Fee-for-benefit: a strategy to improve the quality of health care and control costs through reimbursement incentives.

OBJECTIVES: The purpose of this study was to determine whether reimbursement in direct proportion to expected therapeutic benefit is capable of improving the utilization and cost of health care. BACKGROUND: The benefit associated with a particular medical or surgical treatment varies widely from patient to patient. Nevertheless, payment to the provider of the treatment is essentially invariant under the current fee-for-service system. Under an alternative fee-for-benefit strategy, empiric data are used to construct a multivariate model to predict the expected benefit to an individual patient from a particular health care service on the basis of conventional clinical descriptors. The payers and the providers of the service then openly negotiate an explicit economic relation between expected benefit and monetary payment such that payment is directly proportional to benefit. METHODS: Computer simulations were performed to determine the potential impact of this fee-for-benefit strategy with respect to medical versus surgical treatment of coronary artery disease. RESULTS: Compared with conventional fee-for-service, fee-for-benefit resulted in a 12% improvement in patient benefit (quality-adjusted survival), a 22% reduction in provider payments and a 55% increase in cost/benefit (the ratio of benefit to payment). CONCLUSIONS: The incentives embodied in a fee-for-benefit strategy can be an effective mechanism for encouraging more appropriate health care utilization while simultaneously controlling health care costs.

A 6 year experience with the St. Jude medical valve: hemodynamic performance, surgical results, biocompatibility and follow-up.

After in vitro testing (confirmed in vivo) of three contemporary valve designs (St. Jude, Björk-Shiley and Carpentier-Edwards) demonstrated that the St. Jude valve possessed the most favorable hydrodynamic performance characteristics, a limited clinical trial was begun in high risk patients who might benefit from a prosthesis with improved hemodynamics. Between March 1978 and March 1984, 419 St. Jude prostheses (157 aortic, 156 mitral and 53 double aortic-mitral) were implanted in 366 patients. Ninety-six percent were in New York Heart Association functional class III or IV preoperatively. Early (30 day) mortality was 10.4% overall, and was lower after aortic (5.7%) or double (7.5%) than after isolated mitral valve replacement (16.0%). Forty-four prosthetic mitral valve recipients with severe ischemic mitral regurgitation experienced a 32% early mortality rate; without this group, mitral valve replacement carried a 10% early mortality rate (p less than 0.01). Multivariate logistic regression analysis confirmed that early death was strongly associated with three preoperative patient characteristics (p less than 0.05): ischemic mitral valve disease, depressed left ventricular function (ejection fraction less than 0.55) and advanced functional class (class IV). Late follow-up (7,055 patient-months, mean 22) was 99.7% complete (1 patient lost). Actuarial survival at 4 years was 80, 80 and 79% after aortic, mitral (nonischemic) and double valve replacement, respectively; in the subset with ischemic mitral regurgitation, actuarial survival was 34% (p less than 0.01). Eighty-six percent of survivors were in functional class I or II.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitral valve replacement early after myocardial infarction: attendant high risk of left ventricular rupture.

Between 1969 and 1983, 608 patients underwent mitral valve replacement surgery at Cedars-Sinai Medical Center. Perioperative rupture of the left ventricular myocardium complicated seven operations (1.2%), five of them in the 247 patients with concomitant ischemic heart disease. Six ruptures were fatal. Relative incidences of seven previously hypothesized predisposing factors were determined for patients with and without myocardial rupture. In addition, because of the apparent frequency of association with ischemic heart disease and because all ruptures were posterior or posterolateral, patients were also categorized by prior history of posterior myocardial infarction: 177 patients had none, whereas 49 patients had a remote and 21 patients a recent (less than or equal to 1 month) posterior wall infarct. Four ruptures (accounting for 57% of all ruptures) occurred in the 21 patients (19% incidence) with a recent posterior infarct, compared with only three ruptures in the 587 patients (0.5%) without a recent posterior wall infarct (p = 0.000). None of the factors of age, sex, valve pathology, etiology of valve lesion, concomitant coronary disease, valve substitute or intraoperative myocardial preservation were associated with perioperative rupture. These data establish a low overall incidence of ventricular rupture after mitral valve replacement, high fatality and possible etiologic association with recent posterior wall infarction.

