Hypertension after heart and heart/lung transplantation in childhood--study on the evolution of short-term blood pressure regulation.

Arterial hypertension complicates the follow-up of heart- and heart/lung-transplanted children. We investigated the evolution of BRS as short-time BP regulation mechanism and BP after heart and heart/lung transplantation. Twenty patients (15 males; mean age 15.1 ± 4.3 yr) were studied twice at intervals of 2.96 ± 0.87 yr. BRS was calculated using non-invasive beat-to-beat BP measurement system. HRV was calculated (LF, sympathetic influence; HF, parasympathetic influence). BRS increased in 10 patients (3.67 ± 1.43 ms/mmHg vs. 7.59 ± 3.40 mmHg, p = 0.005) (group 1). Six of 10 patients received antihypertensive medication. BRS decreased or remained unchanged in 10 patients (8.93 ± 7.9 ms/mmHg vs. 5.32 ± 6.6 ms/mmHg, p = 0.008) (group 2) with 9/10 patients necessitating antihypertensive medication. Group 1 showed LF/HF increase (LF/HF 1.03 ± 0.9 vs. 4.36 ± 2.32, p = 0.03); group 2 showed LF/HF decrease (LF/HF 3.7 ± 2.1 vs. 1.84 ± 1.1, p = 0.023). Evolution of BRS after heart and heart/lung transplantation in childhood seems to influence the necessity of antihypertensive medication. With time, increasing short-time BP regulation involving sympathetic reinnervation may improve BP.

Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) with small-airway pathology and obstructive pulmonary physiology may not be the only form of chronic lung allograft dysfunction (CLAD) after lung transplantation. Characteristics of a form of CLAD consisting of restrictive functional changes involving peripheral lung pathology were investigated. METHODS: Patients who received bilateral lung transplantation from 1996 to 2009 were retrospectively analyzed. Baseline pulmonary function was taken as the time of peak forced expiratory volume in 1 second (FEV(1)). CLAD was defined as irreversible decline in FEV(1) < 80% baseline. The most accurate threshold to predict irreversible decline in total lung capacity and thus restrictive functional change was at 90% baseline. Restrictive allograft syndrome (RAS) was defined as CLAD meeting this threshold. BOS was defined as CLAD without RAS. To estimate the effect on survival, Cox proportional hazards models and Kaplan-Meier analyses were used. RESULTS: Among 468 patients, CLAD developed in 156; of those, 47 (30%) showed the RAS phenotype. Compared with the 109 BOS patients, RAS patients showed significant computed tomography findings of interstitial lung disease (p < 0.0001). Prevalence of RAS was approximately 25% to 35% of all CLAD over time. Patient survival of RAS was significantly worse than BOS after CLAD onset (median survival, 541 vs 1,421 days; p = 0.0003). The RAS phenotype was the most significant risk factor of death among other variables after CLAD onset (hazard ratio, 1.60; confidential interval, 1.23-2.07). CONCLUSIONS: RAS is a novel form of CLAD that exhibits characteristics of peripheral lung fibrosis and significantly affects survival of lung transplant patients.

Two-year outcomes in thoracic transplant recipients after conversion to everolimus with reduced calcineurin inhibitor within a multicenter, open-label, randomized trial.

BACKGROUND: Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required. METHODS: In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization. RESULTS: Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P<0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24. CONCLUSIONS: Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.

Health-related quality of life in long-term survivors after heart and lung transplantation: a prospective cohort study.

BACKGROUND: Health-related quality of life (HRQoL) represents an important outcome measure to assess the success of transplantation in the long term. This study evaluated HRQoL in heart (HTx) and lung (LTx) transplant survivors, and assessed potential outcome-related predictors from before to 5 years after transplantation. METHODS: Study participants (n=170) were prospectively followed up from before to 5 years after HTx (n=82) or LTx (n=88), including HRQoL assessments (pretransplantation, 6, 12, and yearly between 24 and 60 months) using the Short Form-36, employment status index, and monitoring of adverse events. RESULTS: Patient groups (HTx vs. LTx) differed with respect to gender (men 74% vs. 48%; P<0.03) and high-urgency waiting status (72% vs. 45%; P<0.0001). Both cohorts showed the most significant HRQoL improvements within the first year posttransplant (P<0.0001), and relatively stable conditions afterward. Marital (P<0.01) and employment status (P<0.01) impacted HRQoL in both groups. The incidence of bronchiolitis obliterans showed significantly lower HRQoL in LTx patients (29.3%; P<0.005). CONCLUSIONS: HTx and LTx patients benefit from the transplant procedure with respect to HRQoL improvements for at least 5 years posttransplant; however, their trajectories during this time interval differ. Further research on organ-type-related predictors of HRQoL is necessary for the development of tailored psychosocial interventions.

