Walter E. Uber

Acute Antibody‐Mediated Rejection Following Heart Transplantation

Acute antibody‐mediated rejection (AMR) in heart transplantation is often associated with hemodynamic compromise, and is associated with increased mortality and development of accelerated transplant coronary artery disease (TCAD). The diagnosis of AMR has historically been controversial and outcomes with aggressive immunosuppressive therapy including plasmapheresis and cyclophosphamide are poor. Advances in diagnostic techniques like the demonstration of immunopathologic evidence for antibody‐mediated rejection by deposition of the complement split product C4d in tissue and detection of anti‐HLA antibodies by flow cytometry will assist in further characterizing AMR. Immunosuppression targeting B‐lymphocytes and use of m‐TOR inhibitors to alter the predilection to develop TCAD and improve survival in AMR remains to be proven.

Esmolol for the management of pediatric hypertension after cardiac operations

OBJECTIVE Hypertension frequently occurs during the immediate postoperative period in children after repair of aortic coarctation but may also occur after repair of other congenital heart defects. Nitroprusside has often been used to control blood pressure in this setting. Because hypertension after coarctation repair is frequently associated with elevations in catecholamines, esmolol, a short-acting beta-blocking agent, may be an effective alternative. Therefore we undertook the first systematic investigation to determine the efficacy and disposition of esmolol in pediatric patients with acute hypertension after cardiac operations. METHODS Twenty patients aged 1 month to 12 years (median 25.6 months) with acute hypertension after cardiac operations received esmolol in an opened-labeled trial. Esmolol was titrated to a blood pressure less than or equal to the 90th percentile for age. RESULTS Ten patients had coarctation repair and the remaining patients underwent repair of other congenital heart defects. On final esmolol dose (mean +/- standard deviation dosage 700 +/- 232 microg/kg/min) there was a significant percent decrease in heart rate and systolic and diastolic blood pressures from postoperative values. Esmolol dose was significantly associated with percent reduction in systolic blood pressure. Final esmolol dose and total body clearance were significantly higher in patients after coarctation repair. There were significant associations between esmolol dose and esmolol blood concentrations at steady state. CONCLUSIONS The dosage required to control hypertension in patients after repair of aortic coarctation was higher than patients who underwent repair of other congenital heart defects. Esmolol was effective in controlling blood pressure in 19 of 20 patients without adverse effects.

Cardiopulmonary bypass with bivalirudin in type II heparin-induced thrombocytopenia.

Cardiopulmonary bypass in patients with type II heparin induced-thrombocytopenia poses significant challenges. Inadequate pharmacokinetic profiles, monitoring, reversibility, and availability often limit alternative anticoagulation strategies. Bivalirudin, a semisynthetic direct thrombin inhibitor, was recently approved for use in patients undergoing percutaneous coronary interventions. Its unique properties, including a relatively short half-life, an anticoagulation effect that closely correlates with activated clotting time, and an alternate metabolic pathway for elimination, make bivalirudin an attractive agent for cardiopulmonary bypass in patients with type II heparin induced-thrombocytopenia. We report our experience using bivalirudin in 2 patients undergoing coronary artery bypass grafting.

Use of Recombinant Activated Factor VII Concentrate to Control Postoperative Hemorrhage in Complex Cardiovascular Surgery

