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Humans can acquire and maintain motor skills throughout their lives through motor learning. Motor learning and skill acquisition are essential for rehabilitation following neurological disease or injury. Adaptation, the initial stage of motor learning, involves short-term changes in motor performance in response to a new demand in the person's environment. Repeated adaptation can improve skill performance and result in long-term skill retention. Locomotor adaptation is extensively studied using split-belt treadmill paradigms. In this study we explored whether bidirectional walking (BDW) on a split-belt treadmill can induce short-term gait adaptations. Twelve healthy volunteers participated in our single session, starting with 2 minutes of normal walking (NW), followed by four 5-minute blocks of BDW with a 1-minute passive rest in between blocks, and ending with another 2-minute of NW. We recorded body kinematics and ground reaction forces throughout the experiment. Participants quickly adapted to BDW with both legs showing decreased step lengths. However, only the backward-walking leg exhibited aftereffects upon returning to NW, indicating short-term adaptation. Notable kinematic changes were observed, particularly in hip extension and pelvis tilt, though these varied among participants. Our findings suggest that BDW induces unilateral adaptations despite bilateral changes in gait, offering new insights into locomotor control and spinal CPG organization., Competing Interests: Competing Interests The authors have no competing interests to declare.

The neural control of posture and movement is interdependent. During voluntary movement, the neural motor command is executed by the motor cortex through the corticospinal tract and its collaterals and subcortical targets. Here we address the question of whether the control mechanism for the postural adjustments at nonmoving joints is also involved in overcoming gravity at the moving joints. We used single-pulse transcranial magnetic stimulation to measure the corticospinal excitability in humans during postural and reaching tasks. We hypothesized that the corticospinal excitability is proportional to background muscle activity and the gravity-related joint moments during both static postures and reaching movements. To test this hypothesis, we used visual targets in virtual reality to instruct five postures and three movements with or against gravity. We then measured the amplitude and gain of motor evoked potentials in multiple arm and hand muscles at several phases of the reaching motion and during static postures. The stimulation caused motor evoked potentials in all muscles that were proportional to the muscle activity. During both static postures and reaching movements, the muscle activity and the corticospinal contribution to these muscles changed in proportion with the postural moments needed to support the arm against gravity, supporting the hypothesis. Notably, these changes happened not only in antigravity muscles. Altogether, these results provide evidence that the changes in corticospinal excitability cause muscle cocontraction that modulates limb stiffness. This suggests that the motor cortex is involved in producing postural adjustments that support the arm against gravity during posture maintenance and reaching. NEW & NOTEWORTHY Animal studies suggest that the corticospinal tract and its collaterals are crucial for producing postural adjustments that accompany movement in limbs other than the moving limb. Here we provide evidence for a similar control schema for both arm posture maintenance and gravity compensation during movement of the same limb. The observed interplay between the postural and movement control signals within the corticospinal tract may help explain the underlying neural motor deficits after stroke.

Musculoskeletal modeling is a new computational tool to reverse engineer human control systems, which require efficient algorithms running in real-time. Human hand pronation-supination movement is accomplished by movement of the radius and ulna bones relative to each other via the complex proximal and distal radioulnar joints, each with multiple degrees of freedom (DOFs). Here, we report two simplified models of this complex kinematic transformation implemented as a part of a 20 DOF model of the hand and forearm. The pronation/supination DOF was implemented as a single rotation joint either within the forearm segment or separating proximal and distal parts of the forearm segment. Torques produced by the inverse dynamic simulations with anatomical architecture of the forearm (OpenSim model) were used as the "gold standard" in the comparison of two simple models. Joint placement was iteratively optimized to achieve the closest representation of torques during realistic hand movements. The model with a split forearm segment performed better than the model with a solid forearm segment in simulating pronation/supination torques. We conclude that simplifying pronation/supination DOF as a single-axis rotation between arm segments is a viable strategy to reduce the complexity of multi-DOF dynamic simulations.