Bridge to thoracic organ transplantation in patients with pulmonary arterial hypertension using a pumpless lung assist device.

We describe a novel technique of pumpless extracorporeal life support in four patients with cardiogenic shock due to end-stage pulmonary hypertension (PH) including patients with veno-occlusive disease (PVOD) using a pumpless lung assist device (LAD). The device was connected via the pulmonary arterial main trunk and the left atrium, thereby creating a septostomy-like shunt with the unique addition of gas exchange abilities in parallel to the lung. Using this approach, all four patients were successfully bridged to bilateral lung transplantation and combined heart-lung transplantation, respectively. Although all patients presented in cardiogenic shock, hemodynamic unloading of the right ventricle using the low-resistance LAD stabilized the hemodynamic situation immediately so that no pump support was subsequently required.

Dramatic improvement in survival after lung transplantation over time: a single center experience.

Lung transplantation (LT) is a recognized procedure for selected patients with end-stage respiratory failure. We performed 123 LT, including 32 single lung, 84 double lung, and 7 heart-lung transplantations in 48 patients with chronic obstructive pulmonary disease (COPD), 13 patients with pulmonary hypertension (PH), 33 with cystic fibrosis (CF), and 29 with interstitial lung disease (ILD) between July 1990 and January 2008. Survival was compared for periods before and after December 2001. The mean age of patients was 44.4 years (range 16-66.5 years); 84 (69%) were men. Before LT, 1 second forced expiratory volume was 28.7% +/- 18.1% and PaCO(2) = 6.3 kPa. Fifty-five patients were on noninvasive ventilation. Cold ischemia time was 320 +/- 91 minutes. Cardiopulmonary bypass (CPB) was used in 77 patients (64%). There were 18 early surgical reinterventions, 8 extracorporeal membrane oxygenations, and 38 bronchial stent insertions among 206 at-risk bronchial sutures. Crude survivals were 69%, 58%, 41%, and 18% at 1, 2, 5, and 10 years, respectively. Comparing before (n = 70 with 15 CF) vs after December 2001 (n = 53 with 17 CF), survivals were 63% vs 78%, 51% vs 71%, and 33% vs 60% at 1, 2, and 5 years, respectively (P = .01) and for CF patients, 52% vs 100%, 52% vs 94%, and 25% vs 94% at 1, 2, and 5 years, respectively (P = .005). There was significant improvement in survival before and after 2001 in 123 LT and particularly among CF patients. Improvement in survival after LT may be related to the sum of numerous changes in our practice since December 2001, including the use of pulmonary rehabilitation pre-LT, extracellular pneumoplegia, statins, macrolides for chronic rejection, monitoring of Epstein-Barr blood load, changes in maintenance immunosuppressants, as well as position movement up the coordinator nurse and learning curve.

Donor brain death mechanisms and outcomes after heart transplantation.

We sought to explore whether the cause of donor brain death influenced recipient outcomes after cardiac transplantation. In retrospect, 358 consecutive donors provided cardiac allografts to adult patients undergoing orthotopic heart transplantation at a single urban US medical center from January 2000 through December 2005. Alternate recipients were excluded. Mechanism and cause of donor brain injury and death were divided into five categories: anoxia (nontraumatic) (n=36), blunt head trauma (n=220), penetrating head trauma (n=83), brain tumor/infection (n=7), and cerebrovascular event (n=12). The five subgroups were categorized as traumatic or nontraumatic. The end points of the study were causes of early and late mortality, survival, and rejection rate. There were 59 deaths in the 6-year period. Total and short-term recipient mortality were found to be statistically higher among heart transplant recipients when the donors suffered from traumatic brain death compared to those whose brain death etiology was nontraumatic (P=.045, P=.033, respectively). Rejection rate was similar in all groups (P=.497). In conclusion, donor traumatic brain death was found to be a valid risk factor for recipient mortality after heart transplantation. Caution should be used when evaluating such donors, particularly in the presence of other risk factors.

A prediction model for estimating pulmonary oxygen uptake during the 6-minute walk test in organ transplant recipients.

