04, Fig. 8).\u003c/p\u003e\n\u003cp\u003eFor all other parameters, including renal, liver and erythrocyte markers, changes over time were not clearly different between groups, with detailed results available in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIndividual outcome-specific models\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt time 0, only PMN elastase showed an initial difference between control and cooled animals (see rows \u0026apos;Cooled\u0026apos; in Supplementary Tables S2-S6).\u003c/p\u003e\n\u003cp\u003eCoagulation Markers: Only fibrinogen showed a trend toward a reduced 1-hour change in the cooled group (1-hour difference = -0.10, CI: -0.22 to 0.01, Supplementary Table S4), but not other parameters.\u003c/p\u003e\n\u003cp\u003eInflammation Markers: In controls, leukocyte count, segmented neutrophils, and lymphocyte proportion shifted notably, with leukocyte count and segmented neutrophils increasing and lymphocytes decreasing. Cooling likely moderated these changes: leukocyte count may rose less in cooled animals (difference = -0.19, CI: -0.32 to -0.002), and lymphocyte decline slowed with cooling (difference = 0.24, CI: 0.034 to 0.48). Cooling also reduced the increase in PMN elastase (difference = -0.046, CI: -0.078 to -0.013), though baseline group differences may have influenced PMN results (see Supplementary\u0026nbsp;Fig. S10).\u003c/p\u003e\n\u003cp\u003eNon-Clustered Parameters (Troponin T, Lactate Dehydrogenase, and Potassium): Troponin T showed no notable change over time in either group, with no clear impact from cooling. Lactate dehydrogenase declined in cooled animals but remained stable in controls, though cooling only slightly accelerated the decline (difference = -0.18, CI: -0.36 to 0.017). Potassium levels rose significantly over time in both groups, without noticeable impact from cooling (Supplementary Fig. S6).\u003c/p\u003e\n\u003cp\u003eFor details on all other parameters, including those included in clusters where rate of change of PCs did not differ clearly between groups, please refer to Supplementary Tables S2-S6.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. Estimated effect of \u003cem\u003etime\u003c/em\u003e (an hour) presence of cooling (\u003cem\u003ecooled\u003c/em\u003e) and the \u003cem\u003etime*cooled\u003c/em\u003e interaction [\u003cem\u003etime*cooled (int)\u003c/em\u003e] \u003cstrong\u003eon each of 11 outcomes\u003c/strong\u003e (Z-standardized). Results are based on a multivariate Bayesian hierarchical model with weakly regularizing prior. For principal components in the \u0026lsquo;Outcome\u0026rsquo; column, correlating parameters are shown (red shows positive and blue negative correlations). \u0026lsquo;\u0026beta;\u0026rsquo;: estimated effect. \u0026nbsp;\u0026lsquo;Q2.5\u0026rsquo; and \u0026lsquo;Q97.5\u0026rsquo;: bounds of 95% credible interval. \u0026lsquo;p\u0026rsquo;: 2*(1-\u003cem\u003eprobability of direction\u003c/em\u003e\u003csup\u003e12\u003c/sup\u003e). See methods for details and abbreviations.\u003c/p\u003e\n\u003ctable style=\"border: none;border-collapse: collapse;width: 558px;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:82.15pt;border:solid #A9D08E 1.0pt;background:#70AD47;padding:0in 3.5pt 0in 3.5pt;height: 14.15pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Calibri Light\";color:white;'\u003eOutcome\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:84.5pt;border-top:solid #A9D08E 1.0pt;border-left: none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #AEAAAA 1.0pt;background:#70AD47;padding:0in 3.5pt 0in 3.5pt;height:14.15pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style='font-family: \"Calibri 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style=\"width:48.85pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;color:black;\"\u003e-0.453\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:65.2pt;border:none;border-bottom:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;color:black;\"\u003e-1.23\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.95pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #AEAAAA 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp 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solid rgb(174, 170, 170);background: rgb(226, 239, 218);padding: 0in 3.5pt;height: 11.35pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:12px;font-family:\"Calibri Light\";color:black;'\u003etime (ctrl)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:48.85pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12px;color:black;\"\u003e0.248\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:65.2pt;border:none;border-bottom:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n 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style=\"font-size:12px;\"\u003e0.121\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:65.2pt;border:none;border-bottom:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e-0.031\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.95pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #AEAAAA 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e0.271\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.95pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n 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style=\"width:68.95pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;color:black;\"\u003e0.8868\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84.5pt;border-top: none;border-left: none;border-bottom: 1pt solid rgb(118, 113, 113);border-right: 1pt solid rgb(174, 170, 170);padding: 0in 3.5pt;height: 