Henryk Welp

Sex Mismatch in Heart Transplantation Is Associated With Increased Number of Severe Rejection Episodes and Shorter Long-Term Survival

BACKGROUNDnHeart transplantation is the criterion standard for treating end-stage heart failure. Male sex of both the donor organ and the recipient is advantageous for survival, possibly owing to hemodynamic or immunologic reasons. The effect of sex mismatch on long-term survival in male heart transplant recipients is less known.nnnPATIENTS AND METHODSnIn this prospective single-center study, we reviewed follow-up data for 57 sex-mismatched and 179 sex-matched men who underwent orthotopic heart transplantation between 1990 and 2002.nnnRESULTSnMedian survival was significantly shorter in the sex-mismatched group (8.1 vs 12.9 years; P < .04). Subgroup analysis revealed that this was even more pronounced in male heart recipients with coronary artery disease (2.4 vs 12.9 years; P < .001). Female donor organs were significantly smaller (left ventricular end-diastolic diameter 49 vs 51 mm; P < .05), and recipients more often experienced clinically relevant episodes of cellular rejection during the first 3 months posttransplantation (International Society for Heart and Lung Transplantation grade 3, 5.6% vs 3.1%; P < .001). Global left ventricular function, and immunosuppressive and inflammatory parameters did not differ.nnnCONCLUSIONnIn male orthotopic heart transplant recipients, sex mismatch is associated with adverse outcome owing to increased number and severity of episodes of graft rejection.

Calcineurin Inhibitor-free Immunosuppression Using Everolimus (Certican) after Heart Transplantation: 2 years' Follow-up from the University Hospital Münster

BACKGROUNDnEverolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)-free immunosuppression using everolimus.nnnMETHODSnAfter heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed.nnnRESULTSnAfter switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 ± 0.6 vs 1.8 ± 1 mg/dL; P < .001; creatinine clearance, 41.8 ± 22 vs 48.6 ± 21.8 mL/min; P < .001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 (P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n = 2), skin disorders (n = 2); reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)].nnnCONCLUSIONnCNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients.

Prospective study of everolimus with calcineurin inhibitor-free immunosuppression in maintenance heart transplant patients: results at 2 years.

Background. Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients. Methods. In a prospective, single-arm, single-center study, CNI-treated heart transplant patients were converted to everolimus and were followed up for 24 months. The primary endpoints were kidney function and arterial hypertension at 12 and 24 months after conversion. Results. Fifty-eight patients were recruited (mean time posttransplant 5.6±3.7 years), 55 of whom (91.7%) had renal impairment. Mean creatinine clearance increased from 43.6±21.1 mL/min to 49.5±21.2 mL/min at month 24 (P=0.02). Median blood pressure increased from 120/80 mm Hg at baseline to 122.5/80 mm Hg (P=0.008 and 0.006 for systolic and diastolic pressure, respectively). Lipid parameters did not change significantly over the 24-month follow-up. Early resolution of most non-renal CNI-related adverse events was sustained. CNI therapy was re-introduced at a mean of 309 days (range, 31–684 days) in eight patients after month 6 due to adverse events (n=13) or withdrawal of consent (n=2). No significant changes in cardiac function parameters were observed. Conclusions. CNI-free immunosuppression with everolimus is an effective and safe option in selected heart transplant maintenance patients. Most adverse effects under everolimus occurred early after conversion and generally resolved without intervention within a few weeks. Refining selection criteria may reduce the need to re-introduce CNI therapy.

