Extracorporeal Life Support Circuit Research Articles

Extraction of ketamine and dexmedetomidine by extracorporeal life support circuits

Extraction of ketamine and dexmedetomidine by extracorporeal life support circuits

23: Optimizing Extracorporeal Life Support (ECLS) Circuit Change Process: A comprehensive Guideline and Practice Revision for Improved Patient Care and Safety

23: Optimizing Extracorporeal Life Support (ECLS) Circuit Change Process: A comprehensive Guideline and Practice Revision for Improved Patient Care and Safety

Thoracoabdominal Normothermic Regional Perfusion Using Mobile Closed Extracorporeal Circuit in Circulatory Death Determination Heart Donors.

Thoracoabdominal normothermic regional perfusion (TA-NRP) is increasingly implemented in donation after circulatory determination of death (DCD). Thoracoabdominal normothermic regional perfusion allows thoracic and abdominal organs to be perfused with warm, oxygenated blood after declaration of death, interrupting ischemia. Evidence is accumulating supporting the use of TA-NRP to improve the outcome of grafts from DCD donors. Thoracoabdominal normothermic regional perfusion may restore and maintain a near-physiological environment during procurement. Moreover, during TA-NRP it is feasible to evaluate the heart in situ. Thoracoabdominal normothermic regional perfusion could be performed through different cannulation techniques, central or peripheral, and, with different extracorporeal circuits. The use of conventional cardiopulmonary bypass and extracorporeal life support (ECLS) devices equipped with open circuits has been described. We report the use of a fully mobile, closed ECLS circuit to implement TA-NRP. The procedure was successfully performed in a peripheral center without a cardiac surgery program through a percutaneous cannulation approach. This strategy resulted in combined heart, liver, and kidney recovery despite a significantly prolonged functional warm ischemia time. The feasibility of TA-NRP using modified but still closed fully mobile ECLS circuits could furtherly support the expansion of DCD programs, increasing the availability of heart for transplantation, and the quality of the grafts, improving recipients' outcome.

The Jena Method: Perfusionist Independent, Standby Wet-Primed Extracorporeal Membrane Oxygenation (ECMO) Circuit for Immediate Catheterization Laboratory and/or Hybrid Operating Room Deployment.

Background: The timely initiation of extracorporeal membrane oxygenation (ECMO) is crucial for providing life support. However, delays can occur when perfusionists are not readily available. The Jena Method aims to address this issue by offering a wet-primed ECMO system that can be rapidly established without the perfusionist's presence. Methods: The goal was to ensure prompt ECMO initiation while maintaining patient safety. The method focuses on meeting hygienic standards, safe primed storage of the circuit, staff training, and providing clear step-by-step instructions for the ECMO unit. Results: Since implementing the Jena Method in 2015, 306 patients received VA-ECMO treatment. Bacterial tests confirmed the sterility of the primed ECMO circuits during a 14-day period. The functionality of all the components of the primed ECMO circuit after 14 days, especially the pump and oxygenator, were thoroughly checked and no malfunction was found to this day. To train staff for independent ECMO initiation, a step-by-step system involves safely bringing the ECMO unit to the intervention site and establishing all connections. This includes powering up, managing recirculation, de-airing the system, and preparing it for cannula connection. A self-developed picture-based guide assists in this process. New staff members learn from colleagues and receive quarterly training sessions by perfusionists. After ECMO deployment, the perfusionist provides a new primed system for a potential next patient. Conclusions: Establishing a permanently wet-primed on-demand extracorporeal life support circuit without direct perfusionist support is feasible and safe. The Jena Method enables rapid ECMO deployment and has the potential to be adopted in emergency departments as well.