The sensorimotor integration during unconstrained reaching movements in the presence of variable environmental forces remains poorly understood. The objective of this study was to quantify how much the primary afferent activity of muscle spindles can contribute to shaping muscle coactivation patterns during reaching movements with complex dynamics. To achieve this objective, we designed a virtual reality task that guided healthy human participants through a set of planar reaching movements with controlled kinematic and dynamic conditions that were accompanied by variable muscle co-contraction. Next, we approximated the Ia afferent activity using a phenomenological model of the muscle spindle and muscle lengths derived from a musculoskeletal model. The parameters of the spindle model were altered systematically to evaluate the effect of fusimotor drive on the shape of the temporal profile of afferent activity during movement. The experimental and simulated data were analyzed with hierarchical clustering. We found that the pattern of co-activation of agonistic and antagonistic muscles changed based on whether passive forces in each movement played assistive or resistive roles in limb dynamics. The reaching task with assistive limb dynamics was associated with the most muscle co-contraction. In contrast, the simulated Ia afferent profiles were not changing between tasks and they were largely reciprocal with homonymous muscle activity. Simulated physiological changes to the fusimotor drive were not sufficient to reproduce muscle co-contraction. These results largely rule out the static set and α-γ coactivation as the main types of fusimotor drive that transform the monosynaptic Ia afferent feedback into task-dependent co-contraction of antagonistic muscles. We speculate that another type of nonlinear transformation of Ia afferent signals that is independent of signals modulating the activity of α motoneurons is required for Ia afferent-based co-contraction. This transformation could either be applied through a complex nonlinear profile of fusimotor drive that is not yet experimentally observed or through presynaptic inhibition.

[This corrects the article DOI: 10.1371/journal.pone.0164050.].

Neural control of movement can only be realized though the interaction between the mechanical properties of the limb and the environment. Thus, a fundamental question is whether anatomy has evolved to simplify neural control by shaping these interactions in a beneficial way. This inductive data-driven study analyzed the patterns of muscle actions across multiple joints using the musculoskeletal model of the human upper limb. This model was used to calculate muscle lengths across the full range of motion of the arm and examined the correlations between these values between all pairs of muscles. Musculoskeletal coupling was quantified using hierarchical clustering analysis. Muscle lengths between multiple pairs of muscles across multiple postures were highly correlated. These correlations broadly formed two proximal and distal groups, where proximal muscles of the arm were correlated with each other and distal muscles of the arm and hand were correlated with each other, but not between groups. Using hierarchical clustering, between 11 and 14 reliable muscle groups were identified. This shows that musculoskeletal anatomy does indeed shape the mechanical interactions by grouping muscles into functional clusters that generally match the functional repertoire of the human arm. Together, these results support the idea that the structure of the musculoskeletal system is tuned to solve movement complexity problem by reducing the dimensionality of available solutions., Competing Interests: The authors have declared that no competing interests exist.

Background: Despite improving results in lung transplantation, a significant number of grafts fail early or late postoperatively. The pulmonary retransplant registry was founded in 1991 to determine the predictors of outcome after retransplantation. We hypothesized that ambulatory status of the recipient and center retransplant volume, which had been previously shown to predict survival after retransplantation, would also be associated with improved graft function postoperatively., Methods: Two hundred thirty patients underwent retransplantation in 47 centers from 1985 to 1996. Logistic regression methods were used to determine variables associated with, and predictive of, survival and lung function after retransplantation., Results: Kaplan-Meier survival was 47% +/- 3%, 40% +/- 3%, and 33% +/- 4% at 1, 2, and 3 years, respectively. On multivariable analysis, the predictors of survival included ambulatory status or lack of ventilator support preoperatively (p = 0.005; odds ratio, 1.62; 95% confidence interval, 1.15 to 2.27), followed by retransplantation after 1991 (p = 0.048; odds ratio, 1.41; 95% confidence interval, 1.003 to 1.99). Ambulatory, nonventilated patients undergoing retransplantation after 1991 had a 1-year survival of 64% +/- 5% versus 33% +/- 4% for nonambulatory, ventilated recipients. Eighty-one percent, 70%, 62%, and 56% of survivors were free of bronchiolitis obliterans syndrome at 1, 2, 3, and 4 years after retransplantation, respectively. Factors associated with freedom from stage 3 (severe) bronchiolitis obliterans syndrome at 2 years after retransplantation included an interval between transplants greater than 2 years (p = 0.01), the lack of ventilatory support before retransplantation (p = 0.03), increasing retransplant experience within each center (fifth and higher retransplant patient, p = 0.04), and total center volume of five or more retransplant operations (p = 0.05)., Conclusions: Nonambulatory, ventilated patients should not be considered for retransplantation with the same priority as other candidates. The best intermediate-term functional results occurred in more experienced centers, in nonventilated patients, and in patients undergoing retransplantation more than 2 years after their first transplant. In view of the scarcity of lung donors, patient selection for retransplantation should remain strict and should be guided by the outcome data reviewed in this article.

