In Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae Infection.

LYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae LYS228 was efficacious in neutropenic thigh models established with Klebsiella pneumoniae producing KPC-2 or NDM-1; pretreatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in kidney, urine, and bladder. The successful treatment of murine infection models established with carbapenem-resistant K. pneumoniae further supports the clinical development of LYS228.

Finite element analysis of stresses developed in the blood sac of a left ventricular assist device.

The goal of this research is to develop a 3D finite element (FE) model of a left ventricular assist device (LVAD) to predict stresses in the blood sac. The hyperelastic stress-strain curves for the segmented poly(ether polyurethane urea) (SPEUU) blood sac were determined in both tension and compression using a servo-hydraulic testing system at various strain rates. Over the range of strain rates studied, the sac was not strain rate sensitive, however the material response was different for tension versus compression. The experimental tension and compression properties were used in a FE model that consisted of the pusher plate, blood sac and pump case. A quasi-static analysis was used to allow for nonlinearities due to contact and material deformation. The 3D FE model showed that blood sac stresses are not adversely affected by the location of the inlet and outlet ports of the device and that over the systolic ejection phase of the simulation the prediction of blood sac stresses from the full 3D model and an axisymmetric model are the same. Minimizing stresses in the blood sac will increase the longevity of the blood sac in vivo.

Hemolysis evaluation of centrifugal pumps using microcapsule suspension.

OBJECTIVES: Bovine and human blood has been widely used for in vitro hemolysis testing to evaluate centrifugal cardiac assist pumps. However, results from such tests are complicated by variations in the susceptibility of individual red blood cells to shear. The objective of this study was to evaluate the use of microcapsule suspension as an alternative to bovine or human blood for hemolysis testing. METHODS: Microcapsule suspensions of 100 micro m maximal diameter (average 79.1 micro m) with a polyurethane membrane were used. Each microcapsule contained a leuco dye, which was used to measure "hemolysis" in the suspension after exposure to mechanical stress. Six centrifugal pumps were used to measure and compare the hemolysis values of microcapsule suspensions, bovine blood and human blood. RESULTS: Correlations were significant between the hemolysis values measured using microcapsule suspensions and those using bovine blood (R = 0.965, p = 0.002) and human blood (R = 0.940, p = 0.005). CONCLUSIONS: Microcapsule suspension can be successfully used instead of blood to compare the relative hemolytic performance of centrifugal blood pumps.

Inhalation efficacy of RFI-641 in an African green monkey model of RSV infection.

Human respiratory syncytial virus (RSV) is a major cause of acute upper and lower respiratory tract infections. RFI-641 is a novel RSV fusion inhibitor with potent in vitro activity. In vivo efficacy of RFI was determined in an African green monkey model of RSV infection involving prophylactic and therapeutic administration by inhalation exposure. Inhalation was with an RFI-641 nebulizer reservoir concentration of 15 mg/ml for 15 minutes (short exposure) or 2 hours (long exposure). Efficacy and RFI-641 exposure was determined by collection of throat swabs, nasal washes and bronchial alveolar lavage (BAL) on selected days. The short-exposure group (15 minutes) exhibited no effect on the nasal, throat or BAL samples. The throat and nasal samples for the long-exposure group failed to show a consistent reduction in viral titers. RFI-641 2 hours exposure-treated monkeys showed a statistically significantly log reduction for BAL samples of 0.73-1.34 PFU/ml (P-value 0.003) over all the sampling days. Analysis indicates that the long-exposure group titer was lower than the control titer on day 7 and when averaged across days. The results of this study demonstrate the ability of RFI-641 to reduce the viral load of RSV after inhalation exposure in the primate model of respiratory infection.

Mannopeptimycins, new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98: antibacterial and mechanistic activities.

