Printing Reinforcing Structures onto Microsieves That Are Floating on a Water Surface.

This article describes the preparation of hierarchically structured microsieves via a suitable combination of float-casting and inkjet-printing: A mixture of hydrophobized silica particles of 600 nm ± 20 nm diameter, a suitable non-water-soluble nonvolatile acrylic monomer, a nonvolatile photoinitiator, and volatile organic solvents is applied to a water surface. This mixture spontaneously spreads on the water surface; the volatile solvents evaporate and leave behind a layer of the monomer/initiator mixture comprising a monolayer of particles, each particle protruding out of the monomer layer at the top and bottom surface. Photopolymerization of the monomer converts this mixed layer into a solid composite membrane floating on the water surface. Onto this membrane, while still floating on the water surface, a hierarchical reinforcing structure based on a photocurable ink is inkjet-printed and solidified. In contrast to the nonreinforced membrane, the reinforced membrane can easily be lifted off the water surface without suffering damage. Subsequently, the silica particles are removed, and thus, the reinforced composite membrane is converted into a reinforced microsieve of 350 nm ± 50 nm thickness bearing uniform through pores of 465 nm ± 50 nm diameter. This reinforced microsieve is mounted into a filtration unit and used to filter model dispersions: its permeance for water at low Reynolds numbers is in accordance with established theories on the permeance of microsieves and significantly above the permeance of conventional filtration media; it retains particles exceeding the pore size, while letting particles smaller than the pore size pass.

Unique 40-year survival after heart transplantation with normal graft function and spontaneous operational tolerance.

Unique 40-year survival after heart transplantation with normal graft function and spontaneous operational tolerance.

Modified implantation technique for the Berlin Heart EXCOR Assist Device in adults.

The Berlin Heart EXCOR ventricular assist device provides pulsatile ventricular assistance. It can be used for univentricular or biventricular support. However, pre-, intra-, and postoperative complications (e.g., bleeding, anastomotic insufficiency) are frequent. We present herein a detailed description of our modified implantation technique in order to facilitate further clinical use of the system.

Surgical strategy for biventricular assist device implantation after previous coronary artery bypass grafting.

In an aging population, numerous patients who underwent previous coronary artery bypass grafting (CABG) are presenting with end-stage ischemic cardiomyopathy. Although redo CABG and cardiological interventions are possible treatment options, orthotopic heart transplantation remains an ultimate option for these patients. However, there is high morbidity and mortality on the waiting list, and mechanical circulatory support is a life-saving concept [Hetzer 2006; Taylor 2009].We developed a simplified and safe technique for implantation of a biventricular assist device as a redo in complex patients after previous CABG and end-stage heart failure.

Potential functional and survival benefit of double over single lung transplantation for selected patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a frequent indication for lung transplantation (LTX) with pulmonary hypertension (PH) negatively affecting outcome. The optimal procedure type remains a debated topic. The aim of this study was to evaluate the impact of pretransplant PH in IPF patients. Single LTX (SLTX, n = 46) was the standard procedure type. Double LTX (DLTX, n = 30) was only performed in cases of relevant PH or additional suppurative lung disease. There was no significant difference for pretransplant clinical parameters. Preoperative mean pulmonary arterial pressure was significantly higher in DLTX recipients (22.7 +/- 0.8 mmHg vs. 35.9 +/- 1.8 mmHg, P < 0.001). After transplantation, 6-min-walk distance and BEST-FEV(1) were significantly higher for DLTX patients (6-MWD: 410 +/- 25 m vs. 498 +/- 23 m, P = 0.02; BEST-FEV(1): 71.2 +/- 3.0 (% pred) vs. 86.2 +/- 4.2 (% pred), P = 0.004). Double LTX recipients demonstrated a significantly better 1-year-, overall- and Bronchiolitis obliterans Syndrome (BOS)-free survival (P < 0.05). Cox regression analysis confirmed SLTX to be a significant predictor for death and BOS. Single LTX offers acceptable survival rates for IPF patients. Double LTX provides a significant benefit in selected recipients. Our data warrant further trials of SLTX versus DLTX stratifying for potential confounders including PH.