A multipurpose Extracorporeal Life Support Circuit: a concept for multiorgan transplant and circulatory support service Healthcare provider

The demand for efficient and adaptable life support systems in the field of Extracorporeal Life Support (ECLS) is steadily increasing. To meet this growing need, there is a requirement for a versatile extracorporeal life support circuit that can be effectively applied in various medical scenarios, especially in tertiary hospitals where multiple ECLS services are utilized. These services include Extracorporeal Membrane Oxygenation (ECMO) for addressing respiratory or cardiac problems, Ventricular Assist Device (VAD) as a bridge to recovery or heart transplant, and Venovenous Bypass (VVB) for assisting liver transplantation. In light of this, we propose the creation of a multipurpose circuit that integrates multiple extracorporeal life support (ECLS) functions to cater to diverse medical needs. This innovative circuit not only offers cost-effectiveness and enhanced safety but also ensures optimal utilization, thereby revolutionizing the realm of life support technologies.

Meropenem extraction by ex vivo extracorporeal life support circuits.

Meropenem is a broad-spectrum carbapenem-type antibiotic commonly used to treat critically ill patients infected with extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. As many of these patients require extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapy (CRRT), it is important to understand how these extracorporeal life support circuits impact meropenem pharmacokinetics. Based on the physicochemical properties of meropenem, it is expected that ECMO circuits will minimally extract meropenem, while CRRT circuits will rapidly clear meropenem. The present study seeks to determine the extraction of meropenem from ex vivo ECMO and CRRT circuits and elucidate the contribution of different ECMO circuit components to extraction. Standard doses of meropenem were administered to three different configurations (n=3 per configuration) of blood-primed ex vivo ECMO circuits and serial sampling was conducted over 24h. Similarly, standard doses of meropenem were administered to CRRT circuits (n=4) and serial sampling was conducted over 4h. Meropenem was administered to separate tubes primed with circuit blood to serve as controls to account for drug degradation. Meropenem concentrations were quantified, and percent recovery was calculated for each sample. Meropenem was cleared at a similar rate in ECMO circuits of different configurations (n=3) and controls (n=6), with mean (standard deviation) recovery at 24h of 15.6% (12.9) in Complete circuits, 37.9% (8.3) in Oxygenator circuits, 47.1% (8.2) in Pump circuits, and 20.6% (20.6) in controls. In CRRT circuits (n=4) meropenem was cleared rapidly compared with controls (n=6) with a mean recovery at 2h of 2.36% (1.44) in circuits and 93.0% (7.1) in controls. Meropenem is rapidly cleared by hemodiafiltration during CRRT. There is minimal adsorption of meropenem to ECMO circuit components; however, meropenem undergoes significant degradation and/or plasma metabolism at physiological conditions. These ex vivo findings will advise pharmacists and physicians on the appropriate dosing of meropenem.

Gaseous Nitric Oxide-Cangrelor Combination to Prevent Clots in Extracorporeal Life Support System

IntroductionThe objective of this study was to investigate the potential synergistic utility of a combination of gaseous nitric oxide (gNO)-intravenous Cangrelor as an effective pharmacological option for the prevention of thrombosis in an animal model of extracorporeal life support (ECLS) circuits. Methods10 newborn lambs were placed on ECLS. 5 of them were administered a combination of gNO and intravenous Cangrelor. The remaining 5 were not administered any anticoagulant. The primary end point was duration of ECLS without clot formation. The secondary outcome measure was the absolute maximum transmembrane pressure gradient. ResultsThe mean duration of ECLS were 168 min (standard deviation 224.98 min) in the control group and 402 min (standard deviation 287.5 min) in the experimental group (P = 0.17). The peak trans-oxygenator pressure difference was 43 mm Hg (standard deviation 23 mm Hg) in the control group and 62 mm Hg (standard deviation 71 mm Hg) in the experimental group(P = 0.64). Two animals in the experimental group were supported up to 12 h without clot formation. Clot formation in the experimental group occurred after placement of the cannulae but prior to initiation of ECLS flows after cannulation. ConclusionsA combination of gNO and Cangrelor is prevents clot formation in an experimental animal model when administered through a clean clot-free circuit. However, the combination s ineffective when there are pre-existing clots in the circuit. A bolus of anticoagulation prior to cannulation is needed prior to testing this combination in future studies with a larger sample size.

