Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy.

OBJECTIVE: To evaluate the potential of modafinil in reducing excessive daytime somnolence (EDS) and enhancing indexes of quality of life and mood in patients with myotonic dystrophy (DM). METHODS: Forty patients with DM were randomized to receive modafinil and placebo for 14 days each, using a double-blind, cross-over design. Before and after each trial, subjects completed handgrip strength testing, spirometry, and quality-of-life measures (RAND). On days 7 and 14, each subject completed the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale (SSS), and the Profile of Mood States (POMS). RESULTS: ESS scores were lower while taking modafinil (mean 248 mm; 95% confidence limit 220 to 276 mm) as compared with placebo (309 mm; 281 to 336 mm) (p < 0.001). Mean SSS scores were also lower during the modafinil trial (3.05; 2.77 to 3.33) than during the placebo trial (3.45; 3.18 to 3.71) (p < 0.05). The POMS indicated that modafinil decreased fatigue-inertia (p < 0.001) and increased vigor-activity and tension-anxiety (p < 0.001) indexes. The total mood disturbance score was also decreased during the modafinil trial as compared with placebo (p < 0.05). The RAND quality-of-life measures of energy (p < 0.001) and health change (p < 0.05) were both significantly enhanced during the modafinil treatment phase. No changes in maximal grip strength or forced expired volume in 1 second were detected over the course of the study. Headache was the most frequently reported adverse event. Four patients withdrew from the study, three because of side effects (two during modafinil ingestion and one during placebo ingestion). CONCLUSION: Modafinil reduces somnolence and improves mood in patients with DM.

Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy.

Seventy-five patients meeting international diagnostic criteria for narcolepsy enrolled in a 6-week, three-period, randomized, crossover, placebo-controlled trial. Patients received placebo, modafinil 200 mg, or modafinil 400 mg in divided doses (morning and noon). Evaluations occurred at baseline and at the end of each 2-week period. Compared with placebo, modafinil 200 and 400 mg significantly increased the mean sleep latency on the Maintenance of Wakefulness Test by 40% and 54%, with no significant difference between the two doses. Modafinil, 200 and 400 mg, also reduced the combined number of daytime sleep episodes and periods of severe sleepiness noted in sleep logs. The likelihood of falling asleep as measured by the Epworth Sleepiness Scale was equally reduced by both modafinil dose levels. There were no effects on nocturnal sleep initiation, maintenance, or architecture, nor were there any effects on sleep apnea or periodic leg movements. Neither dose interfered with the patients' ability to nap voluntarily during the day nor with their quantity or quality of nocturnal sleep. Modafinil produced no changes in blood pressure or heart rate in either normotensive or hypertensive patients. The only significant adverse effects were seen at the 400-mg dose, which was associated with more nausea and more nervousness than either placebo or the 200-mg dose. As little as a 200-mg daily dose of modafinil is therefore an effective and well-tolerated treatment of excessive daytime somnolence in narcoleptic persons.

Immune mechanisms in patients with proven vascular disease.

Lymphocyte transformation and serum levels of immunoglobulins and complement were measured in groups of patients with old myocardial infarction, with peripheral vascular disease and in age- and sex-matched controls. There were no significant differences between the groups in phytohaemagglutinin (PHA) induced lymphocyte transformation, in IgA or in serum complement levels. The levels of IgG and IgM were significantly raised in patients with old proven infarcts while the level of IgM was raised in patients with peripheral vascular disease.

Optimal cardioplegia and 24-hour heart storage with simplified UW solution containing polyethylene glycol.