11.35pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Calibri Light\";color:black;'\u003etime*cooled (int)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:48.85pt;border-top:none;border-left:none;border-bottom:solid #767171 1.0pt;border-right:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e-0.126\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:65.2pt;border:none;border-bottom:solid #767171 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e-0.362\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.95pt;border-top:none;border-left:none;border-bottom:solid #767171 1.0pt;border-right:solid #AEAAAA 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e0.108\u003c/span\u003e\u003c/p\u003e\n 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style=\"width:68.95pt;border-top:none;border-left:none;border-bottom:solid #767171 1.0pt;border-right:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e0.2041\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width:82.15pt;border-top:none;border-left: solid #A9D08E 1.0pt;border-bottom:solid #767171 1.0pt;border-right:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-family:\"Calibri Light\";color:black;'\u003eLactate dehydrogenase\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84.5pt;border-top: none;border-left: none;border-bottom: 1pt solid rgb(169, 208, 142);border-right: 1pt solid rgb(174, 170, 170);background: rgb(226, 239, 218);padding: 0in 3.5pt;height: 11.35pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Calibri Light\";color:black;'\u003etime (ctrl)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:48.85pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;color:black;\"\u003e-0.002\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:65.2pt;border:none;border-bottom:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 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style=\"font-size:12px;color:black;\"\u003e0.9846\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84.5pt;border-top: none;border-left: none;border-bottom: 1pt solid rgb(169, 208, 142);border-right: 1pt solid rgb(174, 170, 170);padding: 0in 3.5pt;height: 11.35pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:12px;font-family:\"Calibri Light\";color:black;'\u003etime (cooled)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:48.85pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan 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style=\"width:68.95pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12px;color:black;\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84.5pt;border-top: none;border-left: none;border-bottom: 1pt solid rgb(169, 208, 142);border-right: 1pt solid rgb(174, 170, 170);padding: 0in 3.5pt;height: 11.35pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:12px;font-family:\"Calibri Light\";color:black;'\u003etime (cooled)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:48.85pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12px;\"\u003e0.499\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:65.2pt;border:none;border-bottom:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12px;\"\u003e0.388\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.95pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #AEAAAA 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12px;\"\u003e0.611\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.95pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:12px;\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84.5pt;border-top: none;border-left: none;border-bottom: 1pt solid rgb(169, 208, 142);border-right: 1pt solid rgb(174, 170, 170);background: rgb(226, 239, 218);padding: 0in 3.5pt;height: 11.35pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Calibri Light\";color:black;'\u003eCooled\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:48.85pt;border-top:none;border-left:none;border-bottom:solid #A9D08E 1.0pt;border-right:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;color:black;\"\u003e0.315\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:65.2pt;border:none;border-bottom:solid #A9D08E 1.0pt;background:#E2EFDA;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;color:black;\"\u003e-0.337\u003c/span\u003e\u003c/p\u003e\n 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113);border-right: 1pt solid rgb(174, 170, 170);padding: 0in 3.5pt;height: 11.35pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-size:12px;font-family:\"Calibri Light\";color:black;'\u003etime*cooled (int)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:48.85pt;border-top:none;border-left:none;border-bottom:solid #767171 1.0pt;border-right:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e0.058\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:65.2pt;border:none;border-bottom:solid #767171 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e-0.112\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.95pt;border-top:none;border-left:none;border-bottom:solid #767171 1.0pt;border-right:solid #AEAAAA 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e0.232\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.95pt;border-top:none;border-left:none;border-bottom:solid #767171 1.0pt;border-right:solid #A9D08E 1.0pt;padding:0in 3.5pt 0in 3.5pt;height:11.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size:12px;\"\u003e0.4924\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIndividual outcome-specific models\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt time 0, only PMN elastase showed an initial difference between control and cooled animals (see rows \u0026apos;Cooled\u0026apos; in Supplementary Tables S2-S6).