SHOCK6: Assessment of anticoagulation status with thrombin time during bivalirudin infusion in patients on extracorporeal life support

The purpose of this study was to evaluate the use of thrombin time (TT) to inform adjustments in anticoagulation strategies for the maintenance of extracorporeal life support (ECLS) circuit patency in patients receiving bivalirudin. Previous studies show the average life span of a circuit is 264 hours. Our single center, retrospective study included 13 adult patients on ECLS receiving bivalirudin who obtained TT to assess the degree of anticoagulation. The primary outcome was the number of oxygenator changes associated with circuit thrombosis. Secondary outcomes were major and minor bleeding, survival to ECLS decannulation and hospital discharge, time on ECLS, and venous thromboembolism (VTE). There were a total of 4 oxygenator changes among 3 out of the 13 patients included in the study. The median time on circuit was 354 hours (216 to 480) before a circuit change was required. Major bleeding occurred in 4 patients and minor bleeding occurred in 8 patients. There were 10 patients who survived to ECLS decannulation and 9 patients survived to discharge. Time on ECLS ranged from 144 to 1032 hours. VTE occurred in 3 patients. Among the 195 TT collected while aPTT was therapeutic for 8 patients, 30% of dose adjustments occurred within the next aPTT check or 24 hours. The use of TT was prompted primarily due to increased fibrin deposits on circuit despite therapeutic aPTT. We observed that the use of TT was associated with longer duration on circuit before an oxygenator change was required. The utility of TT to guide adjustments to anticoagulation strategies for bivalirudin in ECLS warrants further investigation.

BIO11: Ambulatory Rabbit ECLS Model for Long-term Biocompatibility Testing

Background: Thrombosis causes rapid failure of oxygenators within extracorporeal life support (ECLS) circuits. To combat this problem, various groups are developing new surface coatings and anticoagulants, but their testing typically relies on either (a) inexpensive, but overly-brief (< 8 hour) in vitro or small animal in vivo testing or (b) expensive, long-term (days to weeks) testing in large animals. A more inexpensive model is thus needed to assess the long-term biocompatibility of new anticoagulant technologies. In this study, the feasibility of a long-term, ambulatory rabbit ECLS model was assessed. Methods: A miniaturized ECLS circuit was attached to rabbits (2.5-4 kg) under anesthesia using a pumpless arteriovenous (AV) configuration. The circuit contained a miniature artificial lung (surface area of 400 cm2) using the same materials as full-scale artificial lungs. The circuit was tunneled behind the animal’s back and secured just below the scruff of the neck. IV heparin was provided via a battery-powered infusion pump (SAI 3D Mini Infusion Pump) within a small jacket. Twelve non-recovery experiments were used to optimize the model, and two subsequent recovery experiments were run until oxygenator failure (blood flow rate below 5 mL/min for over 2 hours and/or resistance > 5x baseline). Non-recovery experiments were used to optimize the cannulation strategy. This included cannula type and circuit placement on the rabbit. Once optimized, two survival studies were performed. The average circuit blood flow during the first experiment was 50-60 mL/min. The circuit blood flow was then limited to 35-45 mL/min with a Hoffman clamp for the second experiment. Blood flow resistance was measured to assess anticoagulation effectiveness, and physiology was monitored through hepatic and renal panels. Results: Bilateral cannulation was ideal for circuit placement. A flexible 16G single-lumen central line was chosen because of its low blood flow resistance and resistance to kinking. The circuit was tunneled 40 cm, emerging just below the scruff. This enabled safe handling of the animal without impacting its mobility and ability to eat. The recovery experiments lasted 47 and 21 hours prior to oxygenator failure. Animals were completely ambulatory with free access to food and water. Heparin delivery could be controlled simply using the infusion pump, and coagulation could be assessed by drawing blood samples and measuring oxygenator resistance. The first survival rabbit developed hyperlipidemia on Day 1. The cause is unclear at this time but could be attributed to high blood flow through AV circuit. Conclusion: This study demonstrates the feasibility of using a lower-cost rabbit model for long-term anticoagulation testing that requires less staffing. Future studies will use this model to compare the anticoagulation effectiveness of heparin, a selective Factor XIIa inhibitor, and surface coatings for a period of five days.

