Jeremy D. Flynn

Recombinant factor VIIa for refractory bleeding after cardiac surgery secondary to anticoagulation with the direct thrombin inhibitor lepirudin.

A 56‐year‐old man with heparin‐induced thrombocytopenia with thrombosis syndrome (HITTS) received anticoagulation with recombinant hirudin (lepirudin) for emergency coronary artery bypass graft (CABG) surgery and aortic valve replacement. The patient experienced life‐threatening refractory bleeding that was successfully treated with recombinant factor VIIa. He had a history of infective endocarditis that resulted in severe aortic insufficiency, three‐vessel coronary artery disease, and acute renal failure requiring hemodialysis. The patient was transferred from another hospital for the emergency surgery, but before his transfer, he developed HITTS secondary to therapeutic heparin for a deep vein thrombosis of the lower extremity. The presence of HITTS, the urgent nature of the case, and the availability of the direct thrombin inhibitor led the surgical team to select lepirudin for anticoagulation to facilitate cardiopulmonary bypass. After separation from cardiopulmonary bypass, the patient was in a coagulopathic state due to the inability to reverse the lepirudin and the slowed elimination of the drug secondary to inadequate renal function. As a result, the patient experienced excessive generalized oozing that was unresponsive to traditional therapies and blood product transfusions. Recombinant factor VIIa 35 μg/kg was given as rescue therapy. The bleeding slowed, which allowed placement of chest tubes and closing of the sternum. The patient was transferred to the intensive care unit in stable condition with no evidence of thrombosis in the freshly placed bypass grafts or on the bioprosthetic valve. Recombinant factor VIIa appears to be a suitable option as salvage therapy in patients with refractory bleeding secondary to anticoagulation with a direct thrombin inhibitor during cardiac surgery.

Methylene blue for the treatment of septic shock.

Septic shock is a major cause of morbidity and mortality in the intensive care unit, and effective therapies are limited. Methylene blue is a selective inhibitor of guanylate cyclase, a second messenger involved in nitric oxide‐mediated vasodilation. The use of methylene blue in the treatment of septic shock has been repeatedly evaluated over the past 20 years, but data remain scarce. To evaluate the safety and efficacy of methylene blue for the treatment of septic shock, we conducted a literature search of the EMBASE (1974‐June 2009), MEDLINE (1966‐June 2009), and International Pharmaceutical Abstracts (1970‐June 2009) databases. All available studies published in English were reviewed. Observational studies with methylene blue have demonstrated beneficial effects on hemodynamic parameters and oxygen delivery, but use of methylene blue may be limited by adverse pulmonary effects. Methylene blue administration is associated with increases in mean arterial pressure while reducing catecholamine requirements in patients experiencing septic shock; however, its effects on morbidity and mortality remain unknown. Well‐designed, prospective evaluations are needed to define the role of methylene blue as treatment of septic shock.

Fondaparinux as a treatment option for heparin-induced thrombocytopenia.

Heparin‐induced thrombocytopenia (HIT) is an immune‐mediated complication that can occur after exposure to heparin products. Because patients with HIT are at increased risk for thrombosis, anticoagulation is warranted. The direct thrombin inhibitors lepirudin and argatroban are approved by the United States Food and Drug Administration (FDA) for this indication. Bivalirudin, another direct thrombin inhibitor, is approved for use in patients with HIT who must undergo percutaneous coronary intervention. The synthetic pentasaccharide fondaparinux lacks FDA approval for treating patients with HIT; however, a few published reports describe its use. Furthermore, various small‐scale, in vitro studies have demonstrated a lack of cross‐reactivity between fondaparinux and HIT antibodies. Large, in vivo comparison trials must be performed before fondaparinux can become a standard treatment option in the setting of HIT.

