Frazee, Erin N.

Drug pharmacokinetics may be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). Ensuring the optimized effective dosing of antimicrobials on ECMO remains a challenge. To date, limited data are available regarding the optimal use of amphotericin and triazoles during ECMO. We report a case of altered pharmacokinetics, insufficient liposomal amphotericin B and isavuconazole levels, and the need for escalated doses during ECMO in a patient with severe acute respiratory distress syndrome secondary to pulmonary blastomycosis. A 2‐fold increase in the standard total daily dose of both drugs was necessary to overcome low serum concentrations thought to be secondary to drug loss from ECMO circuit sequestration. These findings have important implications for optimizing antimicrobial therapy in patients receiving ECMO to maximize therapeutic efficacy. The use of therapeutic drug monitoring for patients receiving antimicrobial therapy with concurrent ECMO may facilitate appropriate drug dosing to achieve adequate serum concentrations and optimize favorable patient outcomes. Further studies exploring antimicrobial pharmacokinetics during ECMO are needed to inform dosing recommendations in critically ill patients.

Acute kidney injury (AKI) is common in those with newly diagnosed hematologic malignancies. Precipitants of AKI in this population may include tumor lysis syndrome, hypotension and other insults associated with acute illness. In a general population, AKI not only leads to short-term consequences like fluid, electrolyte and acid-base abnormalities, but each episode has been linked to worse long-term outcomes, including chronic kidney disease, cardiovascular events and death. In patients with malignancies, loss of kidney function may be additionally detrimental, as this can jeopardize eligibility for full dose or first line chemotherapy, transplantation or enrollment in clinical trials. The purpose of this study is to determine the impact of AKI on long-term loss of kidney function in patients newly diagnosed with aggressive lymphomas or acute leukemia. We performed a population-based cohort study using data from the Rochester Epidemiology Project (REP). The REP is a medical-record linkage system that integrates data for patients across multiple medical care providers in Olmsted County, MN and surrounding areas to facilitate long-term follow-up. Adults admitted to the hospital between 2005 and 2017 following a new diagnosis of acute leukemia or aggressive lymphoma were evaluated for the exposure of AKI. AKI was defined by the KDIGO serum creatinine (SCr) criterion (Stage 1: 1.5-fold increase from baseline or 0.3mg/dL increase in 48-hours; Stage 2: 2-fold increase from baseline; Stage 3: 3-fold increase from baseline, increase in SCr to >4mg/dL, or initiation of renal replacement therapy). Only the first episode of hospitalization was included. Cox proportional hazards regression was used to compare the primary outcome of loss of kidney function within 12 months of hospitalization [defined as ≥30% decline from baseline estimated glomerular filtration rate (eGFR)] in those with and without AKI. A subgroup analysis was performed in patients with a baseline eGFR <60 mL/min/1.73m2. eGFR calculations used the Chronic Kidney Disease Epidemiology Collaborative equation. Outcome evaluation began 90-days after hospitalization to establish chronicity and was defined only by outpatient SCr values. Within the REP cohort, 1,085 patients were hospitalized following a new diagnosis of acute leukemia or lymphoma who consented to the use of their medical records for research. Sixteen patients with pre-existing end-stage renal disease were excluded, leaving 1,069 included patients for analysis. The majority were white (n=1,002; 93.7%) males (n=624; 58.4%) with a mean (SD) age of 64 (18) years. Mean baseline SCr was 1.0 (0.4) mg/dL with a corresponding eGFR of 80 (27) ml/min/1.73m2. A total of 355 patients (33.2%) experienced AKI during the index hospitalization, most commonly a maximum stage of I (n=231; 21.6%). Stages II and III AKI occurred in 42 (3.9%) and 59 (5.5%) patients, respectively. Cumulative incidence of ≥30% loss of baseline eGFR in the 12 months following hospitalization was 67.9% (95% CI 56.8%-76.1%) for those with any AKI and 38.8% (95% CI 31.8%-45.1%) for those without AKI during the index hospitalization. Patients diagnosed with any stage AKI were more likely to experience this outcome compared to those without AKI (HR 2.6, 95% CI 2.2-3.5, p<0.001) in unadjusted analysis. Amongst those with a baseline eGFR ≤60 ml/min, no significant difference in the outcome was noted (HR 1.7, 95% CI 0.83-3.35, p=0.15). Patients with AKI during initial hospitalization following a new diagnosis of acute leukemia or aggressive lymphoma were significantly more likely to experience ≥30% loss of baseline eGFR in the 12 months following diagnosis. This highlights a critical need to identify interventions which prevent AKI and optimize renal recovery so as to decrease overall morbidity and preserve eligibility for desirable treatment options. Disclosures Barreto: FAST Biomedical, Inc: Consultancy. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees.

