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We have used an anhepatic dog model to demonstrate the efficacy of a bioartificial liver assist device. Six dogs underwent total hepatectomy. Three received only medical care (controls) while the remainder were connected to an extracorporeal liver assist device (ELAD). The control dogs failed to regain consciousness after anesthesia although all lived 4-5 h postoperatively. Plasma ammonia concentration increased by an average of 250 mumol/L between the end of surgery and the demise of the animals. The treated dogs lived 3-12.5 h, and 2 of them required repeated doses of thiamylal sodium to maintain sedation. Plasma ammonia concentration was unchanged after connection to the ELAD except in the longest survivor, whose ammonia began to rise after 8 h on the ELAD. The short survival in the other 2 treated dogs was the result of uncontrolled intraabdominal bleeding. This device is capable of replacing the metabolic function of the liver, and might provide hepatic support in patients awaiting transplantation or in fulminant hepatic failure.

Liver transplantation is currently the only effective therapy for patients with fulminant hepatic failure. The availability of an artificial liver could bridge these patients through the relatively brief crisis period and allow their own livers to regenerate, providing a more favorable outcome and sparing the trauma and expense of transplant. We have developed a device consisting of a highly differentiated human liver cell line cultured in a hollow fiber cartridge. This device is capable of supporting dogs with acetaminophen-induced fulminant hepatic failure for a period long enough for their own livers to resume function. Even though liver function tests such as albumin and prothrombin time became extremely abnormal during the course of the experiment, the dogs did not become encephalopathic. Two of the three treated animals recovered sufficient liver function after 42 to 48 hr of treatment that they could be disconnected from the device, and they survived the experiment. Histological results and serum ALT levels suggest that the device affected the course of the disease in two animals, allowing recovery of hepatocytes that would otherwise have lysed. In the third animal, regenerative nodules demonstrated that, even in the presence of severe liver injury, the device was capable of supporting total liver function.

We have established an improved model of fulminant hepatic failure in dogs. Buthionine sulfoximine is used to inactivate glutathione synthesis, and small increments of acetaminophen are given intravenously to maintain the plasma level at approximately 200 micrograms/ml for 20 hr. This regimen produces severe liver injury along with many of the features seen in humans with acetaminophen poisoning. The first sign of impending liver failure is hypoglycemia. This occurs about 15 hr into the experiment and requires treatment with a continuous infusion of glucose. Between 15 and 20 hr, serum ALT activity begins to rise, indicating the onset of liver necrosis. Over the following 15 to 20 hr ALT activity continues to rise and is accompanied by an increase in bilirubin, a prolongation of the prothrombin time and the development of fetor hepaticus. Thirty to 48 hr after the initial acetaminophen dose, the animals begin to exhibit symptoms of encephalopathy and progress from lethargy to the inability to maintain posture and then coma, seizures and death. Liver biopsy specimens obtained at several stages throughout the study showed progressive necrosis, ultimately resulting in the complete destruction of zones 2 and 3.

Orthotopic liver transplantation (OLT) represents the only therapeutic option for many patients with end-stage liver disease as well as many inborn genetic errors of hepatic metabolism. Despite dramatic progress in methods for OLT, the utilization of this procedure is limited by its considerable morbidity and mortality, by a chronic shortage of organs for transplant, and by difficulty arranging funding for many patients. Many children with fulminant hepatic failure do not receive OLT because this technology is unavailable or unaffordable. Hepatocellular transplantation (HCT), in which isolated, heterologous hepatocytes from a donor liver would be infused into the diseased organ in order to provide essential hepatic functions, could provide a much needed therapeutic alternative to OLT in the treatment of some causes of hepatic insufficiency. Experiments in animals have demonstrated that several genetic deficiencies of hepatic metabolism as well as experimental induced hepatic failure in animals can be reversed by HCT. Despite this experience, HCT has never been attempted in human subjects. This protocol represents the first proposed clinical trial of HCT. We are proposing a clinical trial in which HCT would be attempted as a therapeutic intervention in children with acute hepatic failure who have no other medical or surgical options. This proposal is intended to establish surgical methods for HCT and to evaluate the feasibility of this procedure for treating hepatic disease in humans. It is our expectation that HCT may provide short-term support for patients awaiting organ availability, a "bridge to recovery" allowing patients with fulminant hepatic failure to recover, or a long-term repopulation of the patient's liver with healthy donor cells. One of the major limitations of many animal studies in HCT is that, since the donor hepatocytes are often indistinguishable from those of the host, it has often been difficult to demonstrate a clear correlation between engraftment and the therapeutic effect. In order to verify engraftment independent of the therapeutic response, we propose to "mark" the donor hepatocytes by transducing these cells with a recombinant retroviral vector (LNL6) carrying a marker gene (NEO-R, neomycin phosphoribosyl transferase). The presence of this marker will enhance the ability to identify transplanted cells in the host using assays for the NEO-R gene or transcribed NEO-R mRNA. The LNL6 vector has been approved for human use and has been used as a marker gene for transplanted cells in human subjects without any reported adverse effects. We would like to emphasize that this is a proposal with therapeutic intent.(ABSTRACT TRUNCATED AT 400 WORDS)