Objective: An international series of pulmonary retransplantation was updated to determine the factors associated with pulmonary function, bronchiolitis obliterans syndrome stage, and survival after operation., Methods: One hundred sixty patients underwent retransplantation in 35 centers from 1985 to 1995. Logistic regression methods were used to determine variables associated with 3-month and 2-year survival after retransplantation. Values of forced expiratory volume in 1 second were contrasted between groups by unpaired, two-tailed t tests., Results: The median follow-up in surviving recipients was 780 days. Actuarial survival was 45% +/- 4%, 41% +/- 4%, and 33% +/- 4% at 1, 2, and 3 years, respectively. On multivariable analysis, the only predictor of 3-month survival was preoperative ambulatory status (p = 0.005), whereas center experience with at least five pulmonary retransplantations was the sole predictor of 2-year survival (p = 0.04). The prevalence of stage 3 (severe) bronchiolitis obliterans syndrome was 12% at 1 year, 15% at 2 years, and 33% at 3 years after retransplantation. Retransplant recipients with stage 3 bronchiolitis obliterans syndrome at 1 year had a significantly worse actuarial survival than those with stages 0 to 2 (p < 0.01). By 3 years after retransplantation, the forced expiratory volume in 1 second was significantly lower in patients who underwent reoperation because of obliterative bronchiolitis than in patients who underwent retransplantation because of acute graft failure or an airway complication (p = 0.02). Only 31% of patients who underwent retransplantation because of obliterative bronchiolitis were free of bronchiolitis obliterans syndrome at 3 years versus 83% of patients who underwent retransplantation because of other indications (p = 0.02)., Conclusions: Preoperative ambulatory status predicts early survival and center volume predicts intermediate-term outcome after retransplantation. Improved management strategies are necessary to prevent the development of progressive graft dysfunction after retransplantation for obliterative bronchiolitis.

The authors analyzed factors that may influence the outcome of adult patients with respiratory failure who were treated with ECMO. Between December 1990 and July 1995, the authors used ECMO to support 33 patients (age range, 17-56 years) with respiratory failure from adult respiratory distress syndrome (ARDS; n = 9), primary graft failure after lung transplantation (n = 16), late graft failure after lung transplantation (n = 5), and miscellaneous reasons (n = 3). Twenty (61%) patients were successfully weaned from ECMO, and 13 (39%) survived to hospital discharge. Venoarterial ECMO was used in 46% of survivors, compared with 60% of nonsurvivors (p = 0.43). The time on mechanical support before ECMO and the duration on ECMO for survivors and nonsurvivors was 2.9 +/- 1.8 days vs 5.0 +/- 1.3 days (p = 0.35), and 6.5 +/- 1.8 days vs 5.7 +/- 1.1 days (p = 0.68), respectively. Compared with the nonsurvivors, survivors had higher PF ratios (PaO2/FIO2; 104 +/- 33 vs 81 +/- 8, p = 0.43) before ECMO was initiated, although the differences were not significant. Among the patients who received ECMO for primary graft failure, 75% were weaned from ECMO, and 56% survived to discharge. ECMO is beneficial for adult patients with respiratory failure, especially those with primary graft failure after lung transplantation.