Quantitative assessment of cardiac allograft vasculopathy by real-time myocardial contrast echocardiography: a comparison with conventional echocardiographic analyses and [Tc99m]-sestamibi SPECT.

AIM: To evaluate the additional benefit of visual and quantitative perfusion measurements compared with conventional real-time myocardial contrast echocardiography (MCE) in the detection of CAV. METHODS AND RESULTS: Thirty patients (26 males, age 58 +/- 9.6 years) underwent dobutamine stress echocardiography (DSE) and myocardial perfusion imaging (MPI) as well as coronary angiography (CA) with intravascular ultrasound (IVUS). Ultrasound images were analysed off-line, evaluating (1) wall motion and thickening at high mechanical index ('conventional evaluation'), (2) the MCE loops stored during continuous infusion of contrast agent with regard to visual changes (stress vs. rest, 'visual grading'), and (3) the replenishment curves of the contrast agent at low mechanical index after bubble destruction ('quantitative grading'). CA/IVUS plus MPI showed ischaemia in seven and myocardial scars in nine patients. Sensitivity, specificity, NPV, PPV and accuracy for the detection of ischaemia representing functionally relevant CAV were, respectively, 0.71, 0.83, 0.90, 0.55 and 0.80 for the conventional evaluation alone, 0.71, 0.91, 0.91, 0.71 and 0.87 for additional visual grading and 0.86, 0.91, 0.95, 0.75 and 0.90 for additional quantitative grading. CONCLUSION: Real-time MCE including visual and quantitative analysis is feasible for screening patients after HTX and is highly accurate in the diagnosis of haemodynamically relevant CAV.

Donor-specific HLA alloantibodies: long-term impact on cardiac allograft vasculopathy and mortality after heart transplant.

OBJECTIVES: The clinical significance of anti-HLA-alloantibodies remains controversial. Recent studies have linked development of donor-specific HLA-antibodies to chronic allograft rejection and graft loss after heart, kidney, and lung transplants. We investigated the clinical impact of donor-specific humoral alloreactivity during the follow-up of heart transplant recipients. PATIENTS AND METHODS: The sera of 213 heart transplant recipients were screened by enzyme-linked immunosorbent assay for HLA-antibody production. The antigen specificity of the detected HLA class I and class II antibodies was identified using a Luminex assay. Outcome variables were survival, cardiac allograft vasculopathy, and cellular rejection. RESULTS: The cumulative incidence of alloantibody formation was 23/213 patients (10.8%). The majority of detected alloantibodies were donor-specific for HLA class II. Mean follow-up at antibody measurements was 7 -/+ 4.9 years. Freedom from vasculopathy at 5 and 10 years was 77.9% and 26% in donor-specific HLA-antibody-positive patients compared with 84.6% and 65.2% in antibody-negative controls (P = .025). Freedom from treated, biopsy-proven rejection was 44.4% for donor-specific HLA-antibody-positive patients compared with 70.2% in the controls (P = .06). Multivariate analyses identified donor-specific HLA antibody positivity as an independent risk factor for vasculopathy. CONCLUSIONS: Our results demonstrate a strong correlation between the development of donor-specific HLA antibodies and adverse outcomes after heart transplant. Detection of donor-specific HLA antibodies might identify high-risk patients and offer an opportunity for early clinical intervention and modification of immunosuppression.