Despite advances in preservation solutions, hypothermia remains a critical component of organ preservation for transplantation. Many surgeons involved in multi-organ procurement procedures have expressed concern about the possible detrimental effects of cardiopulmonary bypass and profound hypothermic circulatory arrest on non-thoracic transplant organ function. In order to assess the validity of these concerns, a review of 20 multi-organ harvest procedures performed utilizing cardiopulmonary bypass and profound hypothermic circulatory arrest was undertaken. In all instances this technique was combined with organ flushing utilizing cold preservation solution. Adequate data was available to assess post-transplant organ function of all organs recovered in 16 procedures. Indication for the use of this technique was procurement of a heart-lung bloc in 16 instances and donor instability (hypotension) refractory to volume loading and inotropic agents in 4 instances. Organs obtained, including all organs from unstable donors which would otherwise have been lost, functioned, acceptably. Additionally, blood drained into the pump was used for recipient transfusion in 8 instances. This report documents that cardiopulmonary bypass and profound hypothermic circulatory arrest may be easily combined with traditional procurement flushing techniques and it provides excellent organ preservation for subsequent transplantation. This approach can optimize organ recovery from hemodynamically unstable donors, increasing the number available for transplantation.

This case describes a patient with cholesteryl ester storage disease who underwent liver transplantation for progressive cirrhosis, portal hypertension, ascites, and uncontrollable gastrointestinal bleeding. Four and one-half years posttransplant, her growth improved, cholesterol levels have returned to normal, and she is clinically well except for mild hypersplenism and an elevated blood urea nitrogen (BUN) and creatinine. Serum triglycerides remain elevated, but there have been no signs of progressive renal, intestinal, vascular, or pulmonary disease.

Of the first 16 patients who underwent orthoptic liver transplantation, 81% were observed to be hypothermic at termination of bypass (x = 34.5 degrees C, n = 16). In response, an in-line heat exchanger was added to the bypass circuit. Subsequently, 72% of the next 11 patients terminated bypass normothermic (x = 38.2 degrees C, n = 11). By removing from the sample those patients who incurred low blood flows, 100% of the patients terminated bypass normothermic (x = 38.2 degrees C, n = 8). At temperatures of 30-33 degrees C cardiac arrhythmias have been observed. Hypothermia has been documented to cause thrombocytopenia and neutropenia which can lead to blood loss. These low counts are only partially reversible with platelet infusion and white blood cells (WBC). The use of an in-line heat exchanger during liver transplantation is essential in preventing hypothermia in our experience.

A technique utilizing endobronchial intubation with a Carlens tube and a TDMAC-heparinless shunt is described for management of the actively bleeding aortopulmonary fistula. An illustrative case report is presented.

Among 76 patients with heart wounds treated over a 4 year period, nine had penetrating injuries to the coronary arteries with clinical presentations of pericardial tamponade, electrocardiographic abnormalities of bundle branch block or ST and T wave changes, and hemothorax. The right coronary artery was injured in two patients, the left anterior descending coronary artery in six patients, and the left circumflex coronary artery in one patient. All but one of these injured coronary arteries were treated by ligation. One patient with a proximal left anterior descending coronary artery transection presented with cardiac arrest and was managed successfully by emergency cardiopulmonary support and saphenous vein bypass with ligation of the transected ends of the artery. The only death occurred six days postoperatively in a patient with a right coronary artery laceration and was not related to the heart injury. No late symptomatic or hemodynamic sequelae have been noted among any of these patients. Principles of elective cardiac surgery are readily adaptable to the patient with a coronary artery injury.