Background: Transplantation of lung allografts from the same donor into 2 recipients ("twinning") provides an opportunity to study recipient and donor factors that influence early allograft function., Methods: Twenty-seven pairs of recipients were identified and evaluated using multivariate logistic regression analysis (p < 0.05). Four measures of early graft function were analyzed: alveolar-arterial gradient in the operating room, first alveolar-arterial gradient in the intensive care unit, alveolar-arterial gradient at 24 hours, and days of mechanical ventilation., Results: Analysis of the pooled data without regard to pairing showed that alveolar-arterial gradient in the operating room was influenced by donor age, length of donor hospitalization, recipient mean pulmonary artery (PA) pressure at unclamping, and transplantation of a left lung. The alveolar-arterial gradient in the intensive care unit was correlated with donor age, donor cause of death, and mean PA pressure on arrival in that unit. Only mean PA pressure remained significant at 24 hours. Days of mechanical ventilation was determined by mean PA pressure on arrival in the intensive care unit, drop in mean PA pressure during operation, and diagnosis of the recipient. In the paired analysis, receiving a left lung, recipient diagnosis (pulmonary hypertension worse than others), and need of cardiopulmonary bypass were significantly associated with immediate graft dysfunction, although these influences did not persist beyond the immediate postoperative period. Donor arterial oxygen tension and time of ischemia were not significant predictors in any analysis., Conclusions: Immediate allograft function was associated with donor-related characteristics initially, but these lost importance over the ensuing 24 hours. Recipient PA pressure was an immediate and persisting influence. In the analysis of differences in function between the members of each pair, transplantation of the left lung, recipient diagnosis, and cardiopulmonary bypass were identified, but their influence did not persist beyond the first 6 hours.

A major problem in cardiac transplantation is the death of candidates due to the increasing shortage of donors and the consequent longer waiting periods. To determine whether clinical markers for death could be identified in these patients, 168 adult candidates with heart failure (NYHA class III and IV) listed between August 1987 and December 1989 were analyzed. There were 104 patients with ischemic cardiomyopathy (ISCM) and 64 with idiopathic dilated cardiomyopathy (IDCM). Transplantation was performed in 93 patients (55%). Actuarial 1 year survival was 61% in the ISCM group and 78% in the IDCM group (P = NS). Freedom from sudden death at one year was significantly lower in the ISCM group (73%) than in the IDCM group (96%) (P < 0.01). The rate of patients who did not die from terminal myocardial failure was 83% in the ISCM group and 81% in the IDCM group (P = NS). There were no significant differences between the two groups in right atrial, pulmonary artery, and pulmonary wedge pressures, transpulmonic pressure gradient, pulmonary vascular resistance, cardiac index, and ejection fraction. We conclude that candidates for cardiac transplantation with ISCM are at higher risk for sudden death during the first year on the waiting list than patients with IDCM. These results warrant consideration of aggressive arrhythmia control measures, including an automatic implantable defibrillator, to "bridge" these high risk patients to transplantation.

Between January 1, 1989, and December 31, 1994, we have treated 122 primary heart recipients with FK 506 (group I) and 121 with cyclosporine (group II). Fifty patients in the cyclosporine (CyA) group received no lympholytic induction (CyA alone) and 71 others received lympholytic induction with either rabbit antithymocyte globulin or OKT3 (CyA+LI). The mean follow-up was longer in the FK 506 group than in the CyA groups (3.2 +/- 1.3 vs 2.3 +/- 1.8 years; p< 0.01). Patient survival did not differ on the basis of the type of immunosuppression used. At 3 months after transplantation, the freedom from rejection in the FK 506 group was higher than that of the CyA-alone group (47% vs 22%, p < 0.01) but similar to that of the CyA+LI group (47% vs 53%). The linearized rejection rate (episodes/100 patient-days) of the FK 506 group (0.09 episodes) was lower (p < 0.05) than that of the CyA-alone group (0.26) and the CyA+LI group (0.13). The requirement for pulsed steroids to treat rejection was less in common in the FK 506 group than in either CyA group. Eighteen patients in the CyA group had refractory rejections; all resolved with FK 506 rescue. Two patients in the FK 506 group had refractory rejection that resolved with total lymphoid irradiation (n=1) and methotrexate therapy (n=1). Patients receiving FK 506 had a lower risk of hypertension and required a lower dose of steroids. Although the mean serum creatinine concentration at 1 year was higher in the FK 506 group, this difference disappeared after 2 years. No patients required discontinuation of FK 506 because of its side effects. Our intermediate-term results indicate that FK 506 compares favorably with CyA as a primary immunosuppressant in heart transplantation.