A clinical-laboratory algorithm incorporating optical density value to predict heparin-induced thrombocytopenia

The diagnosis of heparin-induced thrombocytopenia (HIT) is complex and involves integrating both clinical and laboratory findings. Readily available diagnostic tests such as the heparin-dependant antibody assay (HDAA) lack desired specificity when utilised alone. A diagnostic algorithm incorporating the 4T pretest probability score, HDAA, and optical density (OD) value was implemented as a tool to assist in the diagnosis of HIT and with the decision to treat patients. Patients with a 4T score >3 and/or positive HDAA result with an OD ≥1 were considered positive. Utilisation of this algorithm was hypothesised to improve the identification of patients without SRA confirmed HIT and improve overall specificity compared to other diagnostic strategies. Retrospective chart review was conducted and included patients with a positive or equivocal HDAA result and a serotonin release assay result during a two-year period. Each patient was evaluated for the diagnosis of HIT using the algorithm. The specificity and sensitivity of the diagnostic algorithm to identify subjects with SRA confirmed HIT was evaluated. A total of 83 patients were identified for inclusion in the study. The diagnostic algorithm identified 22 patients for direct thrombin inhibitor (DTI) therapy. Nine of these patients were SRA positive. The sensitivity of the algorithm was 0.9 with a specificity of 0.822. The diagnostic algorithm was found to be both more specific and sensitive than other diagnostic strategies including the 4T score alone, HDAA alone, and the combination of the 4T score and HDAA results. This preliminary data suggest a diagnostic algorithm combining 4T score, HDAA, and OD value may be a tool to aid in the identification SRA positive patients for DTI therapy.

Treatment of respiratory syncytial virus pneumonia in a lung transplant recipient: case report and review of the literature.

A 61‐year‐old woman who underwent lung transplantation developed severe respiratory syncytial virus (RSV) pneumonia and experienced respiratory failure requiring mechanical ventilation. She was treated initially with aerosolized ribavirin monotherapy; RSV hyperimmune globulin was later added to her regimen. Lung transplant recipients are acutely susceptible to respiratory infections, including community‐acquired respiratory viruses. Respiratory syncytial virus is particularly difficult to treat in immunocompromised patients because of the lack of proved pharmaceutical agents and solid scientific evidence by which to guide therapy. The most important factor appears to be the early start of therapy; immunocompromised patients who develop RSV pneumonia and subsequent respiratory failure requiring mechanical ventilation have a mortality rate approaching 100%. This case report demonstrates the successful treatment of RSV pneumonia with the combination of aerosolized ribavirin and RSV hyperimmune globulin in a severely ill lung transplant recipient who required mechanical ventilation.

Recombinant Factor VIIa for Refractory Bleeding Following Orthotopic Heart Transplantation

OBJECTIVE To report a case of successful use of recombinant factor VIIa (rFVIIa) for the treatment of refractory bleeding in a patient undergoing orthotopic heart transplantation. Case Summary A 57-year-old white male with idiopathic cardiomyopathy was taken to the operating room for explantation of his left-ventricular assist device and orthotopic heart transplantation. He experienced excessive generalized oozing that required transfusions of multiple units of blood products and significant amounts of Cellsaver (washed red blood cells via autotransfusion) without achieving adequate hemostasis. After ruling out any obvious surgical sources of bleeding and attempting to correct all coagulation deficiencies, the clinicians administered rFVIIa 90 μg/kg. The oozing rapidly declined to a negligible level, chest tubes and sternal wires were placed, and the chest was closed. The patient was on minimal inotropic support and was transferred to the intensive care unit in stable condition. DISCUSSION Cardiac surgery is often associated with significant disruption of the coagulation system, particularly in high-risk patients, such as those undergoing removal of a ventricular assist device and subsequent orthotopic heart transplantation. This can lead to life-threatening bleeding that can require multiple hemostatic agents and significant transfusions to restore hemostasis. Recently, rFVIIa has been utilized as an alternative to massive transfusion for treatment of refractory bleeding in several patient populations, including some cardiac surgery patients. CONCLUSIONS rFVIIa appears to be a viable option as rescue therapy for treatment of refractory bleeding following orthotopic heart transplantation. Despite the anecdotal success of rFVIIa in this setting, further clinical research is needed.

Effects of the angiotensin II subtype 1 receptor antagonist losartan on functional recovery of isolated rat hearts undergoing global myocardial ischemia-reperfusion.

Study Objective. To investigate the effects of the angiotensin II subtype 1 receptor (AT1R) antagonist losartan on functional recovery of isolated rat hearts undergoing global myocardial ischemia‐reperfusion compared with myocardial protective effects of ischemic preconditioning.