\u003c/p\u003e\n\u003cp\u003eCoagulation Markers: Only fibrinogen showed a trend toward a reduced 1-hour change in the cooled group (1-hour difference = -0.10, CI: -0.22 to 0.01, Supplementary Table S4), but not other parameters.\u003c/p\u003e\n\u003cp\u003eInflammation Markers: In controls, leukocyte count, segmented neutrophils, and lymphocyte proportion shifted notably, with leukocyte count and segmented neutrophils increasing and lymphocytes decreasing. Cooling likely moderated these changes: leukocyte count may rose less in cooled animals (difference = -0.19, CI: -0.32 to -0.002), and lymphocyte decline slowed with cooling (difference = 0.24, CI: 0.034 to 0.48). Cooling also reduced the increase in PMN elastase (difference = -0.046, CI: -0.078 to -0.013), though baseline group differences may have influenced PMN results (see Supplementary\u0026nbsp;Fig. S10).\u003c/p\u003e\n\u003cp\u003eNon-Clustered Parameters (Troponin T, Lactate Dehydrogenase, and Potassium): Troponin T showed no notable change over time in either group, with no clear impact from cooling. Lactate dehydrogenase declined in cooled animals but remained stable in controls, though cooling only slightly accelerated the decline (difference = -0.18, CI: -0.36 to 0.017). Potassium levels rose significantly over time in both groups, without noticeable impact from cooling (Supplementary Fig. S6).\u003c/p\u003e\n\u003cp\u003eFor details on all other parameters, including those included in clusters where rate of change of PCs did not differ clearly between groups, please refer to Supplementary Tables S2-S6.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs shown in our two previous studies, regional cooling may influence blood coagulation status in specific types of EC techniques [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A significant limitation of our most recent experiment was the restricted lifespan of the ECC when comparing the cooling method to the standard heparinization approach. This limitation prevented consideration for clinical use, which we attribute primarily to the construction of the used heat exchanger, particularly the aluminum layer in direct contact with blood.\u003c/p\u003e \u003cp\u003eIn the current study, we present an experiment featuring a novel heat exchanger (HE) design, where all components are made from polyethylene certified for use in blood transfusion sets. Both the development and production were entrusted to a company specializing in medical devices with EU certification. We believe this new HE design addresses the biological compatibility issues encountered with previous EC circuit setups in our experiments and meets all legal requirements defined by the EU Medical Devices Regulation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur main goal was to test its technical feasibility, which also required developing a prototype of the EC circuit. In general, EC circuits support or replace the function of vital organs such as the kidneys, heart, lungs, or liver. This broad range of applications requires a wide range of blood flow rates through the circuit \u0026mdash; from as low as 100 ml/hour in CRRT to as high as 5,000 ml/hour in veno-arterial ECMO. Such a wide range places high demands on the design of both the blood pump and the circuit, which must preserve blood integrity and have sufficient biocompatibility. Therefore, among all possible pump types, only peristaltic and centrifugal pumps are currently used. To test our novel heat exchanger in a circuit prototype, where even two heat exchangers will be connected in series, choosing the appropriate blood pump is crucial.\u003c/p\u003e \u003cp\u003eIn theory, peristaltic and centrifugal pumps differ functionally: the former provides a constant flow, while the latter generates constant pressure. In a peristaltic pump, the tubing is cyclically compressed to expel a fixed volume of blood, producing pulsatile pressure peaks with each cycle. In contrast, a centrifugal pump uses a rotating disk to spin the blood, generating pressure via centrifugal force exerted on the pump walls. This pressure remains relatively constant over time, while the flow rate depends on the resistance within the circuit. Therefore, in the event of a circuit obstruction, a peristaltic pump attempts to maintain constant flow, leading to a significant rise in pressure peaks. Conversely, a centrifugal pump limits flow under increased resistance, while maintaining a steady pressure. Blood elements, especially erythrocytes, can be damaged by pumps due to changes in shear forces, leading to hemolysis. This theoretical understanding, supported by clinical findings [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] has led to our decision to use only a centrifugal pump in our experiments. This pump is considered to be more variable and to cause less hemolysis compared to peristaltic one.\u003c/p\u003e \u003cp\u003eIn addition to the pump, other components of the extracorporeal circuit can influence hemolysis. These include tubing kinks and cannulas that are too small, both of which can create localized high shear force [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. To minimize this risk, we use the largest possible cannula size that can be safely inserted into the vena cava, along with tubing of similar diameter (19 French size).