Effectiveness of combined plasma cell therapy and costimulation blockade based desensitization regimen in heart transplant candidates.

BACKGROUND: Desensitization is one of the strategies to reduce antibodies and facilitate heart transplantation in highly sensitized patients. We describe our center's desensitization experience with combination of plasma cell (PC) depletion therapy (with proteasome inhibitor or daratumumab) and costimulation blockade (with belatacept). METHODS: We reviewed five highly sensitized patients who underwent desensitization therapy with plasma cell depletion and costimulation blockade. We evaluated the response to therapy by measuring the changes in cPRA, average MFI, and number of positive beads > 5000MFI. RESULTS: Five patients, mean age of 56 (37-66) years with average cPRA of 98% at 5000 MFI underwent desensitization therapy. After desensitization, mean cPRA decreased from 98% to 70% (p = .09), average number of beads > 5000 MFI decreased from 59 to 37 (p = .15), and average MFI of beads > 5000 MFI decreased from 16713 to 13074 (p = .26). CONCLUSION: Combined PC depletion and CoB could be a reasonable strategy for sustained reduction in antibodies in highly sensitized patients being listed for heart transplantation.

Role of thromboelastography in predicting and defining pump thrombosis in left ventricular assist device patients.

INTRODUCTION: Optimal anticoagulation for left ventricular assist device recipients aims to balance thrombosis and bleeding complications. Routine plasma-based coagulation tests may not accurately reflect overall hemostasis, and surrogate markers are used to help guide clinicians in the diagnosis of pump thrombosis. Thromboelastography derived coagulation index (CI) has been shown to be a parameter that can reflect "normocoagulability" in mechanical circulatory support device patients, but there is minimal data with regard to outcomes available. Our aim was to determine the role of CI in predicting and defining suspected pump thrombosis in HeartMate II™ recipients. MATERIALS AND METHODS: We performed a single center, retrospective longitudinal cohort study with a nested case-control analysis to compare serial CI values over time in adult HeartMate II™ recipients who had confirmed or suspected pump thrombosis to those who did not. RESULTS AND CONCLUSIONS: A multivariate linear mixed model analysis of the suspected pump thrombosis versus no pump thrombosis groups found a significantly lower mean change in CI over time when recipients were followed for 24 months post-implant [0.71 (95% CI 0.1-1.32, p = .02)]; CI was first significant at six months. Within each arm, CI significantly decreased in the no pump thrombosis group, but did not significantly differ within the suspected pump thrombosis group. No significant differences were found between the two groups regarding the outcomes of death, transplant, or neurological events.

Gastrointestinal Bleeding in Left Ventricular Assist Device: Octreotide and Other Treatment Modalities.

Left ventricular assist devices (LVADs) offer a therapeutic strategy for patients with end-stage heart failure. Increased device utilization has also increased the incidence of device-related complications including gastrointestinal bleeding (GIB). Multiple mechanisms have been proposed in the pathophysiology of continuous-flow LVAD-associated GIB including physiologic changes associated with high shear and nonpulsatile flow such as gastrointestinal arteriovenous malformations and acquired von Willebrand syndrome. Strategies to minimize the morbidity and mortality of LVAD-associated GIB are needed. Octreotide, a somatostatin analogue, has been described as an adjunct to current therapies and interventions. Factors that contribute to LVAD-associated GIB may be targeted by the pharmacologic effects of octreotide, including improved platelet aggregation, increased vascular resistance, and decreased splanchnic circulation. Octreotide has demonstrated clinical benefit in several case series and clinical trials for the treatment of LVAD-associated GIB. The focus of this article will be to review the pathophysiology of LVAD-associated GIB, discuss pharmacologic and nonpharmacologic treatment modalities, and review available literature on the role of octreotide in the management of LVAD-associated GIB.

Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival.