BACKGROUND Complex cardiovascular surgery often results in postoperative hemorrhage. Excessive blood product use may cause systemic thrombosis, end-organ dysfunction, and edema preventing chest closure. Recombinant activated factor VII (rFVIIa) concentrate may decrease hemorrhage where other treatment measures failed. We reviewed our experience with rFVIIa after complex cardiovascular surgery. METHODS A retrospective review evaluating 846 complex cardiovascular surgery patients of whom 36 received rFVIIa between January 1, 2001, and December 31, 2006, was performed. Efficacy and safety data were collected for the entire cohort in addition to delayed sternal closure requirements, reoperation, and operative mortality in the patient cohort temporally separated into two groups (pre-rFVIIa era, 2001 to 2003, 1 patient received rFVIIa; rFVIIa era, 2004 to 2006, 35 patients received rFVIIa). RESULTS A total of 36 patients received 41 rFVIIa doses with an in-hospital survival of 91.7%. Hemorrhage was controlled in 83.3% of patients, with 1 dose sufficient in 75.0%. There was a significant decrease (p < 0.005) in all blood product requirements post-rFVIIa compared with pre-rFVIIa administration. In the intensive care unit (n = 6), rFVIIa significantly reduced chest tube output (p = 0.028) and prevented reexploration for bleeding in 5 patients. The requirement for delayed sternal closure was significantly higher in the pre-rFVIIa era versus the rFVIIa era (p = 0.011). The incidence of thrombosis in all patients receiving rFVIIa was 11.1%. In the rFVIIa era, a higher incidence of postoperative renal failure (p = 0.005) and pneumonia (p < 0.002) was detected in patients receiving rFVIIa. CONCLUSIONS Recombinant activated factor VII appears to be effective in patients with refractory coagulopathy undergoing high-risk cardiovascular surgery.

Differential effects of aprotinin and tranexamic acid on outcomes and cytokine profiles in neonates undergoing cardiac surgery

OBJECTIVE Factors contributing to postoperative complications include blood loss and a heightened inflammatory response. The objective of this study was to test the hypothesis that aprotinin would decrease perioperative blood product use, reduce biomarkers of inflammation, and result in improved clinical outcome parameters in neonates undergoing cardiac operations. METHODS This was a secondary retrospective analysis of a clinical trial whereby neonates undergoing cardiac surgery received either aprotinin (n = 34; before May 2008) or tranexamic acid (n = 42; after May 2008). Perioperative blood product use, clinical course, and measurements of cytokines were compared. RESULTS Use of perioperative red blood cells, cryoprecipitate, and platelets was reduced in neonates receiving aprotinin compared with tranexamic acid (P < .05). Recombinant activated factor VII use (2/34 [6%] vs 18/42 [43%]; P < .001), delayed sternal closure (12/34 [35%] vs 26/42 [62%]; P = .02), and inotropic requirements at 24 and 36 hours (P < .05) were also reduced in the aprotinin group. Median duration of mechanical ventilation was reduced compared with tranexamic acid: 2.9 days (interquartile range: 1.7-5.1 days) versus 4.2 days (2.9-5.2 days), P = .04. Production of tumor necrosis factor and interleukin-2 activation were attenuated in the aprotinin group at 24 hours postoperatively. No differential effects on renal function were seen between agents. CONCLUSIONS Aprotinin, compared with tranexamic acid, was associated with reduced perioperative blood product use, improved early indices of postoperative recovery, and attenuated indices of cytokine activation, without early adverse effects. These findings suggest that aprotinin may have unique effects in the context of neonatal cardiac surgery and challenge contentions that antifibrinolytics are equivalent with respect to early postoperative outcomes.

Improvement in long-term ECMO by detailed monitoring of anticoagulation: a case report

Introduction: The use of unfractionated heparin (UFH) as an anticoagulant during long-term extracorporeal support presents a unique challenge for the clinician in balancing the amount of anticoagulant to maintain adequate anticoagulation without causing excessive bleeding. Activated clotting times (ACT) and activated partial thromboplastin times (aPTT) are the most common modality to monitor UFH on extracorporeal membrane oxygenation (ECMO). Limitations to these tests include consumptive coagulopathies, clotting factor deficiencies, platelet dysfunction, and fibrinolysis. The following case report describes the use of alternative monitoring strategies to assess more accurately anticoagulation during ECMO. Case Report: A 20-month-old female presented to the emergency department with a 5-6 day history of cough, fever, tachypnea, and respiratory distress. She was diagnosed with influenza A and B with pneumonia. The patient was placed on veno-venous ECMO (V-V ECMO) after mechanical ventilation failed. On ECMO day eight, the patient developed a thrombus in her inferior vena cava and pleural effusions, obstructing cannula flow. Laboratory tests revealed the ACT was within range, yet the aPTT was dropping, despite increased heparin. Heparin levels were low and antithrombin-III (AT) concentrations were 40%. Recombinant AT was given and subsequent aPTTs were within the therapeutic range. Later, the aPTT decreased to <50 sec, heparin levels were within the therapeutic range, while fibrinogen was >475 mg/ dL, and Factor VIII >150 IU/dL, suggesting an acute phase reaction or ongoing systemic inflammation, increasing the risk for thrombosis. We maintained heparin assays between 0.5-0.7 IU/mL and AT >60% to assure heparin’s effect. The patient showed no signs of excess bleeding, blood product administration, or clots in the circuit, suggesting proper anticoagulation. The patient was successfully weaned on day 33 and is currently alive and at home. Conclusion: Monitoring of anti-Xa UFH and AT proved effective for measuring anticoagulation and detecting inconsistencies in other anticoagulation parameters, leading to steady levels of heparin without further complications.