Mannopeptimycins alpha, beta, gamma, delta, and epsilon are new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98. Mannopeptimycins gamma, delta, and epsilon, which have an isovaleryl substitution at various positions on the terminal mannose of the disaccharide moiety, demonstrated moderate to good antibacterial activities. Mannopeptimycin epsilon was the most active component against methicillin-resistant staphylococci and vancomycin-resistant enterococci (MICs, 2 to 4 micro g/ml for staphylococci and streptococci and 4 to 32 micro g/ml for enterococci), while mannopeptimycins gamma and delta were two- to fourfold less active. Mannopeptimycins alpha and beta, which lack the isovaleryl substitution and the disaccharide moiety, respectively, had poor antibacterial activities. The in vivo efficacies of the mannopeptimycins in Staphylococcus aureus mouse protection studies paralleled their in vitro activities. The median effective doses of mannopeptimycins gamma, delta, and epsilon were 3.8, 2.6, and 0.59 mg/kg of body weight, respectively. The mannopeptimycins were inactive against cell wall-deficient S. aureus and caused spheroplasting of Escherichia coli imp similar to that observed with penicillin G in an osmotically protective medium. Mannopeptimycin delta rapidly inhibited [(3)H]N-acetylglucosamine incorporation into peptidoglycan in Bacillus subtilis and had no effect on DNA, RNA, or protein biosynthesis. On the basis of the observations presented above, an effect on cell wall biosynthesis was suggested as the primary mode of action for mannopeptimycin delta. The mannopeptimycins were inactive against Candida albicans, did not initiate hemolysis of human erythrocytes, and did not promote potassium ion leakage from E. coli imp, suggesting a lack of membrane damage to prokaryotic or eukaryotic cells.

Modifications in surgical implantation of the Penn State electric total artificial heart.

BACKGROUND: Two modifications of the surgical implantation protocol for the Penn State Total Artificial Heart (ETAH) were evaluated: Phrenic nerve ischemia was prevented by minimizing dissection and traction; and hemostasis was augmented and ETAH cuff anastomoses reinforced by using fibrin glue. METHODS: Thirteen Holstein calves underwent orthotopic surgical implantation of the Penn State ETAH between February 1998 and August 2000. Mean hemodynamic and laboratory chemistry variables from the first postoperative week were compared between calves receiving the original (n = 7) and modified (n = 6) protocol. RESULTS: Calves assigned to the modified protocol displayed an improvement in the Po2/FiO2 ratio compared to original (419.4 +/- 17.5 vs 336.3 +/- 35.4, respectively; p = 0.05). All additional parameters were equivalent between groups. The percent survival of animals receiving the modified protocol at 2, 4, and 12 weeks was higher than that of animals that underwent the original protocol. Original-protocol calf deaths consisting of hemothorax (n = 3), and respiratory failure (n = 1) were prevented in the modified protocol. CONCLUSIONS: Our results suggest that manipulations in surgical protocol may promote increased survival in calves implanted with the Penn State ETAH.

The LionHeart LVD-2000: a completely implanted left ventricular assist device for chronic circulatory support.

Management of patients with end-stage cardiac disease remains a vexing problem. Limitations in medical management and a fixed supply of donor organs for cardiac transplant have a continued impact on this growing population of patients. Mechanical circulatory support has proved very successful as a means of bridging patients to cardiac transplant when all medical options have been exhausted. The development of a chronic system of circulatory support has been underway at the Pennsylvania State University for nearly 30 years. These efforts have been recently merged with the industrial partnership with Arrow International toward the development of the LionHeart LVD-2000 (Arrow International, Reading, PA) completely implanted left ventricular support system. We present an overview of the system, details of implantation, a review of preclinical studies, and a synopsis of the first European implants. Early results have demonstrated the system to be safe, effective, and reliable. Transcutaneous energy transmission and the compliance chamber have been validated.

Testing of a 50 cc stroke volume completely implantable artificial heart: expanding chronic mechanical circulatory support to women, adolescents, and small stature men.

