Laser-assisted anastomosis of large-diameter vessels with the carbon dioxide laser.

A low-powered carbon dioxide laser was used to accomplish large-vessel anastomosis in growing minipigs. Results showed excellent patency, near-normal growth rates, and minimal foreign body response.

Development of an implantable ventricular assist system.

BACKGROUND: This study describes the present state of progress in the development of the Jarvik 2000 ventricular assist system. METHODS: Designed for implantation in the human thorax, the system consists of a small (25 cm3, 90 g) intraventricular axial-flow blood pump that transmits power and data via internal electronics and a transcutaneous energy transfer system. The pump is powered by portable internal and external polymer lithium ion batteries. The only moving part, the pump rotor, contains a permanent magnet of a brushless direct-current motor that mounts an axial-flow impeller and partial magnetic thrust support, with blood-immersed radial and thrust bearings. The motor uses a redundant coil and electric lead design, which permits continued operation in case of wire breakage. RESULTS: Seven calves have been supported for an average of 107 days (range, 40 to 162 days) with prototypes of the Jarvik 2000 ventricular assist system. No physiologic complications have occurred. When its user is at rest, the pump produces flows of 5 to 6 L/min with a decreased arterial pulse contour. Renal and hepatic functions have remained normal throughout the duration of all studies. Mean plasma free hemoglobin levels ranged from 4.3 to 11.4 mg/dL (mean, 6.3 mg/dL) for each study. Pathologic analyses of the heart and kidneys revealed no damage related to the device. CONCLUSIONS: These studies indicate that the Jarvik 2000 ventricular assist system is feasible in animals and holds promise for long-term support of patients.

First human use of the Hemopump, a catheter-mounted ventricular assist device.

The Hemopump, a catheter-mounted, temporary ventricular assist device, consists of an external electromechanical drive console and a disposable, intraarterial axial-flow pump (21F). Power is transmitted percutaneously to the pump by a flexible drive shaft within the catheter. The device is positioned in the left ventricle by way of the femoral artery approach or through the ascending aorta. Blood is drawn from the left ventricle through the transvalvular inlet cannula and pumped into the aorta. As of December 1988, the Hemopump had successfully supported the circulation of 7 patients (5 men, 2 women) ranging in age from 44 to 72 years (mean age, 59 years) and suffering from cardiogenic shock (cardiac index less than 2.0 L/min/m2). Indications for use included failure to be weaned from cardiopulmonary bypass in 4 patients, acute myocardial infarction in 1, severe cardiac allograft rejection in 1, and donor heart failure in 1. Duration of support ranged from 26 to 113 hours (mean, 66 hours). Although 5 patients demonstrated transient hemolysis, none experienced infection, thrombosis, or vascular injury. Hemodynamic variables improved in all patients during support by the device. As of December 1988, 5 of the 7 patients were alive more than 30 days after support had been discontinued, and 3 of these patients were discharged from the hospital. On the basis of our initial clinical results, the Hemopump, which does not require a major surgical procedure for insertion, provides effective, temporary circulatory support in patients with potentially reversible cardiac failure.

Improved survival after extended bridge to cardiac transplantation.

In the past, left ventricular assist device (LVAD) support was frequently plagued by complications; thus, bridge to transplantation times were kept short. Increasing evidence suggests that extended bridging provides greater benefit due to improved end-organ perfusion and, thus, generally improved physical condition. To assess whether extended bridging translates into improved long-term survival after transplantation, we reviewed our experience with the HeartMate 1000 IP LVAD (Thermo Cardiosystems, Inc, Woburn, MA). Since January 1988, 19 patients (mean age, 45 +/- 9 years) have undergone extended bridging (mean time, 106 +/- 57 days). Their mean weight was 82 +/- 16 kg, and their mean body surface area was 2.0 +/- 0.2 m2. We define "extended" as the length of support necessary for systemic organ recovery after prolonged heart failure. During support, average pump flow indices ranged from 2.3 to 3.3 L.min-1.m-2, and all patients underwent physical rehabilitation. Between the time of LVAD implantation and explantation, the mean serum creatinine value decreased from 1.63 +/- 0.6 to 1.25 +/- 0.6 mg/dL (p = not significant), and the mean serum total bilirubin value decreased from 2.8 +/- 2.0 to 0.63 +/- 0.11 mg/dL (p < 0.05). All but 1 patient improved from New York Heart Association class IV to class I. Device-related complications were minimal. Twelve control patients ("de facto randomized") who did not receive the LVAD also were evaluated: actuarial survival at 1 year was 0% (p < 0.05); 3 (25%) underwent transplantation and died within 2 months; 9 (75%) died before transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanical circulatory support in children.

