Markus J. Wilhelm

Brain death and its influence on donor organ quality and outcome after transplantation.

Transplantation has evolved as the treatment of choice for many patients with end-stage organ disease. However, despite the .80% one-year functional survival rate of most transplanted organs at the present time, the ultimate goal—to provide long-term treatment for an irreversible process—has not been achieved; the rate of attrition over time has not changed appreciably throughout the entire experience (1). Although recurrent disease, de novo infections, malignancies, and other factors may contribute to late graft deterioration, chronic rejection remains the most important etiologic factor (2). Despite well-characterized functional and morphological changes, the mechanisms leading to this progressive state remain poorly understood. Its pathophysiology has been conceptualized as stemming from both antigendependent and -independent risk factors (3). Although immune-mediated events are considered to be primarily responsible for the late graft changes, it seems increasingly that the influence of nonimmunological events has been underestimated. This concept has been emphasized by recent pooled United Network of Organ Sharing data that show that the survival rates of kidneys from living-unrelated and one haplotype-matched living-related donors are identical despite potentially important differences in genetic relationship with the given recipient (4). In addition, organs from all living donors demonstrate consistently superior results to those from cadaver sources over both the shortand long-term. Various nonimmunological factors that might explain these discrepancies include the effects of initial ischemia/reperfusion injury, inadequate functioning nephron mass, viral infections, and drug toxicity. Brain death is a rarely considered risk factor uniquely relevant to the cadaver donor. Multivariate analysis has emphasized that both initial and long-term results of engrafted cadaver organs may be dependent upon donor demographics and the etiology of the central injury (5). In virtually all experimental studies of organ transplantation, young, healthy living animals are used as donors; in clinical practice, in contrast, a relatively low percentage of organs comes from living donors, as cadavers remain the primary source of supply. Amongst other variables, the difference between the two donor populations implies the effect of profound physiological and structural derangements that may occur during and subsequent to brain death and before the actual engraftment procedure.

Activation of the Heart by Donor Brain Death Accelerates Acute Rejection After Transplantation

BackgroundDonor brain death upregulates expression of inflammatory mediators in the heart. It is hypothesized that these nonspecific changes trigger and amplify acute rejection in unmodified recipients compared with hearts from normal living donors. We examined the inflammatory and immunological consequences of gradual-onset donor brain death on cardiac allografts after transplantation. Methods and ResultsFunctioning hearts were engrafted from normotensive donors after 6 hours of ventilatory support. Hearts from brain-dead rats (Fisher, F344) were rejected significantly earlier (mean±SD, 9.3±0.6 days) by their (Lewis) recipients than hearts from living donor controls (11.6±0.7 days, P =0.03). The inflammatory response of such organs was accelerated, with rapid expression of cytokines, chemokines, and adhesion molecules and brisk infiltration of associated leukocyte populations. Upregulation of major histocompatibility class II antigens increased organ immunogenicity. Acute rejection evolved in hearts from brain-dead donors more intensely and at a significantly faster rate than in controls. ConclusionsDonor brain death is deleterious to transplanted hearts. The resultant upregulation of inflammatory factors provokes host immune mechanisms and accelerates the acute rejection process in unmodified hosts.

