Does Perfadex improve clinical outcomes in lung transplantation?

Does Perfadex improve clinical outcomes in lung transplantation?

S158 Abstracts The Journal of Heart and Lung Transplantation February 2005 were reported healthy and developing well. One child recently had a pace...

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S158

Abstracts

The Journal of Heart and Lung Transplantation February 2005

were reported healthy and developing well. One child recently had a pacemaker placed due to an arrhythmia at approximately 3.5 years old. Current maternal graft function was reported as adequate in 9 recipients. There were 5 maternal deaths reported. Conclusions: Successful pregnancy outcomes are possible for female lung transplant recipients. Whether long-term maternal survival is impacted by pregnancy requires further study. 356 CLINICAL OUTCOME FOLLOWING CONCOMITANT CARDIAC OPERATION AT THE TIME OF LUNG TRANSPLANTATION G.T. Schnickel,1 D.J. Ross,2 F. Mitropolous,1 S. Lackey,1 A. Shefizadeh,1 A. Ardehali,1 1Division of Cardiothoracic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA; 2 Division of Pulmonary Medicine, Critical Care and Hospitalists, David Geffen School of Medicine at UCLA, Los Angeles, CA Introduction: Cardiac procedures at the time of lung transplantation can increase cardiopulmonary bypass time and may adversely affect clinical outcome. We sought to determine the impact of cardiac lesions that require repair at the time of lung transplantation on short-term outcome. Methods: We analyzed the records of all patients who underwent lung transplantation at our institution from March 1, 2000 to August 1, 2004. Patients undergoing an additional cardiac procedure at the time of transplantation were compared to patients who underwent lung transplantation alone during the same time period. The endpoints analyzed to assess outcome were number of days on a ventilator, ICU days, total post-operative hospital days, incidence of ischemia reperfusion injury (IRI), 30-day mortality, and 1 year Kaplan-Meier survival. Results: During this interval, 20 patients underwent a concomitant cardiac procedure at the time of transplantation. These operations included mitral valve repair (n⫽1), tricuspid valve repair (n⫽4), tricuspid and pulmonic valve repair (n⫽1), coronary artery bypass graft (n⫽1), and patent foramen ovale closure (n⫽13). During the same interval, 81 underwent lung transplantation with no cardiac procedure. The results are shown in Table 1.

With concomitant cardiac operation Lung Transplant only

PaO2/FiO2 at 6 hours (mmHg)

Median Ventilator Days

Median ICU days

Median Hospital days

Incidence of IRI

30-day survival

1-year survival

262.45 ⫾ 160.6

2 (range 1 to 202 days)

4 (range 2 to 202 days)

13 (range 7 to 202 days)

0%

100%

87%

252.6 ⫾ 123.4

2 (range 1 to 165 days)

4 (range 2 to 182 days)

13 (range 6 to 277 days)

2.4%

96.3%

95%

p ⫽ ns for all variables

Conclusion: Selected patients with end stage lung diseases can undergo a concomitant cardiac procedure at the time of lung transplantation with favorable short-term results and survival. 357 CLINICAL AND FUNCTIONAL STATUS OF CYSTIC FIBROSIS (CF) HEART-LUNG TRANSPLANT (HLT) RECIPIENTS SURVIVING MORE THAN TEN YEARS K.M. Gyi,1 M.R. Carby,2 M.E. Hodson,1 1Department of Cystic Fibrosis, Royal Brompton and Harefield NHS Trust, London, United Kingdom; 2Department of Transplantation, Royal Brompton and Harefield NHS Trust, Harefield, Middlesex, United Kingdom Background: Actuarial survival following lung transplantation for CF patients with end-stage lung disease has been reported around 40% at