Recent work has shown that UW may be better than standard cardioplegic solutions for short-term heart preservation. In this study we have used a rabbit heart model to evaluate a simplified UW solution in which penicillin, dexamethasone, insulin, allopurinol, and adenosine were omitted and 5% polyethylene glycol (PEG20M) was substituted for hydroxyethyl starch. The test systems consisted of 4-hr cardioplegic storage at 15 degrees C with repeated flushing every 30 min for 2 hr and 24-hr hypoxic low-flow microperfusion (3 ml/g/24 hr) at 0 degrees C. Control groups were arrested with a 15-25 ml flush in iced saline and immediately tested. Cardiac output (CO)* after preservation was measured in a working heart model using an acellular perfusate at 37 degrees C at an aortic pressure of 100 cm H2O. The CO (ml/g heart wt/min) were as follows--Controls: St. Thomas II 20.5 +/- 8.3 (5), UW 34.7 +/- 11.7 (16), PEG20M 41.8 +/- 4.4 (14); 4-hr cardioplegia: St. Thomas II 17.4 +/- 0.9 (4), Bretschneider HTK 14.9 +/- 7.0 (4), UW 25.2 +/- 11.5 (9), PEG20M 41.1 +/- 7.8 (8); 24-hr microperfusion: UW 25.4 +/- 11.1 (18), PEG20M 37.1 +/- 8.2 (18). Following cardioplegic or microperfusion preservation, PEG20M hearts functioned at control levels (P greater than 0.05) and were significantly superior to all other solutions, with approximately double the CO (P less than 0.05, all other groups). We conclude that for heart preservation, 5 components can be eliminated from UW and substitution of PEG20M for HES appears to have improved its performance.

Surgery of tumors of the subdiaphragmatic inferior vena cava. Report of two cases and review of the literature.

Two cases of obstruction of the hepatic inferior vena cava (IVC) are presented. In Case 1, the obstruction was due to a calcified thrombus which presumably developed after lower limb trauma 19 months previously. Complete surgical correction was achieved with the aid of deep hypothermia and circulatory arrest. In Case 2, a right atrial tumor was mimicked by a propagating malignant hepatoma. Palliative removal of the tumor cleared the IVC passage. The etiology of tumors of the IVC and their surgical management are discussed.

Pulmonary valve cyst in an adult. Case report.

A case is described of an asymptomatic woman who had typical findings of mild pulmonic stenosis. Right heart catheterization revealed a 44 mm. Hg gradient across the pulmonary outflow tract, and a filling defect was discovered by angiography. On surgical exploration, the defect was found to be a benign cyst attached to the anterior leaflet of the pulmonary valve.

Platelets, hemostasis, and thromboembolism during treatment of acute respiratory insufficiency with extracorporeal membrane oxygenation.

Twenty-eight patients were supported with long-term extracorporeal membrane oxygenation as a treatment for acute respiratory insufficiency. Clinical, laboratory, and autopsy data concerning platelets, hemostasis, and thromboembolic disease are presented for the periods during and after bypass. During bypass, a "foreign-surface coagulopathy" was encountered which consisted of abnormal bleeding plus frequent, generalized, small and large vessel thromboembolic events. The abnormal bleeding is attributed to heparin, thrombocytopenia, and a qualitative platelet defect. Possible causes of the thromboembolic events including disseminated intravascular coagulation are also discussed, and speculations are offered concerning clinical management and directions for future investigation.

Acquired ventricular septal defects. Evolution of an operation, surgical technique, and results.

The pathology and treatment of 19 patients with acquired ventricular septal defects (VSD's) secondary to myocardial infarction are presented. A new method of repair is described: suturing the free right ventricular wall against the VSD to support the friable septum on the right side in continuity with the patch on the left side of the septum. This removes the force of the left ventricle contraction from the patch and septum to the healthy right ventricle wall. Distal cardiac amputation was also used in several instances. The hospital survival rate was 64 per cent. The late functional and hemodynamic results were excellent.

Endobronchial control of bronchopleural fistulae.

This report describes a proposed solution to the problem of high-flow bronchopleural fistulae in the adult respiratory distress syndrome. Animal studies and clinical application demonstrate the efficacy of this treatment.