\u003c/p\u003e \u003cp\u003eAlthough it is not entirely common in centrifugal pump-driven ECC, we decided to insert two gas bubble traps into our circuit. We aim to avoid unexpected gas bubble formation during sudden temperature changes in the blood, which could interfere with circuit patency (by obstructing HE tubes) or cause embolic complications in the animals [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, Bayesian models did not reveal signs of erythrocyte deterioration in either the control or cooled groups, measured by blood count and free hemoglobin. This suggests that our HE design and cooling method may be without measurable negative effect on red blood cells and appear to be safe for cellular integrity. It is important to note that we encountered no technical issues with the circuit and its patency in any of the experiments.\u003c/p\u003e \u003cp\u003eOur secondary aim was to observe the biological effects of in-circuit cooling on selected organ, coagulation, and inflammation parameters. When blood comes into contact with synthetic surfaces, it exposes the organism to significant mechanical and biological stress, leading to widespread activation of the innate immune system. This response shares characteristics with systemic inflammatory response syndrome [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and also serves as a potent trigger for coagulation.\u003c/p\u003e \u003cp\u003eOur data, analysed using Bayesian models, showed a clear increase in inflammatory markers in the CTRL animals, whereas the cooling intervention appeared to attenuate this response. Specifically, the CTRL group exhibited elevated leukocyte counts, segmented neutrophils, and PMN elastase levels, along with a reduced proportion of lymphocytes. These changes were less pronounced or negligible in the cooled animals, suggesting a trend toward anti-inflammatory effects associated with the cooling method.\u003c/p\u003e \u003cp\u003e Our cooling method reduced the increase in coagulation parameters during the experiments, according to results from Bayesian model analysis. Furthermore, fibrinogen\u0026mdash;a well-known marker of inflammation and pro-coagulation\u0026mdash;tended to increase in the CTRL group but not in the cooled group. Similarly, we observed a reduction in lactate dehydrogenase (LD) levels in the cooled group. LD is an enzyme present in many organs, including erythrocytes, which contain up to 100 times more LD than plasma. Since our study did not reveal any significant haemolysis, we presume that the observed reduction in LD in the cooled pigs may reflect a protective effect of hypothermia. In summary, these non-specific indicators suggest potential anti-inflammatory and anti-coagulative properties of our cooling method.\u003c/p\u003e \u003cp\u003eFinally, Bayesian models did not reveal any clear effect of cooling on liver or kidney function, although the observation period may have been too short to detect potential changes. Similarly, troponin T levels remained unchanged across all groups, suggesting that our experimental setup did not significantly impact cardiac function.\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations\u003c/h2\u003e \u003cp\u003eThe most serious issue we encountered was extensive pig mortality, reaching up to 40%, despite the pilot experiment appearing uneventful. Circulatory failure followed by cardiac arrest was identified as the primary cause of death, likely due to the extensive nature of the surgery combined with significant interference in circulatory dynamics. Pigs are known for their high splanchnic blood flow, which supports their rapid growth [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Insertion of a 19 French cannula into the vena cava reduced the vessel diameter by approximately half (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), which likely causing a dramatic decrease in preload and leading to circulatory instability. The animals experienced persistent hypotension throughout the experiment; the average mean arterial pressure (MAP) at TP-PC was 52 mmHg. With one exception, we were unable to maintain normotension using either volume loading or norepinephrine administration (see Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and Supplementary Table S8 for details).\u003c/p\u003e \u003cp\u003eSerum potassium concentration increased significantly in both groups over the course of the experiment, likely due to a high surgical burden, potentially exacerbated by propofol infusion syndrome. We speculate that the increase in potassium levels cannot be attributed to acidosis, as blood pH remained within normal range in all animals.\u003c/p\u003e \u003cp\u003eIn further experiments, it is necessary to change the cannulation access technique to a less invasive, percutaneously advanced catheter approach, commonly used in humans, which cause no circulation instability. Therefore, we do not consider it reasonable to increase statistical significance by expanding the number of experimental animals.\u003c/p\u003e \u003cp\u003eA further limitation of our study is the limited set of samples used to evaluate the immune response. The primary aim of our work was to demonstrate the technical and functional feasibility of the novel heat exchanger. Consequently, the promising findings related to immune response are based on non-specific results and were not investigated in detail. We suggest that future research should focus on a small, standardized animal model with controlled minimal stress, employing only the percutaneous puncture technique and mimicking sepsis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe innovative heat exchanger used in the ECC demonstrates clinical feasibility. We did not observe any adverse effects on liver, kidney, or other metabolic functions, blood counts, or the stability of the erythrocyte membrane. We confirmed the anticoagulant effect of local hypothermia. Furthermore, we observed signs of an anti-inflammatory effect from the cooling method, which may contribute to organ protection.