Background: Prolonged nonspecific immunosuppression after solid-organ transplantation is associated with an increased risk of certain cancers. This study examined the development of solid-organ tumors after cardiac transplantation., Methods: Thirty-eight solid tumors were identified in 36 (5.9%) of 608 cardiac transplant recipients who survived more than 30 days. Two patients had two types of skin tumors (basal cell and squamous cell). The tumors included the following types: skin (15), lung (10), breast (1), bladder (2), larynx (2), liver (1), parotid (1), testicle (1), uterus (2), melanoma (2), and Merkel's cell (1). Four immunosuppression regimens based on cyclosporin A or FK 506 were used during this period., Results: There was no association between the incidence of solid tumors and the use of lympholytic therapy. After the diagnosis of tumor was made, the actuarial 2-year survival rates of recipients with skin, lung, and other solid tumors were 71%, 22%, and 23%, respectively. Eight of 10 patients with lung cancer were in stage IIIA or higher at the time of diagnosis., Conclusion: Skin and lung tumors are the most frequent solid tumors in heart transplant recipients. Skin tumors (except Merkel's cell carcinoma and melanoma) usually have a benign course, whereas lung and other tumors developing in cardiac transplant recipients carry a poor prognosis. Advanced disease stage at the time of diagnosis is responsible for the dismal outcome of recipients in whom solid tumors develop. Close postoperative tumor surveillance after cardiac transplantation is warranted.

An international series of pulmonary retransplantation was updated to identify the predictors of outcome and the prevalence and recurrence rate of obliterative bronchiolitis after operation. The study cohort included 139 patients who underwent retransplantation in 34 institutions in North America and Europe between 1985 and 1994. Eighty patients underwent retransplantation because of obliterative bronchiolitis, 34 because of acute graft failure, 13 because of intractable airway complications, 8 because of acute rejection, and 4 because of other indications. Survivors were followed up for a median of 630 days, with 48 patients alive at 1 year, 30 at 2 years, and 16 at 3 years after retransplantation. Actuarial survival was 65% +/- 4% at 1 month, 54% +/- 4% at 3 months, 45% +/- 4% at 1 year, 38% +/- 5% at 2 years, and 36% +/- 5% at 3 years; nonetheless, of 90-day postoperative survivors, 65% +/- 6% were alive 3 years after retransplantation. Life-table and univariate Cox analysis revealed that more recent year of retransplantation (p = 0.009), identical match of ABO blood group (p = 0.01), absence of a donor-recipient cytomegalovirus mismatch (p = 0.04), and being ambulatory immediately before retransplantation (p = 0.04) were associated with survival. By multivariate Cox analysis, being ambulatory before retransplantation was the most significant predictor of survival (p = 0.008), followed by reoperation in Europe (p = 0.044). Complete pulmonary function tests were done yearly in every survivor of retransplantation and bronchiolitis obliterans syndrome stages were assigned. Eleven percent of patients were in stage 3 at 1 year, 20% at 2 years, and 25% at 3 years after retransplantation. Values of forced expiratory volume in 1 second decreased from 1.89 +/- 0.13 L early after retransplantation to 1.80 +/- 0.15 L at 1 year and 1.54 +/- 0.16 L at 2 years (p = 0.006, year 2 versus baseline postoperative value). Most of this decrease occurred in patients who underwent retransplantation because of obliterative bronchiolitis, whereas the pulmonary function of patients who underwent retransplantation because of other conditions did not significantly change. We conclude that survival after pulmonary retransplantation is improving. Optimal results can be obtained in patients who are ambulatory before retransplantation. Compared with recent data after primary lung transplantation, bronchiolitis obliterans syndrome does not appear to recur in an accelerated manner after retransplantation. As long as early mortality as a result of infection can be minimized, pulmonary retransplantation appears to offer a reasonable option in highly selected patients.

Objective: The authors review the Pennsylvania Health Care Cost Containment Council reports on coronary artery surgery and compare this reporting structure to others, including the Society for Thoracic Surgeons database, currently used by their own program. The authors review the growing likelihood of a need for outcome measures for all of the surgical subspecialties., Summary and Background Data: Pressure from consumers and insurers will require surgical specialties to be graded by objective outcome measures. Practitioners must be prepared and become involved in the process., Methods: The authors reviewed the data, which grades all of Pennsylvania's hospitals at which coronary artery bypass is performed. Apparently, the major risk factors commonly employed in most other risk adjustment schemes for cardiac surgery have been deleted, and the practitioners might be judged unfairly. The Pennsylvania system appears to be insurance driven to reward low-cost providers who operate on patients with the lowest risk., Results: Review of data suggests that the Pennsylvania Health Care Cost Containment Council's annual publication, A Consumer's Guide for Coronary Artery Bypass Surgery, misrepresents fair risk adjustment in favor of lower-risk patients, thereby encouraging better score cards for those institutions with patients who are less ill. Data regarding charges for the procedure have not been risk adjusted or related to a regional economic index., Conclusions: Surgeons must prepare to better understand relevant models that evaluate outcome. Cardiothoracic surgery is one of the first specialties to feel the pressures of mandated evaluations, and the lessons learned in Pennsylvania should be applicable to other states and their practitioners.