Nine children (aged 1.2-15 years) have been treated with mechanical circulatory support devices at our institution. Indications for treatment were acute cardiac allograft rejection (n = 4), postcardiotomy cardiogenic shock (n = 4), and bridge to cardiac transplantation (n = 1). Eight patients required left ventricular support, and one required biventricular support. A BioMedicus centrifugal pump was used in eight patients, and a Hemopump intra-aortic axial flow device was used in one patient. In two patients, an intra-aortic balloon pump was in place at the time that circulatory support was instituted. Mechanical support time ranged from 2 to 139 h, and the average flow index was 2.31 l/min per m2. Three patients required hemodialysis during support, and one patient required re-exploration because of mediastinal hemorrhage. Recovery of native ventricular function was assessed by transthoracic or transesophageal echocardiography, and weaning from the device was achieved by gradually decreasing pump flow in increments of 0.1 to 0.5 l/min. Seven patients were successfully weaned from support. Two hospital deaths occurred after circulatory support had been discontinued: one patient died of respiratory failure and the other of gram-negative pneumonia and sepsis. The five surviving patients experienced no significant complications, and their hemodynamic indices were normal at the time of discharge. At a mean follow-up of 28.8 months, these patients are leading active unrestricted lives, with no long-term device-related sequelae. Based on this experience, mechanical circulatory support is feasible in children who experience profound circulatory failure from a variety of causes.

Chronic in vivo evaluation of an electrohydraulic total artificial heart.

Development of the Abiomed total artificial heart (TAH) designed for human use is progressing. Implant durations of longer than 60 days have been achieved in calves. The device consists of blood pumps, valves, and a hydraulic atrial flow balancing chamber fabricated from polyetherurethane. The energy converter, a centrifugal hydraulic pump with a rotary fluid switching valve, is positioned between the blood pumps. In two consecutive chronic in vivo studies (47 days and longer than 60 days), cardiac output was maintained in excess of 8 l/min. The atrial flow balancing chamber maintained a mean right-to-left pressure gradient of 7.5 and -1.4 mmHg in each respective study. There were no pulmonary complications. Platelet counts, fibrinogen concentrations, and hematocrit values returned to baseline levels within 20 days, whereas bilirubin, serum glutamic-oxaloacetic transaminase, blood urea nitrogen, and creatinine levels returned to normal within 1 week of implant. After the first post-operative day, plasma free hemoglobin levels of less than 10 mg/dl indicated no device-related hemolysis throughout the duration of the studies. At explant (47 day study), pathologic analysis showed no renal infarcts, no tissue necrosis, and no thermal damage. The device was fully encapsulated by 2-4 mm thick fibrous connective tissue. A newly designed textured-to-smooth surface inflow showed no signs of pannus ingrowth or thrombotic complications. These studies demonstrate that this TAH is suitable for long-term implantation.

In vivo evaluation of an intraventricular electric axial flow pump for left ventricular assistance.

In vivo studies have begun to evaluate a new intraventricular electric axial flow left ventricular assist device (LVAD), the Jarvik 2000, which is a small, valveless pump that is placed inside the left ventricle through the left ventricular apex. The operation, which is performed through a left thoracotomy, may be done without cardiopulmonary bypass and aortic cross-clamping. Outflow is provided through a 16 mm softly woven, Dacron graft anastomosed to the descending thoracic or abdominal aorta. Pump flow, which varies from 2 to 16 l/min in vitro, is changed by adjusting the speed of pump rotation. Preliminary studies were done to evaluate the ease of implantation, hematologic and anatomic compatibility, and pump performance. The device has been implanted in seven healthy, preconditioned calves (83-138 kg), one of which is currently undergoing support. The implantation procedure averaged 3 hours. There were no operative deaths, and blood transfusions were not required. Postoperatively, anticoagulation was achieved with heparin followed by warfarin sodium to maintain prothrombin time or partial thromboplastin time at 1.5-2.0 times baseline. In the six completed studies, support time ranged from 2 to 120 days (mean, 36 days). The seventh calf has been supported for 30 days. In the four long-term studies (20, 70, 120, > 30 days), the mean plasma free hemoglobin values during support were 11.0, 7.7, 6.6, and 3.4 mg/dl, respectively. Under normal conditions, the average daily flow rate ranged from 5 to 6 l/min. During treadmill exercise (10% grade, 1.5 km/h) lasting 20 minutes, peak flow rates exceeded 8 l/min. These pilot studies suggest that this intraventricular axial flow pump is relatively easy to implant, operate, and control. In addition, it is hemocompatible, provides physiologic flow rates, and may be able to provide long-term circulatory support.