Analysis of Platelet Function during Left Ventricular Support with the Incor and Excor System

Improvements in pump technology and the scarcity of donor organs have led to an increased use of mechanical assist devices, but the problem of thromboembolism has still not been solved. We report on our initial experience with sequentially analyzing platelet function in patients provided with the Incor left ventricular assist device (LVAD) and the Excor LVAD system. Thirteen patients 5 to 61 years old with acute or end-stage heart failure were included in a pilot study. Five of the 10 Incor patients underwent LVAD placement under emergency conditions, and 5 were electively scheduled for surgery. All 3 patients with an Excor device had been connected to an extracorporeal membrane oxygenation system prior to insertion of the device. An anticoagulation protocol including heparin, aspirin, and clopidogrel was employed, and the patients were closely monitored with a special platelet analyzing system that allows dose optimization for antiplatelet drugs. Initial platelet function was normal in only 2 patients (15%). During a follow-up period of 1770 days (cumulative >4.8 years), no early (<30 days) bleeding complications related to device implantation occurred. Late cerebral thromboembolic events were noted in 3 patients. One patient experienced severe stroke mandating neurosurgery during mechanical assist, and 1 patient experienced systemic embolism. The PAP platelet analyzer offers a cheap and reliable alternative to the more expensive thromboelastography method for adequately surveying the efficacy of aspirin and clopidogrel treatment, even if late thromboembolic events cannot be prevented.

Prospective study of everolimus with calcineurin inhibitor-free immunosuppression after heart transplantation: results at four years.

BACKGROUNDnImmunosuppression is necessary after transplantation but it is associated with distinct adverse side effects. These negative effects could at least partially be overcome with the mammalian target of Rapamycin (mTOR) inhibitor everolimus. Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients (HTx).nnnMETHODSnIn this prospective, single-arm, single-center study, maintenance patients after HTx were converted from CNI to everolimus. They were followed for 48 months. Primary endpoints were kidney-function and arterial hypertension.nnnRESULTSnForty-eight patients were recruited (mean post-transplant time 5.4 ± 3.5 years). Of these, 36 were followed for the entire 4-year period. Median calculated glomerular filtration rate increased from 40.7 (32.4 to 59.1) mL/minute at baseline to 48.9 (29.7 to 67)) mL/minute at month 48 (p = not significant). Median systolic and diastolic blood pressure, triglycerides, and high-density lipoprotein and low-density lipoprotein cholesterol, did not change significantly in a comparison of the values at baseline and at 48 months. Early resolution of most non-renal CNI-related adverse events was sustained. Due to adverse events, CNI therapy had to be reintroduced in 6 patients (12.5%). No significant changes in cardiac function parameters were observed.nnnCONCLUSIONSnCalcineurin inhibitor-free immunosuppression with everolimus is an effective and safe option in selected maintenance HTx patients. Most adverse effects under everolimus occurred early after conversion and in most cases resolved without intervention within a few weeks. Refining selection criteria may help both in identifying patients who will profit most from switching and in alleviating the need to reintroduce CNI therapy.

Surgery of secondary mitral insufficiency in patients with impaired left ventricular function

BackgroundSecondary mitral insufficiency (SMI) is an indicator of a poor prognosis in patients with ischemic and dilated cardiomyopathies. Numerous studies corroborated that mitral valve (MV) surgery improves survival and may be an alternative to heart transplantation in this group of patients.The aim of the study was to retrospectively analyze the early and mid-term clinical results after MV repair resp. replacement in patients with moderate-severe to severe SMI and left ventricular ejection fraction (LVEF) below 35%.MethodsWe investigated 40 patients with poor LVEF (mean, 28 ± 5%) and SMI who underwent MV repair (n = 26) resp. replacement (n = 14) at the University Hospital Muenster from January 1994 to December 2005. All patients were on maximized heart failure medication. 6 pts. had prior coronary artery bypass grafts (CABG). Twenty-seven patients were in New York Heart Association (NYHA) class III and 13 were in class IV. Eight patients were initially considered for transplantation. During the operation, 14 pts had CABG for incidental disease and 8 had tricuspid valve repair. Follow-up included echocardiography, ECG, and physicians examination and was completed in 90% among survivors. Additionally, the late results were compared with the survival after orthotope heart transplantation (oHTX) in adults with ischemic or dilated cardiomyopathies matched to the same age and time period (148 patients).ResultsThree operative deaths (7.5%) occurred as a result of left ventricular failure in one and multiorgan failure in two patients. There were 14 late deaths, 2 to 67 months after MV procedure. Progress of heart failure was the main cause of death. 18 patients who were still alive took part on the follow-up examination. At a mean follow-up of 50 ± 34 (2–112) months the NYHA class improved significantly from 3.2 ± 0.5 to 2.2 ± 0.4 (p < 0.001). The LVEF improved significantly from 29 ± 5% to 39 ± 16 (p < 0.05). There were no differences in survival after MV repair or replacement. The 1-, 3-, 5-year survival rates in the study group were 80%, 58% and 55% respectively. In the group of patients after oHTX the survival was accordingly 72%, 68%, 66% (p > 0.05).ConclusionHigh risk mitral valve surgery in patients with cardiomyopathy and SMI offers a real mid-term alternative method of treatment of patients in drug refractory heart failure with similar survival in comparison to heart transplantation.