Background: Prolonged methotrexate (MTX) exposure following high-dose methotrexate (HDMTX; ≥1g/m2) occurs in up to 33% of patients and potentially compromises management through increased renal and systemic toxicities.(Pinedo et al, 1977, Joerger et al, 2012) MTX-associated acute kidney injury (AKI) occurs in 5% to 30% of patients.(May et al, 2014) Rescue leucovorin dose escalation in response to an elevated 48-hour MTX concentration or serum creatinine rise is standard-of-care to reduce adverse events. The practice of preemptive leucovorin dose increases in patients with elevated MTX concentrations or previous AKI during prior MTX doses has unclear outcomes. Methods: This retrospective, single-center, cohort study was approved by the Mayo Clinic IRB and performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. We identified patients newly initiated on HDMTX for management of lymphoma between 1/1/2011 and 10/31/2017 at Mayo Clinic in Rochester, MN. Patients were followed longitudinally until HDMTX was discontinued. The primary endpoint was the proportion of patients with an elevated MTX concentration (MTX > 1.0 mcmol/L) at 48 hours for the initial cycle. Secondary endpoints included the incidence of AKI (Kellum et al, 2012) and whether preemptively increased leucovorin doses during subsequent cycles of HDMTX impacted the incidence of a repeated episode of an elevated 48-hour MTX concentration, decreased incidence of AKI, or decreased hospital length of stay (LOS) compared to patients with standard leucovorin dosing (25mg intravenous every 6 hours until MTX < 0.1 mcmol/L). Results: The 321 included patients had a median (IQR) age of 65 (57, 72) years, 190 (59%) were male, and 293 (91%) were Caucasian. Baseline demographics and clinical characteristics are depicted in table 1 with those who had elevated MTX levels during their initial cycle more likely to be Male, Caucasian, have a higher BSA, have Primary DLBCL of the CNS, have bone marrow involvement, have a higher baseline SCr, higher total bilirubin, and lower albumin. The median (IQR) grams of the initial MTX dose was 6.3 (4.3, 7.5) for 84 patients (26%) receiving MTX for prophylaxis and was 12.8 grams (7.5, 16.8) for the 237 patients (74%) receiving MTX as treatment. Chemotherapy regimen distribution included 43 patients (13%) receiving HDMTX 8 grams/m2 monotherapy, 162 patients (50%) receiving HDMTX 8 grams/m2 with Rituximab and Temozolomide (MRT), and 96 patients (30%) receiving HDMTX 3.5 grams/m2 in combination with R-CHOP. Patients received a median of 3 MTX doses (IQR:2 doses, 6 doses). A total of 83 patients (36%) had an elevated MTX concentration after their first MTX dose, and the overall incidence of elevated MTX concentrations was 22% following a total of 1558 MTX doses. Preemptively increasing the leucovorin dose (based on the prior MTX concentration) was associated with a 34% rate of elevated MTX concentrations (160/466 cycles). Giving standard leucovorin (based on the prior MTX concentration) was associated with a 12% rate of elevated MTX concentration (84/713 cycles). Those with a preemptively increased leucovorin dose were more likely to have an elevated MTX concentration in that cycle (OR=2.84, 95% CI: 2.03-3.97, p<0.001). For the secondary endpoint of AKI, the overall incidence was 18% with 107 patients (33%) experiencing AKI after their first MTX dose. In these first dose AKI episodes, 81 cases (25%) were stage 1, 19 (6%) stage 2, and 7 (2%) stage 3 Preemptive leucovorin dose increase was associated with a greater risk of AKI after MTX (OR=1.52, 95% CI: 1.05-2.19, p=0.027). Overall median hospital LOS was 4.1 (3.8, 5.8) days. Hospital LOS was longer in those with preemptively increased leucovorin doses (Median LOS with preemptively increased leucovorin doses: 5 (4.1, 6.1) days; without preemptively increased leucovorin doses: 4 (3.2, 4.3) days; estimated difference=1.1 days, 95% CI: 0.5-1.7, p<0.001). Conclusion: HDMTX leads to a significant incidence of elevated serum 48hr MTX levels and AKI, 22% and 18%, respectively. Rather than protective, we found that preemptively increased leucovorin doses used during subsequent cycles did not improve the incidence of delayed elimination, reduce the incidence of AKI, or shorten hospital LOS per MTX dose. Further investigation is needed to optimize dosing strategies and supportive measures following MTX administration for management of lymphoma patients. Disclosures Barreto: FAST Biomedical, Inc: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding.