Progress in the development of the ABIOMED total artificial heart.

The ABIOMED implantable total artificial hearts in the final phase of engineering development. The system has a compact electrohydraulically driven energy converter sandwiched between two blood pumps, an internal electronics pack, an internal battery, a transcutaneous energy transmission coil for power transmission, and external wearable electronics pack and battery. The current effort is to complete development of the system during 1996 in preparation for formal pre clinical testing of the device. In vivo studies with the current thoracic unit (ABH II) have achieved 108 days of survival verifying the thermal, physiologic, and hematologic compatibility of the system. The abdominal implantable electronics pack showed no thermal dissipation problem. System improvements include scaling down the size of the thoracic unit, and efficiency enhancement in the power and hybrid electronics. The new system (ABH III) retains the flow capacity of greater than 10 L/min. Size reduction results in an atrial to sternal dimension that would fit 98% and 75% of men and women, respectively.

A genetically engineered, nonthrombogenic cellular lining for LVADs: in vitro preconditioning before in vivo implantation.

Because of the clinical success of left ventricular assist devices (LVADs) used for short-term "bridge to transplant" and the limited availability of donor organs, heart assist devices are being considered for long-term implantation as an alternative to heart transplantation. In an effort to improve biocompatibility, our laboratory has developed a nonthrombogenic cellular lining from genetically engineered smooth muscle cells (GE-SMC) for the Thermocardiosystems Heartmate LVAD. Smooth muscle cells have been transduced with the gene for endothelial nitric oxide synthase (NOS III) and produce NO at concentrations that reduce platelet deposition and smooth muscle cell proliferation when tested in vitro. In this investigation, the adhesive capabilities of GE-SMC linings were examined. An in vitro circulatory loop was designed to expose cell lined LVADs to in vivo operating conditions. Cumulative cell loss from cell lined LVADs was less than 10% after 24 hours of flow. Using a protocol for "preconditioning" the cell lining within the mock circulatory loop, the first implantation of an LVAD containing a genetically engineered SMC lining was successfully implemented in a bovine model. Results from this 24 hour study indicate that the flow-conditioned cellular lining remained intact with no evidence of thromboembolization and only minimal changes in coagulation studies.

In vivo evaluation of a trileaflet mechanical heart valve.

Design goals for a mechanical heart valve include duplicating the hemodynamic performance of the natural valve, eliminating the need for anticoagulants, and maintaining safety. The Lapeyre-Dassault (Dassault-Aviation, Paris, France) prosthetic valve, undergoing development, addresses these goals. The unique trileaflet design consists of a solid titanium ring and three leaflets. Prototypes of the valve fabricated with Delrin leaflets were implanted in the mitral position in six calves (70-90 kg). Four calves (Studies 1, 2, 3, 5) had long-term survival of 165, 158, 219, and 281 days, respectively. Two calves were killed, one on Day 37 and one on Day 39, after complications unrelated to the valve developed. In all calves heparin was given intravenously to maintain partial thromboplastin time at 1.5 to 2.0 x baseline for approximately 1 week. In Studies 1 and 2 full anticoagulation and antiplatelet therapy was given (orally administered sodium warfarin to maintain prothrombin time at 1.5 to 2.0 x baseline, along with aspirin (1 g/day) and dipyridamole 400 mg/day). In Study 3, all anticoagulation and antiplatelet therapy was discontinued at 1 month after implant. In Study 5, no anticoagulation therapy was given after the initial week of intravenous heparin; however, antiplatelet therapy was started on the fifth postoperative month and maintained until the study's end at 9 months. At 1, 2, 3, and 5 months, the mean plasma free hemoglobin level in the four long-term animals was 5.0 +/- 2.16, 6.0 +/- 3.83, 8.5 +/- 4.93, and 11.3 +/- 6.74 mg/dl, respectively. Hemolysis was not a problem. Valve performance during normal activity was excellent in all the calves, as evidenced by echocardiography and the overall appearance of good health. In the four completed long-term studies, left heart catheterization showed a mean valve pressure gradient of 11.57 +/- 1.26 mmHg and no apparent valvular regurgitation. Histopathologic examination of major organs showed no evidence of thromboembolic events. This study shows that the innovative design of this trileaflet valve performed well in initial in vivo testing, justifying further development.