Response to Hemostatic Complications During Neonatal Extracorporeal Membrane Oxygenation: Roller Pump and Centrifugal Pump Driven Circuits.

To the Editor: Vermeer et al.1 recently published a case series and in vitro analysis of acute oxygenator failure manifested as a rise in preoxygenator pressure without evidence of gas transfer failure. As practitioners in the field who have fielded similar questions from colleagues describing similar issues, we applaud them for describing this problem that has been informally discussed in meetings and discussion boards for several years. The debate in neonatal extracorporeal life support (ECLS) between roller and centrifugal pumps has a long history.2 While the focus has primarily been on sources of increased hemolysis, the acute failure of the ECLS circuit by oxygenator clogging has received less attention. Vermeer et al.1 began using the RotaFlow in neonatal ECLS because of supply shortages and the availability and experience with adult ECLS. After a disturbing trend of complications, they embarked on a formal assessment of three systems (roller pump, RotaFlow, and PedIVAS) and associated failure rates in the neonatal population. The authors described anticoagulation, heat generation, and overall blood velocity as plausible mechanisms generating the cellular debris that led to the clogging phenomenon. In discussing the velocity, they came very close to what we would consider to be the fundamental problem inherent in the design of any centrifugal pump, which is their best efficiency point (BEP). The BEP is the point at which energy imparted to spinning the impeller generates the most forward bulk flow from the pump. The RotaFlow and PedivAS were designed to operate at 5 and 1.5 L/min, respectively. Schöps et al.3 used computational fluid dynamics to describe zones of recirculation, which do not contribute to the bulk flow of the blood, within adult devices operated at 1 L/min or less. Consequently, blood remains in the pump shear field for an extended time, significantly increasing the risk for hemolysis, which was demonstrated in vitro. Vermeer et al.1 have now provided in vivo evidence for the in silico and in vitro data provided by Schöps et al.3 However, we believe there is still more to the story. Several other factors are likely at play in neonatal ECLS, including cellular fragility4 and hemoglobin greater than 12–13 g/dl, which has been shown to be an independent factor leading to blood damage for neonatal ECLS regardless of pump type.5 A shrinking pool of devices and trained healthcare providers has led to the utilization of devices for the greatest number of patients (adults) in the most vulnerable population (neonates), and these are conditions for which these devices were never designed. Even the PediVAS, which is a pediatric device, is designed to operate at flow nearly three times that required for neonatal ECLS. We believe the study described by Vermeer et al.,1 Schöps et al.,3 Jenks et al.,5 and others in this space are important starting points for the ultimate discussion that a true neonatal ECLS centrifugal blood pump needs to be developed. We hope that such study continues and drives manufacturers to consider the needs of this population, ultimately allowing clinicians to more safely provide the life-saving support that this population needs.

Quantitative Analysis of Clot Deposition on Extracorporeal Life Support Membrane Oxygenators Using Digital and Scanning Electron Microscopy Imaging Techniques.

Device-induced thrombosis remains a major complication of extracorporeal life support (ECLS). To more thoroughly understand how blood components interact with the artificial surfaces of ECLS circuit components, assessment of clot deposition on these surfaces following clinical use is urgently needed. Scanning electron microscopy (SEM), which produces high-resolution images at nanoscale level, allows visualization and characterization of thrombotic deposits on ECLS circuitry. However, methodologies to increase the quantifiability of SEM analysis of ECLS circuit components have yet to be applied clinically. To address these issues, we developed a protocol to quantify clot deposition on ECLS membrane oxygenator gas transfer fiber sheets through digital and SEM imaging techniques. In this study, ECLS membrane oxygenator fiber sheets were obtained, fixed, and imaged after use. Following a standardized process, the percentage of clot deposition on both digital images and SEM images was quantified using ImageJ through blind reviews. The interrater reliability of quantitative analysis among reviewers was evaluated. Although this protocol focused on the analysis of ECLS membrane oxygenators, it is also adaptable to other components of the ECLS circuits such as catheters and tubing. Key features • Quantitative analysis of clot deposition using digital and scanning electron microscopy (SEM) techniques • High-resolution images at nanoscale level • Extracorporeal life support (ECLS) devices • Membrane oxygenators • Blood-contacting surfaces Graphical overview.