The development of a completely implanted total artificial heart at our institution has progressed to successful in vivo and in vitro testing of a device that is nearing clinical testing. This system consists of a 70 cc stroke volume pump originally designed to be used in men of average stature. Implantation of this system remains limited by patient size; hence, many women and adolescent patients will likely be precluded from support because of their smaller stature. A system similar in design, but with a 50 cc stroke volume pump has been developed. The first in vivo study of this device has been undertaken. A calf was supported for 33 days. The animal was extubated and ambulatory within the first 6 hours of implantation, and remained healthy until the thirty-third postoperative day when it suffered an embolic neurologic event. The pump and operating system worked flawlessly throughout the period of support. Further in vivo and in vitro testing will be undertaken. Development of a scaled down total artificial heart system expands this type of circulatory support to those critically ill patients previously deemed poor candidates because of their smaller body habitus.

Therapeutic efficacy of GAR-936, a novel glycylcycline, in a rat model of experimental endocarditis.

GAR-936, a novel glycylcycline, was investigated with a rat model of experimental endocarditis. It was compared with vancomycin against both vancomycin-susceptible and -resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus. GAR-936 exhibited the lowest MICs (2 log(10) CFU, compared to those in untreated controls, for both vancomycin-susceptible and -resistant (VanA and VanB) E. faecalis strains and >4 log(10) CFU for a methicillin-resistant S. aureus isolate. The glycylcycline was more efficacious at a lower administered dose in the rat model of endocarditis than was vancomycin. The efficacy of GAR-936 in this model was apparently not enhanced by a factor in rat serum, as was observed for vancomycin with a time-kill curve. The results of this study demonstrate the therapeutic potential of GAR-936 for the treatment of enterococcal and staphylococcal infections and warrant further investigation.

Saccharomicins, novel heptadecaglycoside antibiotics produced by Saccharothrix espanaensis: antibacterial and mechanistic activities.

Saccharomicins A and B, two new heptadecaglycoside antibiotics, were isolated from the fermentation broth of the rare actinomycete Saccharothrix espanaensis. They represent a novel class of bactericidal antibiotics that are active both in vitro and in vivo against bacteria and yeast (MICs: Staphylococcus aureus, <0.12 to 0. 5; vancomycin-resistant enterococci, 0.25 to 16; gram-negative bacteria, 0.25 to >128; and yeast, >128 microg/ml), including multiply resistant strains. Saccharomicins protected mice from lethal challenges by staphylococci (subcutaneous 50% effective dose range of 0.06 to 2.6 mg/kg of body weight, depending on the S. aureus strain). The 50% lethal dose by the subcutaneous route was 16 mg/kg. Mechanistic studies with Escherichia coli imp and Bacillus subtilis suggested complete, nonspecific inhibition of DNA, RNA, and protein biosynthesis within 10 min of drug treatment. Microscopic examination of drug-treated cells also suggested cell lysis. These data are consistent with a strong membrane-disruptive activity. The antibacterial activities of the saccharomicins against gram-positive bacteria were unaffected by the presence of Ca(2+) or Mg(2+), but activity against gram-negative bacteria was substantially reduced.

In vivo and in vitro stability of modified poly(urethaneurea) blood sacs.

In the present study, we investigate the in vivo and in vitro stability of modified poly(urethaneurea) (BioSpan MS/0.4) blood sacs. Blood sacs were utilized primarily in left ventricular assist devices that were implanted in calves for times ranging from 5 to 160 days. Cyclic testing in vitro was also conducted on similar sacs. Various analytical methods were employed to characterize the sacs after in vivo or in vitro service and corresponding retained "control" sacs. These methods included ATR-FTIR spectroscopy, scanning electron microscopy and gel permeation chromatography. In general, the characteristics of implanted and in vitro cycled sacs were similar to their control sacs. Thermal and microtensile properties were unchanged after testing. The same was true for the ATR-FTIR spectra, indicating relative chemical stability for the time frames explored here. The only significant changes occurred in molecular weight and gross surface morphology. A modest increase in weight average molecular weight was observed for most implanted blood sacs, indicating some type of chain extension or branching reaction in vivo. Although the surface morphologies of implanted blood sacs were often similar to their control sacs, we sometimes observed limited pitting on the nonblood contacting surfaces in regions of the sac that experience maximum bending during service.

In vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) against various gram-positive and gram-negative bacteria.

The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were assessed in an experimental murine thigh infection model in neutropenic mice. Mice were infected with one of several strains of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, or Klebsiella pneumoniae. Most infections were treated with a twice-daily dosing schedule, with administration of 0.75 to 192 mg of GAR-936 or WAY 152,288 per kg of body weight. A maximum-effect dose-response model was used to calculate the dose that produced a net bacteriostatic effect over 24 h of therapy. This dose was called the bacteriostatic dose. More extensive dosing studies were performed with S. pneumoniae 1199, E. coli ATCC 25922, and K. pneumoniae ATCC 43816, with doses being given as one, two, four, or eight equal doses over a period of 24 h. The dosing schedules were designed in order to minimize the interrelationship between the various pharmacokinetic and pharmacodynamic parameters studied. These parameters were time above 0.03 to 32 times the MIC, area under the concentration-time curve (AUC), and maximum concentration of drug in serum (C(max)). The bacteriostatic dose remained essentially the same, irrespective of the dosing frequency, for S. pneumoniae 1199 (0.3 to 0.9 mg/kg/day). For E. coli ATCC 25922 and K. pneumoniae ATCC 43816, however, more frequent dosing led to lower bacteriostatic doses. Pharmacokinetic studies demonstrated dose-dependent elimination half-lives of 1.05 to 2.34 and 1.65 to 3.36 h and serum protein bindings of 59 and 71% for GAR-936 and WAY 152,288, respectively. GAR-936 and WAY 152,288 were similarly effective against the microorganisms studied, with small differences in maximum effect and 50% effective dose. The glycylcyclines were also similarly effective against tetracycline-sensitive and tetracycline-resistant bacteria. Time above a certain factor (range, 0.5 to 4 times) of the MIC was a better predictor of in vivo efficacy than C(max) or AUC for most organism-drug combinations. The results demonstrate that in order to achieve 80% maximum efficacy, the concentration of unbound drug in serum should be maintained above the MIC for at least 50% of the time for GAR-936 and for at least 75% of the time for WAY 152,288. The results of these experiments will aid in the rational design of dose-finding studies for these glycylcyclines in humans.

Steady state hemodynamic and energetic characterization of the Penn State/3M Health Care Total Artificial Heart.

Total Artificial Heart (TAH) development at Penn State University and 3M Health Care has progressed from design improvements and manufacturing documentation to in vitro and in vivo testing to characterize the system's hemodynamic response and energetic performance. The TAH system is completely implantable and intended for use as an alternative to transplantation. It includes a dual pusher plate pump and rollerscrew actuator, welded electronics and battery assembly, transcutaneous energy transmission system, telemetry, and a compliance chamber. In vitro testing was conducted on a Penn State mock circulatory loop with glycerol/water solution at body temperature. Tests were performed to characterize the preload and afterload response, left atrial pressure control, and power consumption. A sensitive preload response was demonstrated with left atrial pressure safely maintained at less than 15 mm Hg for flow rates up to 7.5 L/min. Variations in aortic pressure and pulmonary vascular resistance were found to have minimal effects on the preload sensitivity and left atrial pressure control. In vivo testing of the completely implanted system in its final configuration was carried out in two acute studies using implanted temperature sensors mounted on the electronics, motor, and energy transmission coil in contact with adjacent tissue. The mean temperature at the device-tissue interface was less than 4 degrees C above core temperature.

In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936).