Progress in the development of a transcutaneously powered axial flow blood pump ventricular assist system.

Development of the Jarvik 2000 intraventricular assist system for long-term support is ongoing. The system integrates the Jarvik 2000 axial flow blood pump with a microprocessor based automatic motor controller to provide response to physiologic demands. Nine devices have been evaluated in vivo (six completed, three ongoing) with durations in excess of 26 weeks. Instrumented experiments include implanted transit-time ultrasonic flow probes and dual micromanometer LV/AoP catheters. Treadmill exercise and heart pacing studies are performed to evaluate control system response to increased heart rates. Pharmacologically induced cardiac dysfunction studies are performed in awake and anesthetized calves to demonstrate control response to simulated heart failure conditions. No deleterious effects or events were encountered during any physiologic studies. No hematologic, renal, hepatic, or pulmonary complications have been encountered in any study. Plasma free hemoglobin levels of 7.0 +/- 5.1 mg/dl demonstrate no device related hemolysis throughout the duration of all studies. Pathologic analysis at explant showed no evidence of thromboembolic events. All pump surfaces were free of thrombus except for a minimal ring of fibrin, (approximately 1 mm) on the inflow bearing. Future developments for permanent implantation will include implanted physiologic control systems, implanted batteries, and transcutaneous energy and data transmission systems.

Five month survival in a calf supported with an intraventricular axial flow blood pump.

We are studying in vivo an intraventricular axial flow blood pump (Jarvik 2000) designed for long-term left ventricular support. The small (25 cc, 85 g) valveless pump has been placed intraventricularly in seven calves; pumps have functioned for as long as 5 months. In the four most recent long-term studies completed, calves have survived for 70, 120, 155, and 162 days (in that order); weight gain has averaged 0.56 kg/day. One study is ongoing at more than 30 days. Under resting physiologic conditions in the normal calf, the continuous flow pump produces flows of 5-6 L/min with a decreased arterial pulse contour. The device has caused no physiologic complications. Calves in the completed studies had mean free plasma hemoglobin levels of 11.4, 7.1, 6.5, and 4.3 mg/dl, respectively. We have modified the inflow structures of the device, and these results suggest that a thrombus free design with no pannus at or around the inlet of the pump can be achieved. Histopathologic analyses of the heart and kidneys in studies of as long as 5 months show no deleterious effects of this device. These studies demonstrate the feasibility of a small implanted intraventricular blood pump for long-term use. Future developments for permanent implantation will include implanted physiologic control systems, transcutaneous energy transmission systems, and implanted batteries.

Inaccuracies in manufacturer-reported deflated PTCA balloon profiles.

Deflated balloon profile is an important consideration in the selection of PTCA catheters. In order to test the accuracy of manufacturer-reported balloon profiles, we measured deflated shoulder and mid-balloon profile in 107 unused catheters (2.0, 2.5, and 3.0 mm) from 6 manufacturers using a precision hole gauge with a resolution of .001 inches. A significant difference was defined as a discrepancy greater than or equal to 0.003 inches from the manufacturer's reported profile. During Phase I, measurements were obtained at room temperature on catheters directly out of the package. Of the 36 models tested, 21/36 (56%) had measured shoulder profiles that were larger than their reported profile, and 29/36 (81%) had mid-balloon profiles that were larger than their reported profile. During Phase II, measurements were made at body temperature following a 60 second inflation at 120 psi (8.16 atm). Of 33 models tested, 18/33 (55%) had measured shoulder profiles that were larger than their reported profile; 26/33 (79%) had mid-balloon profiles that were larger than their reported profile. The term "profile" is imprecisely defined. Manufacturer-reported deflated PTCA balloon profiles are not always accurate. Independent and uniform testing of balloon profiles is necessary for valid comparisons between balloons and manufacturers.