BACKGROUND: Classification of acute rejection (AR) based on etiology and timing may provide a means for enhancing therapeutic results and allograft survival. This study evaluated graft and patient survival after the first AR episodes among kidney transplant recipients with an early or late antibody-mediated rejection (AMR), acute cellular rejection (ACR) or mixed AR (MAR). METHODS: A prospective institutional review board-approved database was queried to identify biopsy-proven first AR episodes occurring from January 2005 to October 2012. The ACR was defined by Banff criteria; borderline AR was excluded. The AMR was defined as 3 of 4 criteria: renal dysfunction, donor specific antibody, C4d positivity on biopsy, and histological changes. The MAR met criteria for both ACR and AMR. Early AR occurred within six months post-transplant. AR episodes were then assigned to 1 of the 6 categories--early AMR, early ACR, early MAR, late AMR, late ACR, and late MAR. RESULTS: One hundred eighty-two kidney transplant recipients identified with a first AR episode. Mean follow-up was 773 days (± 715 days). No difference was observed in patient survival. Death-censored graft survival was 84%. Death-censored graft loss was higher with late versus early AMR (P = 0.01) and late versus early ACR (P = 0.03), but not late versus early MAR (P = 0.3). CONCLUSIONS: The AR type demonstrated a hierarchy for graft survival with ACR better than MAR better than AMR, which persisted for both early and late AR. Improvement in long-term results of AR may require development of specific treatment for individual AR types.

A case-based approach to the practical application of dexmedetomidine in critically ill adults.

Dexmedetomidine is a selective α(2) -adrenoceptor agonist that offers unique sedation because patients are readily awakened while administration continues and the drug does not suppress the respiratory center. Limitations of use include higher acquisition cost, inability to produce deep sedation, and bradycardia and hypotension. Using a case-based approach, the purpose of this review was to qualitatively assess the role of dexmedetomidine in the care of the critically ill and in the management of alcohol withdrawal, and to formulate recommendations regarding its clinical application. Sixty-six studies were identified that investigated dexmedetomidine for the provision of sedation. These studies were heterogeneous in design and patient populations; most investigated patients did not require heavy sedation, and few used propofol as the comparator. In general, though, the aggregate results of all studies demonstrate that dexmedetomidine provides comfort, possibly shortens the duration of mechanical ventilation to facilitate extubation, reduces the occurrence of acute brain dysfunction, and facilitates communication, but the drug is associated with hemodynamic instability and requires the supplemental use of traditional sedative and analgesic agents. These outcomes need to be substantiated in additional studies that include assessments of cost-effectiveness. Dexmedetomidine should be considered when patients require mild to moderate levels of sedation of short to intermediate time frames, and they qualify for daily awakenings with traditional sedative therapies. The data for dexmedetomidine in relation to alcohol withdrawal are limited to 12 retrospective reports representing a total of 127 patients. Its role for this indication requires further study, but it may be considered as adjunctive therapy when clinicians are concerned about respiratory suppression associated with escalating doses of γ-aminobutyric acid agonists. Regardless of the indication for dexmedetomidine, the practitioner must closely monitor patient comfort and the occurrence of hemodynamic deviations with the realization that as-needed administration of traditional sedatives and analgesics will be required and some degree of bradycardia and hypotension expected but intervention rarely required.

Leflunomide efficacy and pharmacodynamics for the treatment of BK viral infection.

BACKGROUND AND OBJECTIVES: BK virus is an infection in kidney transplantation patients jeopardizing graft survival. Unfortunately, there is no consensus on treatment of BK viremia and nephropathy. Leflunomide has been studied for the treatment of BK viremia and nephropathy, but there are limited data on the utility of leflunomide therapeutic drug monitoring. This study aimed to determine if a pharmacodynamic relationship exists between BK viral load reduction and leflunomide metabolite, A77 1726, serum concentrations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study was a retrospective, single-center, longitudinal analysis of patients identified with BK viremia with or without nephropathy. Patients were grouped according to whether they received leflunomide. All BK viral PCR and A77 1726 concentrations were analyzed to determine pharmacodynamics, and were correlated with clinical outcomes. RESULTS: Of 76 patients identified, 52 received leflunomide therapy and 24 did not. Patients who received leflunomide were further analyzed according to A77 1726 concentrations and BK clearance; there was no difference in BK clearance. There was a lack of correlation between A77 1726 concentrations and log change in BK viral PCR concentration. Multivariate analysis demonstrated that mycophenolate mofetil discontinuation, BK viremia without nephropathy, and mean BK viral load were significantly associated with BK viral clearance; leflunomide use lacked this association. CONCLUSIONS: Pharmacodynamic analysis revealed no association between A77 1726 concentrations and BK viral PCR reductions. Multivariate analysis demonstrated that leflunomide therapy was not associated with BK viral clearance. Randomized studies are needed to determine the utility of leflunomide for BK viremia and nephropathy.