We developed a multivariate prediction equation for estimating the highest obtainable pulmonary oxygen uptake (VO2p) during the 6-minute walk test (6-MWT) in 54 organ transplant recipients: heart/heart-double-lung (n=14), kidney/kidney-pancreas (n=16), liver (n=14), double lung (n=8), bone marrow (n=2). They were of age, 48+/-12 years. Participants performed a 6-MWT during which expired gases were collected and analyzed with a portable metabolic system interfaced with a wireless heart rate monitor. The following variables significantly contributed to the model for predicting the highest obtainable 6-MWT VO2p: 6-MWT distance (m), age (years), gender (male=0, female=1), resting heart rate, peak heart rate, weight (kg), and transplant type (kidney/kidney-pancreas=1, other=0), where: VO2p=1.253+0.022 (6-MWT distance)+0.112 (age) -3.192 (gender) -0.104 (resting heart rate)+0.127 (peak 6-MWT heart rate)-0.084 (weight)+2.116 (transplant type). The explanatory variables in our final model accounted for 78% of the variance in 6-MWT VO2p. In conclusion, the addition of an easily estimated 6-MWT VO2p will provide added clinical information of functional capacity following an exercise rehabilitation intervention or during routine follow-up for organ transplant recipients.

Delayed gastric emptying scintigraphy in cystic fibrosis patients before and after lung transplantation.

BACKGROUND: The purpose of this study was to assess the rate of gastric emptying (GE) in cystic fibrosis patients scheduled for lung transplantation. METHODS: Thirty patients (20 males, 10 females, 22.6 +/- 6.4 years) were evaluated by GE scintigraphy before (1.58 +/- 1.11 years) and early after (5.8 +/- 2.6 weeks) heart-lung transplantation (n = 13) or lung transplantation (n = 17). Solid retention rates at 2 hours (RR2) and 3 hours (RR3) and half-emptying times (T50) of solids and liquids obtained before transplantation were compared with those after transplantation. Data were also compared with those obtained from a control group of 53 healthy volunteers. RESULTS: Before surgery, 20 patients (67%) showed a delayed GE (T50 of solids: patients 160.86 +/- 59.21 minutes vs controls 75.43 +/- 15.13 minutes, p < 0.0001), and 4 of them also had a delayed T50 of liquids. After surgery, the T50 of solids was considered unreliable (too much stasis) in 24 patients. Thus, analyses were done on the basis of solid retention rates. Twenty-nine patients (97%) showed very delayed GE compared with controls (p < 0.0001), 20 of whom also had a delayed T50 of liquids. RR2 and RR3 were significantly higher after surgery than before (RR2 = 86 +/- 17% and RR3 = 77 +/- 22% vs 50 +/- 24% and 27 +/- 24% after and before surgery, respectively, p < 0.0001). However, there was no correlation between pre- and post-transplantation scintigraphy results. CONCLUSIONS: Delayed GE of solids was a frequent abnormality in patients with end-stage cystic fibrosis, with a dramatic delay after surgery in almost all patients. These results emphasize the need for early management of such patients by dietary manipulation or prokinetic medications.

Short-term testing of heart rate variability in heart-transplanted children: equal to 24-h ECG recordings?

INTRODUCTION: Heart rate variability (HRV) is reduced in adults and children after cardiac transplantation. Testing of HRV has been used to assess re-innervation of the cardiac graft; its reliability in ruling out acute graft rejection is still under investigation. This study used a short-term test on HRV in 23 heart and heart-lung transplanted children and adolescents and compared the results with 24-h ECG recordings. PATIENTS AND METHODS: Twenty-three subjects (16.3+/-4.2 yr; 10 females) underwent a 10-min HRV test at two occasions and one 24-h ECG. HRV was calculated according to the time domain method (RR interval, standard deviation of RR interval) and the frequency domain method (total power, LF and HF for assessment of sympathovagal modulation of heart rate). RESULTS: Correlation between the short-term tests and 24-h ECG was high with regard to the frequency domain analysis of HRV. Correlation was less pronounced in the time domain method. CONCLUSIONS: In heart and heart-lung-transplanted children and adolescents, due to reduced overall HRV short-term testing may give as reliable data as 24-h ECG. Therefore, especially when power spectral analysis has to be performed as a longitudinal assessment of re-innervation of the cardiac graft, short-term testing may offer an easily applicable and non-invasive diagnostic tool. Further studies are warranted to investigate whether HRV testing may contribute to rule out acute graft rejection.

Thoracic transplantation in the United States: an analysis of UNOS Registry data.

