Yulong Guan

Microfiltration platform for continuous blood plasma protein extraction from whole blood during cardiac surgery.

This report describes the design, fabrication, and testing of a cross-flow filtration microdevice, for the continuous extraction of blood plasma from a circulating whole blood sample in a clinically relevant environment to assist in continuous monitoring of a patients inflammatory response during cardiac surgeries involving cardiopulmonary bypass (CPB) procedures (about 400,000 adult and 20,000 pediatric patients in the United States per year). The microfiltration system consists of a two-compartment mass exchanger with two aligned sets of PDMS microchannels, separated by a porous polycarbonate (PCTE) membrane. Using this microdevice, blood plasma has been continuously separated from blood cells in a real-time manner with no evidence of bio-fouling or cell lysis. The technology is designed to continuously extract plasma containing diagnostic plasma proteins such as complements and cytokines using a significantly smaller blood volume as compared to traditional blood collection techniques. The microfiltration device has been tested using a simulated CPB circulation loop primed with donor human blood, in a manner identical to a clinical surgical setup, to collect plasma fractions in order to study the effects of CPB system components and circulation on immune activation during extracorporeal circulatory support. The microdevice, with 200 nm membrane pore size, was connected to a simulated CPB circuit, and was able to continuously extract ~15% pure plasma volume (100% cell-free) with high sampling frequencies which could be analyzed directly following collection with no need to further centrifuge or modify the fraction. Less than 2.5 ml total plasma volume was collected over a 4 h sampling period (less than one Vacutainer blood collection tube volume). The results tracked cytokine concentrations collected from both the reservoir and filtrate samples which were comparable to those from direct blood draws, indicating very high protein recovery of the microdevice. Additionally, the cytokine concentration increased significantly compared to baseline values over the circulation time for all cytokines analyzed. The high plasma protein recovery (over 80%), no indication of hemolysis and low level of biofouling on the membrane surface during the experimental period (over 4 h) were all indications of effective and reliable device performance for future clinical applications. The simple and robust design and operation of these devices allow operation over a wide range of experimental flow conditions and blood hematocrit levels to allow surgeons and clinicians autonomous usage in a clinical environment to better understand the mechanisms of injury resulting from cardiac surgery, and allow early interventions in patients with excessive postoperative complications to improve surgical outcomes. Ultimately, monolithic integration of this microfiltration device with a continuous microimmunoassay would create an integrated microanalysis system for tracking inflammation biomarkers concentrations in patients for point-of-care diagnostics, reducing blood analysis times, costs and volume of blood samples required for repeated assays.

Mechanical performance comparison between RotaFlow and CentriMag centrifugal blood pumps in an adult ECLS model

Introduction: Centrifugal blood pumps have been widely adopted in conventional adult cardiopulmonary bypass and circulatory assist procedures. Different brands of centrifugal blood pumps incorporate distinct designs which affect pump performance. In this adult extracorporeal life support (ECLS) model, the performances of two brands of centrifugal blood pump (RotaFlow blood pump and CentriMag blood pump) were compared. Methods: The simulated adult ECLS circuit used in this study included a centrifugal blood pump, Quadrox D membrane oxygenator and Sorin adult ECLS tubing package. A Sorin Cardiovascular® VVR® 4000i venous reservoir (Sorin S.p.A., Milan, Italy) with a Hoffman clamp served as a pseudo-patient. The circuit was primed with 900ml heparinized human packed red blood cells and 300ml lactated Ringer’s solution (total volume 1200 ml, corrected hematocrit 40%). Trials were conducted at normothermia (36°C). Performance, including circuit pressure and flow rate, was measured for every setting analyzed. Results: The shut-off pressure of the RotaFlow was higher than the CentriMag at all measurement points given the same rotation speed (p < 0.0001). The shut-off pressure differential between the two centrifugal blood pumps was significant and increased given higher rotation speeds (p < 0.0001). The RotaFlow blood pump has higher maximal flow rate (9.08 ± 0.01L/min) compared with the CentriMag blood pump (8.37 ± 0.02L/min) (p < 0.0001). The blood flow rate differential between the two pumps when measured at the same revolutions per minute (RPM) ranged from 1.64L/min to 1.73L/min. Conclusions: The results obtained in this experiment demonstrate that the RotaFlow has a higher shut-off pressure (less retrograde flow) and maximal blood flow rate than the CentriMag blood pump. Findings support the conclusion that the RotaFlow disposable pump head has a better mechanical performance than the CentriMag. In addition, the RotaFlow disposable pump is 20-30 times less expensive than the CentriMag.

