Pump-oxygenator System Research Articles

Computed Tomography Is Predictive of Significant Neurologic Injury in Children Supported on Extracorporeal Membrane Oxygenation.

Computed Tomography Is Predictive of Significant Neurologic Injury in Children Supported on Extracorporeal Membrane Oxygenation.

Device-Induced Hemostatic Disorders in Mechanically Assisted Circulation

Mechanically assisted circulation (MAC) sustains the blood circulation in the body of a patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) or on ventricular assistance with a ventricular assist device (VAD) or on extracorporeal membrane oxygenation (ECMO) with a pump-oxygenator system. While MAC provides short-term (days to weeks) support and long-term (months to years) for the heart and/or lungs, the blood is inevitably exposed to non-physiological shear stress (NPSS) due to mechanical pumping action and in contact with artificial surfaces. NPSS is well known to cause blood damage and functional alterations of blood cells. In this review, we discussed shear-induced platelet adhesion, platelet aggregation, platelet receptor shedding, and platelet apoptosis, shear-induced acquired von Willebrand syndrome (AVWS), shear-induced hemolysis and microparticle formation during MAC. These alterations are associated with perioperative bleeding and thrombotic events, morbidity and mortality, and quality of life in MCS patients. Understanding the mechanism of shear-induce hemostatic disorders will help us develop low-shear-stress devices and select more effective treatments for better clinical outcomes.

Effects of Purge-Flow Rate on Microbubble Capture in Radial Arterial-Line Filters

The process of microbubble filtration from blood is complex and highly dependent on the forces of flow and buoyancy. To protect the patient from air emboli, arterial-line filters commonly use a micropore screen, a large volume housing with purpose-built shape, and a purge port to trap, separate, and remove circulating microbubbles. Although it has been proposed that an insufficient buoyancy force renders the purge port ineffective at removing microbubbles smaller than 500 μm, this research attempts to investigate the purge flow of an arterial-line filter to better understand the microbubble removal function in a typical radial filter design. As its primary objective, the study aims to determine the effect of purge-flow rate on bubble capture using air bolus injections from a syringe pump with 22-gauge needle and Doppler ultrasound bubble detection. The measureable bubble size generated in the test circuit ranged between 30 and 500 μm, while purge flow was varied between .1 and .5 L/min for testing. Statistical analysis of the test data was handled using a repeated measures design with significance set atp< .05 level. Outcomes demonstrated that higher purge flows yielded higher bubble counts, but the effect of purge-flow rate on bubble capture decreased as bubble size increased. Results also showed that purge flow from the test filter was capable of capturing all bubble sizes being generated over the entire flow range tested, and confirms utility of the purge port in removing microbubbles smaller than 500 μm. By analyzing bubble counts in the purge flow of a typical radial-filter design, this study demonstrates that currently available micropore filter technology is capable of removing the size range of bubbles that commonly pass through modern pump-oxygenator systems and should continue to be considered during extracorporeal circulation as a measure to improve patient safety.

Board #325 - Technology Innovation Development of Educational Perfusion Simulation Software for Cardiopulmonary Bypass (Submission #9144)