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThe work was supported from European Regional Development Fund - Project \u0026bdquo;Fighting Infectious Diseases\u0026rdquo; (No. CZ.02.1.01/0.0/0.0/16_019/0000787).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eR.J., T.F. and S.J. wrote the manuscript, T.F. conducted the statistical analysis, D.J., B.L., B.O., P.R., R.J., M.V. and M.M. performed the animal experiments, L.V. and K.J. supervised the project. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData are published in the files Supplementary_FIgs_Tabs and Suppl_Results.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSalath\u0026eacute;, C. et al. Epidemiology and outcomes of elderly patients requiring renal replacement therapy in the intensive care unit: an observational study. \u003cem\u003eBMC Nephrol\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e (2021).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKaragiannidis, C. et al. Extracorporeal membrane oxygenation: evolving epidemiology and mortality. \u003cem\u003eIntensive Care Med\u003c/em\u003e.\u003cstrong\u003e42,\u0026nbsp;\u003c/strong\u003e889-896 (2016).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLi, R. et al. 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Evaluation of prolonged \u0026apos;Permissive Hypotension\u0026apos;: results from a 6-hour hemorrhage protocol in swine.\u0026nbsp;\u003cem\u003eTrauma Surg Acute Care Open\u003c/em\u003e \u003cstrong\u003e4,\u003c/strong\u003e doi: 10.1136/tsaco-2019-000369 \u0026nbsp;(2019).\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Extracorporeal circuit, hypothermia, biocompatibility, coagulation, inflammation","lastPublishedDoi":"10.21203/rs.3.rs-6680449/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6680449/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTo evaluate a novel anticoagulation strategy in an extracorporeal circuit, we introduce a device that induces local hypothermia as blood flows through the circuit. Using a pig model, we assess its technical feasibility, biocompatibility, and safety.16 pigs were randomly assigned to either the \u0026lsquo;cooled\u0026rsquo; or \u0026lsquo;control\u0026rsquo; group and underwent midline laparotomy to establish extracorporeal circulation (blood flow 500 ml/min) via the caudal vena cava for up to four hours. During the experiment, blood samples were collected at four time points at the baseline and at the 15th, 60th, and 240th minute of the experiment. In the \u0026lsquo;cooled\u0026rsquo; group, blood was cooled to 20\u0026deg;C and rewarmed to 37\u0026deg;C, while in the control group, blood was maintained at 37\u0026deg;C. A total of 6 \u0026lsquo;cooled\u0026rsquo; and 4 \u0026lsquo;control\u0026rsquo; pigs survived the experiment. Our findings confirm the technical feasibility of the proposed device, which effectively maintained the required temperature differentials and kept the pressure differentials in the circuit within 150 mmHg. No issues with circuit patency were observed. Additionally, no adverse effects were detected on renal, liver, cardiac, or erythrocyte function. On the contrary, our data suggests that local hypothermia in the extracorporeal circuit reduces blood coagulation and may mitigate surgery induced inflammation or stress.\u003c/p\u003e","manuscriptTitle":"Novel heat exchanger in extracorporeal circuit: technical and biological feasibility","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-09 08:36:27","doi":"10.21203/rs.3.rs-6680449/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-30T06:37:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-20T09:03:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-13T18:57:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"241411438857718030482605582477806099575","date":"2025-06-10T09:23:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-10T00:21:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247093935323058503436129008898416876626","date":"2025-06-03T14:57:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"88185114811283022112400046835706623952","date":"2025-06-03T08:42:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-03T07:43:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-28T09:25:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-21T05:40:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-20T15:05:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-05-16T11:34:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"647710ff-e55d-4174-8672-e913357cbc85","owner":[],"postedDate":"June 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":49472078,"name":"Biological sciences/Biotechnology"},{"id":49472079,"name":"Health sciences/Medical research/Pre clinical studies"},{"id":49472080,"name":"Biological sciences/Physiology/Circulation"}],"tags":[],"updatedAt":"2025-10-27T16:32:58+00:00","versionOfRecord":{"articleIdentity":"rs-6680449","link":"https://doi.org/10.1038/s41598-025-20798-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-10-22 16:17:06","publishedOnDateReadable":"October 22nd, 2025"},"versionCreatedAt":"2025-06-09 08:36:27","video":"","vorDoi":"10.1038/s41598-025-20798-w","vorDoiUrl":"https://doi.org/10.1038/s41598-025-20798-w","workflowStages":[]},"version":"v1","identity":"rs-6680449","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6680449","identity":"rs-6680449","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}