Conversion to sirolimus and mycophenolate can attenuate the progression of bronchiolitis obliterans syndrome and improves renal function after lung transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the major problem after lung and heart-lung transplantation (LTx/HLTx). Sirolimus (Sir) and Mycophenolate (MMF) showed a promising efficacy in the treatment of BOS in animal models. The first clinical experience in converting LTx/HLTx-recipients with BOS from calcineurin inhibitor-(CNI)-based immunosuppression to a Sir-MMF based immunosuppression is reported herein. METHODS: Six LTx- and five HLTx-recipients (eight men; 0.9 to 8 years after transplantation) with CNI-based immunosuppression (plus MMF) in whom BOS was diagnosed were included in the study. Mean patient age was 37+/-13 years (range 17-62 years). Sir was started with 6 mg and continued adjusted to according target trough levels (8-14 ng/ml). Subsequently, the CNIs were tapered down and finally stopped. Follow up included self determined pulmonary function tests, microbiological screening, chest radiographs, and laboratory studies RESULTS: Two acute rejection episodes occurred during the study period. The incidence of infection was 2.2+/-1.3 infections/patient-year after conversion. Mean FEV1 decreased after a mean follow up of 14.8+/-1.4 months: from 2.1+/-0.7 l prior conversion to 1.3+/-0.6l after conversion (P=0.03). However, graft function remained stable in three patients and progression of BOS slowed down in three patients. Overall, 2 of 10 patients died due to ongoing BOS while awaiting retransplantation CONCLUSIONS: After BOS was diagnosed, conversion to MMF and Sir stabilized graft function only in some of the converted patients. Therefore, earlier administration of Sir-based immunosuppression might be a more promising approach. Whether conversion to CNI-free immunosuppression can actually ameliorate the extent or progression of BOS has to be investigated in randomized trials.

Effect of diabetes mellitus on sympathetic neuronal regeneration studied in the model of transplant reinnervation.

UNLABELLED: The transplanted heart is initially denervated but undergoes subsequent sympathetic reinnervation. It thus provides a unique model for studying regeneration as a specific component of autonomic nerve biology. The aim of this study was to determine the effect of diabetes mellitus on the regenerational capacity of sympathetic neurons using molecule-targeted PET. METHODS: Twenty-two nonrejecting, otherwise healthy cardiac transplant recipients underwent PET with the (11)C-labeled physiologic neurotransmitter epinephrine at 4.0 +/- 3.3 y after surgery. Sympathetic reinnervation was defined as regional restoration of epinephrine retention to values within normal limits. RESULTS: Reinnervation was observed in 8 of 12 patients with no evidence of diabetes and in 6 of 10 patients with a long-term history of diabetes mellitus. The regional extent of reinnervation (4.7% +/- 5.3% of left ventricle vs. 19.1% +/- 20.6% for nondiabetic recipients, P = 0.04) and the regeneration rate (0.8% +/- 1.0% of left ventricle per year vs. 8.0% +/- 10.1% for nondiabetic recipients, P = 0.04) were significantly reduced in diabetic subjects. In a multivariate model, diabetes mellitus was an independent determinant of allograft reinnervation. Finally, the reappearance of innervation was found to correlate with an improved chronotropic and inotropic response to stress in a standardized, symptom-limited exercise test including radionuclide angiography. CONCLUSION: The regenerational capacity of the sympathetic nervous system of the heart is reduced, but not abolished, by diabetes mellitus. This study on cardiac transplant recipients further supports a general link between impaired glucose handling and cardiac autonomic nerve function.

Ascending Aortic Disease is Associated with Earlier Menopause and Shorter Reproductive Life Span.

OBJECTIVES: The incidence of cardiovascular morbidity and mortality in premenopausal women is comparatively low, but increases sharply after menopause. The principal aim of this study was to determine whether women with ascending aortic disease (AAD) have a different reproductive history from that of an age-matched control group. METHODS: In this retrospective study, women who had undergone ascending aortic aneurysm (AscAA) repair between 2000 and 2010 were asked to complete a questionnaire concerning risk factors and reproductive history. Data from 142 women with AAD were evaluated, and a subgroup (n = 64) with AscAA ≥5 cm was analyzed and compared to an age-matched random control group without known aortic diseases. RESULTS: Almost all women were menopausal at the time of the questionnaire (98.4% vs. 90.6%, AscAA ≥5 cm subcohort vs. control, p = 0.12) and all subjects presented with a comparable age of menarche (13.7 ± 2.6 years vs. 14.2 ± 1.8 years, AscAA ≥5 cm subcohort vs. control, log-rank 0.04, p = 0.84). However, mean menopausal age was significantly lower in the case subcohort than in controls (48.1 ± 4.8 years vs. 50.6 ± 5.8 years, AscAA ≥5 cm subcohort vs. control, log-rank 8.35, p = 0.004), and reproductive life span was correspondingly shorter (34.2 ± 5.2 years vs. 36.2 ± 5.7 years, p = 0.04). Furthermore, hypertension was more prevalent in women with AscAA ≥5 cm compared to controls (89.1% vs. 61.9%, AscAA ≥5 cm subcohort vs. control, p < 0.001). CONCLUSION: Women who experience menopause at an earlier age than the regional mean could profit from screening for cardiovascular disease in general and particularly for AAD. Screening would enable early aneurysm detection and could, therefore, reduce morbidity and mortality.