Clinical experience with the Hemopump.

Complications associated with surgical procedures generally required for implantation of left ventricular assist devices (LVADs) may limit them from providing adequate circulatory support for patients suffering from profound left ventricular failure (LVF). Such problems are minimized with the use of the Hemopump, a recently developed intraarterial LVAD. This 7 mm transvalvular axial flow blood pump is percutaneously powered by an external console with a flexible drive cable. Since April 1988, we have used the device effectively in 12 patients. Indications for device application included postcardiotomy shock in eight patients, acute allograft rejection in two, severe allograft failure in one, and acute myocardial infarction in one. The Hemopump was inserted from the femoral approach in eight patients, the ascending aorta in three, and the abdominal aorta in one. During the first 12 hr of support, cardiac index (CI) ranged from 1.14-2.98 L/min/m2, and pump flow was 3.0 to 3.6 L/min. As the patients' hearts recovered, the pump speed was gradually reduced. Circulatory support ranged from 26 to 139 hr; 10 of 12 patients were successfully weaned. The mean CI before device removal was 2.74 +/- 0.4 L/min/m2, and the pump flow was 2.14 +/- 0.69 L/min. No device-related infections or thromboembolic episodes occurred. Plasma-free hemoglobin remained within acceptable levels during pumping. Six patients survived more than 30 days after pump removal. Thus, the Hemopump can provide safe, stable, temporary circulatory support and can be expeditiously applied with minimal complications.

Anatomic considerations for abdominally placed permanent left ventricular assist devices.

To determine anatomic parameters for a permanent, electrically actuated left ventricular assist device (LVAD), the effects of abdominal placement of pneumatic LVADs used as temporary support for patients awaiting heart transplantation was studied. Understanding the anatomic constraints imposed by the abdominal viscera in LVAD placement is crucial, because improper placement can result in compression or obstruction of adjacent structures. Anatomic compatibility was assessed in four men (age 22-48 years) who were supported by the LVAD for over 1 month (range 35-132 days). The pump was intraperitoneally placed in the left upper quadrant. Radiographic techniques were employed, including CT scanning (with patients supine) and contrast imaging (patients in anatomical position), and the pump and conduits appeared to be properly positioned, with minimal compression of the body of the stomach, and no obstruction of adjacent organs. Three patients returned to a solid food diet and exercised daily by stationary cycling and walking. No signs of migration or erosion of the pump were present at the time of LVAD removal and cardiac transplantation. Successful clinical experience with short-term use of the LVAD suggests that the electrically actuated device can be well tolerated in patients requiring permanent left ventricular assistance.

Simplified method of hemofiltration in ventricular assist device patients.

Hypervolemia frequently complicates the management of ventricular assist device (VAD) patients as a result of increased intravenous fluid administration and concomitant renal dysfunction. Although acute hemodialysis (AHD) can be used to treat such patients, it requires additional equipment, vascular access cannulations, and personnel. Moreover, hypotension during AHD may occur as a result of rapid shifts in intravascular volume. From January 1987 to March 1988, we treated nine selected VAD patients who had hypervolemia and acute renal failure with a simplified hemofiltration technique. A continuous arteriovenous hemofiltration (CAVH) cartridge was connected from the outflow circuit of a centrifugal blood pump to a large-bore central venous catheter. With CAVH, gradual removal of 272 cc/hour of ultrafiltrate was accomplished for periods up to 241 hours. No episodes of hypotension, thromboembolism, or other deleterious effects occurred. In our series, the CAVH technique was effective in treating hypervolemia in selected VAD patients.

Anastomosis of bypass grafts using a low-powered CO2 laser.

