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ABSTRACT Milrinone is a bipyridine phosphodiesterase inhibitor with positive inotropic and vasodilatory effects. As interest in longer term use of intravenous therapy increases, it becomes essential to monitor its plasma concentration owing to a narrow therapeutic range, an increased half-life in renal failure and toxicity associated with high levels. A high-performance liquid chromatography (HPLC) method with mass (MS) detection using a triple quadrupole mass spectrometer is presented. The method was compared with the UV/HPLC method and validated according to current international guidelines. Coefficients of variation of less than 7.5% were obtained across the therapeutic range and 18.3% at 2.4 ng/mL, the lower limit of quantitation. Plasma from 13 cardiac surgery patients receiving standard intravenous doses of milrinone were measured. Eight patients achieved therapeutic milrinone levels within 3-4 h post start of infusion, one was borderline sub-therapeutic and four patients achieved levels that were above the upper limit of the therapeutic range and potentially toxic. This method offers high sensitivity, is rapid, easy to use and requires minimal amount of sample. We believe this method could become the reference procedure for clinical monitoring of milrinone and help to improve the safety of the use of this drug in patients with cardiac failure. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Inotropes are some of the most commonly used drugs in intensive care. However, their value in treating patients with heart failure is limited and prolonged use is associated with an increased mortality. Nevertheless inotropic agents increase cardiac contractility and can improve the cardiac output of patients with heart failure. [ABSTRACT FROM AUTHOR]

Acute heart failure and cardiogenic shock are medical emergencies requiring urgent medical intervention. This article defines each syndrome and reviews the latest evidence regarding their clinical presentation, management and prognosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To determine the effects of a small dose of beta blocker on neurohumoral and cardiopulmonary responses after cardiac transplantation. BACKGROUND--Cardiac transplant recipients have a reduced exercise capacity and abnormal cardiovascular responses to exercise. The sympathoadrenal response to exercise has been shown to be abnormal with high venous noradrenaline. The effect of beta blockade on these neurohumoral mechanisms has not been defined. METHODS--10 non-rejecting cardiac transplant recipients were studied. Patients carried out graded exercise to a symptom limited maximum. Blood samples were taken during exercise. Concentrations of noradrenaline, adrenaline, and atrial natriuretic peptide and plasma renin activity were measured. The next day, the exercise and sampling procedure were repeated after an oral dose of propranolol (40 mg). RESULTS--Patients tolerated exercise poorly after beta blockade, which was reflected in the maximum workload reached. Heart rate and blood pressure were significantly higher at rest and during exercise before beta blockade. Although there was no significant difference when resting, mean (SEM) noradrenaline concentrations during peak exercise were higher after beta blockade (16.2 (2) v 23.6 (2.9) nmol/l, p = 0.001). Adrenaline concentrations at peak exercise were also greater after beta blockade (0.89 (0.31) v 1.18 (0.38) nmol/l, p = 0.055). Atrial natriuretic peptide concentrations tended to be higher after beta blockade (118.75 (50.2) v 169.79 (39.3) pmol/l, p = 0.36). There was no significant change in plasma renin activity. CONCLUSIONS--A small oral dose of a competitive beta blocker such as propranolol has an adverse effect on exercise tolerance and cardiovascular response to exercise in cardiac transplant recipients. There are also increased concentrations of circulating noradrenaline and therefore, sympathetic activity during exercise. beta blockers should be used with caution in cardiac transplant recipients. [ABSTRACT FROM PUBLISHER]