Blood platelets and extracorporeal circulation; kinetic studies on dogs on cardiopulmonary bypass.

Platelet kinetics and functions were studied in dogs during extracorporeal circulation. A transient platelet sequestration in the liver occurs during the bypass. This reversible disappearance is accompanied by a loss of the ability of platelets to adhere or aggregate. The platelets which return to the circulation have normal functions and a normal life span. The irreversible damage is mainly due to the direct blood-gas interface. Impairment of lung function by platelet aggregates is discussed and the importance of an in vivo model to study the factors which affect the platelets, such as antiaggregating agents, is pointed out.

Effects of acute right ventricular ischemia on ventricular interactions during prosthetic left ventricular support.

Systolic ventricular interactions may be partially responsible for right ventricular failure that sometimes occurs during clinical use of prosthetic left ventricular assist devices. In this hypothesis, it is proposed that the left ventricular assist device reduces left ventricular pressure and its contribution to right ventricular performance, thus impairing right ventricular output. On the other hand, these effects may be small compared with other causes of right ventricular failure such as ischemia. To test the systolic interaction hypothesis in the normal and ischemic right ventricle, we used a left ventricular assist device to pressure unload the left ventricle of anesthetized pigs, and we compared its effect on right heart function before and after 2 minutes of acute right coronary artery occlusion as a model of right heart failure. Pigs were instrumented for measurements of septal to left ventricular and right ventricular free wall dimensions with ultrasonic crystals, ventricular chamber pressures, and cardiac output with a pulmonary artery blood flow probe. Without right ventricular ischemia, the left ventricular assist device produced an 80% +/- 6% reduction in left ventricular pressure-time integral while maintaining aortic pressure. This resulted in a leftward septal shift with an 11.6% +/- 1.8% decrease in left ventricular septal-to-free wall dimension and a 12.5% +/- 2.4% increase in right ventricular septal-to-free wall dimension, with no changes in right ventricular cardiac output or stroke work. In contrast, right coronary artery occlusion alone produced right heart failure, with a 50% +/- 6% reduction in right ventricular global stroke work and 26% +/- 6% and 27% +/- 3% reductions in cardiac output and right ventricular peak systolic pressure, respectively. This right heart failure persisted during left ventricular unloading with the left ventricular assist device, which resulted in further leftward septal shifting and unchanged but still depressed stroke work and flow output. These findings support the hypothesis that a preexisting pathologic condition is the dominant factor in determining right ventricular function during prosthetic left ventricular support and that direct anatomic interactions play a minor role.

In vivo evaluations of a new thromboresistant polyurethane for artificial heart blood pumps.

To reduce the risk of thromboembolic complications in prosthetic blood pumps, we have developed a new segmented polyurethane elastomer. This material is unique because its mechanical properties for long-term durability and surface properties for biocompatibility have been separated and developed in two distinct materials. Improved thromboresistance is then obtained by a 1% concentration of a new polymeric surface-modifying additive blended with the base polyurethane before fabrication of the blood pump. To evaluate this material in vivo, we performed 10 implants, in calves, of the Pierce-Donachy prosthetic ventricle with blood-pumping sacs and cannulas fabricated from the new surface-modifying additive copolymer blend (Thoratec's BPS-215M). In four control implants the blood sacs and cannulas were fabricated from Ethicon's Biomer segmented polyurethane, which is the present clinical standard for most artificial hearts and circulatory support devices. The blood pumps were connected from the apex of the left ventricle to the descending aorta in male Holstein calves weighing 82 to 108 kg and were driven pneumatically in the full-to-empty mode with flows averaging 5 to 6 L/min. Each calf was medicated with aspirin and dipyridamole throughout the study period and was electively put to death after 4 weeks for evaluation of explanted blood sacs and for examination of the kidneys for infarction. All 10 explanted blood sacs made with the surface-modifying additive copolymer blend were shiny and completely free of thrombus. Three of the four explanted Biomer blood sacs showed visible red thrombus, and all four showed small areas of white thrombus. The average surface area of the Biomer blood sacs covered with thrombus was 45 +/- 32 mm2. Use of a semiquantitative scale to assess renal infarction demonstrated that nine of 10 animals with a surface-modifying additive copolymer blend blood sac had infarction less severe than the mean infarct score of the animals with a Biomer sac. The surface-modifying additive copolymer blend has excellent mechanical and physical properties necessary for use in artificial heart blood pumps. From these experiments, we conclude that the surface-modified polyurethane blend is superior to Biomer polyurethane in blood compatibility and in freedom from thromboembolic risk. This material is now approved by the Food and Drug Administration for investigational device exemption studies in the Pierce-Donachy prosthetic ventricle.