Successful treatment of refractory bleeding after bridging from acute to chronic left ventricular assist device support with recombinant activated factor VII.

Cardiac surgery often is associated with a significant disruption of the coagulation system, particularly in high risk patients such as those undergoing placement of ventricular assist devices. This type of severe coagulopathy can lead to life threatening bleeding that can require massive transfusions to restore hemostasis. Recently, recombinant activated factor VII (rFVlla) has been +used as an alternative to massive transfusion for the treatment of refractory bleeding in several patient populations, including cardiac surgery patients. In the case reported here, the patients risk was compounded by multiple operations in a short period of time and circulatory collapse that was initially managed with a shortterm left ventricular assist device. After multiple failed attempts at weaning the patient from circulatory assistance, he was taken back to the operating room for conversion to a chronic, implantable device. This procedure was complicated by a severe coagulopathy secondary to a myriad of factors commonly encountered after the use of cardiopulmonary bypass. The administration of rFVlla resulted in a rapid cessation of bleeding without thrombotic complications. This is the first case reported involving an acute to chronic bridge patient. Despite the anecdotal success of rFVlla, further clinical research is needed to establish both the safety and economic feasibility of this agent.

Utilization of Pharmacist Responders as a Component of a Multidisciplinary Sepsis Bundle

Background: Sepsis and septic shock remain a significant burden on the US health care system. A multidisciplinary response system (Coordinated Response to Sepsis, CaRTS) that included a pharmacist responder was implemented for patients with newly suspected sepsis. Objective: To evaluate the time to appropriate antibiotic administration among patients with the CaRTS intervention compared with historical controls. Method: The CaRTS intervention included an electronic order set as well as activation of a multidisciplinary team of pharmacy and nursing personnel to coordinate resuscitation and medication administration. The CaRTS group was compared to historical controls. The primary outcome of the study was the proportion of patients with appropriate antibiotic administration within 1 hour of recognition of sepsis. Secondary outcomes included achievement of mean arterial pressure (MAP) ≥65 mm Hg and central venous pressure (CVP) of 8 to 12 mm Hg within 6 hours. Result: The CaRTS intervention was used for 49 patients and 59 historical controls were included for analysis. Patients with the CaRTS intervention had a greater than 20 times higher odds of antibiotic administration within 1 hour compared with controls (odds ratio [OR] 22.4, 95% confidence interval [CI] 7.5-69) and were more likely to have a CVP ≥8 mm Hg at 6 hours (OR 2.4, 95% CI 1.0-5.6) compared with controls. CaRTS patients achieved statistically nonsignificant increases in MAP ≥65 mm Hg (OR 2.2, 95% CI 0.7-7.7). Conclusion: Utilization of a multidisciplinary sepsis bundle that included a pharmacist responder improved the proportion of patients receiving appropriate antibiotics within 1 hour of recognition of sepsis compared to historical controls.

Pharmacotherapy of Lung Transplantation An Overview

Lung transplantation has become a viable treatment therapy for end-stage lung disease patients. The most common etiologies of end-stage lung disease, which can require a transplant are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), and pulmonary fibrosis (PF). Listing criteria are institution and program specific. Approximately 1500 lung transplants were performed in 2008; and at 5 years post transplant, one-half are expected to survive. The surgery itself is associated with various complications, including surgical, infectious, and mechanical. Immunosuppression is paramount to the management of these patients, the goal being prevention of T cell activation to prevent rejection of the new organ. The patients commonly receive an induction agent with a T cell depleting antibody and high-dose corticosteroids. Maintenance immunosuppression begins immediately after the surgery, consisting of a combination of a calcineurin inhibitor, antimetabolite, and corticosteroids. Side effect profiles from the various agents will determine the choice of agents, and patients may have modifications throughout the therapy. The role of the pharmacist spans the inpatient management of acute complications to medication selection, management of maintenance immunosuppression, as well as monitoring for adverse drug reactions and drug–drug interactions. A multidisciplinary collaborative approach must be taken to ensure the best outcomes for this patient population.