Within the last 15 years, annual heart transplants performed in the U.S. were relatively stable, with an average of 2280 per year. The total number of lung transplants has steadily increased every year, reaching 1406 in 2005; the trend of increasing annual case numbers seemed more obvious for double lung transplants, which have become dominant since 2002. Heart-lung transplantation remains a rare treatment procedure, with an annual average of 50 since 1988. Overall 10-year graft survival rates for heart, double lung, single lung, and heart-lung transplant recipients were 48.7%, 29.7%, 17.5%, and 25.8%, respectively. Both short-term (1-year) and long-term (5-year) graft survival rates were improved in heart and lung transplantation. The effect of the transplant year was more significant in short-term graft survival. Risk factors that have a significant impact on the graft survival of thoracic transplants include HLA mismatches, pre-transplant PRA, transfusions between listing and transplantation, previous transplantation, treated rejection within the first year post-transplant, donor CMV status, and drug-treated infection prior to transplantation or prior to discharge.

Physical functional outcomes after cardiothoracic transplantation.

The study of patient healthcare outcomes after cardiothoracic transplantation has increased substantially over the last 2 decades. Physical function after heart, lung, and heart-lung transplantation has been studied using both subjective and objective measures. The majority of reports in the literature on physical function after cardiothoracic transplantation are descriptive and observational. The purposes of the article are to review and critique the existing literature on cardiothoracic recipients' subjective and objective physical function, including respiratory function for heart-lung and lung transplant recipients. In addition, the literature on sexual function in cardiothoracic recipients is examined, the gaps in the literature are identified, and recommendations are given for future research.

Scintigraphic results in patients with lung transplants: a prospective comparative study.

AIM: We addressed the feasibility of scintigraphy in the postoperative monitoring of lung transplants. METHOD: 37 patients (22 women, 15 men, 37 +/- 15 years) in good clinical condition were examined after lung transplantation. Scintigraphic procedures for assessing ventilation (133Xe), perfusion (99mTc microspheres) and aerosol-inhalation (99mTc aerosol) were performed for all patients. The findings were compared with those of established diagnostic modalities. RESULTS: All lung transplants showed homogeneous ventilation but with a non-physiologic difference of over 20% between both pulmonary lobes in one-third of the cases. There was a difference between the impairement of perfusion and ventilation in the presence of an impaired Euler-Liljestrand reflex in 14/37 (38%) patients. Furthermore, bronchoscopy and aerosol-inhalation scans often did not correlate, e. g. a bronchoscopically evident stenosis was not necessarily associated with an increased activity, and vice versa. Although peripheral mucociliary clearance was preserved after transplantation, stasis in central airways resulted in significantly impaired global clearance. CONCLUSION: Ventilation and perfusion scintigraphy reveal in a significant number of lung recipients pathologic findings and therefore can be recommended for postoperative monitoring. From a clinical point of view aerosol-inhalation scintigraphy (clearance) is not of any additional value.

Population pharmacokinetics of cyclosporine in cardiopulmonary transplant recipients.

A population pharmacokinetic analysis of cyclosporine (CsA) was performed, and the influence of covariates on CsA oral clearance and relative bioavailability was investigated. Data from 48 recipients of heart-lung (n = 21) or single (n = 18) or double (n = 9) lung transplant were included in the study. Patients received oral CsA as either a conventional formulation (Sandimmune) or a microemulsion (Neoral). Steady-state CsA concentrations were measured before and at approximately 2 and 6 hours after the morning dose of CsA at the end of weeks 1, 2, 3, 4, 13, 26, 39, and 52 posttransplantation. A total of 1004 CsA concentration observations were analyzed using mixed effects-modeling (NONMEM). A 1-compartment pharmacokinetic model and first-order oral absorption were used to fit the data. The absorption rate constants were fixed at 0.25 L/h for Sandimmune and 1.35 L/h for Neoral formulations. Oral clearance (CL/F) was estimated to be 22.1 L/h (95% confidence intervals [CI] 19.5-24.7 L/h). Itraconazole (ITRA), cystic fibrosis (CF), and weight (WT) were identified as significant covariates for CL/F according to the final model: CL/F = 22.1 - 11.3 x ITRA + 23.5 x CF + 0.129 x (WT - 58.7) L/h; where ITRA = 1 if the patient was taking concomitant itraconazole, otherwise 0; CF = 1 if the patient had cystic fibrosis, otherwise CF = 0; and WT is patient weight in kilograms. The relative oral bioavailability of Sandimmune to Neoral was 0.82. The bioavailability of both preparations increased during the first month posttransplantation. Age, gender, and type of transplant (single, double, or heart-lung) were not identified as significant covariates for CsA clearance. The population pharmacokinetic model developed identified some sources of variability in CsA pharmacokinetics; however, an appreciable degree of variability is still present in this patient population.

Lung graft dysfunction in the early postoperative period after lung and heart lung transplantation.