The mechanical efficiency of left ventricular contraction and relaxation, the asynchrony of the onset of left ventricular relaxation, the time constant of left ventricular isovolumic pressure decay, and left ventricular chamber and myocardial stiffness were analysed in 32 patients after cardiac (24) and heart-lung transplantation (8). After cardiac transplantation left ventricular myocardial stiffness was increased and a mild degree of incoordinate contraction and relaxation was seen. In contrast, after heart-lung transplantation diastolic function was almost normal. Impairment of passive diastolic properties was significantly related to the ischaemic time of the donor heart and the donor's age. The index of left ventricular asynchrony was related to the ischaemic time and the recipient's age. The interval between transplantation and study did not influence the number of rejection episodes. This study confirms the presence of diastolic dysfunction after cardiac transplantation. Impairment of diastolic function seems to be related to the ischaemic time of the donor heart and to a mismatch between the size of the donor heart and the recipient's needs. [ABSTRACT FROM PUBLISHER]

The exercise capacity and cardiopulmonary response to progressive dynamic exercise of eight healthy recipients of heart-lung transplants were compared with those of matched recipients of orthotopic cardiac transplants and normal controls. In both transplant groups the maximum workloads were lower than that in the normal group. The transplant recipients had higher pre-exercise heart rates and lower maximum heart rates than the normal controls. Ventilation during submaximal exercise was similar in the heart transplant group and the controls. The heart-lung group had an increased ventilatory response associated with lower end tidal carbon dioxide concentrations. Exercise capacity after combined heart-lung transplantation is similar to that after cardiac transplantation. Transplant recipients have an abnormal heart rate response during exercise related to cardiac denervation. The altered ventilatory response in heart-lung recipients may be the result of pulmonary denervation. [ABSTRACT FROM PUBLISHER]

The operation of combined heart-lung transplantation results in acute denervation of the heart, lungs, and airways below the level of the trachea. The bronchoconstrictor response to inhaled methacholine of 12 recipients of heart-lung transplants was compared with that of 12 recipients of heart transplants having similar medication and 12 normal subjects. The median dose of methacholine that produced a reduction of at least 20% in the FEV1 (PC20) for the recipients of heart-lung transplants (8 mg/ml) was significantly lower than that for the recipients of heart transplants (64 mg/ml) and normal subjects (greater than 64 mg/ml). The increased airway reactivity may be related to the effects of chronic pulmonary denervation or subclinical inflammation in the airways. The effect of denervation on the response to full inspiration during bronchoconstriction was studied in six patients with heart-lung transplants by means of partial and maximal forced expiratory manoeuvres. Four showed bronchodilation after a deep breath, indicating that this response can occur after extrinsic pulmonary denervation in man. The patients with heart-lung transplants described a "tight" sensation in the anterior chest during bronchoconstriction, indicating that this sensation is not dependent on pulmonary innervation. [ABSTRACT FROM AUTHOR]

This paper reports on the use of the Nottingham Health Profile as a measure of patient quality of life before and after combined heart and lung transplantation at Harefield Hospital. A total of 125 profiles from 48 patients were analysed. In both section 1 and section 2 of the profile, large and statistically significant (p less than 0.05) improvements in quality of life were associated with transplantation. The profile proved easy to use either as part of an interview during assessment for transplantation or as a postal follow-up postoperatively. [ABSTRACT FROM AUTHOR]

This article focuses on a study related to incidence and clinical significance of left ventricular assist device (LVAD) failure. Management of life threatening LVAD mechanical failure is becoming increasingly important with increasing use of these devices for prolonged periods as a bridge to recovery, as destination therapy, or as a bridge to transplantation, with support lengthening due to shortage of donors. Life threatening mechanical pump failure can be successfully managed in the majority of patients, encouraging the longer term use of these devices.