Pulmonary pathology in acute respiratory insufficiency: lung biopsy as a diagnostic tool.

Forty-two patients underwent open-lung biopsy during the early phase of acute respiratory insufficiency. Correlation between the gross appearance of the lung at operation and the microscopic findings was good. Although only fair correlation was found between lung and tracheal cultures, the findings of two positive cultures in the lung only was of utmost importance. Biopsying multiple areas from the same operation showed identical pathology in 86 per cent of cases. The mortality rate of open-lung biopsy was zero; the morbidity rate was 4 per cent. The over-all survival rate of acute respiratory insufficiency (ARI) due to trauma was 39 per cent; that of pneumonia, 11 per cent. In 17 (33 percent) patients specific diagnoses and/or specific therapies were employed as a direct result of the biopsy or the thoracotomy. The incidence and prognostic implications of fibrosis and microthromboembolism are presented and discussed. Open-lung biopsy has been extremely safe and valuable in characterizing and managing ARI.

Thromboembolic complications after mitral valve replacement with Hancock xenograft.

Case histories of 140 patients who had mitral valve replacement with the Hancock xenograft were reviewed according to the incidence of thromboembolic complications. There were 16 patients with preoperative and/or postoperative low-output syndrome (Group A.) Eight of these patients died, and six had autopsies which showed major thrombi on the heterograft valve. In 126 long-term survivors (followed 1 to 33 months) nine thromboembolic events occurred (thromboembolic incidence 5.3 percent per patient-year). All patients with emboli were in atrial fibrillation. Additional predisposing factors included a history of systemic emboli and the presence of atrial clots at the time of surgery. The majority (7/9) of emboli occurred during the first 3 postoperative months. Two emboli occurred immediately following the operation (before oral anticoagulation therapy could have been begun). Five occurred in patients who were not on anticoagulation (Group B) and two occurred under warfarin treatment (Group C). There was no thromboembolic event in patients taking aspirin (Group D). It is concluded that hemodynamically stable patients have a decreased risk of thromboembolism and do not require anticoagulation. Patients with atrial fibrillation have an increased thromboembolic risk and should be on a regimen of warfarin for 3 months postoperatively and then on aspirin therapy.

Importance of preoperative liver function as a predictor of survival in patients supported with Thoratec ventricular assist devices as a bridge to transplantation.