Early Postoperative Outcomes and Blood Product Utilization in Adult Cardiac Surgery The Post-Aprotinin Era

Background— Aprotinin was a commonly used pharmacological agent for homeostasis in cardiac surgery but was discontinued, resulting in the extensive use of lysine analogues. This study tested the hypothesis that early postoperative adverse events and blood product utilization would affected in this post-aprotinin era. Methods and Results— Adult patients (n=781) undergoing coronary artery bypass, valve replacement, or both from November 1, 2005, to October 31, 2008, at a single institution were included. Multiple logistic regression modeling and propensity scoring were performed on 29 preoperative and intraoperative variables in patients receiving aprotinin (n=325) or lysine analogues (n=456). The propensity-adjusted relative risk (RR) for the intraoperative use of packed red blood cells (RR, 0.75; 95% confidence interval [CI], 0.57 to 0.99), fresh frozen plasma (RR, 0.37; 95% CI, 0.21 to 0.64), and cryoprecipitate (RR:0.06; 95% CI, 0.02 to 0.22) were lower in the aprotinin versus lysine analog group (all P<0.05). The risk for mortality (RR, 0.53; 95% CI, 0.16 to 1.79) and neurological events (RR, 0.87; 95% CI, 0.35 to 2.18) remained similar between groups, whereas a trend for reduced risk for renal dysfunction was observed in the aprotinin group. Conclusions— In the post-aprotinin era, with the exclusive use of lysine analogues, the relative risk of early postoperative outcomes such as mortality and renal dysfunction have not improved, but the risk for the intraoperative use of blood products has increased. Thus, improvements in early postoperative outcomes have not been realized with the discontinued use of aprotinin, but rather increased blood product use has occurred with the attendant costs and risks inherent with this strategy.

Developing an Anti-Xa-Based Anticoagulation Protocol for Patients with Percutaneous Ventricular Assist Devices.

Because of the complexities associated with anticoagulation in temporary percutaneous ventricular assist device (pVAD) recipients, a lack of standardization exists in their management. This retrospective analysis evaluates current anticoagulation practices at a single center with the aim of identifying an optimal anticoagulation strategy and protocol. Patients were divided into two cohorts based on pVAD implanted (CentriMag (Thoratec; Pleasanton, CA) / TandemHeart (CardiacAssist; Pittsburgh, PA) or Impella (Abiomed, Danvers, MA)), with each group individually analyzed for bleeding and thrombotic complications. Patients in the CentriMag/TandemHeart cohort were subdivided based on the anticoagulation monitoring strategy (activated partial thromboplastin time (aPTT) or antifactor Xa unfractionated heparin (anti-Xa) values). In the CentriMag/TandemHeart cohort, there were five patients with anticoagulation titrated based on anti-Xa values; one patient developed a device thrombosis and a major bleed, whereas another patient experienced major bleeding. Eight patients received an Impella pVAD. Seven total major bleeds in three patients and no thrombotic events were detected. Based on distinct differences between the devices, anti-Xa values, and outcomes, two protocols were created to guide anticoagulation adjustments. However, anticoagulation in patients who require pVAD support is complex with constantly evolving anticoagulation goals. The ideal level of anticoagulation should be individually determined using several coagulation laboratory parameters in concert with hemodynamic changes in the patient’s clinical status, the device, and the device cannulation.