Activation of inflammatory mediators in rat renal isografts by donor brain death

BACKGROUND Brain death (BD) has been thought to influence the early course of transplanted organs by triggering a series of nonspecific inflammatory events that in turn may increase the kinetics and intensity of the immunological host responses. In this study early nonspecific, cellular, and molecular changes occurring in kidney isografts from BD donors are compared with those from normal anesthetized, ventilated controls. METHODS After induction of brain death, the animals were mechanically ventilated for 6 hr before organ removal. Only rats with stable blood pressure (mean arterial pressure >80 mmHg) were included. Serum creatinines were measured daily. Representative grafts were harvested 6 hr after brain death and between 1 hr and 5 days after engraftment for morphology, immunohistology, and reverse transcriptase-polymerase chain reaction. The presence of serum cytokines was assessed by enzyme linked immunoabsorbant assay. RESULTS Serum creatinine levels rose slightly in recipients from BD donors. Serum interleukin-1beta levels increased within 6 hr versus controls (P<0.05). mRNA levels of interleukin-1beta and macrophage inhibitory protein-1 in the kidneys were up-regulated transiently before engraftment (6 hr after BD) and 1 hr after revascularization (P<0.05). By immunohistology, numbers of infiltrating polymorphonuclear leukocytes peaked at 24 hr in parallel with intragraft induction of P- and E-selectin, complement, and other proinflammatory chemokines and cytokines. At 5 days, the isografts from BD donors were highly infiltrated by host leukocyte populations associated with intense up-regulation of their products. In contrast, those from control donors remained relatively normal through this initial follow-up period. CONCLUSIONS The intense nonimmune inflammation produced in isografts after donor BD may represent the initial stages of a continuum between an initial nonspecific and later immune reactivity, when placed in the context of allotransplantation.

Accelerated rejection of renal allografts from brain-dead donors.

ObjectiveTo define the potential influences of donor brain death on organs used for transplantation. Summary Background DataDonor brain death causes prompt upregulation of inflammatory mediators on peripheral organs. It is hypothesized that this antigen-independent insult may influence the rate and intensity of host alloresponsiveness after engraftment. MethodsThe rates of survival of unmodified Lew recipients sustained by kidney allografts from brain-dead, normal anesthetized, and anesthetized ventilated F344 donors were compared. Brain death was induced by gradually increasing intracranial pressure under electroencephalographic control. Tracheotomized brain-dead animals and anesthetized controls were mechanically ventilated for 6 hours before transplant nephrectomy. The rate and intensity of the acute rejection event were examined by histology, immunohistology, and reverse transcriptase–polymerase chain reaction. ResultsAnimals bearing kidneys from brain-dead donors died of renal failure secondary to acute rejection at a significantly faster rate than those from anesthetized living controls or anesthetized animals ventilated for 6 hours. Within 3 hours after placement and reperfusion of brain-dead donor grafts, significant neutrophil infiltration was observed, followed by increasing numbers of macrophages and T cells. mRNA of proinflammatory mediators detected in kidneys within 6 hours of brain death and upregulated even before transplantation increased thereafter and appeared to accelerate and amplify host alloresponsiveness, as manifested by the rapid expression of chemokines, cytokines, adhesion molecules, and major histocompatibility complex class II antigens in the engrafted organ. The process evolved in the controls less intensely and at a slower rate. ConclusionsDonor brain death is a significant risk factor for peripheral organs used for transplantation. The activated state of such organs appears to trigger host immune mechanisms that accelerate the process of acute rejection. The effects of this central injury may explain in part the less satisfactory performance of cadaver organs in human transplantation compared with those from living sources.

Left ventricular pressure and volume unloading during pulsatile versus nonpulsatile left ventricular assist device support

BACKGROUND Nonpulsatile axial or centrifugal pumps are the latest generation of left ventricular assist devices (LVAD). Whether left ventricular (LV) unloading and outcome in these devices is similar to pulsatile LVADs during long-term support has not been investigated. We compared LV unloading and mortality between different types of LVAD support (pulsatile versus nonpulsatile). METHODS In 31 patients undergoing long-term LVAD implantation (nonpulsatile = 10, pulsatile = 21) preoperative and postoperative echocardiographic and hemodynamic assessment with right heart catheterization had been obtained. RESULTS All patients had similar echocardiographic, hemodynamic, and clinical heart failure characteristics at baseline. The degree of LV pressure unloading was the same in both device types, caused by similar reduction of mean pulmonary pressure (18.6 +/- 5.1 versus 18.3 +/- 7.5 mm Hg) and pulmonary capillary wedge pressure (8.9 +/- 4.4 versus 8.0 +/- 7.0 mm Hg). Left ventricular volume unloading was pronounced with a pulsatile device owing to a statistically significant higher pump output (5.1 +/- 1.0 L/min) in comparison with nonpulsatile LVADs (3.6 +/- 0.9 L/min, p < 0.001). Echocardiographic-determined end-systolic indicators confirm this augmentation in pulsatile LVADs. Etiology or the time interval of hemodynamic reassessment had no impact in left ventricular pressure unloading, but LV volume unloading decreased between day 60 and 120 in patients with nonpulsatile LVADs. The preoperative and postoperative transplant mortality was comparable in both groups. CONCLUSIONS Left ventricular pressure unloading is similar in patients with nonpulsatile as compared with pulsatile implantable long-term assist devices. Left ventricular volume unloading is pronounced in pulsatile LVADs.