Clinical determinants of ventricular sympathetic reinnervation after orthotopic heart transplantation.

BACKGROUND: It has been demonstrated that ventricular sympathetic reinnervation after cardiac transplantation improves exercise performance. The extent of reinnervation increases with time but is variable. Little is known about other influencing factors. METHODS AND RESULTS: Seventy-seven nonrejecting transplant recipients were cross-sectionally studied by PET with the catecholamine analogue C-11 hydroxyephedrine at 4.8+/-3.5 years after transplantation. Results were compared with history-derived parameters related to recipient's clinical course before, during, and after surgery; donor characteristics; and immunogenetics. Partial reinnervation was observed in 52 patients (extent, 21+/-16% of left ventricle). Complete denervation was found in 25 patients at various times after transplantation. Reinnervation extent correlated with time after surgery (r=0.387; P<0.001) but also inversely with donor age (r=-0.309, P=0.006) and recipient age (r=-0.243, P=0.032). Maximal hydroxyephedrine retention correlated inversely with frequency of rejection episodes (r=-0.267, P=0.019), was reduced when aortic complications occurred perioperatively (9 patients), and correlated inversely with aortic cross-clamp time (r=-0.331, P=0.006). Other parameters were not associated with reinnervation. Patients were surveyed for clinical complications over >12 months after PET (until 7.3+/-4.2 years after transplantation), but significant effects of reinnervation on outcome were not observed. CONCLUSIONS: The present data suggest that sympathetic reinnervation after cardiac transplantation is not simply a function of time. Reinnervation is more likely with young age, fast and uncomplicated surgery, and low rejection frequency. Despite few effects on prognosis in otherwise healthy recipients, improved understanding of clinical determinants may contribute to enhance allograft reinnervation and thereby augment exercise capacity in the future.

Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac-transplant recipients with chronic renal failure.

BACKGROUND: Calcineurin-inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this study was to introduce a CNI-free immunosuppressive regimen to HTx recipients with late posttransplant renal impairment and to evaluate the impact of conversion to this new immunosuppression (mycophenolate mofetil [MMF] and sirolimus [Sir]) treatment on renal function. METHODS AND RESULTS: Thirty-one HTx patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine greater than 1.9 mg/dL were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Mean patient age was 50+/-14 (range 19-74) years. Conversion was started with 6 mg Sir, continued with 2 mg, and the dose was adjusted to achieve target trough levels between 8 and 14 ng/mL. MMF was continued with trough level adjusted (1.5-4 microg/mL). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up (first and every 3 months after conversion) included endomyocardial biopsies, echocardiography, and laboratory studies. Survival was 90% after a mean follow-up of 13+/-95 months. No acute rejection episode was detected during the study period. Renal function improved significantly after conversion: creatinine preconversion vs. postconversion: 3.14+/-0.76 mg/dL vs. 2.14+/-0.83 mg/dL, P =0.001. Cystatin preconversion vs. postconversion: 2.95+/-1.06 mg/L vs. 2.02+/-1.1 mg/L, P =0.01. In three patients, hemodialysis therapy was stopped completely after conversion. Graft function remained stable. Fractional shortening preconversion vs. postconversion: 36.9+/-6% vs. 36.4+/-6%. There were no serious adverse events. One patient had to be excluded because of noncompliance. CONCLUSIONS: Conversion from CNI-based immunosuppression to MMF and Sir in HTx patients with chronic renal failure was safe, preserved graft function, and improved renal function.

Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression.