The 9-t-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines. This new derivative, like the first glycylcyclines, the N,N-dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 microgram/ml, showed good activity against strains expressing tet(M) (ribosomal protection), tet(A), tet(B), tet(C), tet(D), and tet(K) (efflux resistance determinants). TBG-MINO exhibited similar activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, < or = 0.5 microgram/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline. The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by Escherichia coli, S. aureus, and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by S. aureus including MRSA strains and strains containing tet(K) or tet(M) resistance determinants (median effective doses [ED50s], 0.79 to 2.3 mg/kg of body weight). TBG-MINO demonstrated efficacy against infections caused by tetracycline-sensitive E. coli strains as well as E. coli strains containing either tet(M) or the efflux determinant tet(A), tet(B), or tet(C) (ED50s, 1.5 to 3.5 mg/kg). Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO.

In vitro activities of aminomethyl-substituted analogs of novel tetrahydrofuranyl carbapenems.

CL 188,624, CL 190,294, and CL 191,121 are novel aminomethyl tetrahydrofuranyl (THF)-1 beta-methylcarbapenems. The in vitro antibacterial activities of these THF carbapenems were evaluated and compared with those of biapenem, imipenem, and meropenem against 554 recent clinical isolates obtained from geographically distinct medical centers across North America. The antibacterial activities of the THF carbapenems were equivalent to that of biapenem, and the THF carbapenems were slightly more active than imipenem and less active than meropenem against most of the members of the family Enterobacteriaceae but lacked significant activity against Pseudomonas isolates. In general, CL 191,121 was two- to fourfold more active than CL 188,624 and CL 190,294 against the staphylococcal and enterococcal isolates tested. CL 191,121 was twofold less active than imipenem against methicillin-susceptible staphylococci and was as activity as imipenem against Enterococcus faecalis isolates. Biapenem and meropenem were two- and fourfold less active than CL 191,121, respectively, against the methicillin-susceptible staphylococci and E. faecalis. All the carbapenems displayed equivalent good activities against the streptococci. Biapenem was slightly more active than the other carbapenems against Bacteroides fragilis isolates. Time-kill curve studies demonstrated that the THF carbapenems were bactericidal in 6 h against Escherichia coli and Staphylococcus aureus isolates. The postantibiotic effect exerted by CL 191,121 was comparable to or slightly longer than that of imipenem against isolates of S. aureus, E. coli, and Klebsiella pneumoniae.

In vivo activities of peptidic prodrugs of novel aminomethyl tetrahydrofuranyl-1 beta-methylcarbapenems.

A series of novel aminomethyl tetrahydrofuranyl (THF)-1 beta-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight against Escherichia coli and 0.9 mg/kg against Staphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs with L-amino acids demonstrated improved efficacy after oral administration, while the D forms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of < 1 mg/kg against infections caused by S. aureus, E. coli, Enterobacter cloacae, or penicillin-susceptible Streptococcus pneumoniae were obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious against Morganella morganii, Serratia marcescens, penicillin-resistant S. pneumoniae, extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, and E. coli infections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to > 32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.

Postoperative pulmonary complications in calves after implantation of an electric total artificial heart.

In long-term studies testing the Penn State Total Artificial Heart involving 30 calves, seven calves died of pulmonary complications within 2 weeks after receiving the implant (Group 1 [G1]) and seven calves survived from 2 weeks to 3 months without infection (Group 2 [G2]). Comparative studies were performed using multiple variables: cardiopulmonary bypass (CPB) time, cardiac index, central venous pressure, leukocyte count, hematocrit, total protein, albumin, serum glutamic oxaloacetic transaminase (GOT), creatinine, water balance, and transfused blood volume. In G1, CPB time was longer than in G2 (182 +/- 19 vs 156 +/- 17 minutes, respectively, p = 0.018). Postoperative minimum total protein and albumin in G1 were lower than those in G2 (56.5% +/- 6.0% and 59.0% +/- 5.5% of preoperative values vs 68.4% +/- 8.5% and 67.8% +/- 6.1%, respectively, p = 0.011 and 0.015). Water balance in G2 was more positive than in G1 (11.7 +/- 6.8 vs 1.4 +/- 8.3 L, respectively, p = 0.020). Other variables showed no significant differences. Microscopic findings of the lung in G1 were congestion, hemorrhage, aggregation of neutrophils, and proteinaceous material within the interstitial tissues and alveoli.