Left ventricular dysfunction has been described in the transplanted heart. To further define these abnormalities in cardiac performance and relate for the first time diastolic to systolic function in the transplanted heart, we investigated 28 clinically stable recipients of orthotopic heart transplantation. Patients underwent blood pool radionuclide angiography performed at rest early after transplantation (18 +/- 13 days, mean +/- SD) and at rest and at exercise late after transplantation (248 +/- 194 days). Systolic ventricular performance was assessed by right and left ventricular ejection fractions, whereas diastolic left ventricular function was evaluated by the peak diastolic filling rate and its time of occurrence. Early after transplantation the left ventricular ejection fraction (54.0% +/- 6.0%) was significantly lower (p less than 0.001) than that of normal subjects of similar ages (61% +/- 6.6%). Mean right ventricular ejection fraction (47% +/- 6.0%) was comparable with that of normal subjects (49% +/- 4%) and abnormal in only three of 21 patients. Rest peak diastolic filling rate and time to peak diastolic filling rate were comparable with values from normal subjects in our laboratory. Late after transplantation resting left and right ventricular ejection fractions, peak diastolic filling rate, and time to peak diastolic filling rate were similar to the values found early after transplantation. During exercise significant increases occurred in the left ventricular ejection fraction (p less than 0.02), the right ventricular ejection fraction (p less than 0.02), and the peak diastolic filling rate (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Major abdominal vascular injuries present problems in diagnosis, exposure, and management. Combined injuries to the abdominal aorta and vena cava are particularly lethal due to extensive blood loss, difficulty in sequential exposure, and the high incidence of associated injuries. Between 1953 and December 1974, ninety-one patients required emergency operations for abdominal aortic trauma at our city-county charity hospital. Twenty-nine of these had combined injuries to the abdominal aorta and vena cava, ten of whom had either an audible bruit preoperatively or a palpable thrill at exploration suggesting acute fistulas. Twenty-three injuries were secondary to gunshot wounds. Ten were located in the suprarenal aorta and vena cava. Management involved a variety of technics including intravascular shunts, adaptive exposures, Dacron prostheses, and autotransfusion. Survival rate was 27 per cent. Sixty-two per cent of the deaths were a function of extreme difficulty in controlling hemorrhage and exposure. There were no late recurrences of arteriovenous fistulas. Successful management of acute traumatic injury to both the abdominal aorta and vena cava requires rapid, aggressive surgical management, adaptive sequential control maneuvers, and application of technics and principles developed for elective vascular surgery.

Today, surgeons are able to manage both blunt and penetrating wounds of the heart with increasing success, including those with associated intracardiac injuries. After diagnosis by cardiac catheterization, substantial intracardiac lesions are repaired using cardiopulmonary bypass. Among more than 300 patients treated for cardiac wounds in our city-county hospital in recent years, 15 were found to have marded intracardiac defects. These defects included ventricular septal defects, aorta--right ventricle fistulas, aortic valve injuries, a mitral valve injury, and a coronary artery--right ventricle fistula. Thirteen of the 15 patients required repair of the intracardiac defects. One was repaired acutely and 12 were repaired electively. All 15 patients were alive and asymptomatic at the time of writing.

Though successfully transplanted hearts respond in such a way that individuals remain remarkably asymptomatic, they do not function normally. Characterization of early hemodynamic patterns and their evolvement has not been done. The evolution of hemodynamic indices in 20 patients receiving orthotopic heart (n = 17) or combined heart-lung (n = 3) transplants is therefore documented. In 15 isolated heart recipients, right heart catheterization was performed at 24 to 48 hours, 1 to 2 weeks, 4 to 8 weeks, and greater than 3 months after surgery at the time of routine endomyocardial biopsy. Early, patients had elevated mean blood pressure (96 +/- 14 mm Hg, mean +/- standard deviation), mean right atrial pressure (15 +/- 6 mm Hg), right ventricular end-diastolic pressure (16 +/- 7 mm Hg), mean pulmonary artery pressure (30 +/- 7 mm Hg), and mean pulmonary capillary wedge pressure (19 +/- 6 mm Hg), but normal resting heart rate (96 +/- 14 beats/min) and cardiac output (5.6 +/- 1.6 L/min). Heart rate, blood pressure, and output did not change during follow-up, but right atrial pressure decreased dramatically (4 +/- 2 mm Hg at 3 months), as did right ventricular end-diastolic pressure (4 +/- 4 mm Hg), mean pulmonary artery pressure (21 +/- 8 mm Hg), and pulmonary capillary wedge pressure (11 +/- 4 mm Hg). Analysis of right heart filling dynamics revealed an abnormal inspiratory rise in mean right atrial pressure (15 +/- 6 and 27 +/- 7 mm Hg at 24 to 48 hours) that subsequently resolved. In eight patients whose resting follow-up right heart pressures normalized, rapid volume challenge uncovered occult restrictive right atrial pressure patterns that increased from 4 +/- 4 to 9 +/- 4 mm Hg after infusion of saline solution. Kussmaul's response was not apparent with prevolume infusion, but volume expansion caused appearance of this hemodynamic pattern. All patients had early evidence of tricuspid insufficiency, but in two patients, the Doppler regurgitant fraction was over 50%. These two individuals had hemodynamics similar to the other 15 patients initially, but in contrast, their right heart filling pressures did not change during follow-up. Other significant echocardiographic findings included enlarged atria and increased left ventricular mass in all patients. In two of three combined heart-lung transplant patients, similar hemodynamic patterns were evident. Rejection indices did not correlate with hemodynamic observations. Thus a characteristic evolvement of hemodynamics in heart and heart-lung transplants that mimic dynamics associated with restrictive myocardial disease is documented.(ABSTRACT TRUNCATED AT 400 WORDS)