Background: We and others have demonstrated that a low level of donor cell chimerism was present for years after transplantation in tissues and peripheral blood of heart and lung recipients; it was associated, in the latter, with a lower incidence of chronic rejection. To augment this phenomenon, we initiated a trial combining simultaneous infusion of donor bone marrow with heart or lung allotransplantation., Methods: Between September 1993 and January 1995, 15 nonconditioned patients received either heart (n = 10) or lung (n = 5) allografts concurrently with an infusion of unmodified donor bone marrow (3.0 x 10(8) cells/kg), and were maintained on immunosuppressive regimen consisting of tacrolimus and steroids., Results: There was no complication associated with the infusion of donor bone marrow. Chimerism was detectable in 73% of bone marrow-augmented patients up to the last sample tested. Of the 5 control recipients who did not receive bone marrow infusion, only 1 had detectable chimerism by flow on postoperative day 15, which dwindled to an undetectable level by postoperative day 36. None of the patients had evidence of donor-specific immune modulation by mixed lymphocyte reaction., Conclusions: The combined infusion of donor bone marrow and heart or lung transplantation, without preconditioning of the recipient, is safe and is associated with an augmentation of donor cell chimerism.

Background: A prospective clinical trial was undertaken to compare the efficacy of tacrolimus (FK 506) versus cyclosporine as the primary immunosuppressive agent after lung transplantation., Methods: Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease., Results: One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p = 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05)., Conclusions: This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.

Background: Obliterative bronchiolitis (OB) occurs in up to 40% of patients in the intermediate term after lung transplantation. In recent years an increasing number of recipients with end-stage OB have been treated with retransplantation., Methods: Seventy-two patients with OB underwent retransplantation at 26 North American and European centers a median of 590 days after their first transplant operation. The predictors of survival were determined using life table and Cox proportional hazards methods, and the recurrence rate of OB was determined in survivors., Results: The actuarial survival rate was 71% +/- 5% at 1 month, 43% +/- 6% at 1 year, and 35% +/- 6% at 2 years; nonetheless, of the 90-day postoperative survivors, 63% +/- 7% were alive 2 years after retransplantation. Institutional experience with more than three pulmonary retransplantations (p = 0.008), reoperation in Europe (p = 0.013), donor-recipient ABO blood group identity (p = 0.018), and more recent year of retransplantation (p = 0.03) were associated with survival. On multivariate analysis, reoperation after 1989 (p < 0.001), retransplantation performed in Europe (p = 0.017), and being ambulatory immediately before reoperation (p = 0.022) were found to be predictive of a positive outcome. Pulmonary function test analyses confirmed that the forced expiratory volume in 1 second decreased from postoperative baseline values by 11% +/- 9% at 1 year and 27% +/- 10% at 2 years (p = 0.02; year 2 versus baseline). Fourteen percent of patients were in stage 3 of the bronchiolitis obliterans syndrome at 1 year postoperatively, with 33% affected at 2 years., Conclusions: The results of pulmonary retransplantation for OB are improving. Current evidence indicates that OB does not recur in an accelerated manner after retransplantation, although pulmonary function does worsen again by 2 years. Pulmonary retransplantation is appropriate only in selected patients with OB who are ambulatory and are operated on at experienced centers.