The purpose of this study was to evaluate the feasibility of using a low-powered CO2 laser to perform end-to-side anastomoses of bypass grafts. The internal jugular veins of 13 domestic swine were removed and used as grafts to bypass their ligated carotid arteries. Each end of the vein graft was apposed to the artery with four to six temporary stay sutures, and a waveguide delivery CO2 laser with a power density of 900 mW/mm2 was used to perform the anastomoses, after which the sutures were removed. The animals were sacrificed postoperatively at five time intervals: 2 to 4 hours, 5 days, 1 month, 3 months, and 5 months. Of the 10 anastomoses studied at 2 to 4 hours, 70% were fully patent, none thrombosed, and 30% disrupted. Of the 16 anastomoses studied between 5 days and 5 months postoperatively, 88% were patent, 12% thrombosed, and none disrupted. None of the animals developed aneurysms at any stage of this investigation. Histologic analysis of acute studies revealed thermal damage such as charring of tissue, unraveling of the collagen fibrils, and the formation of microvacuoles. Within 3 months, the anastomotic sites showed localized healing with intimal fibromuscular proliferation and dense fibrous tissue. Good apposition of tissue was found to be of great importance in achieving patency of vessels in this procedure.

Separation of the natural atria in experimental implantation of total artificial heart.

Atrial connections in a single-unit total artificial heart (TAH) may be difficult to make because of the rigidity of the device and the fixed position of the atrial inlets. We developed a technique to separate the natural atrial borders in an experimental implantation of a unitary TAH. In this technique, the interatrial groove was dissected to separate the posterior wall of the right atrium from the roof of the left atrium before cardiopulmonary bypass (CPB) was initiated. After initiation of CPB and cardiectomy, the atrial septum was separated completely, and the right atrial wall was reconstructed with glutaraldehyde-treated autopericardium. We believe that this simple adjunctive technique provides increased mobility of the atrial cuffs and allows for an easier connection of the unitary TAH.

Extended clinical support with an implantable left ventricular assist device.

Clinical evaluations are under way of an intracorporeal (abdominally positioned) pulsatile left ventricular assist device (LVAD) that is capable of providing support for extended periods (greater than 30 days) in patients awaiting heart transplantation. The LVAD, developed by Thermo Cardiosystems Inc. (Woburn, MA), has uniquely textured blood contacting surfaces and requires only minimal antithrombotic therapy. It has been used at the Texas Heart Institute as a bridge to transplantation in 11 patients, including 2 who are currently receiving support. Four patients required extended LVAD support (35-132 days); of those, three are doing well at 1.5, 8.5, and 13 months, respectively, after transplantation, and one died of liver failure 49 days after transplantation. The LVAD was operated in a fixed-rate mode to maintain pump flows at 4-8 L/min, resulting in stabilization of hemodynamic and secondary organ function in all patients. Blood chemistry and hematologic values returned to normal during LVAD support in three of four patients. Postoperative anticoagulation was gradually reduced over the course of the trials. The two most recent patients (35 and 132 days) received only oral dipyridamole (75 mg X 3/day) and aspirin (80 mg/day) after the early recovery period (four-six days), resulting in normal prothrombin and partial thromboplastin times. Plasma hemoglobin levels remained within acceptable limits, and there was no evidence of thromboembolism. Blood contacting surfaces were coated with a thin, adherent, biologically derived lining. The initial results indicate that the intracorporeal LVAD, with textured blood contacting surfaces, can effectively support the failing heart for extended periods (greater than 30 days) with minimal antithrombotic therapy.

The development of a clinically relevant canine model of postperfusion syndrome.

Investigation into the complex etiology of the postperfusion syndrome (PPS) has been limited by access to only retrospective human case studies, and performance of animal studies that examine biochemical predictors of injury rather than the PPS itself. To determine whether a reproducible canine model of the clinical syndrome was possible, seven dogs underwent cardiopulmonary bypass (CPB) with a bubble oxygenator for 0 (n = 1, sham), 2 (n = 1), 4 (n = 1), and 6 (n = 4) hours. Arterial oxygenation, chest radiographs, serum creatinine, and total leukocyte and platelet counts continued to change through the second postoperative day, illustrating the need for prolonged follow-up (48 hours) to accurately detect postperfusion organ dysfunction. The dogs that did not undergo CPB for 6 hours (n = 3) did not develop important pulmonary dysfunction postoperatively, but three of the four dogs undergoing 6 hours of CPB developed profound, persistent, arterial hypoxemia associated with radiographic, histologic, and hemodynamic evidence of severe PPS. Early evidence of renal dysfunction was also apparent within 84 hours of 6 hour CPB. It is concluded that the canine long duration (6 hour) CPB model, with prolonged (48 hour) postoperative monitoring, generates a reproducible, clinically relevant model of human PPS.