Dynamic in vitro and in vivo performance of a permanent total artificial heart.

In vivo characterization studies were performed to compare the dynamic in vivo performance of the Penn State/3M Health Care electric total artificial heart to existing in vitro data. Fully implanted systems were utilized including the artificial heart, controller, backup batteries, compliance chamber, and transcutaneous energy transmission. Catheters were implanted to measure central venous pressure (CVP), left atrial pressure (LAP), right atrial pressure (RAP), pulmonary artery pressure (PAP), and aortic pressure (AoP). Cardiac output (CO) was determined from the implanted controller, and systemic vascular resistance (SVR) was calculated. Steady state data were collected for each animal along with data regarding the transient responses to changes in preload and afterload. Preload was manipulated through volume changes. Afterload changes were accomplished through vasoactive agents. Increased preload caused little change in cardiac output because the pump output was nearly maximum at baseline. LAP, AoP, and SVR increased with increasing RAP. Decreased preload caused a reduction in CO, LAP, and SVR. Afterload increase resulted in a slight decrease in flow and an increase in system power and SVR. Afterload reduction was accompanied by a decrease in preload and a concomitant reduction in flow. Overall, the system response was similar to the response observed in vitro.

Recent improvements in a completely implanted total artificial heart.

The total artificial heart under development by the Pennsylvania State University and 3M Health Care has undergone a number of design improvements to improve reliability, manufacturability, implantability, and performance. These improvements are nearing completion in preparation for formal durability testing. The redesigned implanted electronics canister, consisting of a welded titanium shell with hermetic connectors, contains the control, telemetry, and energy transmission electronics, as well as a 9 cell, 800 mAhr Ni-Cd battery pack. Functional changes include a reduction in the battery recharge time from 14 hours to 4 hours, and a new inductive telemetry system. The energy transmission system operating frequency has been increased from 160 kHz to 200 kHz. Electromagnetic interference filters and a more efficient control mode have also been implemented. The energy converter has been modified to incorporate a new motor with integral Hall effect position sensors, and new cable, and compliance chamber conduit fittings. High flex life cable is now used for the motor and coil cables. Two prototype durability mock circulatory loops have been built and are being tested. Substantial progress has been made in the completion of manufacturing documentation, and in the implementation of a quality system.

In vivo observation of cavitation on prosthetic heart valves.

In this study, a method to determine the existence of prosthetic heart valve cavitation in vivo is presented. Pennsylvania State University Left Ventricular Assist Devices (LVADs) were implanted in two separate calves for this study. Björk-Shiley Monostrut (Irvine, CA) 27 mm and 25 mm valves with Delrin occluders were used in the mitral and aortic positions, respectively. A high fidelity, piezoelectric pressure transducer was mounted approximately 1.25 cm proximal to the mitral valve and measured the high frequency pressure fluctuations caused by cavitation bubble formation and collapse after valve closure. The root mean square (RMS) value of the mitral pressure signal during a 5 ms interval after valve closure was used as a measure of cavitation intensity. The pressure signals observed in vivo were similar to ones observed in vitro with the same type of pressure transducer and were associated with the visually observed cavitation. The percentage of beats with cavitation increased from 20.3% to 67.7% when pump filling was decreased by increasing beat rate. A blood test conducted during post-operative days 1-3 showed a significant increase in plasma hemoglobin during the low filling condition. However, blood tests conducted later (post-operative days 7-44) did not show a significant change in plasma hemoglobin during low filling conditions.