Introduction Simulation-based education is gaining widespread acceptance as a teaching tool in medicine. Its particular advantage is that no harm can come to patients.1 Realistic full-scale simulation is now possible using a sophisticated manikin, software, and a full complement of actual medical equipment. Simulation training is particularly useful for teaching students how to manage rare or infrequent events. In a simulation environment, however, the arena for measuring performance is limited. On one hand, there is full-scale (high-fidelity) patient simulation with “real” physical inputs and “real” environmental interactivity.2 On the other hand, the conditions are created by computer-based simulations and partial-task training devices. Computer-based simulations rely on the participant to transform a two-dimensional screen-based experience into a meaningful representation of a real-life situation. We developed computer-based simulation as a first step to educate students about a technique and its troubles. There are many types of simulation tool; these tools change as the technology develops. Computer-based software applications can be used effectively to teach students. We describe computer software that we created to educate students about extracorporeal circulation. Description We developed software for simulation education of an extracorporeal circulation that is under continuous development in our laboratory. We based the software on the integrated hardware system, Perfusion Education System. The system comprises only the computer that runs the control application. It does not include the hydraulic simulator or an electronic interface unit such as a hardware system. The monitor can display part of a heart-lung machine and the relevant safety devices, vital simulation data, the stage of the operation, and the anesthesia status. Using the software, the perfusionist performs extracorporeal circulation surgery based on the monitor’s information using a cursor according to the surgeon’s scenario. The arterial pump flow is controllable by operating a sliding lever. Balancing the arterial pump flow and the venous flow is required while controlling the total blood volume. For example, if the trainee makes an error by not getting proper insufflation gas to the oxygenator, the PaO2 levels are reduced, as shown in the patient’s blood analysis via user interface monitoring. Thus, the trainee is able to understand the basic operation using this application before undergoing actual machine training. Conclusion Using the monitor, trainees are able to perform the fundamental extracorporeal circulation operation by operating an arterial flow pump and other manipulations. With this software, it is possible to study an operation and become familiar with a fundamental pump-oxygenator system at a desk, without having to work directly with a heart-lung machine. This software can be a useful adjunct during student education. As for real vital parameters, nearly full-scale simulations are possible by using the numerical model already devised. This is not only an educational tool, since in the future, it can be used as a rehearsal perfusion simulation system in which patient data can be input. It enables educators to establish a protocol that determines if the hemodynamics predicted are real. In summary, we developed computer-based software for perfusion simulation in an attempt to provide a comprehensive solution. This software will enable perfusionist educators to teach trainees to address a wide variety of clinical problems. With more applications, novel techniques can be more widely explored and confirmed before use on patients.

