Calcineurin Inhibitor-Based Maintenance Immunosuppression in Lung Transplant Recipients: Optimal Serum Levels for Managing Acute Rejection and Renal Function.

BACKGROUND: Although effective for curtailing alloimmune responses, calcineurin inhibitors (CNIs) have an adverse-effect profile that includes nephrotoxicity. In lung transplant (LTx) recipients, the optimal serum levels of the CNI tacrolimus necessary to control alloimmune responses and minimize nephrotoxicity are unknown. METHODS: This retrospective, single-center study reviewed tacrolimus whole blood trough levels (BTLs), grades of acute cellular rejection (ACR), acute rejection scores, and creatinine clearance (CrCl) obtained in LTx recipients within the first year after their transplant procedure. Comparisons were made between the first 90 days post LTx (when tacrolimus BTLs were maintained >10 µg/L) and the remainder of the post-LTX year (when BTLs were <10 µg/L). RESULTS: Despite tacrolimus mean BTLs being higher during the first 90 days post LTx compared with the remainder of the first post-LTx year (10.4 ± 0.3 µg/L vs 9.5 ± 0.3 µg/L, P < .0001) there was no association with lower grades of ACR (P = .24). The intensity of ACR (as determined by acute rejection scores) did not correlate with tacrolimus mean BTLs at any time during the first posttransplant year (P = .79). During the first 90 days post LTx there was a significant decline in CrCl and a correlation between increasing tacrolimus mean BTLs and declining CrCl (r = -0.26, P = .03); a correlation that was not observed during the remainder of the year (r = -0.09, P = .52). CONCLUSIONS: In LTx recipients, maintaining BTLs of the CNI tacrolimus >10µg/L did not result in superior control of acute rejection responses but was associated with declining renal function.

Effectiveness of short vs long-course perioperative antibiotics in lung transplant recipients with donor positive respiratory cultures.

Lung transplant recipients are at increased risk for infection in the early postoperative phase, thus perioperative antibiotics are employed. This retrospective study evaluated the efficacy of short- vs long-course perioperative antibiotics in lung transplant patients. Lung transplant patients with donor positive cultures between August 2013 and September 2019 were evaluated, excluding those with cystic fibrosis, death within 14 days and re-transplants. The primary outcome was 30-day freedom from donor-derived respiratory infection. A total of 147 patients were included (57 short vs 90 long-course). Median perioperative antibiotic duration was 6 days in the short-course vs 14 days in the long-course group (P < .0001). Thirty-day freedom from donor-derived respiratory infection was present in 56 (98%) patients in the short-course vs 85 (94%) patients in the long-course group (P = .41). There was no difference in development of Clostridioides difficile infections (P = .41), while cumulative ventilator time and time to post-op extubation were longer in the long-course group (P = .001 and .004, respectively). Among lung transplant recipients with positive donor respiratory cultures, short-course perioperative antibiotics were as effective as long-course antibiotics in preventing donor-derived bacterial respiratory infections.

Early COVID-19 infection after lung transplantation.

COVID-19, the clinical syndrome caused by the novel coronavirus, SARS-CoV-2, continues to rapidly spread, leading to significant stressors on global healthcare infrastructure. The manifestations of COVID-19 in solid organ transplant recipients are only beginning to be understood with cases reported to date in transplant recipients on chronic immunosuppression. Herein, we report the first case of COVID-19 in a lung transplant recipient in the immediate posttransplant period, and we describe the epidemiologic challenges in identifying the source of infection in this unique situation.

Risk Factors and Outcomes Associated with Prolonged Subtherapeutic Anticoagulation with Bivalirudin: A Retrospective Cohort Study.