ten years. However limited information is available about the clinical status of these long-term survivors. Method: Clinical and functional status were retrospectively reviewed of 31 CF patients who underwent HLT at Harefield hospital between 1984 and 1993 and survived ten years or more following surgery. Detailed clinical data was available for all except two patients. Results: Mean age was 40 years (26 – 49). 17 recipients were male. Survival range from 10 to 16.4 years, five having surviving more than 15 years. 27 patients are still alive at the end of follow up. There were four deaths, three due to bronchiolitis obliterans syndrome (BOS) and one due to post transplant lymphoproliferative disease (PTLD). Median FEV1 at 10 years was 89% of base line. BOS grade at 10 years were: grade 0 (20), grade I (2), grade III (7). Four patients had mild bronchiectasis with intermittent pseudomonas colonisation. Two patients had re-transplantation (HLT-1, single lung transplant-1) for BOS. Ten patients required long-term dialysis. Four subsequently underwent renal transplantation. Only one patient developed symptomatic graft coronary artery disease requiring coronary artery stenting. Post transplant malignancy included PTLD (3), cervical cancer in situ (1) and oesophageal cancer (1). One had a successful pregnancy. Ten patients were diabetic, 5 developed this post transplant. 17 patients were working full or part time. Ten other patients have no limitation in daily activity. Conclusion: Chronic rejection and side-effects of prolonged immunosuppressive drug administration are the main causes of morbidity in long term survivors after HLT. Despite this a significant proportion CF HLT recipients can survive beyond a decade without BOS. 358 DOES PERFADEX IMPROVE CLINICAL OUTCOMES IN LUNG TRANSPLANTATION? R.F. Kelly, A.R. Walker, A.C. Johnson, D.S. Nath, M.E. Prekker, C.S. Herrington, P.S. Dahlberg, Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis, MN Introduction: Use of a low-potassium based preservation fluid improves gas exchange in experimental models of lung transplantation. Its efficacy in reducing the incidence of primary graft dysfunction (PGD) in the clinical setting, however, is controversial. Methods: We measured ISHLT PGD grades, oxygenation index, lung compliance, extubation times and 90-day mortality in 85 consecutive (2001–2003) lung recipients who received allografts preserved with Perfadex and compared them to the previous 85 consecutive (1999 – 2001) patients where modified Euro-Collins solution was used. Recipients were classified as having ISHLT grade III PGD if the lowest arterial oxygenation to fraction of inspired oxygen (P/F) ratio within 48 hours post-transplantation was less than 200. Results: The two cohorts were similiar. There were no differences in donor or recipient age, type of transplant, ischemic times, or preoperative pulmonary artery pressures. There were no significant differences between the groups in any of the primary endpoints (Table 1).

Post-operative Characteristics

Grade III PGD

Oxygenation Index

Lung compliance

Extubation 90-day mortality

T0 T24 Worst T0-48 T0 T24 Worst T0-48 T0 T24 Worst T0-48 T48

Perfadex Group

Modified Euro-Collins Group

p value

18% 6% 27% 3.8 (3.7) 3.4 (2.4) 2.8 (1.3) 36.0 (11.4) 32.4 (12.0) 34.7 (14.6) 67% 12% mean (stand dev)

25% 9% 11% 4.4 (4.1) 4.2 (2.9) 3.0 (1.8) 38.9 (12.4) 32.0 (10.2) 35.3 (12.0) 70% 11% mean (stand dev)

0.4 0.6 0.7 0.3 0.1 0.4 0.7 0.9 0.8 0.9 0.8

The Journal of Heart and Lung Transplantation Volume 24, Number 2S

Abstracts

Conclusions: Lung preservation with Perfadex compared to preservation with modified Euro-Collins solution does not improve 90-day mortality rates or measures of early gas exchange in patients following lung transplantation. 359 METABOLIC CONSEQUENCES OF LUNG TRANSPLANTATION V.G. Valentine,1 D.M. Fuchs,1 L. Seoane,1 G.A. Lombard,1 S.G. LaPlace,1 D.E. Taylor,1 1Lung Transplantation, Ochsner Clinic Foundation, New Orleans, LA Introduction: The rates of hypertension (HTN), chronic renal insufficiency (CRI), hypercholesterolemia (CHOL), diabetes mellitus (DM), and obesity following lung transplantation (LT) are not well-documented. Herein we describe the incidences and likelihood ratios (LR) of developing the aforementioned metabolic consequences with respect to underlying pulmonary diagnosis. Methods: Diagnoses in the 194 patients who underwent LT between November 1990 and August 2004 included emphysema (n⫽62), CF (n⫽58), and IPF (n⫽43) patients. CRI was defined as serum creatinine ⬎ 1.6 mg/dl, and obesity was defined as BMI ⬎ 30 kg/m2. Results: The follow-up period was 37 ⫾ 30 months (range 0 – 140). Age at LT was 43 ⫹ 16 years. Incidence of metabolic complications that developed after LT are described below. For comparison BOS incidence is shown.

HTN (%) CRI (%) CHOL (%) DM (%) Obesity (%) BOS (%)

Pre

1-yr

3-yr

5-yr

13 1 3 7 2 4

56 46 16 32 12 15

76 75 30 30 22 44

81 77 47 28 14 65

S159

N. Partovi,1,2 L. Ting,2 M.H.H. Ensom,2 W. Riggs,2 R.D. Levy,3 Pharmaceutical Sciences, Vancouver General Hospital; 2 Pharmaceutical Sciences, University of British Columbia; 3 Faculty of Medicine, University of British Columbia, Vancouver, Canada 1