Infection and rejection remain the greatest threats to the survival of pulmonary allograft recipients. Furthermore, a relationship may exist between these events, because the occurrence of one may predispose to the other. By using multivariate analysis for repeated events, we analyzed the risk factors for bacterial, fungal, and viral infection, grade II or greater acute rejection, and death among 239 lung transplant recipients who received 250 allografts between January 1988 and September 1993. A total of 90 deaths, 491 episodes of acute rejection, and 542 infectious episodes occurred during a follow-up of 6 to 71 months. The hazard or risk patterns of death, infection, and rejection each followed an extremely high risk during the first 100 days after transplantation, a second modest risk period at 800 to 1200 days, and a lower constant risk. Infection and graft failure manifested by diffuse alveolar damage were the major causes of early death (< 100 days), whereas infection and chronic rejection were primary causes of later death after pulmonary transplantation. By multivariate analysis, cytomegalovirus mismatching risk for primary infection was the most significant risk factor for death, rejection, and infection. Absence of cytomegalovirus prophylaxis was also a risk factor for early and late death and late infection. Survival of recipients who received cytomegalovirus prophylaxis was significantly improved. Immunosuppression based on cyclosporine versus FK 506 was a risk factor for late death and late infection. Graft failure manifested by diffuse alveolar damage/adult respiratory distress syndrome was a significant risk for death late after transplantation. These data suggest the following: (1) The hazard for death, infection, and rejection after pulmonary transplantation appears biphasic; (2) lower survival is associated with ischemia-reperfusion lung injury represented by diffuse alveolar damage/adult respiratory distress syndrome; (3) cytomegalovirus mismatch, absence of cytomegalovirus prophylaxis, and development of cytomegalovirus disease are significant threats for death, rejection, and infection after pulmonary transplantation; (4) prevention of cytomegalovirus disease should improve survival by decreasing the prevalence of infection and rejection.

The indications for single, bilateral, and heart-lung transplantation for patients with pulmonary hypertension remain controversial. We retrospectively analyzed the results from 11 single, 22 bilateral, and 24 heart-lung transplant procedures performed between January 1989 and January 1993 on 57 consecutive patients with pulmonary hypertension caused by primary pulmonary hypertension (n = 27) or Eisenmenger's syndrome (n = 30). Candidates with a left ventricular ejection fraction less than 35%, coronary artery disease, or Eisenmenger's syndrome caused by surgically irreparable complex congenital heart disease received heart-lung transplantation. All other candidates received single or bilateral lung transplantation according to donor availability. Although postoperative pulmonary artery pressures decreased in all three allograft groups, those in single lung recipients remained significantly higher than those in bilateral and heart-lung recipients. The cardiac index improved significantly in only the bilateral and heart-lung transplant recipients. A significant ventilation/perfusion mismatch occurred in the single lung recipients as compared with bilateral and heart-lung recipients because of preferential blood flow to the allograft. Graft-related mortality was significantly higher and overall functional recovery as assessed by New York Heart Association functional class was significantly lower at 1 year in the single as compared with bilateral and heart-lung recipients. Thus bilateral lung transplantation may be a more satisfactory option for patients with pulmonary hypertension with simple congenital heart disease, absent coronary arterial disease, and preserved left ventricular function. Other candidates will still require heart-lung transplantation.

An intravenous membrane oxygenator is being developed to supplement oxygen and carbon dioxide exchange in patients with temporary and potentially reversible lung failure in either a lung transplantation setting or in cases of acute respiratory distress from multiple causes. Our device incorporates a pulsatile balloon that is centrally located and around which are mounted microporous hollow fibers. Oxygen is vaccuumed through the fibers with resultant gas exchange. The rhythmic pulsations of the balloon enhance cross-flow and three-dimensional convective mixing at the blood-fiber interface and thus promote more efficient oxygen-carbon dioxide exchange. Seven intravenous membrane oxygenator prototypes have been designed and fabricated. Modifications in design have led to a progressive improvement in gas flux. Gas exchange performance measured in vitro and with both saline solution and fresh ox blood have shown gas exchange as high as 203 ml/min/m2 for oxygen and 182 ml/min/m2 for carbon dioxide. In vivo dog experiments with the device positioned in the inferior vena cava and right atrium have shown over a 50% increase in oxygen flux with balloon activation versus the static situation without changes in hemodynamics. The size of the prototype tested in animals can be scaled up fivefold for anticipated human trials. Our results indicate that our intravenous membrane oxygenator prototypes now under development may be an alternative to extracorporeal membrane oxygenation in the treatment of temporary respiratory failure.