Background: Heart transplantation (HTx), the gold standard therapy for advanced heart failure, is limited by donor availability; alternative therapies are now becoming available., Aim: We examined the outcome of HTx with current immunosuppressive and adjunctive therapy., Design and Methods: We analysed the outcome of 399 consecutive patients who underwent transplantation at our centre (1995-2007). Prior to HTx 23% (98) required inotropic support, 8.5% (34) an intra-aortic balloon pump and 11% (43) a ventricular assist device., Results: Actuarial patient survival was 86% at 30 days, 79% at 1 year and 62% at 10 years. Survival was similar regardless of the heart failure severity, P=0.22. The cumulative incidence of allograft vasculopathy, Costanzo grade≥2, was 7% at 5 years and 23% by 10 years with an 11% cumulative probability of requiring a percutaneous coronary intervention by 10 years. Allograft function was preserved with a mean±SD left ventricular ejection fraction of 73±7% at 1 year and 74±8% at 10 years. The cumulative incidence of malignancy by 10 years was 27% (skin malignancy 13% and post transplant lymphoproliferative diseases 10%). The cumulative incidence of developing chronic kidney disease (CKD) with an estimated glomerular filtration rate≤45 ml/min/1.73 m2 was 42% at 1 year, 62% at 5 years and 72% at 10 years and of requiring long-term renal replacement therapy was 10.6% at 10 years., Conclusion: HTx provided good medium-term survival for patients with advanced heart failure, independent of its severity. The incidence of allograft vasculopathy was lower than reported previously but malignancy and CKD remain cause for concern.

Here we report a case wherein both donor-specific and third-party, paternal, HLA class II specific antibodies developed following a spontaneous miscarriage resulting in antibody-mediated rejection in a patient who had undergone an orthotopic cardiac transplant six years earlier.

Background: We examined waiting time for adult heart transplantation in the UK and sought to determine whether recipients with particular ABO blood groups were disadvantaged., Methods: Data were obtained from the National Transplant Database. Registration outcome data were analyzed for 622 new, non-urgent, adult, heart-only registrations from April 1, 1999 to March 31, 2003. Unadjusted waiting times of the 618 first registrations were summarized using Kaplan-Meier estimates., Results: Death rates were relatively low, with no significant difference in the proportions of patients among the different blood groups who died while waiting. A smaller proportion of blood group O patients were transplanted at 1 year after registration, with a significant difference in waiting time to transplant between blood groups (p < 0.0001). Blood group A and AB patients were generally transplanted sooner than O and B patients, with median waiting times of 81 days (95% CI: 67 to 114) and 76 days (95% CI: 52 to 178) vs 214 days (95% CI: 162 to 308) and 174 days (95% CI: 78 to 249), respectively., Conclusions: Although no particular blood group was disadvantaged in terms of mortality on the heart transplant list, blood group O and B patients waited significantly longer for transplantation. The difference was at least partly due to a large proportion of blood group O hearts being used for non-O patients. To address this imbalance, the UK Transplant Cardiothoracic Advisory Group (CTAG) changed the allocation protocol, so that "out-of-zone" offers of blood group O donors for non-urgent patients are now restricted to O and B recipients.

Cystic fibrosis (CF) patients requiring transplantation for respiratory failure may undergo either heart-lung (HLT) or bilateral sequential lung (BSLT) transplantation. The choice of operation varies between surgeons, centres and countries. The current authors investigated whether operation type influenced outcome in adult CF patients transplanted in the UK between July 1995 and June 2002. Propensity scores for receipt of BSLT versus HLT were derived using logistic regression. Cox regression was used to compare survival. In total, 88 BSLTs and 93 HLTs were identified. Patient characteristics were similar overall, but HLT recipients were more likely to be on long-term oxygen therapy and to have had prior resuscitation. There were 72 deaths (29 BSLT and 43 HLT) within 4 yrs. There was a trend towards higher unadjusted survival following BSLT, but, after adjustment, no difference was found (hazard ratio = 0.77; 95% confidence interval 0.29-2.06). Time to the first rejection episode and infection rates were also similar. A total of 82% of hearts from HLT recipients were used as domino heart transplants. In conclusion, after adjusting for comorbidity, donor factors and ischaemia time, it was found that heart-lung and bilateral sequential lung transplantation achieved a similar outcome. The use of domino heart transplantation ameliorated the impact of heart-lung transplantation on total organ availability.

Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppressive regimens following heart transplantation, but their use is associated with nephrotoxicity. We evaluated a CNI elimination protocol in 14 patients with renal impairment at 48.3 +/- 36.0 months after heart transplantation. The mean serum creatinine was 321 +/- 107 micromol/L; cyclosporine (n=13) or tacrolimus (n=1) was discontinued with sirolimus commenced immediately, initially aiming for a target trough level of 16 (12 to 20) ng/mL. If patients were not receiving mycophenolate (MMF) this was initiated at 1 g bid. The transfer period was covered with a tapering course of corticosteroids. In addition to monitoring clinical status, hematology, biochemistry, and sirolimus levels, graft function was assessed by echocardiography, ECG, and, where indicated, endomyocardial biopsy. Renal function improved in 12 patients (with 6 having a greater than 40% decrease in serum creatinine), remained unchanged in 1, and deteriorated in 1. Two patients who were converted at 15 and 139 months after transplantation experienced grade 3A rejection. One patient experienced a fall in ejection fraction without histologic evidence of rejection. Sirolimus was discontinued in three patients because of side effects: bone marrow suppression, presumed lymphocytic pneumonitis, and generalized acneform rash complicated by an axillary abcess; 50% of patients continue on sirolimus. In conclusion, withdrawal of CNIs after heart transplantation resulted in an improvement in renal function in most patients: 43% experienced a substantial improvement. CNI elimination protocols need to be refined to reduce the risk of breakthrough rejection and to minimize side effects while protecting renal function after heart transplantation.

Background: Mechanical device failure can be life-threatening and is becoming increasingly important as left ventricular assist devices (LVADs) are being used for longer periods as a bridge to transplantation (period lengthening due to donor shortage) or recovery, or as destination therapy. However, its incidence and clinical management have not been widely studied., Methods: We investigated the incidence and management of major device failure for a total of 102 Thoratec/TCI HeartMate and Thoratec PVAD devices implanted at our institution since 1995., Results: The cumulative probability of device failure was 6%, 12%, 27% and 64% at 6 months, 1 year, 18 months and 2 years, respectively. Major failure occurred in 8 (7.8%) patients. Four patients presented as emergency cases with vented electric (VE) failure, and 3, with failure due to a seized motor, were supported on the pneumatic driver to explantation, transplantation or device change. Another patient had a ruptured pump diaphragm and was maintained for 12 hours, but died of a Type B aortic dissection. Four patients underwent elective device change, including 2 of a VE pump, 1 with inlet valve regurgitation and fractured power cable at 414 days, and 1 with inlet valve regurgitation at 656 days, all of whom underwent transplantation or explantation. One patient with VE failure was maintained on the pneumatic driver, then underwent Thoratec paracorporeal ventricular assist device (PVAD) implantation and was transplanted. One Thoratec PVAD patient developed LVAD thrombus, underwent pump replacement, and was transplanted. A further patient on the implantable pneumatic (IP) HeartMate developed a pneumoperitoneum due to a leak at the junction of the pneumatic driveline, which was repaired by inserting a new driveline, and underwent heart/kidney transplantation., Conclusions: Life-threatening mechanical device failure is not uncommon and increases with time, but can be managed successfully in most patients. Improvements in design and manufacture should further enhance outcome with LVADs.

Background: Left ventricular assist device (LVAD) treatment is known to lead to structural and functional cellular modifications in the heart. The relevance of these changes for clinical recovery is unknown., Methods and Results: We compared properties of cardiomyocytes obtained from tissue taken at explantation of the LVAD in patients with clinical recovery with those obtained from hearts of patients who did not show clinical recovery, thus requiring transplantation. Compared with myocytes taken at implantation, both the recovery and nonrecovery groups showed approximately 50% reduction in cell capacitance, an index of cell size. However, action potential duration shortened, L-type Ca2+ current fast inactivation was more rapid, and sarcoplasmic reticulum Ca2+ content was increased in the recovery compared with the nonrecovery group., Conclusions: These results show that specific changes in excitation-contraction coupling, and not regression of cellular hypertrophy, are specifically associated with clinical recovery after LVAD and further identify sarcoplasmic reticulum Ca2+ handling as a key functional determinant in patients with heart failure.