Esmolol: a new ultrashort-acting beta-adrenergic blocking agent for rapid control of heart rate in postoperative supraventricular tachyarrhythmias.

Prompt control of heart rate is important for successful treatment of supraventricular tachyarrhythmias early after open heart surgery when sympathetic tone is high and ventricular response rates may be rapid. Esmolol, a new ultrashort-acting (9 minute half-life) beta-receptor blocking agent, was given by continuous intravenous infusion for up to 24 hours in 24 patients (21 with isolated coronary bypass surgery and 3 with valve replacement) 1 to 7 days after surgery. Atrial fibrillation was present in 9 patients, atrial flutter in 2 and sinus tachycardia in 13. Eleven patients had received intravenous digoxin (average dose 0.6 mg, average serum level 1.19 mg/100 ml) before esmolol infusion without adequate control of the supraventricular tachyarrhythmia. After a 1 minute loading infusion of esmolol (500 micrograms/kg per min), maintenance dose, titrated to heart rate and blood pressure response, varied from 25 to 300 micrograms/kg per min. After esmolol administration, at an average dose of 139 +/- 83 micrograms/kg per min, mean heart rate decreased from 130 +/- 15 to 99 +/- 15 beats/min. Within 5 to 18 minutes after initiation of therapy, all patients had achieved a 15% reduction in heart rate at a maintenance dose of 150 micrograms/kg per min or less. A 20% reduction in heart rate was attained in 19 of the 24 patients, and conversion to sinus rhythm occurred during esmolol infusion in 5 of the 11 patients with atrial flutter or fibrillation. Transient asymptomatic hypotension (less than 90/50 mm Hg) was seen in 13 patients, requiring cessation of esmolol therapy in 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Bileaflet, tilting disc and porcine aortic valve substitutes: in vivo hydrodynamic characteristics.

The St. Jude valve is a new bileaflet disc cardiac valve prosthesis designed to avoid some of the hemodynamic drawbacks of other prostheses. The in vivo flow characteristics of the St. Jude aortic valve (42 patients) were studied and compared with those of three other commonly used aortic prostheses. Björk-Shiley (12 patients), Hancock (27 patients) and Carpentier-Edwards (15 patients). The studies, performed 24 to 48 hours after surgery, included measurements at rest and during augmentation of valve flow by infusion of isoproterenol. The mean performance index for valves of all sizes is higher for the St. Jude than for either porcine valve, both at rest and during isoproterenol infusion (p less than 0.05). Utilizing data both at rest and with isoproterenol, the relation of valve flow and mean systolic gradient for each size of St. Jude valve (19 to 25 mm) indicates the occurrence of small increases in gradient (5.3 to 8.2 mm Hg) as valve flow increases, ranging from 161 to 436 ml/systolic X min. A direct comparison of valve flow and gradient data for all size 25 and 23 mm prostheses at rest indicates a tendency for a lower mean systolic gradient in both mechanical valves than in either porcine valve (p = 0.07). With isoproterenol augmentation of valve flow in 25 mm valves, the gradient is less (p less than 0.05), and the effective orifice area and performance index are larger (p less than 0.05) for the St. Jude than for either porcine valve.(ABSTRACT TRUNCATED AT 250 WORDS)

Fascicular conduction disturbances and ischemic heart disease: adverse prognosis despite coronary revascularization.