Treatment of BK viremia in a pediatric heart transplant recipient

A 9-year-old, 16-kg (body surface area 0.7 m2) girl, 8 years post-transplant, was referred to our heart transplant clinic after a family relocation. She had developed renal insufficiency, which was attributed to calcineurin-induced nephrotoxicity. Multiple months prior to her presentation to our clinic, she was switched to a lower dose of tacrolimus, and sirolimus was added to her anti-rejection regimen. Despite these changes, her renal function worsened with a peak serum creatinine of 1.9 mg/dl, and she developed hematuria. Further evaluation included urine and serum BK viral polymerase chain reaction tests, which were positive at 1.22e10 copies/ml and 7.13e5 copies/ml, respectively (SmartCycler; Cepheid, Sunnyvale, CA). Creatinine clearance at that time was measured by a 24-hour urine collection to be 20 ml/min/1.73 m2. Subsequent renal biopsy performed showed BK virus nephropathy (Figure 1). Figure 1 Immunohistochemical stain for big “T” antigen specific for polyoma virus replication. The tubule in the center of the figure is positive for big T antigen, as demonstrated by its dark brown color. The patient was initiated on leflunomide (Arava; Sanofi Aventis, Bridgewater, NJ) to aggressively treat BK virus nephropathy and to decrease the risk of rejection. Leflunomide was started 2 weeks after stopping the sirolimus. The tacrolimus goal level while on leflunomide was 8 to 10 ng/ml. Her leflunomide regimen consisted of 40 mg/day for 2 days, and then maintenance therapy at 10 mg/day.1 Teriflunomide (Mayo Medical Laboratories, St. Paul, MN) levels were checked monthly, with goal of 30 to 60 μg/ml. Liver chemistries, electrolytes and complete blood counts were checked bi-weekly. She was maintained on leflunomide 10 mg/day for the vast majority of treatment (range 7.5 to 15 mg/day). Therapy was withheld twice during the course of treatment due to mild rise in transaminases. After 10 months of therapy, serum BK viral load decreased to 1,176 copies/ml and creatinine was 1.1 mg/dl (Figure 2). Leflunomide treatment was stopped based on improved kidney function and reduced BK viremia. She was maintained on tacrolimus alone until teriflunomide levels were undetectable, and then sirolimus was restarted. The patient has maintained a serum creatinine of 1.2 mg/dl at 5 months after stopping leflunomide. Figure 2 Serum creatinine and serum BK viral load over time, with Week 0 being the time of biopsy. Therapy was held from Weeks 18 to 22 (influenza) and Weeks 36 to 38 (teriflunomide level 81 μg/ml). Leflunomide began at Week 4.

Topical thrombin preparations and their use in cardiac surgery

Coagulopathic bleeding may lead to increased morbidity and mortality after cardiac surgery. Topical bovine thrombin has been used to promote hemostasis after surgical procedures for over 60 years and is used frequently as a topical hemostatic agent in cardiac surgery. Recently, use of bovine thrombin has been reported to be associated with increased risk for anaphylaxis, thrombosis, and immune-mediated coagulopathy thought secondary to the production of antifactor V and antithrombin antibodies. In patients who develop bovine thrombin-induced immune-mediated coagulopathy, clinical manifestations may range from asymptomatic altera- tions in coagulation tests to severe hemorrhage and death. Patients undergoing cardiac surgical procedures may be at increased risk for development of antibodies to bovine thrombin products and associated complications. This adverse immunologic profile has led to the development of alternative preparations including a human and a recombinant thrombin which have been shown to be equally efficacious to bovine thrombin and have reduced antigenicity. However, the potential benefit associated with reduced antigenicity is not truly known secondary to the lack of long-term experience with these products. Given the potentially higher margin of safety and less stringent storage concerns compared to human thrombin, recombinant thrombin may be the most reasonable approach in cardiac surgery.