A prospective, pilot trial was started to evaluate the effect of a sirolimus-based immunosuppressive regimen on acute and chronic rejection in de novo lung transplant patients. Primary lung transplant (LTx) recipients received a sirolimus- and tacrolimus-based immunosuppressive therapy immediately after transplantation. Both immunosuppressants were administered with trough level adjusted, while steroid administration was minimized. Four patients were enrolled (2 single-lung transplants, 1 double-lung transplant, 1 heart-lung transplant) in the study. Mean ischemia time was 387 +/- 92 minutes. Acute rejection (at least Grade A1 ISHLT) was detected in 1 patient. Incidence of infection was 0.6 infection per 100 patient-days (3 Aspergillus infections). Until hospital discharge mean sirolimus trough level was 6.2 +/- 1.2 ng/ml. Depending upon mean sirolimus trough levels of each patient, severe wound-healing complications were seen in 3 patients, resulting in bronchial airway dehiscence in 2 patients with lethal outcome in 1 patient. As a result of these complications, we revised the study design after inclusion of only 4 patients: Sirolimus administration is now started after completion of bronchial wound-healing. Sirolimus-based immunosuppressive therapy administered immediately after lung transplantation seems to be associated with severe wound-healing complications of the bronchial anastomosis.

Ten-year results of a randomized trial comparing tacrolimus versus cyclosporine a in combination with mycophenolate mofetil after heart transplantation.

BACKGROUND: Long-term results of prospective randomized trials comparing triple immunosuppressive strategies combining tacrolimus (TAC) or cyclosporine A (CsA) with mycophenolate mofetil (MMF) and steroids after heart transplantation (HTX) are rarely published. Therefore, we collected long-term follow-up data of an intervention cohort 10 years after randomization. METHODS: Ten-year follow-up data of 60 patients included in a prospective, randomized trial between 1998 and 2000 were analyzed as intention-to-treat (TAC-MMF n=30; CsA-MMF n=30). Baseline characteristics were well balanced. Cardiac allograft vasculopathy (CAV) was graduated in accordance with the new ISHLT classification. RESULTS: Survival at 1, 5, and 10 years was 96.7%, 80.0%, and 66.7% for TAC-MMF and 90.0%, 83.3%, and 80.0% for CsA-MMF (P=ns). Freedom from acute rejection (AR) was significantly higher in TAC-MMF versus CsA-MMF (65.5% vs. 21.7%, log-rank 8.3, P=0.004). Freedom from ISHLT≥CAV1 after 5 and 10 years was in TAC-MMF 64.0% and 45.8%, and in CsA-MMF 36.0% (log-rank 3.0, P=0.085) and 8.0% (log-rank 9.0, P=0.003). No difference in long-term results for freedom from coronary angioplasty or stenting, renal dysfunction, diabetes mellitus, CMV infection, or malignancy was detected. CONCLUSION: Cross-over effects because of treatment switch may result in impairment of significance between the groups. The long-term analysis resulted in a significant difference in manifestation of CAV between the groups after 10 years. Less rejection in the TAC-group might have contributed to the lower incidence of CAV. Superior freedom from AR and CAV in the TAC-MMF group did not result in better long-term survival.

Combination antifungal therapy for invasive pulmonary aspergillosis in a heart transplant recipient.

Invasive pulmonary aspergillosis is a severe complication after solid organ transplant, with a high mortality rate. We present a 45-year-old male heart transplant recipient who developed fever, progressive worsening of dyspnea, and productive cough without response to antibiotics. Diagnosis of invasive pulmonary aspergillosis was made based on clinical, laboratory, and radiographic findings. The patient was treated successfully with combined antifungal therapy (voriconazole and micafungin). This case report highlights the importance of a high degree of clinical suspicion to allow curative treatment of invasive aspergillosis and the efficiency of new antifungal drugs.

Extracorporeal membrane oxygenation in 108 patients with low cardiac output ­ a single-center experience.