Can Perioperative Right Ventricular Support Prevent Postoperative Right Heart Failure in Patients With Biventricular Dysfunction Undergoing Left Ventricular Assist Device Implantation

OBJECTIVESnDepending on the pre-existing condition of the right ventricle (RV), left ventricular assist device (LVAD) implantation may have a detrimental effect on RV function, subsequently leading to right heart failure. This study details the authors experience with perioperative mechanical RV support in patients with biventricular impairment but primarily scheduled for isolated LVAD implantation.nnnDESIGNnRetrospective study.nnnSETTINGnTwo center study, university hospital.nnnPARTICIPANTSnThis study included LVAD recipients with preoperative biventricular impairment who received an additional right ventricular assist device (RVAD) after a failed weaning attempt from cardiopulmonary bypass due to acute RV failure.nnnINTERVENTIONSnOutcomes of 25 patients who underwent LVAD and unplanned temporary RVAD implantation were analyzed.nnnMEASUREMENTS AND MAIN RESULTSnAll patients experienced significant preoperative RV impairment (tricuspid annular plane systolic excursion: 10.2±26.3 mm; right atrium pressure: 17.9±10.4 mmHg) and pulmonary hypertension (pulmonary artery pressure: 54.8±25.7 mmHg). In 15 patients, additional tricuspid valve annuloplasty was performed. Mean duration of temporary RVAD support was 11.1±7.2 days. In 23 patients (92%), the RVAD was removed successfully. None of the patients developed RV failure after RVAD removal. Hospital survival and the 1-year survival rate of the study group were 68% and 56%, respectively.nnnCONCLUSIONSnThe results of perioperative RVAD support in LVAD recipients with biventricular dysfunction are encouraging. Temporary RVAD support allows an already compromised RV to become attuned to the hemodynamic conditions after LVAD implantation. This strategy provides patients with preoperative impaired RV function a high likelihood to permanently undergo LVAD support only.

Is Implantation of a Left Ventricular Assist Device in Patients With Critical or Impending Cardiogenic Shock an Absolute Contraindication? Looking Back at Our Past Experience Trying to Identify Contraindicative Risk Factors.

Poor survival has been demonstrated after ventricular assist device (VAD) implantation for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 and 2 patients compared with more stable levels. However, risk factors within this high-risk cohort have not been determined so far. The aim of the present study was to identify risk factors associated with this very high mortality rate. Between February 1993 and January 2013, 298 patients underwent VAD implantation in our institution. One hundred nine patients were in INTERMACS level 1 and 49 patients were in INTERMACS level 2 and were therefore defined as hemodynamically critical (overall 158 patients). Assist devices implanted were: HVAD HeartWare nu2009=u200918; Incoru2005nu2009=u200911; VentrAssistu2005nu2009=u20092; DeBakeyu2005nu2009=u200922; and pulsatile systems nu2009=u2009105. After cumulative support duration of 815.35 months, Kaplan-Meier analysis revealed a survival of 63.9, 48.8, and 40.3% at 1, 6, and 12 months, respectively. Cox regression analyses identified ageu2009>u200950 (Pu2009=u20090.001, odds ratio [OR] 2.48), white blood cell countu2009>u200913.000/μL (Pu2009=u20090.01, OR 2.06), preoperative renal replacement therapy (Pu2009=u20090.001, OR 2.63), and postcardiotomy failure (Pu2009<u20090.001, OR 2.79) as independent predictors of mortality. Of note, last generation VADs were not associated with significantly better 6-month survival (Pu2009=u20090.59). Patients without the aforementioned risk factors could yield a survival of 79.2% at 6 months. This single-center experience shows that VAD implantation in hemodynamically unstable patients generally results in poor early outcome, even in third-generation pumps. However, avoiding the aforementioned risk factors could result in improved outcome.