In patients with ischemic heart disease, fascicular conduction disturbances are associated with increased mortality. This study reveals that increased mortality also exists for certain types of fascicular conduction disturbances after myocardial revascularization. In 227 consecutive patients undergoing bypass surgery, 24 had preoperative and an additional 52 developed at surgery a fascicular conduction disturbance. At 66 +/- 14 months of follow-up, 6 (4%) of 148 control patients without pre- or postoperative fascicular conduction disturbances had died from cardiac causes. Although right bundle branch block and left hemifascicular block were the most common form of fascicular conduction disturbance, only 1 of 55 of these patients died (p = NS). Mortality rates were much higher for patients with left bundle branch block or an intraventricular conduction defect; 8 (38%) of 21 died from cardiac causes (p less than 0.05). A high risk subgroup was identified by comparing 14 consecutive patients with left bundle branch block or an intraventricular conduction defect who survived more than 1 year postoperatively with 21 consecutive patients with these same conduction defects who died within 1 year of surgery. The following variables were significantly (p less than 0.05) different (survivors versus nonsurvivors): age (58 +/- 7 versus 65 +/- 9 years); class IV angina (2 of 14 versus 16 of 21), prior myocardial infarction (9 of 14 versus 21 of 21), left ventricular ejection fraction (53 +/- 18 versus 41 +/- 15%), three vessel disease (9 of 14 versus 20 of 21) and left ventricular aneurysm (2 of 14 versus 13 of 21).(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrinolytic therapy of St. Jude valve thrombosis under guidance of digital cinefluoroscopy.

Fibrinolytic therapy is an alternative to urgent reoperation for patients with St. Jude prosthetic valve thrombosis, but requires an accurate method for repeated assessment of prosthetic function. Since the St. Jude valve is not well visualized by conventional cinefluoroscopy, digital subtraction techniques were developed that improved visualization of the value and allowed assessment of leaflet separation and velocity. A 74 year old woman with prosthetic valve thrombosis 5 years after St. Jude aortic valve placement had an opening angle of 58 degrees (normal range 10 to 13; n = 8) with a maximal opening velocity of 1.37 degrees/ms (normal range 2.46 to 2.93). The closing angle was 125 degrees (normal range 120 to 127) with a maximal closing velocity of 1.38 degrees/ms (normal range 2.24 to 3.60). The patient received 250,000 U of streptokinase intravenously, then 100,000 U/h for 72 hours. Improvement in auscultatory findings occurred at 12 hours; repeat digital cinefluoroscopy showed an opening angle of 20 degrees with a maximal velocity of 2.77 degrees/ms, and a closing angle of 126 degrees with a maximal velocity of 1.91 degrees/ms. Digital cinefluoroscopy 4 weeks after discharge on warfarin and dipyridamole therapy was unchanged. There have been no thromboembolic complications after 6 months of follow-up. Thus, digital cinefluoroscopy is a new noninvasive technique that permits accurate measurement of normal and abnormal St. Jude leaflet function. Intravenous streptokinase dissolution of prosthetic valve thrombosis under digital cinefluoroscopic guidance may be an acceptable alternative to emergency reoperation. The frequency and significance of residual subclinical leaflet dysfunction after fibrinolytic therapy and the indications for elective reoperation require further evaluation.

Treatment of severe platelet dysfunction and hemorrhage after cardiopulmonary bypass: reduction in blood product usage with desmopressin.

Impairment of platelet function commonly occurs after cardiopulmonary bypass, and may result in substantial bleeding. Because desmopressin acetate (a synthetic analogue of vasopressin) shortens bleeding time in a variety of platelet disorders, a controlled clinical trial of intravenous desmopressin was performed in 39 patients with excessive mediastinal bleeding (greater than 100 ml/h) and a prolonged template bleeding time (greater than 10 minutes) more than 2 hours after termination of cardiopulmonary bypass. Twenty-three desmopressin recipients and 16 control patients (no desmopressin) were similar in surgical procedure, pump time, platelet count, template bleeding time and amount of bleeding before therapy (p = NS). Compared with the control group, the patients receiving desmopressin (20 micrograms; mean 0.3 micrograms/kg) utilized fewer blood products (29 +/- 19 versus 15 +/- 13 units/patient; p less than 0.05), especially platelets (12 +/- 9 versus 4 +/- 7 units/patient; p = 0.004), while achieving a similarly effective reduction in mediastinal bleeding (4.8- and 4.3-fold, p = 0.001 for both). Severe platelet dysfunction was partially corrected within 1 hour after desmopressin infusion, during which interval no blood products were administered: the template bleeding time shortened (from 17 to 12.5 minutes, p less than 0.05), whereas the platelet count remained unchanged (at 96 +/- 35 and 105 +/- 31 X 10(3)/mm3, p = NS). The plasma levels of two factor VIII components increased: procoagulant activity (VIII:C) from 0.97 +/- 0.43 to 1.52 +/- 0.74 units/ml (p less than 0.05) and von Willebrand factor (VIII:vWF) from 1.28 to 1.78 units/ml (p less than 0.05); these increases correlated with the shortening of the bleeding time (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic differentiation of pathologic and physiologic stenosis in mitral porcine bioprostheses.