UNLABELLED: Patient selection is crucial for the success of ventricular assist devices as a bridge to heart transplantation. PURPOSE: The objective of this study was to identify preoperative markers for survival and end-organ recovery in patients having a ventricular assist device. METHODS: A retrospective study was performed on 32 severely ill patients with end-stage cardiac failure being mechanically bridged to heart transplantation with the Thoratec Ventricular Assist Device System (Thoratec Laboratories Corporation, Pleasanton, Calif) in a single center between 1984 and 1995. The preoperative cardiac index averaged 1.6 L/min per square meter with a pulmonary capillary wedge pressure of 29 mm Hg. Because of a high incidence of hepatic or renal dysfunction, or both (total bilirubin: 3.5 +/- 6.2 mg/dL; creatinine: 2.0 +/- 1.3 mg/dL), biventricular support was used in most patients (28/32). A total of 30 preoperative and 4 perioperative variables were evaluated for their association with survival and liver recovery. RESULTS: Nineteen patients (59.4%) survived to transplantation and 13 died. All 19 patients undergoing transplantation were discharged alive with a 1-year survival of 94.4%. All patients without liver recovery died of multiorgan failure. Direct and indirect bilirubin measurements were the only significant predictors for survival to discharge (P = .036, .045); all other factors failed to show significance. As direct bilirubin levels increased (normal range, 3 times normal, and >3 times normal), patient survival decreased (82 %, 56%, and 33 %, respectively). In addition, bilirubin and liver enzyme levels before insertion of the assist device were significantly associated with liver recovery during support with the device. CONCLUSION: In our patient population with ventricular assist devices, liver function is the most predictive factor of patient survival in bridging to transplantation.

Risk-benefit analysis of warfarin therapy in Hancock mitral valve replacement.

The purpose of this investigation was to analyze the thromboembolic and/or major bleeding complications of 124 consecutive but nonrandomized patients who had only mitral valve replacement with the Hancock porcine xenograft between September, 1974 and June, 1979. These patients were treated either with or without anticoagulants. Four basic study groups were created: Group 1, warfarin; Group 2, aspirin; Group 3, no anticoagulants; and Group 4, warfarin and aspirin. Group 5 combined Groups 1 and 4 (warfarin and warfarin plus aspirin) and Group 6 combined Groups 2 and 3 (aspirin and no anticoagulants). The cardiac rhythm, history of embolism, and intraoperative findings of a thrombus in the left atrium were examined as risk factors for later thromboembolism . Follow-up time was 3.03 years (range 2.0 to 4.2 years). The embolic rate was not significantly different in any group (n = NS). In Groups 5 and 6 the embolic rate was 2.97 and 3.25 embolisms per 100 patient-years, respectively. Warfarin therapy resulted in significant major bleeding episodes, including two deaths (p less than 0.05). The number of patients with a history of a previous embolism, the finding of an intraoperative left atrial thrombus, or abnormal cardiac rhythm was insufficient to test embolic risk in the four treatment groups. We conclude that long-term warfarin therapy increases the risk of bleeding complications but may not significantly influence the incidence of thromboembolism arising from the Hancock porcine xenograft mitral valve. Other and larger studies are needed to confirm this last point.

Preoperative and postoperative comparison of patients with univentricular and biventricular support with the thoratec ventricular assist device as a bridge to cardiac transplantation.

OBJECTIVES: The goal of this study was to determine whether there are differences in populations of patients with heart failure who require univentricular or biventricular circulatory support. METHODS: Two hundred thirteen patients who were in imminent risk of dying before donor heart procurement and who received Thoratec left (LVAD) and right (RVAD) ventricular assist devices at 35 hospitals were divided into three groups: group 1 (n = 74), patients adequately supported with isolated LVADs; group 2 (n = 37), patients initially receiving an LVAD and later requiring an RVAD; and group 3 (n = 102), patients who received biventricular assistance (BiVAD) from the beginning. RESULTS: There were no significant differences in any preoperative factors between the two BiVAD groups. In the combined BiVAD groups, pre-VAD cardiac index (BiVAD, 1.4 +/- 0.6 L/min per square meter, vs LVAD, 1.6 +/- 0.6 L/min per square meter) and pulmonary capillary wedge pressure (BiVAD, 27 +/- 8 mm Hg, vs LVAD, 30 +/- 8 mm Hg) were significantly lower than those in the LVAD group, and pre-VAD creatinine levels were significantly higher (BiVAD, 1.9 +/- 1.1 mg/dl, vs LVAD, 1.4 +/- 0.6 mg/dl). In addition, greater proportions of patients in the BiVAD groups required mechanical ventilation before VAD placement (60% vs 35%) and were implanted under emergency conditions than in the LVAD group (22% vs 9%). The survival of patients through heart transplantation was significantly better in patients who had an LVAD (74%) than in those who had BiVADs (58%). However, there were no significant differences in posttransplantation survival through hospital discharge (LVAD, 89%; BiVAD, 81%). CONCLUSION: Patients who received LVADs were less severely ill before the operation and consequently were more likely to survive after the operation. As the severity of illness increases, patients are more likely to require biventricular support.