Of 1,393 consecutive patients operated on for aneurysm of the abdominal aorta between 1964 and 1978, 61 consecutive patients had undergone emergency operation for ruptured abdominal aortic aneurysm, for an incidence of 4.4% (61 of 1,393). There were 57 men and four women; their mean age was 77.5 years, with a range of 49 to 93 years. In 21 patients the diagnosis of aneurysm had been known from 1 day to 5 years prior to rupture. Hypotension (less than 100 mm Hg systolic) was present in 27.9% of patients (17 of 61) on admission to hospital and prior to operation in a total of 44.3% patients (27 of 61). Operation was begun in eight patients with an initially unrecordable blood pressure. The perioperative mortality rate (30 day) was 14.8% (nine of 61). The two factors most influencing survival were age [no patient younger than 60 years died vs. 40% of patients (four of 10) older than 80 years] and the magnitude of blood loss (survivors lost a total of 4,513 ml vs. 8,500 ml in those who died). Thus the most common cause of death was myocardial infarction (six of eight) in elderly patients, secondary to poorly tolerated severe hypovolemia. The results of this study suggest the need for avoidance of technical problems during operations, earlier referral of patients with known abdominal aortic aneurysms, especially the elderly, and early diagnosis with immediate operation for ruptured aneurysms.

Activation of T-lymphocytes is accompanied by the release of interleukin-2 receptors (IL-2R) in a soluble form that can be measured as an index of the activation process. We performed a prospective, blinded study of the dynamic changes in soluble IL-2R levels in serum in 12 patients undergoing lung or heart-lung transplantation. The levels of soluble IL-2R were markedly elevated during episodes of rejection (geometric mean value X divided by SEM = 3,770 X divided by 1.06 versus 411 X divided by 1.08 U/ml for normal controls, p less than 0.0001). Levels of soluble IL-2R were 2,105 X divided by 1.16 U/ml with rejection episodes in single lung recipients versus 5,560 X divided by 1.30 in recipients of two lungs (p = 0.005). Soluble IL-2R levels were 1,468 X divided by 1.05 during episodes of nonbacterial infections, 1,879 X divided by 1.34 with bacterial infections, and 5,056 X divided by 1.08 with sepsis (p less than 0.001 for each category compared to normals). Levels of soluble IL-2R exceeded 6,750 U/ml only with rejection episodes and were greater than 4,100 U/ml either with rejection, clinical sepsis, or overwhelming bacterial infection. We conclude that marked elevations of soluble IL-2R are associated with rejection, intermediate elevations with either rejection or infection, and that low levels of soluble IL-2R exclude rejection.

We have determined the clinical course of 200 consecutive patients (mean age, 67.5 years) in whom epicardial pacing was established by the left subcostal route by insertion of 2 sutureless myocardial electrodes and a demand bipolar generator. There was 1 intraoperative death (0.5%). The overall 30-day perioperative mortality was 4 of 200 patients (2.0%). The principal postoperative complications included postpericardiotomy syndrome in 8 patients (4.0%), pneumonia or marked atelectasis in 2 patients (1.0%), and pulmonary embolus in 1 patient. Hemiplegia developed in 2 patients at 9 and 10 days, respectively, after operation, and transient monoparesis developed in another patient (1.5%). There were no wound infections, but the one wound dehiscence required resuturing. Follow-up has been completed in all patients from 1 to 39 months postoperatively (mean, 14.9 months). There have been 21 late deaths. Late lead thresholds were recorded for 45 individual leads from 26 patients up to 35 months after operation. The results obtained indicate that for patients undergoing primary implantation, the sutureless myocardial electrode provides reliable lead function. However, patients who required reoperation because of previous pacemaker failure due to threshold rise have done poorly as a group and may be better managed with lithium high-output pacemaker generators.