Porcine bioprostheses are physiologically stenotic valves. Degenerative calcification leading to pathologic stenosis is an increasingly recognized serious late complication of mitral valve replacement with a porcine bioprosthesis. Hemodynamic differentiation of pathologic from physiologic stenosis is important for identification of porcine bioprosthetic valve dysfunction. In 42 patients with a normal Hancock porcine bioprosthesis (standard model, sizes 27 to 33 mm), mean diastolic flow (65 to 461 ml/s), mean gradient (2.0 to 13.4 mm Hg) and effective orifice area (1.1 to 4.4 cm2) were determined at rest, during epicardial pacing (90, 110 and 130/min) and with isoproterenol infusion. A statistically significant increase in mean gradient occurred with increases in flow and decreases in valve size (p less than 0.05). Effective orifice area increased significantly as flow rate increased and as valve size increased (p less than 0.05). These measurements were compared with those in 16 patients with pathologically confirmed porcine bioprosthetic valve stenosis: 8 patients with reoperation (1.1% per patient-year) 3 to 8.5 years after mitral valve replacement and 8 previously reported abnormal cases. Stenotic failure rate was inversely related to valve size (2.1, 1.4, 0.5 and 0% per patient-year for sizes 27 to 33 mm). Stenotic and normal bioprostheses were not accurately differentiated on the basis of a single value for gradient or effective orifice area. A mathematical model that related flow to the square root of the mean gradient allowed complete separation of stenotic from normal prosthetic valve function, after valve size was accounted for and normal confidence limits were established (r = 0.74 to 0.94, sizes 27 to 33, p less than 0.0001). The effective orifice area-flow relation did not provide accurate differentiation of abnormal from normal function. Thus, normal mitral bioprostheses have significant transvalvular gradients whose magnitude depends on flow. Risk of stenotic failure is increased in the smaller valves, which have a larger gradient at implantation. Differentiation of pathologic from physiologic stenosis cannot be made on the basis of a single value for gradient or effective orifice area. Accurate hemodynamic differentiation is achieved by relating mean gradient to mean diastolic flow rate and valve size.

Cine computed tomographic evaluation of aortocoronary bypass graft patency.

Evaluation of the patency of coronary bypass grafts has previously required hospitalization for invasive angiography. This report of three cases documents the unique capability of cardiac cine computed tomography to easily and accurately define coronary bypass graft patency. In each case, the findings altered therapeutic decisions. This early experience justifies wider application of this technique and suggests that it may eliminate the need for diagnostically motivated graft angiography. Large scale studies to establish the sensitivity and specificity of cardiac cine computed tomography for determining graft patency are indicated.

Bileaflet, tilting disc and porcine aortic valve substitutes: in vitro hydrodynamic characteristics.