A new skeletal muscle linear-pull energy convertor as a power source for prosthetic circulatory support devices [corrected].

Previous studies show that stimulated skeletal muscle wrapped around the heart or a blood pumping pouch can provide partial circulatory assistance. However, skeletal muscle is accustomed to pulling in direct tension, and power obtained from using the muscle in wraparound configurations is very inefficient. Therefore we have developed a new skeletal muscle-powered, linear-pull energy convertor for powering a wide range of implanted devices, including circulatory support blood pumps such as counterpulsation devices or complete prosthetic ventricles. This energy convertor system is powered by a skeletal muscle such as the latissimus dorsi, which is stimulated with a pulse generator. With the muscle left intact and in situ as much as possible, its insertion at the humerus is removed and reattached to a small-cylinder hydraulic energy convertor that is firmly attached to the ribs. Mechanical force in direct tension from the muscle is converted to high-pressure, low displacement; hydraulic energy (at approximately 200 psi). The output of this hydraulic energy convertor is connected by a small-diameter tube to a hydraulic actuator to drive the pusher plate of an implantable ventricular assist device located in the thoracic cavity or abdomen or another suitable blood pump. Preliminary in vitro tests from an engineering model of the Thoratec muscle-powered ventricular assist device show flow outputs of 5.2 L/min at a mean arterial pressure of 99 mm Hg. The muscle-powered ventricular assist device is a specific application designed to provide completely implantable circulatory support as an alternative to heart transplantation. It will enable patients to experience a quality of life free from batteries and the electrical power-conditioning hardware required with electromechanical systems.

Recovery of major organ function in patients awaiting heart transplantation with Thoratec ventricular assist devices. Thoratec Ventricular Assist Device Principal Investigators.

The time course of recovery of hepatic and renal function was determined in 193 patients receiving Thoratec ventricular assist devices while awaiting transplantation at 41 hospitals in eight countries. The duration of circulatory support averaged 26 days (maximum 248 days) and the average ventricular assist device blood flow index was 2.7 +/- 0.5 L/min/m2 compared with a preoperative cardiac index of 1.4 +/- 0.7 L/min/m2. Renal and hepatic function improved in most patients in 1 to 3 weeks of support. When comparing patients with the longest durations on the ventricular assist device (60 to 248 days) to patients with the shortest durations (< 7 days), laboratory values were significantly improved: creatinine (-29%, from 1.7 +/- 1.2 to 1.2 +/- 0.5 mg/dl), blood urea nitrogen (-32%, from 37 +/- 27 to 25 +/- 14 mg/dl), serum glutamic-oxaloacetic transaminase (-81%, from 397 +/- 702 to 76 +/- 45 IU) and total bilirubin (-79%, from 7.0 +/- 8.6 to 1.5 +/- 0.7 mg/dl). However, the posttransplantation survival through hospital discharge was not significantly different: 88% (14 of 16) for patients supported for at least 60 days and 86% (43 of 50) for patients who underwent transplantation after only 1 week of support. Therefore renal and hepatic function improve during ventricular assist device support, but the survival rate after transplantation is not related to duration and is comparable to that of conventional heart transplantation for short or long periods of ventricular assist support. Although it is clearly important not to proceed to transplantation in patients with irreversible organ failure who have ventricular assist devices, these data suggest that as long as the patient is on the path to recovery, the outcome is basically the same as for patients who have full recovery of renal and hepatic function.