Invited Commentary

The seminal report of 20-year survivors after cardiac transplantation, by Biefer and colleagues [1Biefer H.R.C. Sündermann S.H. Emmert M.Y. et al.Surviving 20 years after heart transplantation: a success story.Ann Thorac Surg. 2014; 97: 499-505Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] portrays a remarkable success story for this life-extending therapy. The 55% actuarial survival at 20 years defines a highly effective, although not curative, therapy for an otherwise fatal condition. The evolution of heart transplantation has been well chronicled in the annals of transplant history [2Kirklin J.K. Young J.B. McGiffin D.C. History of cardiac transplantation.in: Kirklin J.K. Young J.B. McGiffin D.C. Heart transplantation. Churchill Livingstone, New York, NY2002: 3-13Google Scholar]. After Barnard's historic first successful heart transplant in 1967, survival over the next year was generally miserable, with mortality among the first 100 patients exceeding 50% by the eighth postoperative day and a median survival of only 29 days! By the end of the next decade (before the introduction of cyclosporine), survival at 1 year was barely more than 60%. Few would have predicted a subsequent experience in which nearly half the patients are still alive 20 years after transplantation, outcomes that would impress even the most ardent skeptic. So, what lessons and paradigm shifts in the cardiac surgical landscape have emanated from this experience? Cardiac transplantation set the paradigm for other complex cardiac surgical endeavors with its evolution from a solely surgical-driven event to a comprehensive, multidisciplinary endeavor. The recognition of the need for multiple medical subspecialties to collaborate and share in “ownership” of patient outcomes was critical to the achievement of near routine long-term survival. This paradigm, rare in cardiac surgery before 1980, became the standard for two other areas of complex cardiac surgery—infant cardiac surgery and mechanical circulatory support—in which participants from multiple disciplines are involved in the decision-making process for surgery, daily rounding, and longer-term patient care management, and often during the operation itself. This multidisciplinary commitment to successful cardiac transplantation (and later, lung transplantation) spawned an international society (International Society for Heart and Lung Transplantation) that attracted specialists from numerous disciplines nearly from the time of its inception in 1981. During the first 25 years after the advent of successful operations with cardiopulmonary bypass [3Kirklin J.W. DuShane J.W. Patrick R.T. et al.Intracardiac surgery with the aid of a mechanical pump-oxygenator system (Gibson type): report of eight cases.Mayo Clin Proc. 1955; 30: 201Google Scholar], success for most cardiac procedures was measured by hospital mortality. Cardiac transplantation was perhaps the first instance in which success required longer-term survival metrics. Improved outcomes mandated routine long-term surveillance and proactive intervention, concepts that have expanded to the care of patients receiving circulatory support [4Pamboukian S.V. Tallaj J.A. Brown R.N. et al.Improvement in 2-year survival for ventricular assist device patients after implementation of an intensive surveillance protocol.J Heart Lung Transplant. 2011; 30: 879-887Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar] and infants with complex conditions such as hypoplastic left heart syndrome that require staged surgical palliation. Finally, the era of government regulation in cardiac surgery really began in the mid 1980s when the United Network of Organ Sharing was awarded a federal contract for data collection from all heart transplant centers [2Kirklin J.K. Young J.B. McGiffin D.C. History of cardiac transplantation.in: Kirklin J.K. Young J.B. McGiffin D.C. Heart transplantation. Churchill Livingstone, New York, NY2002: 3-13Google Scholar]. A system evolved whereby government oversight of outcomes after transplantation linked Medicare reimbursements to satisfactory institutional performance in cardiac transplantation. Public reporting of cardiac surgical outcomes is now common in many states, and more recently the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) was created as a partnership between the National Heart, Lung, and Blood Institute, the Centers for Medicare and Medicaid Services, and the Food and Drug Administration [5Kirklin J.K. Naftel D.C. Stevenson L.W. et al.INTERMACS database for durable devices for circulatory support: first annual report.J Heart Lung Transplant. 2008; 27: 1065-1072Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar]. Federal oversight of transcutaneous aortic valve replacement (TAVR) procedures is now occurring through required participation in the national TAVR registry. So, despite the limited (by donor availability) number of patients who have received a heart transplant for end-stage heart disease, this amazing procedure and multifaceted discipline have generated far-reaching effects on the overall field of cardiac surgery. Surviving 20 Years After Heart Transplantation: A Success StoryThe Annals of Thoracic SurgeryVol. 97Issue 2PreviewWe report the long-term outcomes of patients who survived 20 years or greater after heart transplantation. Full-Text PDF

Fifty Years of Open Heart Surgery at the Mayo Clinic

Fifty Years of Open Heart Surgery at the Mayo Clinic

The evolution of the helical reservoir pump-oxygenator system at the University of Minnesota

Open heart surgery was not possible before the early 1950s. The development of controlled cross-circulation at the University of Minnesota in 1953 was a major contributing factor toward operating safely on the interior of the heart. Cross-circulation required connecting a donor's arterial and venous blood vessels to those of a smaller recipient whose heart could then be opened for corrective surgery. At that time no mechanical system was available to serve the role of the donor. The need to replace the donor was recognized. The author describes his experience with the development of the helical reservoir bubble oxygenator, which replaced the donor in cross-circulation supported open heart surgery. Other sidelights of the author's experience during the early days of open heart surgery at the University of Minnesota Department of Surgery are also recounted.

Development of silicone rubber hollow fiber membrane oxygenator for ECMO.

Silicone rubber hollow fiber membrane produces an ideal gas exchange for long-term ECMO due to nonporous characteristics. The extracapillary type silicone rubber ECMO oxygenator having an ultrathin hollow fiber membrane was developed for pediatric application. The test modules were compared to conventional silicone coil-type ECMO modules. In vitro experiments demonstrated a higher O2 and CO2 transfer rate, lower blood flow resistance, and less hemolysis than the conventional silicone coil-type modules. This oxygenator was combined with the Gyro C1E3 centrifugal pump, and three ex vivo experiments were conducted to simulate pediatric V-A ECMO condition. Four day and 6 day experiments were conducted in cases 1 and 2, respectively. Case 3 was a long-term experiment up to 2 weeks. No plasma leakage and stable gas performances were achieved. The plasma free hemoglobin was maintained within a normal range. This compact pump-oxygenator system in conjunction with the Gyro C1E3 centrifugal pump has potential for a hybrid total ECMO system.