BACKGROUND: For short-term ventricular and pulmonary support the extracorporeal membrane oxygenation (ECMO) system using the Bio-Medicus centrifugal pump (Medtronic®, Minneapolis, MN, USA) was applied in 108 patients with cardiac low-output. METHODS: From December 1996 to July 2006 the ECMO was implanted in 108 patients (73 adult, mean age: 49.3±18.0 yrs and 35 children, mean age: 1.3 ± 2.7 yrs) with mostly postcardiotomy cardiac low output. The surgical procedures included congenital heart surgery (n=35), heart transplantation (HTx) (n=21), coronary artery bypass operation (CABG) and/or valvular operation (n=33), other operations (n=6) and 13 patients with ECMO support for bridge to recovery. RESULTS: The mean supporting time was 5.1±5.6 days. Overall, 30-day-survival was 40.2%. Best survival rates were seen after congenital heart surgery (24/35, 65.7%) and after HTx (9/21, 42.9%); the worst rates were in the group of CABG and/or valvular operations (5/33, 15.2%), only ECMO support (3/13, 23.1%) and other operations (1/6, 16.7%). Fifty-four patients died while supported by ECMO, 15 were weaned from ECMO but died in hospital, 39 patients were weaned and survived. Causes of death were multi-organ failure (40.6%), bleeding (23.2%), persistent cardiac low output (21.7%), thrombembolic events (8.7%), and graft failure (5.8%). Markers for adverse outcome were identified as older age, high body weight, increased AST/GOT levels, and lower thrombocyte count in adults; and as higher levels of serum creatinine in pediatric patients. CONCLUSIONS: ECMO support showed best results in pediatric patients after congenital heart surgery and in patients after HTx in contrast to multimorbid, older patients with often irreversible myocardial damage.

Effect of inpatient rehabilitation on quality of life and exercise capacity in long-term lung transplant survivors: a prospective, randomized study.

BACKGROUND: The purpose of this study was to examine the effect of an inpatient rehabilitation program on health-related quality of life (HRQOL) and exercise capacity (EC) in long-term (>1 year after lung transplantation) survivors (LTSs) in comparison to a control group (CG). METHODS: Sixty LTSs, 4.5 ± 3.2 years after lung transplantation (LTx), were randomly assigned to two equally sized groups that were stratified for gender and underlying disease. Thirty LTSs (age 49 ± 13 years, 13 male and 17 females, 19 double LTxs, 7 BOS Stage ≥ 1) attended an inpatient rehabilitation program (intervention group, IG) for 23 ± 5 days. The CG (age 50 ± 12 years, 13 males and 17 females, 20 double LTxs, 2 BOS Stage ≥ 1) received medical standard therapy (physiotherapy). Patients were evaluated by cardiopulmonary exercise testing, 6-minute walk test (6MWT), SF-36, SGRQ and the Quality of Life Profile for Chronic Diseases questionnaire before and after (18 ± 3 days) the program. RESULTS: The groups were statistically indistinguishable in terms of clinical data. Each treatment group significantly improved their sub-maximal EC (6MWT: IG, 493 ± 90 m vs 538 ± 90 m, p < 0.001; CG, 490 ± 88 m vs 514 ± 89 m, p < 0.001) and maximal EC (VO(2peak): IG, 17.0 vs 18.5 ml/min/kg, p = 0.039; CG, 18.0 vs 19.5 ml/min/kg, p = 0.005), without reaching statistical significance between the groups. In both study groups, patients HRQOL tended to improve. Significant correlations were found between EC parameters and HRQOL scales. CONCLUSIONS: Our data suggest that structured physical training may improve exercise tolerance in LTS. Our study results did not demonstrate a significant benefit of an inpatient over an outpatient exercise program.

Off-pump coronary surgery for allograft vasculopathy 8 years after heart transplant.

Cardiac allograft vasculopathy is a severe complication after heart transplant, and is the major cause of death in patients surviving 1 year after transplant. We present a 59-year-old patient undergoing off-pump, coronary artery bypass surgery, 8 years after heart transplant. Owing to toxic liver disease, the lipid lowering therapy with statins had to be stopped 6 years after transplant, and coronary artery disease developed rapidly within 2 years. Off-pump, coronary bypass surgery was performed using a new, multisuction cardiac positioner; a disposable stabilizer; and a proximal seal system to avoid clamping of the aorta. The patient received 3 bypass grafts: the left internal thoracic artery; to the left anterior descending coronary artery; 1 saphenous vein graft to the marginal branch of the circumflex artery; and 1 saphenous vein graft to the right coronary artery. His postoperative course was uneventful.

Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients.

BACKGROUND: Bronchoalveolar lavage (BAL) neutrophilia may identify patients prone to develop bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). This study assessed the predictive value of BAL neutrophilia in stable recipients. METHODS: Evaluated were 63 consecutive recipients 3 to 12 months after LTx demonstrating no acute rejection (AR) and lymphocytic bronchitis (LB; B < or = 1 without infection; BOS, 0). Recipients were subdivided into never-BOS (follow-up > or = 12 months) and ever-BOS groups (i.e., BOS development > or = 1 after bronchoscopy). RESULTS: The groups were statistically indistinguishable for demographic data and preceding AR and LB episodes. Onset of BOS was at a median of 232 days (range, 87-962) after bronchoscopy. The ever-BOS group (16 patients) demonstrated a significantly higher percentage of neutrophils compared with the never-BOS group (47 patients) at the time of bronchoscopy (33.6% +/- 2.1% vs 9.9% +/- 1.1%, p < 0.05). By Cox regression analysis, a BAL neutrophil percentage of > or = 20% remained a significant predictor for BOS > or = 1 (hazard ratio, 3.57; 95% confidence interval, 1.71-8.40, p < 0.05) distinct from known potential BOS predictor variables. The positive and negative predictive value of BAL neutrophilia of > or = 20% for future BOS was 0.72 and 0.93, respectively (p < 0.05). CONCLUSION: BAL neutrophilia in stable recipients is of predictive value to identify recipients at risk for BOS. These data warrant prospective confirmation and further studies to evaluate the benefit of preemptive therapy for potential BOS patients.

Defining algorithms for efficient therapeutic drug monitoring of mycophenolate mofetil in heart transplant recipients.

Pharmacokinetics of mycophenolate mofetil (MMF) show large interindividual variability. Concentration-controlled dosing of MMF based on routine therapeutic drug monitoring, which requires area under the concentration-time curve (mycophenolic acid [MPA]-AUC0-12h) determinations, is uncommon. Dose adjustments are based on predose concentrations (C0h) or side effects. The aim of this study was to compare C0h with postdose concentrations (C0.5h-C12h) and to develop practical methods for estimation of MPA-AUCs on the basis of a limited sampling strategy (LSS) in heart transplant recipients under MMF and tacrolimus maintenance immunosuppression. Full MPA-AUC0-12h profiles were generated by high-performance liquid chromatography in 28 patients. Statistical analysis for MPA-AUC0-12h was performed by a case resampling bootstrap method. Bland and Altmann analysis was performed to test agreement between "predicted AUC" and "measured AUC." C1h provided the highest coefficient of determination (r2 = 0.57) among the concentrations determined during the 12-hour interval, which were correlated with AUC. All other MPA levels were better surrogates of the MPA-AUC0-12h when compared with C0h (r2 = 0.14). The best estimation of MPA-AUC0-12h was achieved with four sampling points with the algorithm AUC = 1.25*C1h + 5.29*C4h + 2.90*C8h + 3.61*C10h (r2 = 0.95). Since LSS with four time points appeared unpractical, the authors prefer models with three or two points. To optimize practicability, LSS with sample points within the first 2 hours were evaluated resulting in the algorithms: AUC = 1.09*C0.5h + 1.19*C1h + 3.60*C2h (r2 = 0.84) and AUC = 1.65*C0.5h + 4.74*C2h (r2 = 0.75) for three and two sample points, respectively. The results provide strong evidence for the use of either LSS or the use of time points other than C0h for therapeutic drug monitoring of MMF. Using the algorithms for the estimation of MPA-AUC0-12h based on LSS within the first 2 hours after MMF dosing may help to optimize treatment with MMF by individualization of dosing.