Factor XII Silencing Using siRNA Prevents Thrombus Formation in a Rat Model of Extracorporeal Life Support.

Heparin anticoagulation increases the bleeding risk during extracorporeal life support (ECLS). This study determined whether factor XII (FXII) silencing using short interfering RNA (siRNA) can provide ECLS circuit anticoagulation without bleeding. Adult male, Sprague-Dawley rats were randomized to four groups (n = 3 each) based on anticoagulant: (1) no anticoagulant, (2) heparin, (3) FXII siRNA, or (4) nontargeting siRNA. Heparin was administered intravenously before and during ECLS. FXII or nontargeting siRNA were administered intravenously 3 days before the initiation of ECLS via lipidoid nanoparticles. The rats were placed on pumped, arteriovenous ECLS for 8 hours or until the blood flow resistance reached three times its baseline resistance. Without anticoagulant, mock-oxygenator resistance tripled within 7 ± 2 minutes. The resistance in the FXII siRNA group did not increase for 8 hours. There were no significant differences in resistance or mock-oxygenator thrombus volume between the FXII siRNA and the heparin groups. However, the bleeding time in the FXII siRNA group (3.4 ± 0.6 minutes) was significantly shorter than that in the heparin group (5.5 ± 0.5 minutes, p < 0.05). FXII silencing using siRNA provided simpler anticoagulation of ECLS circuits with reduced bleeding time as compared to heparin. http://links.lww.com/ASAIO/A937.

Cefepime Extraction by Extracorporeal Life Support Circuits

Extracorporeal life support (ECLS) devices are lifesaving for critically ill patients with multi-organ dysfunction. Despite this, patients supported with ECLS are at high risk for ECLS-related complications, including nosocomial infections, and mortality rates are high in this patient population. The high mortality rates are suspected to be, in part, a result of significantly altered drug disposition by the ECLS circuit, resulting in suboptimal antimicrobial dosing. Cefepime is commonly used in critically ill patients with serious infections. Cefepime dosing is not routinely guided by therapeutic drug monitoring and treatment success is dependent upon the percentage of time of the dosing interval that the drug concentration remains above the minimum inhibitory concentration of the organism. Thisex vivostudy measured the extraction of cefepime by continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) circuits. Cefepime was studied in four closed-loop CRRT circuit configurations and a single closed-loop ECMO circuit configuration. Circuits were primed with a physiologic human blood–plasma mixture and the drug was dosed to achieve therapeutic concentrations. Serial blood samples were collected over time and concentrations were quantified using validated assays. Inex vivoCRRT experiments, cefepime was rapidly cleared by dialysis, hemofiltration, and hemodiafiltration, with greater than 96% cefepime eliminated from the circuit by 2 hours. In the ECMO circuits, the mean recovery of cefepime was similar in both circuit and standard control. Mean (standard deviation) recovery of cefepime in the ECMO circuits (n = 6) was 39.2% (8.0) at 24 hours. Mean recovery in the standard control (n = 3) at 24 hours was 52.2% (1.5). Cefepime is rapidly cleared by dialysis, hemofiltration, and hemodiafiltration in the CRRT circuit but minimally adsorbed by either the CRRT or ECMO circuits. Dosing adjustments are needed for patients supported with CRRT.

Cefepime Extraction by Extracorporeal Life Support Circuits.