The desire for a low profile mechanical valve with better fluid dynamic performance led to the design and development of the St. Jude Medical bileaflet prosthesis. Comparative in vitro flow studies indicate that it has better pressure drop characteristics than the Björk-Shiley (convexo-concave) and Carpentier-Edwards porcine valves in current clinical use, especially in the small sizes. In the 21 to 27 mm aortic valve size range the St. Jude valve has an average performance index of 0.66, compared with 0.46 and 0.32 for the Björk-Shiley and Carpentier-Edwards valves, respectively. In contrast, the St. Jude valve has larger regurgitant volumes than both the Björk-Shiley and Carpentier-Edwards valves. Velocity measurements with a laser-Doppler anemometer indicate relatively centralized flow with small amounts of turbulence downstream of the St. Jude valve. The flow is unevenly distributed between the central and side orifices. The turbulent shear stresses are, however, large enough to cause sublethal or lethal damage to blood elements. Wall shear stresses are smaller than those measured downstream of the Björk-Shiley valve. Regions of flow separation were observed just downstream from the sewing ring, which could lead to excess tissue growth along the sewing ring. The results of this study indicate that overall in vitro fluid dynamic performance of the St. Jude valve is superior to that of the two other commonly used prostheses.

Clinical and nonclinical predictors of the cost of coronary bypass surgery: potential effects on health care delivery and reimbursement.

BACKGROUND: Health care providers are being pressured to lower the cost of care. Because of the inherent cost variability in providing health care, as reimbursement falls, providers may not be able to cover all costs. Understanding the underlying causes of this wide variability is important in determining optimum pricing. Prior studies on the cost of coronary bypass surgery have determined which clinical variables affect cost, yet none have studied nonclinical variables that can influence the cost of coronary bypass surgery. METHODS: In a cohort of 882 consecutive patients with treatment classified in the diagnosis-related group (DRG) 107, we examined 55 clinical and nonclinical variables obtained from our prospective database. For explanatory purposes, we used multiple linear regression to determine the variables that were predictive of direct cost and the magnitude of contribution of each variable. RESULTS: Eleven clinical and 4 nonclinical variables were predictive of direct cost. Nonclinical variables added significant cost-predictive information beyond that of the traditional clinical variables, and their magnitude of effect was equal to or greater than the traditional clinical variables. CONCLUSIONS: Nonclinical patient characteristics add important predictive information concerning the cost of coronary bypass surgery to traditional clinical variables. These data will be important in developing contracting strategies, in the evaluation of individual physician performance, and in modifying national methods of reimbursement.

Adverse 5-year outcome after coronary artery bypass surgery in blacks.

BACKGROUND: Coronary heart disease is the leading cause of death among blacks, but little is known about the late results of coronary artery bypass surgery in this population. It is not known whether differences in preoperative medical characteristics or medical health insurance affect outcome. We studied the effects of medical risk factors on survival outcome after coronary artery bypass surgery in a population of medically insured black and white patients. METHODS: Racial status and outcomes from surgery were determined in 3728 consecutive patients who had coronary artery bypass surgery at the authors' institution from January 1, 1984, to June 30, 1992. Coronary artery bypass surgery (excluding valve replacement) was performed in 115 black and 3113 white patients. RESULTS: Late survival probability was worse for blacks than whites at 1 year (84% vs 92%) and at 5 years (64% vs 82%, P=.001, Wilcoxon test). Most deaths were due to cardiac events in both groups (68% in blacks vs 67% in whites). Blacks had more hypertension (84% vs 54%), diabetes mellitus (36% vs 23%), and more were current smokers (21% vs 14%) (all P<.05, Fisher's exact test). Medical insurance coverage for blacks and whites was as follows: Medicare (60% vs 57%), private (38% vs 42%), and Medi-Cal (2% vs 2%). Operative mortality (30 days) was similar (5.2% for blacks vs 4.1% for whites; P=.48, Fisher's exact test). In a Cox regression model, race predicted long-term survival and persisted as an important risk factor after adjusting for preoperative factors related to patient survival (adjusted hazard ratio, 2.10; 95% confidence interval, 1.43 to 3.07). CONCLUSIONS: In this group of predominantly medically insured patients undergoing coronary artery bypass surgery, the risk of death in blacks at 5 years was twice that of whites.

High-efficiency gene transfer to autologous rabbit jugular vein grafts using adenovirus-transferrin/polylysine-DNA complexes.