BACKGROUND: Bivalirudin, a direct thrombin inhibitor, is a treatment option for the management of heparin-induced thrombocytopenia (HIT) and other coagulation disorders. To date, no published studies have identified patients at risk for or the consequence of subtherapeutic bivalirudin therapy. OBJECTIVES: The primary objective was to identify factors associated with failure to achieve early therapeutic anticoagulation (ETA) with bivalirudin, defined as achievement of two consecutive therapeutic activated partial thromboplastin times (aPTTs) within 24 hours. Secondary objectives included evaluating whether failure to achieve ETA was a risk factor for clinical outcomes of interest including thromboembolism, hemorrhage, and mortality. PATIENTS/METHODS: This was a retrospective cohort study. Patients between the ages of 18 and 89 years treated with bivalirudin for 24 hours or longer were identified and classified as either achieving or failing to achieve ETA. RESULTS: Nonadherence to the dosing protocol (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.07-2.71) and creatinine clearance (CrCl) of 60 ml/min or greater (OR 2.99, 95% CI 1.12-7.97) were significantly associated with failure to achieve ETA in univariate analyses. Conversely, increasing age (OR 0.98, 95% CI 0.97-0.99) was significantly associated with achievement of ETA. Failure to achieve ETA was associated with a 4-fold increase in the odds of thromboembolism. CONCLUSIONS: Younger age, normal renal function, and nonadherence to the dosing protocol when targeting therapeutic anticoagulation is associated with increased risk of failure to achieve ETA. This confers an elevated risk of thromboembolism when using bivalirudin for the management of HIT or other coagulation disorders.

Impact of anticoagulation strategy and agents on extracorporeal membrane oxygenation therapy.

INTRODUCTION: Extracorporeal membrane oxygenation mandates balancing the risk of thromboembolic complications with bleeding. We aimed to evaluate pragmatic anticoagulation regimens during extracorporeal membrane oxygenation and compare thromboembolic and bleeding outcomes. METHODS: This retrospective, single-center study reviewed patients on venovenous or venoarterial extracorporeal membrane oxygenation for a minimum of 24 hours over a 5-year period. The primary outcome was composite thromboembolic events per day of extracorporeal membrane oxygenation. Secondary outcomes included composite bleeding complications, percent of measured activated partial thromboplastin times in goal range, and comparing events with therapeutic anticoagulation for the majority of the extracorporeal membrane oxygenation run (>50% of time on extracorporeal membrane oxygenation) versus non-therapeutic anticoagulation (therapeutic anticoagulation <50% of time). RESULTS: For the primary analysis, 100 patients received heparin, 10 received bivalirudin, and 43 were transitioned between heparin and bivalirudin. No significant differences were identified comparing the heparin group to the bivalirudin (RR = 0.427, p = 0.156) or transitioned group (RR = 1.274, p = 0.325). There were no differences in the rate of bleeding events when comparing the heparin group to the bivalirudin (RR = 0.626, p = 0.250) or transitioned group (RR = 0.742, p = 0.116). An increased number of adjustments to the anticoagulants was associated with a statistically higher rate of bleeding events per day (p = 0.006). CONCLUSION: There were no differences in thromboembolic or bleeding events when comparing different anticoagulant regimens. Adjustments to the anticoagulants are more likely to occur when bleeding is observed. Due to variability in anticoagulation, there is a need to standardize anticoagulation with extracorporeal membrane oxygenation.

Correction to: Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

In the print publication the name of the seventh author was incorrectly published.

Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

Cystic fibrosis (CF) is a common indication for lung transplantation (LTx) in children and adults with severe and irreversible lung disease. In the setting of LTx in the CF population, immunosuppressive medications are used to prevent allograft rejection despite the majority of these patients being chronically infected with numerous, and often antibiotic-resistant, pathogens. There is limited evidence for the optimal post-LTx immunosuppression regimen in patients with CF, particularly in children. This article provides a review of immunosuppression regimens in the pediatric and adult CF post-LTx population, investigating drug dosing and monitoring, and medication combinations. Currently used immunosuppressive medications and related systemic adverse effects are reviewed. With limitations of data in the pediatric population, future research should address immunosuppression in these children to help guide pediatric drug management as a means to optimize clinical outcomes after LTx.

Considerations for analgosedation and antithrombotic management during extracorporeal life support.

Despite the immense growth in extracorporeal life support (ECLS) technology and experience, opportunity remains to better characterize the pharmacotherapeutic considerations during ECLS. Analgosedation can be particularly challenging in the ECLS population due to in drug-circuit interactions that may lead to decreased systemic concentrations and pharmacodynamic effect. ECLS also requires the use of antithrombotic agents to mitigate the prothrombotic state created by the artificial surface in the ECLS circuit. There are a number of coagulation monitoring tests available. However, optimal monitoring and management in ECLS has not been established. Heparin continues to be the anticoagulant of choice for most ECLS centers, however, there is growing interest in the use of parenteral direct thrombin inhibitors (DTI) in this population. Advances in understanding pharmacotherapeutic management have not kept up with the technological advances in this population. More investigation is warranted to gain a greater understanding of the pharmacotherapeutic implications, facilitate standardized evidence-based practices, and improve patient centered outcomes.