Background: Hypercholesterolemia is frequent after heart transplantation. Statins can reduce cholesterol levels but their use in heart transplant patients is complicated by pharmacokinetic interactions with cyclosporin and the risk of serious adverse effects including rhabdomyolysis. Fluvastatin has been used safely to treat hypercholesterolemia in renal transplant patients but there are few data relating to its use after heart transplantation. Therefore, we conducted a randomised blinded placebo controlled trial., Methods and Results: Seventy-nine patients, 3 months to 12 years after heart transplantation with a low density lipoprotein (LDL) cholesterol between 3.5 and 8.0 mmol/l were randomly assigned, in a 2:1 ratio, to receive either fluvastatin 40 mg od (n=52) or matching placebo (n=27). Changes in total cholesterol (TC) in the fluvastatin and placebo groups were -17.0% and +4.5%, respectively, (p<0.001); the corresponding changes in LDL were -20.5% and +4.8% (P<0.001) and in triglycerides -14.5% and +7.1% (p=0.012) at the end of the 1-year study period. Withdrawals were more frequent in the fluvastatin group (23% vs. 11% p=0.24). Two deaths occurred during the study (the rate expected from International Society of Heart Lung Transplantation registry) and appeared to be unrelated to the study medication. There were no episodes of rhabdomyolysis or other serious drug-related side effects., Conclusions: Fluvastatin (40 mg/day) was both an effective and a safe treatment for hypercholesterolemia in patients who had undergone heart transplantation more than 3 months previously.

The discovery of cyclosporine proved to be a breakthrough that helped transform the status of both heart and lung transplantation from experimental to established therapeutic procedures. Cyclosporine inhibits the early phase of T-cell activation and thus of the alloimmune response. It proved to be highly effective in prophylaxis against acute rejection but its use has been limited by dose-related renal toxicity. Consequently, it has generally been used in regimens that combine it with other immunosuppressive agents with the aim of preventing acute rejection while minimising toxicity. For many years 'triple therapy' using cyclosporine, azathioprine and corticosteroids was the most commonly used regimen for both heart and lung transplantation. Other agents have now become available that provide more effective prophylaxis against acute rejection than azathioprine; these include, mycophenolate and the TOR inhibitors sirolimus and everolimus. Everolimus has also been shown to inhibit the early phase of cardiac allograft vasculopathy. Unfortunately, the TOR inhibitors also potentiate the nephrotoxicity of cyclosporine. Both mycophenolate and the TOR inhibitors are subject to pharmacokinetic interactions with cyclosporine. We are now entering a new phase of clinical immunosuppression where we need to learn how to best combine the agents that are currently available to provide the safest and most effective immunosuppression for patients undergoing heart or lung transplantation.

Background: Left ventricular assist devices (LVADs) are frequently used to maintain patients with severe heart failure until heart transplantation becomes possible. Some patients may experience recovery of LV function during such support. Therefore, it is essential to be able to monitor changes in LV function in this setting., Methods: We studied LV function in 10 patients (median age 34 years, 9 male) who had LVADs implanted because of severe heart failure due to dilated cardiomyopathy a median of 4 months previously. Median pre-implant ejection fraction was 27% and all patients had been on maximal medical therapy, including intravenous inotropic support, prior to insertion of the LVAD., Results: During LVAD support there were cyclical variations in LV dimensions, fractional shortening (FS) and transmitral flow, related to changes in the phase relationship of the LV and the LVAD. The "best" FS occurred when LV systole coincided with device filling and the "worst" FS when LV systole coincided with device ejection. Median FS with the pump switched off was 18% (10% to 32%). Pump-off FS was significantly greater than the "worst" FS with the pump on (5%, p = 0.002), and similar to the "best" pump-on FS (19%, p = NS)., Conclusions: LV function could be studied echocardiographically during LV support and brief periods of interruption in support. Function varied according to the phase relationship of the LV and LVAD. The "best" FS measured during LVAD support was more closely related to the FS with the device switched off than the "worst" pump on FS. The "best" pump-on LV function is therefore most representative of intrinsic LV performance and can be used as a guide to recovery and the potential need for pump-off studies.