Development of Pump-Oxygenator Systems and the Origins of Open-Heart Surgery: A Personal Memoir

Intracardiac surgery requires the use of a pump-oxygenator to maintain life while the heart is taken out of its usual circuit. Open-heart surgery became practical with the introduction of perfusion systems in the early 1950s. Many factors merged at this time to initiate the beginnings of open-heart surgery.

The Past 50 Years of Cardiovascular Surgery

The Past 50 Years of Cardiovascular Surgery

Transient adhesion of platelets in pump-oxygenator systems: influence of SMA and nitric oxide treatments

We employed gamma scintigraphy to quantify the transient accumulations of platelets in pump-oxygenator systems employed in cardiopulmonary bypass (CPB). A flat sheet microporous polypropylene membrane oxygenator (Cobe Duo) was employed, with and without siloxane/caprolactone oligomer coating (SMA) (n = 8 each). The effect of nitric oxide gas infusion on platelet deposition was also evaluated for the uncoated Cobe Duo system (n = 10 each). Scintigraphic images of radiolabelled cells were obtained and converted to numbers of all platelets, labeled and unlabeled, adhering to the pump and oxygenator surfaces. These numbers were compared, by study group, for a 90-min period of normothermic CPB in the adult pig, employing standard prime and anticoagulation regimens. Platelets adhered in large numbers to control oxygenators, reaching maxima (> 20% of the circulating platelet mass) 30 min following institution of CPB, and decreasing for the duration of CPB. SMA treatment significantly decreased platelet adhesion following a 5-10-min transient accumulation period. Nitric oxide infusion significantly reduced platelet adhesion throughout the CPB period. Platelet accumulations on the high fluid shear centrifugal pump surfaces increased monotonically to maxima at about the same time as for the oxygenators, but did not decrease thereafter. Higher platelet surface densities were observed on the centrifugal pump surfaces than on the oxygenator surfaces. CPB with the untreated circuit tended to reduce circulating platelet counts vs theoretical values based on hemodilution alone. In contrast, SMA significantly increased the circulating platelet count versus the untreated control group. These results indicate that platelet adherence to the foreign surfaces of CPB equipment are influenced in characteristic ways by time and fluid shear. SMA treatment and nitric oxide infusion both reduce platelet adhesion to oxygenator surfaces. SMA treatment spares these cells for the circulation.

Peripheral bypass-induced pulmonary and coronary vascular injury. Association with increased levels of tumor necrosis factor.