Within the first year, 15-20% of coronary artery saphenous bypass vein grafts (SVGs) occlude because of thrombosis or progressive intimal hyperplasia. One potential new strategy to reduce this complication would be to introduce antithrombotic or antiproliferative genes in vein grafts before implantation. The success of this approach requires an efficient DNA delivery system. In the present study we tested the feasibility of using adenovirus-transferrin/polylysine-DNA complexes (TfAdpl/DNA) to achieve high-efficiency gene transfer into vascular interposition vein grafts. All studies used the Escherichia coli LacZ (beta-galactosidase [beta-Gal]) reporter gene under the control of the cytomegalovirus (CMV) earlier promoter and enhancer (pCMV/LacZ). Autologous rabbit jugular vein segments were incubated ex vivo for 60 min in a solution of TfAdpl/DNA complexes (1.2 x 10(10) biotinylated adenovirus particles, 2,430 ng of streptavindylated polylysine. 10 micrograms of plasmid DNA, and 9 micrograms of transferrin-polylysine per ml), and then reimplanted across the ligated right carotid artery. Control veins were incubated in TfAdpl solution in which DNA was omitted. A total of six grafts were treated with TfAdpl/DNA, and two grafts were treated with TfAdpl. Veins were harvested 3 (n = 3) and 7 (n = 3) days later and beta-Gal activity was determined by X-Gal chromogen staining. All six TfAdpl/DNA-treated grafts stained intensely blue, whereas control grafts were negative. Microscopic examination of serial sections revealed intracellular blue granules consistent with beta-Gal activity to be present in all of the endothelial cells and in numerous medial and advential cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia therapy: individual benefit and societal cost.

The US health care system is under increasing pressure to lower costs while maintaining quality of care. Providers will be forced to (1) measure the benefits of a particular therapy, and (2) demonstrate that the benefits justify the costs. The major components of therapeutic benefit are survival and quality of life. Chronic anemia may have little impact on survival, but studies have measured significant decrements in quality of life without therapy and increments in quality of life with therapy. This disease also presents important societal financial concerns due to its many competing therapies. The annual cost of treatment can vary from an average of a few dollars for iron supplementation to an average of $6,000 for a course of recombinant human erythropoietin. Physicians need to integrate information on therapeutic outcomes and cost to maximize individual benefit and justify the costs. The choice of therapy for anemia associated with cancer is complex because the onset of the anemia is multifactorial, and the effects of anemia may be masked by the underlying malignancy. There are insufficient data supporting a specific recommendation for transfusion or recombinant human erythropoietin therapy. The current cost-conscious environment in the United States presents an opportunity for health care providers to formally document the benefits of anemia therapy and justify the societal costs based on those benefits. Anemia is an excellent example of a condition that allows the formal analysis of disease impact and the effectiveness and cost of therapy because (1) it has multiple therapies, (2) the cost of therapy varies widely, and (3) the therapies have variable benefit depending on the individual patient. Using a model based on chronic renal failure, an outcomes structure was developed by which the impact of anemia and the therapies used to manage it can be measured. Its potential application to anemia in patients with cancer is discussed.

A stable prostacyclin analog, beraprost sodium, attenuates platelet accumulation and preservation-reperfusion injury of isografts in a rat model of lung transplantation.

BACKGROUND: Recent studies have shown that the extent of platelet accumulation in the vasculature of transplanted organs correlates with the degree of preservation-reperfusion injury. In this study, we examined the effect of a stable prostacyclin analog, beraprost sodium, which possesses potent antiplatelet activity, on parameters of platelet accumulation and preservation-reperfusion injury of isografts in a rat model of lung transplantation. METHODS: The heart-lung blocks of donor rats were flushed with and preserved in modified Euro-Collins solution at 4 degrees C for 6 hr or 24 hr. The left lung was transplanted into recipient rats and reperfused for 1 hr. Lung injury was evaluated by the pulmonary blood flow ratios to the lung isografts, the weight gain of the isografts, and histological examination. Small portions of the lung isografts were excised and stained with an antibody specific for rat platelets. A scoring system was developed to semiquantitate the intensity of antibody staining (score 0-4). The recipient rats received oral administration of beraprost sodium (0.3 mg/kg) before lung transplantation. Control animals received no beraprost sodium. RESULTS: In the 6-hr preservation study, administration of beraprost sodium significantly reduced the score for platelet accumulation (1.8+/-0.4 vs. 3.3+/-0.5, P<0.01). This observation was accompanied by a significantly decreased degree of preservation-reperfusion injury as evidenced by an increased blood flow ratio (13.7+/-2.6% vs. 4.5+/-3.6%, P<0.01) and a reduced weight gain (0.7+/-0.2 g vs. 1.1+/-0.2 g, P<0.01). Histological examination revealed severe capillary congestion in three of six cases in the control group, while no capillary congestion was observed in the beraprost group. In the 24-hr preservation study, no differences were seen in platelet accumulation scores or parameters of lung injury. CONCLUSION: Beraprost sodium, an antiplatelet agent, reduces platelet accumulation and preservation-reperfusion injury of lung transplants at 6 hr in this rat isograft model.