BACKGROUND: We present a retrospective study of 9 years of experience in the management of graft dysfunction in the early postoperative period after lung transplantation (LT) and heart lung transplantation (HLT). MATERIAL AND METHODS: There were 190 LT and HLT (22.63% single LT, 71.05% bilateral sequential LT, and 7.36% HLT) performed from 1993 to 2002. Hemodynamic and respiratory parameters were monitored during the operative technique and critical care for the first 24 hours. We analyzed ischemic time, bypass need, and type of transplant. RESULTS: Lung graft dysfunction occurred in 37.2% of patients, but only in 12.2% was it severe. Nearly all patients were ventilated on a 50% fraction of inspired oxygen during the first 24-48 hours; 61.56% of patients were extubated before the first 5 postoperative day and 38.43% thereafter. The mean ischemia time for the first lung was 220 +/- 28 minutes: for the second lung, it was 378 +/- 31 minutes. The anesthetic time was 500-600 minutes. The variables associated with a significantly increased graft dysfunction were as follows: bilateral LT, and cardiopulmonary bypass requirement. The residence in the intensive care unit (ICU) was longer for patients with graft dysfunction than for those without that problem. Mortality directly related to graft dysfunction was only 4.07%. CONCLUSIONS: A correlation among graft ischemia and early postoperative morbidity and duration of ICU stay did not have a significant impact on mortality.

Parent-reported health status after pediatric thoracic organ transplant.

BACKGROUND: Thoracic organ transplantation is a life-changing event for a child and family from both a physical and a psychosocial perspective. Accurate pre-transplantation counseling and effective post-transplantation follow-up depend on a good understanding of post-transplantation health status, especially as perceived by families. METHODS: The Child Health Questionnaire-Parent Form 50 (CHQ-P50), an instrument that assesses parent-reported health status of pediatric patients, was administered to 47 pediatric thoracic organ transplant recipients (41 heart, 6 lung) 5 to 18 years of age. RESULTS: Transplant recipients scored lower on the Physical Health Summary (PhS) score than the general population, as evidenced by a lower median score (50.6 vs 55.1, p < 0.0001) and a difference in the distribution of quartiles (p = 0.001), skewed toward the lower quartiles of the general population. The distribution of PhS scores in transplant recipients was comparable to scores of 3 groups of pediatric patients with other chronic health conditions (juvenile rheumatoid arthritis, epilepsy and asthma). The distribution of the Psychosocial Health Summary (PsS) scores was similar to that of the general population, but the median score was lower (51.5 vs 53.2, p = 0.02). Transplant patients clearly scored lower than the general population on 4 of 12 sub-scales, including those assessing general health, physical functioning, family activities and parental emotional impact. No difference was found in sub-scales reflecting self-esteem, mental health, behavior, pain, peer interactions, family cohesion or parental time demands. CONCLUSIONS: Thoracic organ transplantation in children ages 5 to 18 years is associated with an ongoing deficit in parent-perceived physical health status.

Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients.

BACKGROUND: Aerosolized administrations of amphotericin B deoxycholate (AmBd) and amphotericin B lipid complex (ABLC) in lung transplant recipients were compared for safety and tolerability. The incidence of invasive fungal infections in patients receiving aerosolized amphotericin B formulations as sole prophylaxis was determined. METHODS: A prospective, randomized (1:1), double-blinded trial was conducted with 100 subjects. AmBd and ABLC were administered postoperatively by nebulizer at doses of 25 mg and 50 mg, respectively, which were doubled in mechanically ventilated patients. The planned treatment was once every day for 4 days, then once per week for 7 weeks. Treatment-related adverse events and invasive fungal infections were quantitated for 2 months after study drug initiation. RESULTS: Intent-to-treat analysis revealed study drug was discontinued for intolerance in 6 of 49 (12.2%) and 3 of 51 (5.9%) patients in the AmBd- and ABLC-treated groups, respectively (p=0.313). Subjects receiving AmBd were more likely to have experienced an adverse event (odds ratio 2.16, 95% confidence interval 1.10, 4.24, p=0.02). Primary prophylaxis failure within 2 months of study drug initiation was observed in 7 of 49 (14.3%) AmBd-treated patients and 6 of 51 (11.8%) ABLC-treated patients. No fungal pneumonias were observed. Only two (2%) patients experienced documented primary prophylaxis failure with Aspergillus infections within the follow-up period. CONCLUSIONS: Both aerosol AmBd and ABLC appear to be associated with a low rate of invasive pulmonary fungal infection in the early posttransplant period. Patients receiving ABLC were less likely to experience a treatment-related adverse event.