Although cardiopulmonary bypass is associated with systemic complement activation and neutrophil sequestration, it is unclear whether bypass-induced vascular injury is localized and dependent on organ ischemia. We hypothesized that other factors perhaps related to placement of a bypass circuit or to blood perfusion of a pump-oxygenator system may produce vascular injury caused by systemically circulating mediators. In dogs, we determined whether application of a systemic venoarterial bypass circuit with pump-oxygenator perfusion but without pulmonary or cardiac flow diversion (peripheral bypass) leads to vascular injury. Since several features of the postperfusion syndrome after bypass resemble sequelae of endotoxin exposure, we also measured circulating endotoxin and tumor necrosis factor levels. Anesthetized dogs underwent 2 hours of exposure to a pump-oxygenator with peripheral venoarterial bypass. We used a double indicator measurement of pulmonary and coronary vascular permeability (protein leak index [PLI]) as indexes of vascular injury. Compared with controls (n = 7), the pulmonary PLI of dogs undergoing bypass (n = 11) increased more than threefold (18.8 +/- 2.3 vs 63.3 +/- 7.6 x 10(-4) min-1; P < .05) and the coronary PLI increased more than twofold (P < .05). The rate of disappearance of intravascular radiolabeled protein increased threefold after bypass (disappearance t1/2, 241 +/- 35 vs 84 +/- 15 minutes, control vs bypass; P < .05), suggesting a generalized increase in vascular permeability. Circulating endotoxin was detectable in blood samples from 8 of 8 bypass animals (range, 0.24 to 4.56 ng/mL) compared with 2 of 5 controls (P < .05). Tumor necrosis factor levels increased significantly with bypass (6.7 +/- 3.8 vs 146.7 +/- 33.6 U/mL, baseline vs bypass; P < .05) and were only slightly and nonsignificantly increased in controls (7.0 +/- 4.4 vs 18.2 +/- 5.9 U/mL; P = NS). Peak tumor necrosis factor but not peak endotoxin levels correlated with pulmonary and with coronary protein leak. As expected, circulating complement (CH50) levels decreased significantly during bypass, reflecting systemic complement activation. However, the levels correlated poorly with the severity of vascular injury. We conclude that peripheral pump-oxygenator bypass causes coronary and pulmonary vascular injury that is independent of blood flow diversion and is associated with the appearance of circulating levels of endotoxin and tumor necrosis factor, which may play a role in bypass-induced vascular injury.

Detection of microbubbles released by oxygenators during cardiopulmonary bypass by intraoperative transesophageal echocardiography

Despite the improvements in cardiopulmonary bypass techniques, release of microbubbles in the systemic arterial circulation still occurs. It is believed that microemboli, prolonged arterial hypotension, defective cerebral blood flow autoregulation and nonpulsatile flow during cardiopulmonary bypass play a role in determining neurologic damage after cardiopulmonary bypass. 1,2 Gaseous and particulate microemboli may originate from the pump-oxygenator system as well as from the cardiac chambers and pulmonary veins. 1,3 In this study, transesophageal echocardiography was used to detect microbubbles reaching the arterial circulation during cardiopulmonary bypass. Two different types of oxygenators (bubbles and hollow fibers) were used to assess differences in their production of microbubbles.

Carotid body hypercapnia does not elicit ventilatory acclimatization in goats

The carotid body (CB) perfusion model utilizes surgical vascular ligations to allow isolated blood supply to a single in situ CB in awake goats. The contralateral CB was excised. By use of an extracorporeal pump-oxygenator system the blood gas composition perfusing the CB can be controlled independently from that of the systematic arterial system including the brain. Using this model we compared the responses of systemically normoxic goats to CB hypercapnia and CB hypoxia. In 6 goats CB sitmulation with hypercapnic-normoxic blood (mean Pcb CO 2 = 78Torr, mean Pcb O 2 ≅ 100 Toor) produced acute hyperventillation (mean decrease in Pa CO 2 of 5.2 Torr, P < 0.05) which remained constant over the 4-h perfusion period, Lack of a progressively increasing hyperventilation indicates that ventilatory acclimatization did not occur with hypercapnic CB perfusion. Hypoxic-normocapnic CB stimulation (mean Pcb O 2 = 40 Torr, mean PcB CO 2 = 39 Torr) produced an acute mean in Pa CO 2 of 5.5 Torr ( P < 0.05) in 6 additional goats. In contrast to CB hypercapina, the acute hyperventilation induced by CB hypoxia was followed by a progressive time-dependent additional mean decrease in Pa CO 2 of 5.6 Torr ( P < 0.05) over a 4-h period (ventilatory acclimatization). These data are compatible with the concept of separate mechanisms for hypercapnia and hypoxia in the CB suggest that the early phase of ventillatory acclimatization to hypoxia in goats may result from a time-dependent increase in CB afferent output.

The influence of blood pressure on trans-synovial flow in the rabbit.