Improved Cerebral Oxygen Saturation and Blood Flow Pulsatility With Pulsatile Perfusion During Pediatric Cardiopulmonary Bypass

Brain monitoring techniques near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) ultrasound were used in pediatric patients undergoing cardiopulmonary bypass for congenital heart defect (CHD) repair to analyze the effect of pulsatile or nonpulsatile flow on brain protection. Regional cerebral oxygen saturation (rSO2) and cerebrovascular pulsatility index (PI) were measured by NIRS and TCD, respectively, in 111 pediatric patients undergoing bypass for CHD repair randomized to pulsatile (n = 77) or nonpulsatile (n = 34) perfusion. No significant differences in demographic and intraoperative data, including surgical risk stratification, existed between groups. Patients undergoing pulsatile perfusion had numerically lower decreases in rSO2 from baseline for all time points analyzed compared with the nonpulsatile group, with significant ∼12% lower decreases at 40 and 60 min after crossclamp. Patients undergoing pulsatile perfusion had numerically lower decreases in PI from baseline for the majority of time points compared with the nonpulsatile group, with significant ∼30% lower decreases between 5 and 40 min after crossclamp. Pulsatile flow has advantages over nonpulsatile flow as measured by NIRS and TCD, especially at advanced time points, which may improve postoperative neurodevelopmental outcomes.

Physiologic Benefits of Pulsatile Perfusion During Mechanical Circulatory Support for the Treatment of Acute and Chronic Heart Failure in Adults

A growing population experiencing heart failure (100,000 patients/year), combined with a shortage of donor organs (less than 2200 hearts/year), has led to increased and expanded use of mechanical circulatory support (MCS) devices. MCS devices have successfully improved clinical outcomes, which are comparable with heart transplantation and result in better 1-year survival than optimal medical management therapies. The quality of perfusion provided during MCS therapy may play an important role in patient outcomes. Despite demonstrated physiologic benefits of pulsatile perfusion, continued use or development of pulsatile MCS devices has been widely abandoned in favor of continuous flow pumps owing to the large size and adverse risks events in the former class, which pose issues of thrombogenic surfaces, percutaneous lead infection, and durability. Next-generation MCS device development should ideally implement designs that offer the benefits of rotary pump technology while providing the physiologic benefits of pulsatile end-organ perfusion.

Evaluation of membrane oxygenators and reservoirs in terms of capturing gaseous microemboli and pressure drops.

An increasing amount of evidence points to cerebral embolization during cardiopulmonary bypass (CPB) as the principal etiologic factor of neurologic complications. In this study, the capability of capturing and classification of gaseous emboli and pressure drop of three different membrane oxygenators (Sorin Apex, Terumo Capiox SX25, Maquet QUADROX) were measured in a simulated adult model of CPB using a novel ultrasound detection and classification quantifier system. The circuit was primed with 1000 mL heparinized human packed red blood cells and 1000 mL lactated Ringers solution (total volume 2000 mL, corrected hematocrit 26-28%). After the injection of 5 mL air into the venous line, an Emboli Detection and Classification Quantifier was used to simultaneously record microemboli counts at post-pump, post-oxygenator, and post-arterial filter sites. Trials were conducted at normothermic (35 degrees C) and hypothermic (25 degrees C) conditions. Pre-oxygenator and post-oxygenator pressure were recorded in real time and pressure drop was calculated. Maquet QUADROX membrane oxygenator has the lowest pressure drops compared to the other two oxygenators (P < 0.001). The comparison among the three oxygenators indicated better capability of capturing gaseous emboli with the Maquet QUADROX and Terumo Capiox SX25 membrane oxygenator and more emboli may pass through the Sorin Apex membrane oxygenator. Microemboli counts uniformly increased with hypothermic perfusion (25 degrees C). Different types of oxygenators and reservoirs have different capability of capturing gaseous emboli and transmembrane pressure drop. Based on this investigation, Maquet QUADROX membrane oxygenator has the lowest pressure drop and better capability for capturing gaseous microemboli.

An investigational study of minimum rotational pump speed to avoid retrograde flow in three centrifugal blood pumps in a pediatric extracorporeal life support model.

During extracorporeal life support with centrifugal blood pumps, retrograde pump flow may occur when the pump revolutions decrease below a critical value determined by the circuit resistance and the characteristics of the pump. We created a laboratory model to evaluate the occurrence of retrograde flow in each of three centrifugal blood pumps: the Rotaflow, the CentriMag, and the Bio-Medicus BP-50. At simulated patient pressures of 60, 80, and 100 mmHg, each pump was evaluated at speeds from 1000 to 2200 rpm and flow rates were measured. Retrograde flow occurred at low revolution speeds in all three centrifugal pumps. The Bio-Medicus pump was the least likely to demonstrate retrograde flow at low speeds, followed by the Rotaflow pump. The CentriMag pump showed the earliest transition to retrograde flow, as well as the highest degree of retrograde flow. At every pump speed evaluated, the Bio-Medicus pump delivered the highest antegrade flow and the CentriMag pump delivered the least.

Transcranial Doppler ultrasonography: a reliable method of monitoring pulsatile flow during cardiopulmonary bypass in infants and young children.