10 years of emergency endovascular aneurysm repair for ruptured abdominal aortoiliac aneurysms: lessons learned.

Objective:To evaluate a single centers 10-year experience with emergency endovascular aneurysm repair (eEVAR) in 102 patients with ruptured abdominal aortoiliac aneurysms (RAAA). Methods:Data from 102 patients (mean age, 73 ± 9 years) with RAAA treated by eEVAR from January 1998 to April 2008 were retrospectively reviewed. From January 2000, all patients were treated according to an intention-to-treat protocol. The only exclusion criterion was unsuitable anatomy. 31/102 patients had moderate shock and 14/102 patients had severe shock with a systolic blood pressure <70 mm Hg or <50 mm Hg, respectively. 71/102 procedures were carried out under local anesthesia. Endograft types used were mainly bifurcated (92/102). Open abdomen treatment (OAT) because of abdominal compartment syndrome (ACS) was used when signs of organ failure occurred and/or bladder pressure rose >20 mm Hg. Results:The 30-day mortality for eEVAR was 13% (13/102). Technical success (defined as successful deployment of the endograft, absence of extravasation in the postprocedural contrast enhanced CT scan and hemodynamic stabilization) was 99% (101/102). Nineteen unstable patients (19%) required transfemoral supraceliac aortic balloon occlusion. ACS was detected and treated by OAT in 20 patients (20%). 16 type I, 26 type II and 1 type III endoleaks were detected on postoperative CT examination. Two patients had a combined type I and II endoleak. 11 patients were retreated for immediate correction of 10 type I and 2 type II endoleaks. 6 type I and 1 type III low-flow endoleaks were observed and resolved spontaneously within 30 days. Major 30-day morbidity was 35%. Conclusion:In this 102 patient contemporary series of eEVAR for RAAA, endografting proved to be safe with a 30-day mortality of 13%. Key components of this favorable outcome result were adequate preoperative diagnostic imaging, hypotensive hemostasis, selective transfemoral supraceliac aortic balloon occlusion, predominantly local anesthesia, detection and treatment of ACS, and attention to logistics. Widespread adoption of these treatment components is recommended.

Improvements in Early Behavior of Rat Kidney Allografts After Treatment of the Brain-Dead Donor

ObjectiveTo improve the quality of organs from brain-dead donors by assessing the influence of alternative strategies on the early behavior of kidneys after transplantation into unmodified hosts. Summary Background DataKidneys transplanted from living donors perform consistently better than those from cadaver sources. The authors have recently shown that donor brain death produces inflammatory changes in peripheral organs within hours, amplifies coincident ischemia–reperfusion injury, and accelerates acute and chronic rejection. Normalization of the graft by donor hormone treatment has hitherto been unsuccessful. MethodsA standardized rat model of brain death was used. Experimental groups included recipients of allogeneic grafts from living and brain-dead donors (F344→LEW). Donors were treated immediately after induction of brain death either with intravenous steroids, which block inflammatory cytokine release, or a soluble P-selectin glycoprotein ligand (sPSGL), which blocks initial selectin-mediated cellular adhesion. Kidney grafts were examined serially up to 10 days by morphology, immmunohistology, and reverse transcriptase–polymerase chain reaction. ResultsOverall survival of ummodified recipients of kidneys from brain-dead donors was significantly reduced versus living donors. Animals with organs from brain-dead donors that had received steroids or sPSGL survived significantly longer than those from untreated brain-dead donors. The intensity of ischemia–reperfusion injury and of acute rejection was reduced. Cellular infiltration and transcription of mRNA of representative proinflammatory mediators were diminished. ConclusionsTreatment of organ donors at the time of brain death markedly improves organ quality after kidney transplantation, upgrading it to that from a living donor.