Fluid exchange across the synovium lining the cavity of extended knees was studied in twenty rabbit hindquarters. The isolated hindquarters were perfused with blood from an extracorporeal pump-oxygenator system at controlled arterial pressure (PA) and venous pressure (PV). Intra-articular pressure (PJ) was set at 18 cmH2O in most experiments. The rate of trans-synovial absorption of Krebs solution (QS), measured by a drop-counter, was a negative linear function of PA (70-160 mmHg) and of PV (2-42 cmH2O). The sensitivity of exchange to venous pressure ( dQS / dPV , mean -0.25 +/- 0.03 microliter min-1 mmHg-1) was greater than its sensitivity to arterial pressure ( dQS /dPA, mean -0.17 +/- 0.02 microliter min-1 mmHg-1). The ratio of the slopes, ( dQS / dPV )/( dQS /dPA), indicated the pre- to post-capillary vascular resistance ratio. From this ratio and PA, PV, synovial capillary pressures PC were calculated by the equation of Pappenheimer & Soto - Rivera (1948). Trans-synovial absorption rate was a negative linear function of PC. This observation supports the application to the synovial cavity of Starling's hypothesis for fluid exchange between interstitial spaces and plasma (Starling, 1896). The slope dQS /dPC equalled the net hydraulic conductance of the blood-joint barrier (synovium plus capillary endothelium), and averaged -0.425 +/- 0.025 microliter min-1 mmHg-1 at PJ = 18 cmH2O. When PJ was subatmospheric, as is common in extended normal joints, fluid exchange (measured indirectly as dPJ /dt) was only approximately 1/4 as sensitive to blood pressure as at PJ = 18 cmH2O. This observation supported the view that the conductance of the blood-joint barrier depends on PJ.

Constant-pressure aortic root perfusion versus cardioplegia and hypothermia: Comparison of methods of myocardial protection

Both coronary perfusion and hypothermic cardioplegia are widely used methods of myocardial protection during aortic valve replacement. A theoretical objection to coronary perfusion is that it is not synchronized with cardiac contractions. Accordingly, a special pump was designed to provide perfusion at a constant range of pressure. Twenty dogs were studied during 4 hours of bypass. In six dogs no manipulations were carried out and hearts were allowed to beat in a nonworking state. Seven dogs underwent 2 hours of aortic cross-clamping and constant-pressure aortic root perfusion. Seven dogs underwent 2 hours of uninterrupted aortic occlusion with myocardial protection being maintained by cold potassium-induced arrest, Contractility did not change significantly in any of the three groups. All animals demonstrated significant hyperemia after bypass but normal endocardial/epicardial flow ratios. Although compliance deteriorated in all groups, the most striking changes were seen following 4 hours of bypass alone or constant-pressure aortic root perfusion. Hypothermic potassium arrest, in contrast, provided a slightly greater degree of myocardial protection, perhaps both by limiting the degree of ischemic injury directly and by excluding the heart from the circulating blood and the pump oxygenator system.

CO2-dependent component of the neurogenic vascular tone in the cat.

Complete vascular isolation of the hindlimbs was performed in vagotomized cats under Sodium Pentobarbital anesthesia. The hindlimbs were perfused at constant flow with blood kept at a constant and physiological PO2, PCO2, and pH values by means of a specially designed pump-oxygenator system. The animals were hyperventilated with different CO2 mixtures (0%, 5%, 7% and 10% in O2) thereby changing blood gases and pH levels in the upper body but not in the hindlimb vascular bed. At body PaCO2 (mm Hg) of 13.7 +/- 1.0 (means +/- SE), 30.6 +/- 1.05, 40,4 +/- 0,9 and 58.4 +/- 2.9 the hindlimb perfusion pressure (mm Hg) was, respectively 124 +/- 7.6, 138 +/- 7.4, 156 +/- 11.9 and 187 +/- 15.1. These changes in perfusion pressure were still present after complete peripheral chemoreceptor denervation but were abolished after section of the spinal cord at the T5 level. Since hindlimb perfusion pressure fell when body PaCO2 was lowered below physiological levels it is concluded that part of the neurogenic vascular tone of the hindlimbs is maintained by a CO2 mediated stimulation of supraspinal structures.