Assessment of pathological changes associated with chronic allograft rejection and tolerance in two experimental models of rat lung transplantation.

Lung transplantation is now routinely performed for a wide range of end-stage cardiopulmonary disorders. Despite overcoming the problems associated with early acute rejection, chronic rejection (CR) in the form of obliterative bronchiolitis has emerged as the primary cause of late graft loss. The mechanisms involved in the development of CR of lung allografts are poorly understood, and no effective therapy is currently available. To better understand the pathological events associated with CR and tolerance, we examined two models of lung allograft rejection established in our laboratory. First, we exchanged left lung allografts between moderately histoincompatible inbred rat strains (WKY-->F344: n = 42 and F344-->WKY: n = 40). The WKY-->F344 model was previously shown to develop spontaneous tolerance, while the converse model (F344-->WKY) showed persistent acute rejection. The purpose of this investigation was to assess histopathological changes associated with long-term grafts left in place up to 140 days after transplant. To confirm that tolerance had developed, skin-grafting experiments were performed. Five skin grafts from each strain were placed on lung allograft recipients on day 35 after transplant and skin allograft survival was assessed and compared with controls. Acute rejection (AR) was graded histologically (stage O-IV) and the pathologic intensity of inflammation and CR were graded (0-4: 0 = 0%, 1 = 1-25%, 2 = 26-50%, 3 = 51-75%, and 4 = 76-100%) on percentage of involvement with the following categories being examined: (a) lymphocytic infiltration (perivascular, peribronchial, and peribronchiolar) and (b) vasculitis, edema, hemorrhage, and necrosis. Finally, chronic rejection was diagnosed by the presence of intimal hyperplasia, interstitial fibrosis, peribronchiolar fibrosis, bronchiolitis obliterans, and bronchiectasis. The WKY-->F344 animals showed progressive AR (stage III, day 21). Thereafter, the AR subsided spontaneously and was stage 0 on day 140. There were no signs of CR in these animals. In the F344-->WKY model, the AR progressed up to stage III-IV (day 21) and maintained for several weeks at stage III. Thereafter, pictures of the lungs showed CR on days 49, 70, and 98. There were significant differences between the two models during the chronic phase, such as interstitial fibrosis (0 +/- 0 vs. 1.8 +/- 1.3, P < 0.005), peribronchiolar fibrosis (0 +/- 0 vs. 3.6 +/- 0.55, P < 0.01), vasculitis (0.2 +/- 0.45 vs. 2.0 +/- 0, P < 0.008), and intimal hyperplasia (0.2 +/- 0.45 vs. 2.6 +/- 0.9, P < 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Prolongation of skin allograft survival is associated with reduced Th1 cytokine responses in the WKY-->F344 rat model.