The use of activated recombinant factor VII in a patient with fulminant hepatic failure requiring placement of an intracranial pressure monitor.

OBJECTIVE: To evaluate the use of recombinant activated factor VII (rFVIIa) in a patient with fulminant hepatic failure (FHF) requiring placement of an intracranial pressure monitor. CASE SUMMARY: A 21-year-old female with no significant medical history was admitted to an outside hospital with elevated results of liver function tests. Subsequently, the patient was diagnosed with autoimmune hepatitis. Systemic corticosteroids were started, but her condition continued to decompensate. She was transferred to our tertiary care facility 5 days after initial presentation. The liver function test results remained elevated (eg, total bilirubin 27 mg/dL), and international normalized ratio (INR) was 3.57. The medical team decided to place an intracranial pressure monitor, with the neurosurgery team's goal being an INR less than 1.5 before placement of the monitor. After multiple units of fresh frozen plasma (FFP) failed to lower the patient's INR, rFVIIa 40 µg/kg was administered. A rapid decrease of the INR allowed the neurosurgery team to perform the procedure without complications. DISCUSSION: The use of rFVIIa allowed for decrease of this patient's INR after multiple units of FFP had failed to correct it. The utility of INR as a marker of coagulopathy in fulminant hepatic failure has been debated, but it is currently used as the standard laboratory test prior to invasive procedures, as in the case presented here. CONCLUSIONS: The use of rFVIIa for rapid decrease of INR in a patient with FHF prior to an invasive procedure was safe and efficacious. When considering the use of rFVIIa, clinicians should be aware of the risk of thrombosis. In our experience, and in the limited literature on the matter, rFVIIa 40 µg/kg appears to be an appropriate dose for decrease of the INR. Further studies are needed to confirm this finding.

Clinical usefulness of recombinant activated factor VII in patients with liver failure undergoing invasive procedures.

OBJECTIVE: To evaluate the use of recombinant activated factor VII (rFVIIa) in patients with liver failure undergoing invasive procedures. METHODS: An OVID/MEDLINE and PubMed search (1997-June 2011) was performed to identify literature on the use of rFVIIa to reduce bleeding risk in patients with liver failure undergoing invasive procedures. STUDY SELECTION AND DATA EXTRACTION: English-language data evaluating the efficacy of rFVIIa to reverse coagulopathies prior to invasive procedures in patients with liver disease were included. DATA SYNTHESIS: Following administration of rFVIIa, prothrombin time (PT) and international normalized ratio (INR) response is within 30 minutes. Doses ranging from 20 to 120 µg/kg have been studied, with a reduction in PT seen in a dose-dependent manner. One study in patients with no bleeding administered 5, 20, and 80 µg/kg sequentially during a 24-day period. All doses provided reversal of prolonged PT within 10 minutes, and the duration was dose-dependent. In a study of 15 patients with fulminant liver failure, requiring intracranial pressure monitor placement, a rFVIIa dose of 40 µg/kg was compared to fresh frozen plasma. In patients who received rFVIIa, the PT and INR normalized, compared to none of the patients in the fresh frozen plasma group. CONCLUSIONS: Retrospective and prospective data demonstrate that rFVIIa effectively reverses elevated PT and INR, reducing the risk of bleeding and safely facilitating invasive procedures. Based on available data, a dose of 20-40 µg/kg 30 minutes prior to an invasive procedure should be considered in patients with acute or chronic liver failure at risk for bleeding complications. A major limitation of rFVIIa use is the high cost of therapy. A prospective, randomized trial could help determine the appropriate dose of rFVIIa, timing of dose in relationship to procedure, and usefulness of subsequent doses.