Extracorporeal life support (ECLS) devices are lifesaving for critically ill patients with multi-organ dysfunction. Despite this, patients supported with ECLS are at high risk for ECLS-related complications, including nosocomial infections, and mortality rates are high in this patient population. The high mortality rates are suspected to be, in part, a result of significantly altered drug disposition by the ECLS circuit, resulting in suboptimal antimicrobial dosing. Cefepime is commonly used in critically ill patients with serious infections. Cefepime dosing is not routinely guided by therapeutic drug monitoring and treatment success is dependent upon the percentage of time of the dosing interval that the drug concentration remains above the minimum inhibitory concentration of the organism. This ex vivo study measured the extraction of cefepime by continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) circuits. Cefepime was studied in four closed-loop CRRT circuit configurations and a single closed-loop ECMO circuit configuration. Circuits were primed with a physiologic human blood-plasma mixture and the drug was dosed to achieve therapeutic concentrations. Serial blood samples were collected over time and concentrations were quantified using validated assays. In ex vivo CRRT experiments, cefepime was rapidly cleared by dialysis, hemofiltration, and hemodiafiltration, with greater than 96% cefepime eliminated from the circuit by 2 hours. In the ECMO circuits, the mean recovery of cefepime was similar in both circuit and standard control. Mean (standard deviation) recovery of cefepime in the ECMO circuits (n = 6) was 39.2% (8.0) at 24 hours. Mean recovery in the standard control (n = 3) at 24 hours was 52.2% (1.5). Cefepime is rapidly cleared by dialysis, hemofiltration, and hemodiafiltration in the CRRT circuit but minimally adsorbed by either the CRRT or ECMO circuits. Dosing adjustments are needed for patients supported with CRRT.

Nitric Oxide on Extracorporeal Life Support-Circuit Modifications for a Safe Therapy.

Nitric oxide (NO) incorporation into the sweep gas of the extracorporeal life support (ECLS) circuit has been proposed as a strategy to ameliorate the insults caused by the systemic inflammatory response. This technical study describes circuit modifications allowing nitric oxide to be incorporated into the circuit and describing and validating the oxygenator sweep flow rates necessary to achieve consistent safe delivery of the therapy. For patients requiring sweep rates less than 2 L/min, a simplified setup, incorporating a pressure relief valve/low flow meter in the gas delivery line, was placed in line between the blender/NO injector module and the NO sampling port/oxygenator. This setup allows titration of sweep to low flows without the need to blend in CO2 while maintaining the manufacturer recommendation of a minimum 2 L/min of sweep gas to safely deliver NO without nitric dioxide (NO2) buildup. This setup was tested three times at three different FiO2 rates and eleven different desired low sweep flows to test for reproducibility and safety to build an easy-to-follow chart for making gas flow changes. For patients requiring oxygenator sweep rates greater than 2 L/min, the pressure relief valve/low flow meter apparatus is not needed. Maintaining consistent sweep rate and nitric oxide delivery is required in order to utilize this therapy in ECLS. We demonstrated gas delivery across all flow rates. There were no issues delivering 20 parts per million of NO and negligible NO2 detection. The results from testing this setup were used to provide the specialist a chart at which to set the low flow meter to produce the desired flow rate at which the patient needs. This has been used clinically on 15 ECLS patients with success.

BIO4: A Dual-Action Nitric Oxide-Releasing Slippery Surface Coating for Extracorporeal Organ Support: First Evaluation at Clinically Relevant Blood Flow Rate for Partial Lung Support