Left ventricular performance and coronary flow after coronary embolization with plastic microspheres.

Coronary flow, left ventricular circumference, and left ventricular pressure were observed in the isovolumically contracting, isolated canine heart supported with arterial blood from a donor. Systolic pressure, heart rate, and coronary perfusion pressure were held constant while the coronary bed was progressively embolized with either large (average 865 mu) or small (average 10 mu) polystyrene microspheres. During embolization with large microspheres, coronary flow diminished progressively. After sufficient embolization, decreased ventricular performance was indicated by a rise in end-diastolic pressure. During embolization with small microspheres, coronary flow initially increased, which suggests the effective release of a vasodilator substance. Return of coronary flow to control levels occurred only after the end-diastolic pressure rose, on the average, to above 30 mm Hg. After embolization with both sizes of microspheres, ventricular diastolic pressure-volume relationships showed decreased ventricular compliance. This was attributed, in part, to edema of the ventricular wall and, in part, to focal shortening of the sarcomeres where the circulation was compromised. Embolization with both sizes of microspheres ultimately caused a decrease in ventricular performance, although when the systolic pressure was increased the usual relationship between peak developed wall stress, and end-diastolic pressure showed less of a descending limb than that found in the nonembolized, isolated heart. It is felt that the data summarized above have bearing on ventricular performance and coronary flow in clinical situations where hearts are perfused through pump oxygenator systems and are thereby subject to embolization from aggregated clumps of platelets and fibrin.

Corory vasodilatation following diazepam (Valium).

1. The effects of diazepam (Valium) on coronary and systemic vascular resistance were studied in anaesthetized dogs on cardiopulmonary bypass under conditions of constant heart rate and aortic pressure.2. Pharmacological doses of diazepam uniformly produced coronary vasodilation lasting 30 min; systemic vascular resistance also decreased, but to lesser degree.3. When coronary blood flow was maintained constant at physiological levels, diazepam produced no changes in left ventricular contractility, as assessed by peak LV isovolumetric pressure, dp/dt max, force-velocity, and length-tension relations, whereas previous experiments had demonstrated a positive inotropic effect in a similar preparation in which coronary blood flow was responsive to alterations in coronary vascular resistance.4. In five dogs, complete separation of the coronary and systemic circulations was accomplished by a double pump-oxygenator system; direct intracoronary administration of diazepam produced coronary vasodilatation, but coronary pressure and flow were not altered by administration of diazepam to the systemic circulation.5. It is concluded that diazepam augments myocardial contractility by increasing coronary blood flow. This relationship is independent of extracardiac humoral mechanisms, and appears to require the delivery of diazepam to the coronary circulation.

SIMILARITY BETWEEN A SUBSTANCE PRODUCED BY THE HEART IN VITRO AND THE 18-MONOACETYL DERIVATIVE OF d-ALDOSTERONE

Cat kidneys perfused with heparinized blood from heart-lung circuits (Davey & Lockett, 1960; Lockett, 1966) reabsorbed 99% of the filtered water and sodium. By contrast, kidneys similarly isolated but perfused from pump-oxygenator circuits reabsorbed only 96·5% of the altered Na and 98% of the filtered water (Lockett, 1967 a). The excessive leak of Na and water from kidneys perfused from a pump-oxygenator system was corrected by insertion of a heart (perfused through the coronary arteries) into the perfusion circuit. The isolated heart released a substance into the blood stream in response to reduction in atrial filling (Lockett, 1967b); an apparently identical substance was extracted, in very small amount, from heart muscle (Lockett, 1967b; Ilett & Lockett, 1968). The physico-chemical properties of the heart substance were consistent with a steroidal structure and the renal actions were qualitatively similar to those of aldosterone but differed markedly in latency of action.