BACKGROUND: We have reported previously that F344 rats develop a spontaneous tolerance to WKY lung allografts and show long-term retention of donor-specific skin grafts placed 35 days after lung transplantation. In this study, we investigated the immunologic mechanisms that may be responsible for the prolonged skin graft survival in animals tolerized with lung allografts. METHODS: In the rejection group, WKY skin grafts were placed on normal F344 rats, whereas, in the tolerance group, the skin grafts were placed on F344 rats that had received a WKY lung transplant 35 days before skin grafting. Th1 (interleukin [IL]-2 and interferon-gamma [IFN-gamma]) and Th2 (IL-4 and IL-10) cytokine as well as transforming growth factor-beta1 mRNA expression in skin grafts and in draining lymph nodes were determined by reverse transcription-polymerase chain reaction. Macrophage and lymphocyte infiltration in skin grafts and the number of Langerhans cells in epidermal sheets of the grafts were examined by immunohistochemistry. RESULTS: IL-2 and IFN-gamma mRNA expression was significantly decreased in both the skin grafts and the draining lymph nodes of the tolerance group, compared to the rejection group, whereas IL-10 and transforming growth factor-beta1 mRNA expression was similar in both groups and IL-4 mRNA was rarely detected. Decreased and delayed CD8+, macrophage, and natural killer cell infiltration in the skin grafts from the tolerance group was also detected. Similar reduction in the number of Langerhans cells in the epidermis of the grafts from both groups was seen on day 1 after skin grafting, and thereafter the number remained stable in both groups. CONCLUSIONS: Reduced expression of Th1 cytokines and decreased infiltration of CD8+ cells, macrophages, and natural killer cells in the skin grafts may be responsible for prolongation of skin graft survival in the tolerance group.

Hydrophobic extracts of a Chinese herb (CMX-13) exhibit potent immunosuppressive properties and prevent acute rejection in a highly histoincompatible model of rat lung transplantation.

BACKGROUND: The potential of higher plants as sources for new immunosuppressive medications is well recognized. In our experiments we investigated the immunosuppressive effect of a highly refined and potent extract of a Chinese herbal preparation, CMX-13, on inhibiting acute allograft rejection (AR) in a highly histoincompatible rat lung transplant model, BN-->LEW, and on lymphocyte activation and cytokine gene expression in vitro. METHODS: Left lung transplants: the control group (group 1) received only dimethylsulfoxide (DMSO) which is the solvent for CMX-13. Group 2 received intramuscular cyclosporin A (CsA, 25 mg/kg) on day 2 posttransplant. Group 3 and 4 received i.p. CMX-13 (0.5 mg/day, low dose and 5 mg/day, high dose, respectively) on day 1, 2, and 3 posttransplant. All animals were killed on day 6 posttransplant. Several pathological categories of inflammation were examined. In vitro experiments: rat spleen cells were incubated with Con A or irradiated stimulator cells with/without serial dilutions of CMX-13 or CsA. Cell proliferation was measured by 3H-thymidine incorporation. mRNA expression of interleukin-2 and interferon-gamma was examined by reverse transcriptase-polymerase chain reaction. RESULTS: The severity of AR in animals receiving high dose CMX-13 was significantly reduced (stage II, P<0.05) compared with controls (stage IV). Significant differences were also seen when more specific parameters of inflammation were examined (necrosis, 0 vs. 1.7+/-1.0, P<0.05; interalveolar hemorrhage, 0 vs. 3.0+/-0.9, P<0.05). The responses seen in the animals treated with high dose CMX-13 were similar to those in the CsA group. CMX-13 inhibited T cell proliferative responses induced by Con A and alloantigen stimulation in a dose-dependent manner that were similar to CsA. Interleukin-2, and interferon-gamma mRNA expression in Con A-stimulated spleen cells was not inhibited by CMX-13 although CsA showed significant inhibition. CONCLUSIONS: 1) CMX-13 significantly reduces the stage of AR and parameters of inflammation in a highly histoincompatible rat lung transplant model. 2) CMX-13 has equal potency to CsA in the inhibition of Con A and alloantigen stimulated rat spleen cell proliferation. 3) CMX-13 showed no inhibitory effects on IL-2 and gamma-IFN mRNA expression, suggesting that its mechanism of action is different from CsA. 4) CMX-13 or derivatives may have potential utility as an immunosuppressive agent(s) in modulation of AR and management of other inflammatory and immunological disorders.