Background: Numerous biomaterials are developed to mitigate untoward effects of blood exposure to foreign surfaces on blood-contacting medical devices, such as extracorporeal life support (ECLS); however, limited testing is performed using clinical blood flow conditions and device components. A liquid infused nitric oxide-releasing (LiNORel) material was developed to prevent surface protein adsorption while eluting nitric oxide (NO) to minimize platelet activation and aggregation. The study objective was to assess LiNORel applied to full-scale ECLS circuit tubing during 6 h ex vivo circulation of porcine blood at a clinically relevant flow rate. We hypothesized that LiNORel reduces thrombus deposition and platelet sequestration versus unmodified tubing. Methods: Heparinized blood (0.75 U/mL) was collected from mechanically ventilated swine (n=9, 45-55kg) with ARDS following polytrauma in an unrelated multi-day ICU study. Blood was divided into circuits with the following (500 mL/circuit): CTRL – unmodified tubing; LI – tubing with liquid infused surface modification; NO – tubing with NOrelease modification; LiNORel – tubing with liquid infused and NO-release modifications. Circuits included a blood reservoir, centrifugal pump, and 2 tubing segments (1 m, 3/8” ID). Circulation was performed for 6 h at 1.5 L/min flow rate. Heparin was sparingly administered to maintain activated clotting times (ACT) of 125-160s. Data included: heparin administered, blood gas, methemoglobin (MetHb) as an indicator of NO toxicity, pump revolutions per minute. At baseline, 3- and 6 h, a blood panel was performed to assess platelet count/activation, thromboelastography, PT, aPTT, fibrinogen, D-dimer, von Willebrand factor (vWF) activity and plasma free hemoglobin. Post-circulation thrombus deposition was analyzed. Data were analyzed for within-group time-dependent changes and between group differences. All tests were two-sided (p<0.05 for significance). Results: Circuits remained patent in all groups with ACT in range. Numerically (n.s.), CTRL received more heparin (100±49 U) to maintain ACT (NO=50±32 U, LI=33±27, LiNORel=47±33 U). There was no group difference in blood gases and MetHb. Numerically, reduction in platelet count at 6 h was greatest in CTRL and least in LiNORel (n.s., Fig 1A). Activated platelets were elevated at 6 h in CTRL vs NO (p=0.013) and LiNORel (p=0.020) (Fig 1B). Numerically, procoagulant platelets were elevated in CTRL (Fig 1C). No group differences in thromboelastography, PT, aPTT and fibrinogen were observed. D-dimer was elevated at 6 h in CTRL (p=0.007) and LI (p=0.027) groups. vWF was elevated at 6 h in CTRL (p=0.001). Clot deposition was minimal and not different between groups. Conclusions: LiNORel reduced platelet activation in this model which utilized a clinically relevant blood flow rate and full-scale circulation tubing for partial lung support. Additional testing in vivo for multi-day duration is ongoing in our laboratory. Figure 1. Platelet count (A), concentration of activated platelets indicated by expression of P-selectin (B) and concentration of procoagulant platelets indicated by phosphatidyl serine expression (C) during 6-hours ex vivo circulation. Circuit tubing consisted of Control (CTRL) – uncoated standard tubing; Nitric Oxide (NO) – tubing with embedded nitric oxide donor; Liquid Infused (LI) – tubing swelled with non-adhesive lubricant layer; Liquid-infused Nitric Oxide Release (LiNORel) – tubing with embedded nitric oxide donor and non-adhesive lubricant layer combination coating. †Indicates significant difference between LiNORel and CTRL. ‡Indicates significant difference between NO and CTRL. *Indicates significant difference within NO group from baseline (BL). **Indicates significant difference within CTRL group from BL. ***Indicates significant difference within LiNORel group from BL. ****Indicates significant difference within LI group from BL. All tests two-sided with p<0.05 for significance.