Purpose: The purpose of this study was to characterize the pharmacokinetics of mycophenolic acid (MPA) and its glucuronidated metabolites, MPAG (phenolic-glucuronide) and AcMPAG (acyl-glucuronide), in stable lung transplant recipients. Methods: Fifteen adult patients were enrolled. Upon administration of morning mycophenolate Mofetil (MMF) dose, blood samples were collected at 0, 0.3, 0.6, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours post-dose. Total MPA, MPAG, and AcMPAG concentrations were measured by a validated HPLC method and pharmacokinetic parameters analyzed by non-compartmental modeling. Results: Patient characteristics included: 7 males and 8 females, on average 4.8 years post-transplant (range: 0.2 – 12.3 yr), mean (⫾SD) age of 50.5 ⫾ 11.9 yr and weight 71.3 ⫾ 19.4 kg. Mean albumin concentration was 38 ⫾ 5 g/L and serum creatinine was 124 ⫾ 44 umol/L. All patients also were on prednisone, with 8 on tacrolimus and 7 on cyclosporine. MMF dosage ranged from 1.5 to 3 grams daily (36.4 ⫾ 10.6 mg/kg/day; range:18.3 - 54.0 mg/kg/day). Mean (⫾SD) for MPA were: area-under-the-curve0 –12h (AUC) 37.23 ⫾ 16.37 ␮g*h/ mL; maximal concentration (Cmax) 9.43 ⫾ 4.90 ␮g/mL; time to Cmax (Tmax) 1.60 ⫾ 2.36 h; and minimum concentration (Cmin) 0.95 ⫾ 0.39 ␮g/mL. AUC ratios of MPAG:MPA and AcMPAG:MPA were 20.50 ⫾ 7.32 and 0.91 ⫾ 2.11, respectively. Conclusions: This is the first study to determine the pharmacokinetics of MPA and its glucuronidated metabolites in the lung transplant population. We observed wide variability in MPA pharmacokinetics which were not explained by differences in patient’s weight, creatinine, and albumin levels. Further studies should focus on determining if genetic variability in UDP-glucuronosyltransferase enzymes can explain the observed wide interpatient variability and on identifying MMF dosing strategies that optimize immunosuppressive efficacy and minimize toxicity in lung allograft recipients.

The results of the Cox proportional hazards are shown below: 361

Incidence of HTN

Incidence of CRI

Incidence of CHOL

Incidence of DM

CF Emphysema IPF CF Emphysema IPF CF Emphysema IPF CF Emphysema IPF

LR

95% CI

p-value

0.88 0.97 1.2 0.66 1.9 0.61 0.6 2.0 0.78 2.2 0.6 0.77

0.59–1.3 0.67–1.4 0.78–1.9 0.43–1.00 1.3–2.9 0.37–1.0 0.33–1.1 1.2–3.3 0.39–1.5 1.4–3.5 0.35–0.99 0.42–1.4

0.54 0.88 0.4 0.051 ⬍0.01 0.055 0.09 ⬍0.01 0.47 ⬍0.01 0.047 0.39

Conclusions: Subsequent development of HTN, CRI, and CHOL occurs as frequently as BOS in LT patients. The emphysema group is more likely to develop CRI and CHOL, while the CF population is more likely to develop DM. Properly attending to the metabolic consequences of LT may improve outcomes and perhaps uncover putative beneficial effects from the assortment of medications required, such as the statin derivatives for CHOL. 360 PHARMACOKINETICS OF MYCOPHENOLATE AND ITS GLUCURONIDATED METABOLITES IN STABLE LUNG TRANSPLANT RECIPIENTS

MEASURING THE IMPACT OF INFECTION ON T CELL IMMUNITY IN LUNG TRANSPLANT RECIPIENTS TREATED WITH A T CELL DEPLETION PROTOCOL A. Zeevi,1 A.L. Girnita,1 K.J. Spichty,1 H. Shahid,1 D. Zaldonis,1 J. Britz,2 R. Kowalski,2 J. Woodcock,2 D. Post,2 K.R. McCurry,1 1 Pathology, UPMC, Pittsburgh, PA; 2Cylex Inc., Baltimore, MD Aim and Method: We measured the recovery of T-cell immunity as assessed by ConA reactivity and T cell memory responses to CMV and EBV in a cohort of 64 lung transplant (LTx) recipients treated with Thymoglobulin (Thy, 36) and Campath (28). We used the Cylex T Cell Memory assay to assess T cell immunity at various times post LTx. and correlated with clinical outcomes. The assay involves co-incubation of whole blood samples with anti-CD3 coated magnetic beads and antigen. T cell activity measured within 24 hr is detected by ATP production. Results: The ConA responses in both Thy and Campath groups were significantly lower as compared to control subjects early (⬍6 months) post-LTx. (control ATP 360⫾132 ng/ml vs. LTx. ATP⬍150 ng/ml). Overall, the recovery of ConA reactivity was similar in Thy and Campath LTx. In contrast, in LTx patients having infection episodes (n⫽9) (bacterimia, pneumonia) the ConA responses were significantly suppressed in comparison with non-infected LTx (n⫽57) (34⫾14 vs 142⫾104 p⬍0.005). During the first 6 months post-LTx CMV specific memory responses were negative in 7/7 Thy and 5/6 Campath R⫺/D⫹ patients (ATP level ⬍10 ng/ml,