Clinical symptoms are sudden chest pain, dyspnea, and, less commonly, dysphagia and hoarseness. Physically, subcutaneous air and a typical crunching sound are present. When chest pain and dyspnea are present, anxiety and panic attack are frequent. Panic disorders are often observed in anorexic patients: when chest pain and/or dyspnea or dysphagia appear, spontaneous PM should be considered. At present, 20 cases of spontaneous PM have been described in the literature. PM in anorexic patients is sometimes produced by selfinduced vomiting. Our patient had no history of vomiting, and the thorough diagnostic procedures (thoracic computed tomographic scan, esophageal radiologic evaluation, and laryngopharyngoscopy) showed no signs of esophageal or upper airway laceration. The pathophysiologic mechanism of PM in our patient can be explained by an alveolar wall rupture, with consequent air leak into the mediastinum. The air was interestingly confined to the mediastinum only: no signs of pneumothorax were evident. PM is sometimes observed in AN: self-induced vomiting causing an esophageal laceration is frequently the cause of PM in these patients. Anorexic patients with severe malnutrition are at high risk for PM or pneumothorax.

Continuous monitoring of inflammation biomarkers during simulated cardiopulmonary bypass using a microfluidic immunoassay device - a pilot study.

This work demonstrates the use of a continuous online monitoring system for tracking systemic inflammation biomarkers during cardiopulmonary bypass (CPB) procedures. The ability to monitor inflammation biomarkers during CPB will allow surgical teams to actively treat inflammation and reduce harmful effects on postoperative morbidity and mortality, enabling improved patient outcomes. A microfluidic device has been designed which allows automation of the individual processing steps of a microbead immunoassay to allow continuous tracking of antigen concentrations. Preliminary experiments have demonstrated that the results produced by the microimmunoassay are comparable to results produced from a standard enzyme-linked immunosorbent assay (r = 0.98). Additionally, integration of the assay with a simulated CPB circuit has been demonstrated with temporal tracking of C3a concentrations within blood continuously sampled from the circuit. The presented work describes the motivation, design challenges, and preliminary experimental results of this project.

Evaluation of HL-20 roller pump and Rotaflow centrifugal pump on perfusion quality and gaseous microemboli delivery.

The purpose of this study was to compare the HL-20 roller pump (Jostra USA, Austin, TX, USA) and Rotaflow centrifugal pump (Jostra USA) on hemodynamic energy production and gaseous microemboli (GME) delivery in a simulated neonatal cardiopulmonary bypass (CPB) circuit under nonpulsatile perfusion. This study employed a simulated model of the pediatric CPB including a Jostra HL-20 heart-lung machine (or a Rotaflow centrifugal pump), a Capiox BabyRX05 oxygenator (Terumo Corporation, Tokyo, Japan), a Capiox pediatric arterial filter (Terumo Corporation), and ¼-inch tubing. The total volume of the experimental system was 700mL (500mL for the circuit and 200mL for the pseudo neonatal patient). The hematocrit was maintained at 30% using human blood. At the beginning of each trial, a 5mL bolus of air was injected into the venous line. Both GME data and pressure values were recorded at postpump and postoxygenator sites. All the experiments were conducted under nonpulsatile perfusion at three flow rates (500, 750, and 1000mL/min) and three blood temperatures (35, 30, and 25°C). As n=6 for each setup, a total of 108 trials were done. The total number of GME increased as temperature decreased from 35°C to 25°C in the trials using the HL-20 roller pump while the opposite effect occurred when using the Rotaflow centrifugal pump. At a given temperature, total GME counts increased with increasing flow rates for both pumps. Results indicated the Rotaflow centrifugal pump delivered significantly fewer microemboli compared to the HL-20 roller pump, especially under high flow rates. Less than 10% of total microemboli were larger than 40µm in size and the majority of GME were in the 0-20µm class in all trials. Postpump total hemodynamic energy (THE) increased with increasing flow rates and decreasing temperatures in both circuits using these two pumps. The HL-20 roller pump delivered more THE than the Rotaflow centrifugal pump at all tested flow rates and temperature conditions. Results suggest the HL-20 roller pump delivers more GME than the Rotaflow centrifugal pump but produces more hemodynamic energy under nonpulsatile perfusion mode.

Microemboli detection and classification during pediatric cardiopulmonary bypass.

Microemboli may be a cause of postoperative neurological morbidity. Improved detection of microemboli may lead to better strategies to minimize embolization and improve neurological outcomes. Transcranial Doppler may have limited sensitivity for very small microemboli. The Emboli Detection and Classification (EDAC) Quantifier offers increased sensitivity (10 μm) and potentially improved capability for microemboli monitoring. EDAC was used to measure microemboli in the cardiopulmonary bypass circuit during 33 pediatric heart operations. More microemboli were detected in the venous than the arterial line (median, 11,830 vs 1298). Venous microemboli tended to be larger in size than arterial microemboli (>40 μm; 59% vs 7%). Increased venous and arterial microemboli were seen at the onset of bypass; increased venous microemboli were also seen with clamp removal. Thousands of microemboli <40 μm are transmitted to pediatric patients during heart surgery. Initiation of bypass may be a key offender and may result from air in the venous line. Although the significance of microemboli remains unknown, increased awareness may lead to improved techniques to minimize microemboli, with improvement in neurological outcomes.