Predictors of dexmedetomidine-associated hypotension in critically ill patients.

BACKGROUND: Dexmedetomidine is commonly used for sedation in the Intensive Care Unit (ICU), and its use may be associated with hypotension. We sought to determine predictors of dexmedetomidine-associated hypotension. METHODS: Retrospective, single-center study of 283 ICU patients in four adults ICUs over a 12 month period. Univariate analyses were performed to determine factors associated with dexmedetomidine-related hypotension. Risk factors significant at the 0.20 level in the univariate analysis were considered for inclusion into a step-wise multiple logistical regression model. RESULTS: Hypotension occurred in 121 (42.8%) patients with a median mean arterial pressure (MAP) nadir of 54 mmHg. Univariate analyses showed an association between hypotension and age (P = 0.03), Acute Physiology and Chronic Health Evaluation II (APACHE II) score (P = 0.02), baseline MAP (<0.001), admission to the cardiothoracic ICU (P = 0.05), history of coronary artery disease (P = 0.02), and postcardiac surgery (P = 0.0009). Admission to the medical ICU was associated with a decrease in development in hypotension (P = 0.03). There was a trend for hypotension with weight (P = 0.09) and history of congestive heart failure (P = 0.12) Only MAP prior to initiation (odds ratio [OR] 0.97, 95% confidence interval [95% CI] 0.95-0.99; P < 0.0001), APACHE II scores (OR 1.06, 95% CI 1.01-1.12; P = 0.017), and history of coronary artery disease (OR 0.48, 95% CI 0.26-0.90, P = 0.022) were independently associated with hypotension by multivariable analysis. CONCLUSIONS: Dexmedetomidine-associated hypotension is common. Preexisting low blood pressure, history of coronary artery disease, and higher acuity were identified as independent risk factors for dexmedetomidine-associated hypotension.

Development and implementation of a nurse-driven, sliding-scale nomogram for bivalirudin in the management of heparin-induced thrombocytopenia.

PURPOSE: A simplified dosing nomogram to assist nurses in adjusting the rate of i.v. bivalirudin administration in cases of heparin-induced thrombocytopenia (HIT) is described. SUMMARY: To facilitate the availability of bivalirudin [corrected] as an alternative direct thrombin inhibitor (DTI) for patients with HIT at The Ohio State University Wexner Medical Center (OSUWMC), a team of clinical pharmacists developed a nomogram designed to simplify infusion dosage adjustments by nurses. In contrast to bivalirudin nomograms requiring patient-specific, percentage-based dose adjustments, the nomogram developed at OSUWMC specifies fixed adjustments (0.005 or 0.01 mg/kg/hr) according to the current activated partial thromboplastin time (aPTT) value relative to aPTT goals. During pilot testing over three years, the nomogram was used to guide dosage adjustments in 65 adult patients receiving continuous infusions of bivalirudin for suspected or confirmed HIT in intensive care units. Overall, the use of the nomogram resulted in adequate anticoagulation, with 53.7% of all measured aPTT values in the target range; 30.5% of aPTT values were below target, and 15.8% of values were above target. The median time to steady state was 11.0 hours (range, 5.0-31.8 hours), and bleeding rates were consistent with those reported in the literature. Nurse adherence to the nomogram was 100%, and no dosing errors occurred during a total of 487 dosage changes. Based on the pilot study results, the nomogram was refined to improve initial dosing for patients with creatinine clearance values of >30 mL/min; other refinements were made to enhance the safety of bivalirudin therapy for HIT in patients with severe renal impairment. CONCLUSION: A nurse-driven, sliding-scale nomogram for bivalirudin therapy in patients with HIT provided a simple dosing protocol and resulted in a high rate of adherence by nurses.

Prothrombin complex concentrate for warfarin-induced bleeding in a patient with a mechanical aortic valve.

Reversal of anticoagulation-induced bleeding in the perioperative period can be challenging, particularly with an unstable patient with a mechanical valve. We present a case of life-threatening bleeding successfully managed with a prothrombin complex concentrate as an alternative to fresh frozen plasma.