Background: Bronchiolitis obliterans syndrome (BOS) is a leading cause of morbidity and mortality after lung and heart-lung transplantation. Present treatment is directed at the augmentation of pharmacologic immunosuppression., Methods: This study examines the effect of substituting cyclosporine with tacrolimus on the forced expiratory volume in 1 second (FEV(1)) and on the forced expiratory flow between 25% and 75% of vital capacity (FEF(25%-75%)) in 32 patients who developed BOS. The proportional rates of decline of FEV(1) and FEF(25%-75%) before and after treatment with tacrolimus were calculated. The actuarial survival of responders and non-responders to tacrolimus was compared. Pre-operative and post-operative factors were investigated to determine any difference between the 2 groups., Results: There were significant reductions in the rates of decline of FEV(1) and FEF(25%-75%) when the rates in the 3 months before conversion to tacrolimus were compared with subsequent rates at 0 to 3 months, 3 to 6 months, 6 to 9 months and 9 to 12 months after conversion. The rates of decline of FEV(1) and FEF(25%-75%) in the 3 months before conversion were 0.11 liters/month and 0.13 liters/s per month, respectively. This compares with the rates of decline for FEV(1) and FEF(25%-75%) for the 3 months after conversion to tacrolimus of 0.04 liters/month (p = 0.023) and 0.04 liters/s per month (p = 0.022), respectively. The actuarial survival at 1 year from the time of conversion to tacrolimus for the responder sub-group and the non-responder sub-group were 89.2% and 75%, respectively, and at 4 years after conversion were 61.3% and 56.3%, respectively (p = 0.92)., Conclusions: Tacrolimus rescue therapy is effective at stabilizing lung function in patients with BOS, and this effect is apparent up to 12 months after conversion from cyclosporine.

Background: Donor availability is currently the major factor limiting the use of heart transplantation as a treatment for severe heart failure. Heterotopic heart transplantation may address this issue by allowing the use of smaller donor organs, which otherwise may not be used., Methods: We analyzed the outcome of 42 consecutive, adult heterotopic transplantations performed between 1993 and 1999 at our center and compared them with the 303 consecutive orthotopic transplants performed in adult patients during the same period., Methods: Univariate analysis showed a relative risk for death of 1.8 at 1 year after transplantation for the heterotopic group compared with the orthotopic transplantation group (p = 0.04). Multiple regression analysis using a proportional hazards model showed that donor-recipient size-mismatch, i.e., donor body surface area < or =75% of recipient body surface area (p = 0.0001), donor age (p = 0.0001), and use of a female donor (p = 0.04) were significant risk factors but heterotopic transplantation per se was not. A Kaplan-Meier survival analysis of heterotopic vs orthotopic transplantation showed that 30-day survival was 76% vs 87%. By 1 year, this was 59% vs 74%. At 3 years, the comparison was 56% vs 69%. Repeating this analysis after sub-dividing the heterotopic group into those size-matched vs size-mismatched, the 1-year survival was 81% vs 45%, respectively (p = 0.02)., Conclusions: Heterotopic transplantation using a size-matched graft resulted in similar survival to that seen after orthotopic transplantation during the same period. Heterotopic transplantation with an undersized graft resulted in significantly decreased survival.