Nitric Oxide on Extracorporeal Life Support-Circuit Modifications for a Safe Therapy

Nitric oxide (NO) incorporation into the sweep gas of the extracorporeal life support (ECLS) circuit has been proposed as a strategy to ameliorate the insults caused by the systemic inflammatory response. This technical study describes circuit modifications allowing nitric oxide to be incorporated into the circuit and describing and validating the oxygenator sweep flow rates necessary to achieve consistent safe delivery of the therapy. For patients requiring sweep rates less than 2 L/min, a simplified setup, incorporating a pressure relief valve/low flow meter in the gas delivery line, was placed in line between the blender/NO injector module and the NO sampling port/oxygenator. This setup allows titration of sweep to low flows without the need to blend in CO2while maintaining the manufacturer recommendation of a minimum 2 L/min of sweep gas to safely deliver NO without nitric dioxide (NO2) buildup. This setup was tested three times at three different FiO2rates and eleven different desired low sweep flows to test for reproducibility and safety to build an easy-to-follow chart for making gas flow changes. For patients requiring oxygenator sweep rates greater than 2 L/min, the pressure relief valve/low flow meter apparatus is not needed. Maintaining consistent sweep rate and nitric oxide delivery is required in order to utilize this therapy in ECLS. We demonstrated gas delivery across all flow rates. There were no issues delivering 20 parts per million of NO and negligible NO2detection. The results from testing this setup were used to provide the specialist a chart at which to set the low flow meter to produce the desired flow rate at which the patient needs. This has been used clinically on 15 ECLS patients with success.

In vitro hemocompatibility screening of a slippery liquid impregnated surface coating for extracorporeal organ support applications.

Clot formation, infection, and biofouling are unfortunate but frequent complications associated with the use of blood-contacting medical devices. The challenge of blood-foreign surface interactions is exacerbated during medical device applications involving substantial blood contact area and extended duration of use, such as extracorporeal life support (ECLS). We investigated a novel surface modification, a liquid-impregnated surface (LIS), designed to minimize protein adsorption and thrombus development on medical plastics. The hemocompatibility and efficacy of LIS was investigated first in a low-shear model with LIS applied to the lumen of blood incubation vials and exposed to human whole blood. Additionally, LIS was evaluated in a 6 h ex vivo circulation model with swine blood using full-scale ECLS circuit tubing and centrifugal pumps with clinically relevant flow rate (1.5 L/min) and shear conditions for extracorporeal carbon dioxide removal. Under low-shear, LIS preserved fibrinogen concentration in blood relative to control polymers (+40 ± 6 mg/dL vs polyvinyl chloride, p < .0001), suggesting protein adsorption was minimized. A fibrinogen adhesion assay demonstrated a dramatic reduction in protein adsorption under low shear (87% decrease vs polyvinyl chloride, p = .01). Thrombus deposition and platelet adhesion visualized by scanning electron microscopy were drastically reduced. During the 6 h ex vivo circulation, platelets in blood exposed to LIS tubing did not become significantly activated or procoagulant, as occurred with control tubing; and again, thrombus deposition was visually reduced. A LIS coating demonstrated potential to reduce thrombus formation on medical devices. Further testing is needed specialized to clinical setting and duration of use for specific medical target applications.

Remdesivir and GS-441524 Extraction by Ex Vivo Extracorporeal Life Support Circuits.

Patients with severe, COVID-related multi-organ failure often require extracorporeal life support (ECLS) such as extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT). An ECLS can alter drug exposure via multiple mechanisms. Remdesivir (RDV) and its active metabolite GS-441524 are likely to interact with ECLS circuits, resulting in lower than expected exposures. We evaluated circuit-drug interactions in closed loop, ex vivo ECMO and CRRT circuits. We found that mean (standard deviation) recovery of RDV at 6 hours after dosing was low in both the ECMO (33.3% [2.0]) and CRRT (3.5% [0.4]) circuits. This drug loss appears to be due primarily to drug adsorption by the circuit materials and potentially due to metabolism in the blood. GS-441524 recovery at 6 hours was high in the ECMO circuit 75.8% (16.5); however, was not detectable at 6 hours in the CRRT circuit. Loss in the CRRT circuit appears to be due primarily to efficient hemodiafiltration. The extent of loss for both molecules, especially in CRRT, suggests that in patients supported with ECMO and CRRT, RDV dosing adjustments are needed.

Hybrid and parallel extracorporeal membrane oxygenation circuits

Hybrid and parallel extracorporeal membrane oxygenation circuits