In an era of progressive cost containment and public scrutiny, the wisdom of aggressive surgical therapy for high-risk candidates has been questioned. At our center in the previous 24 months, 728 patients with coronary artery disease were entered into The Society of Thoracic Surgeons national database, and the hospital outcomes plus length of stay were analyzed. Patients were separated according to the predicted mortality based on the groupings in The Society of Thoracic Surgeons database: 0 to 5% (453 patients); 5% to 10% (126 patients); 10% to 20% (96 patients); 20% to 30% (17 patients); and 30% and greater (36 patients). There was a close correlation with the predicted rates of mortality. Importantly, the preoperative risk stratification demonstrated a strong correlation with the significant morbidity and excessive length of stay in the highest-risk groups (predicted risk of 20% to > or = 30%). The incidences of the most common complications in the group with the highest predicted risk (> or = 30%) were 28%, renal failure; 33%, ventilator dependence; and 17%, cardiac arrest. In addition, at short-term follow-up (6 to 8 months), a 24.3% mortality was identified in patients with a predicted mortality that exceeded 20%. These data quantify the risks and morbidities associated with the care of seriously ill patients with coronary artery disease and demonstrate the need for professional and public discussions focusing on the association of a high preoperative risk status and the consumption of resources.

Single lung transplantation for pulmonary hypertension (PH) remains a controversial therapy. We retrospectively studied 48 consecutive recipients of single-lung allografts to determine if preoperative PH was associated with increased mortality or morbidity. Recipients were divided into two groups; those who did have preoperative PH, defined as mean pulmonary arterial pressure less than or equal to 30 mm Hg (n = 29; group 1), and those recipients with PH who had a mean pulmonary arterial pressure greater than 30 mm Hg (n = 19; group II). Mean pulmonary arterial pressure and pulmonary vascular resistance decreased significantly after transplantation in recipients with PH. These values remained significantly higher as compared with those in recipients without pretransplantation PH. Postoperative pulmonary ventilation/perfusion scans demonstrated significant ventilation/perfusion mismatch in lung allografts with pretransplantation PH (p < 0.05). The mean duration of intensive care unit stay was significantly longer in recipients with PH. Although operative mortality was similar between the groups, preoperative PH was associated with significantly lower 1-year survival (53% versus 72%; p < 0.05) and New York Heart Association functional class (p < 0.05). We conclude that preoperative PH in single-lung transplant recipients is associated with significantly increased mortality, prolonged intensive care unit stay, and less symptomatic improvement. Thus, despite a shortage of donor organs, single-lung transplantation may be suboptimal therapy in patients with PH. Further study comparing single versus bilateral lung transplantation for PH is necessary.

We have conducted a unique prospective randomized study to compare the effect of FK506 and cyclosporine (CsA) as the principal immunosuppressive agents after pulmonary transplantation. Between October 1991 and March 1993, 74 lung transplants (35 single lung transplants [SLT], 39 bilateral lung transplant [BLT]) were performed on 74 recipients who were randomly assigned to receive either FK or CsA. Thirty-eight recipients (19 SLT, 19 BLT) received FK and 36 recipients (16 SLT, 20 BLT) received CsA. Recipients receiving FK or CsA were similar in age, gender, preoperative New York Heart Association functional class, and underlying disease. Acute rejection (ACR) was assessed by clinical, radiographic, and histologic criteria. ACR was treated with methylprednisolone, 1 g i.v./day, for three days or rabbit antithymocyte globulin if steroid-resistant. During the first 30 days after transplant, one patient in the FK group died of cerebral edema, while two recipients treated with CsA died of bacterial pneumonia (1) and cardiac arrest (1) (P = NS). Although one-year survival was similar between the groups, the number of recipients free from ACR in the FK group was significantly higher as compared with the CsA group (P < 0.05). Bacterial and viral pneumonias were the major causes of late graft failure in both groups. The mean number of episodes of ACR/100 patient days was significantly fewer in the FK group (1.2) as compared with the CsA group (2.0) (P < 0.05). While only one recipient (1/36 = 3%) in the group treated with CsA remained free from ACR within 120 days of transplantation, 13% (5/38) of the group treated with FK remained free from ACR during this interval (P < 0.05). The prevalence of bacterial infection in the CsA group was 1.5 episodes/100 patient days and 0.6 episodes/100 patient days in the FK group. The prevalence of cytomegaloviral and fungal infection was similar in both groups. Although the presence of bacterial, fungal, and viral infections was similar in the two groups, ACR occurred less frequently in the FK-treated group as compared with the CsA-treated group in the early postoperative period (< 90 days). Early graft survival at 30 days was similar in the two groups, but intermediate graft survival at 6 months was better in the FK group as compared with the CsA group.