Heparin-Induced Thrombocytopenia During Extracorporeal Membrane Oxygenation

HEPARIN-INDUCED THROMBOCYTOPENIA (HIT) is an immune-mediated adverse effect of heparin therapy. Two clinical entities of HIT can be distinguished: HIT I and HIT II. HIT I is a harmless pharmacologic phenomenon associated with decreased platelet count within 24–48 h after initiation of heparinization. Unlike HIT II, it is not associated with thrombosis and does not necessitate discontinuation of heparin. In contrast, HIT II can cause both bleeding and thrombotic complications. It is the most important and most frequent drug-induced immunologic thrombocytopenia. Besides orthopedic and vascular surgery patients, patients after cardiac surgery are at highest risk of developing HIT II (1–5%). Its clinical importance is based on its strong association with venous and arterial thrombosis and thromboembolism (heparin-induced thrombocytopenia with associated thrombosis, HITT). HIT is caused by the development of an IgG antibody that recognizes multimolecular complexes of platelet factor 4 (PF4) and heparin. This so-called heparin-PF4-IgG complex leads to platelet activation and release of additional PF4 from alpha granules in platelets when bound to the platelet Fc receptor. Note that heparin forms a necessary part of the complex leading the further PF4 release. PF4 released in excess binds to heparin-like molecules on the surface of endothelial cells leading to immunemediated endothelial cell injury and heightening the risk for HITT and disseminated intravascular coagulation (DIC). The mainstay of therapy in HIT/HITT is the avoidance of further exposure to heparin in any form, avoidance of platelet transfusions and deferral of vitamin-K-antagonists until platelet recovery. Early use of alternative anticoagulants is inevitable when the indication for anticoagulation persists or in individuals with HITT. Extracorporeal membrane oxygenation (ECMO) remains a last line life-saving therapeutic option in patients suffering from

Continuous Glucose Monitoring in Patients Undergoing Extracorporeal Ventricular Assist Therapy

Background Dysregulations of blood glucose (BG) are associated with adverse outcome in critical illness; controlling BG to target appears to improve outcome. Since BG-control is challenging in daily intensive care practice BG-control remains poor especially in patients with rapidly fluctuating BG. To improve BG-control and to avoid deleterious hypoglycemia, automated online-measurement tools are advocated. We thus evaluated the point-accuracy of the subcutaneous Sentrino® Continuous Glucose Monitoring System (CGM, Medtronic Diabetes, Northridge, California) in patients undergoing extracorporeal cardiac life support (ECLS) for cardiogenic shock. Methods Management of BG was performed according to institute’s standard aiming at BG-levels between 100–145 mg/dl. CGM-values were recorded without taking measures into therapeutic account. Point-accuracy in comparison to intermittent BG-measurement by the ABL-blood-gas analyzer was determined. Results CGM (n = 25 patients) correlated significantly with ABL-values (r = 0.733, p<0.001). Mean error from standard was 15.0 mg/dl (11.9%). 44.2% of the readings were outside a 15% range around ABL-values. In one of 635 paired data-points, ABL revealed hypoglycemia (BG 32 mg/dl) whereas CGM did not show hypoglycemic values (132mg/dl). Conclusions CGM reveals minimally invasive BG-values in critically ill adults with dynamically impaired tissue perfusion. Because of potential deviations from standard, CGM-readings must be interpreted with caution in specific ICU-populations.