A model of gradual onset brain death for transplant-associated studies in rats

BACKGROUND The relatively few studies that have examined the systemic events after brain death have primarily involved large animals. For more precise definition of the physiology of this central catastrophe and its influence on peripheral organs, we have established a reproduceable model of gradual onset brain death in rats. METHODS The central injury is induced by graded inflation of a Fogarty catheter placed intracranially under EEG and blood pressure monitoring. The rats were mechanically ventilated for 6 hr before removal of their kidneys. Complications and mortality are discussed. RESULTS The majority (83%) of the 100 experimental animals could be used as organ donors. After a transient period of autonomic storm, the mean arterial blood pressure remained consistently between 80-100 mmHg, not appreciably different from controls. Despite normotension, the transplanted kidneys from brain dead donors showed a significantly longer interval to regain uniform cortical color and turgor than kidneys from control animals. CONCLUSIONS We describe a controlled model of gradual onset brain death in the rat in which normotension can be sustained for several hours before the kidneys are removed for transplantation. Despite stable donor blood pressure, ischemia of peripheral organs may explain in part the increased incidence of delayed graft function of cadaver kidneys compared with those from living donors. This model is suitable for transplant-related studies involving organs from donors with irreversible central injury.

Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

BACKGROUND In patients with heparin-induced thrombocytopenia undergoing cardiac operations, anticoagulation with heparin should be avoided. The low-molecular-weight glycosaminoglycan Orgaran has been used as an alternative, but the overall experience is limited. METHODS Two patients with heparin-induced thrombocytopenia underwent cardiopulmonary bypass using Orgaran for anticoagulation. A 30-year-old woman suffered from emboli to her brain through a secondary atrial septal defect, a 14-year-old boy from ischemia of his left leg due to recurrent embolism originating from the mitral valve. In both cases, cardiopulmonary bypass was performed in a routine manner, except for using low-dose Orgaran instead of heparin. Anticoagulation was monitored during cardiopulmonary bypass by measuring Orgaran plasma levels and activated clotting time. RESULTS No thromboembolic or bleeding complications occurred during and after atrial septal defect repair and mitral valve replacement, respectively. In the former case, thrombotic material from the inferior vena cava was removed during hypothermic circulatory arrest within the same procedure. Activated clotting time did not correlate with plasma levels of Orgaran. CONCLUSIONS Orgaran might be a useful alternative for anticoagulation during extracorporeal circulation. Adequate dosages and measurement of plasma levels are recommended for its use in cardiopulmonary bypass.

Cardiac Pacemaker Infection: Surgical Management With and Without Extracorporeal Circulation

BACKGROUND Pacemaker infections are rare, but serious complications of pacemaker therapy. The generator pocket, the pacing leads, or both may be involved. METHODS We report on 12 patients with infected pacemaker systems. Four patients suffered from localized generator pocket infections, 6 had infected leads, and 2 patients had both. Pacemaker systems were completely removed in all patients. When the infection was limited to the generator pocket, the pacemaker system was removed at the original implantation site. Extracorporeal circulation was employed for the explantation of infected pacing leads. RESULTS No complications occurred in patients with localized generator pocket infections. One patient with infected leads who was preoperatively already in a serious clinical condition died of septic shock in the early postoperative period; another patient died of pulmonary complications after tricuspid valve replacement 14 months after pacemaker explantation. No recurrent infections were observed. CONCLUSIONS Explantation of the complete pacemaker system has proved a reliable method to eradicate infection. Complications have been rare, except in patients in a critically ill state who undergo cardiopulmonary bypass.