Abstract Introduction: Clinical tumor lysis syndrome (TLS), which manifests most often as acute kidney injury (AKI) is a common and devastating complication of rapidly proliferating hematologic malignancies. Epidemiologic studies of attributable risk factors for AKI in this setting are small, focus on only aggressive lymphomas rather than the more prevalent intermediate risk disease subtypes, and predate contemporary risk stratification, diagnostic criteria, and supportive care. Additionally, early administration of rasburicase to enhance uric acid (UA) elimination has been adopted without robust evidence in support of its impact on clinical outcomes, specifically, prevention of AKI. Methods: This was a retrospective cohort study of adult lymphoma patients at intermediate or high risk for TLS treated at Mayo Clinic between 2009 and 2017. Patients were excluded if they had AKI at hospital admission, received pre-admission rasburicase, or were on dialysis. Consensus definitions were used to stratify TLS risk and stage AKI. The incidence of new AKI in the setting of TLS was described along with predictors of its development, including early rasburicase use. Results: Of the 461 patients with a new lymphoma diagnosis during the study timeframe at intermediate or high risk of TLS, 78 were excluded, primarily due to prevalent AKI at hospital admission. The 383 included patients were predominantly at intermediate risk for TLS (73%) and had a diagnosis of Diffuse Large B-cell Lymphoma (64%). Incidence of new onset AKI during hospitalization was 6% and 91% of cases were stage 1. All new onset AKI occurred within the first 5 days of hospital admission. Independent predictors of new AKI included age > 60 years, history of chronic kidney disease or cardiovascular disease, and UA >8 mg/dL at any time during hospital admission. Rasburicase was given to 48 patients, 6 (13%) of whom still went on to develop AKI. Rapid UA reduction with rasburicase did not impact the risk of developing AKI (HR 2.3; p = 0.11). Uric acid level at the time of administration did not modify the effect of rasburicase on prevention of AKI (p = 0.36 for the interaction term). Conclusion: In conclusion, for lymphoma patients at intermediate or high risk for TLS, if not present at admission, AKI only infrequently developed during the course of a patient's hospitalization. Predictors of AKI included advanced age, comorbid conditions, and elevated UA levels. Early rasburicase administration, regardless of UA level, did not alter AKI risk. Disclosures No relevant conflicts of interest to declare.

Objectives: Midodrine is an α1-agonist approved for orthostatic hypotension. Recently, it has received attention as an oral vasopressor to facilitate ICU discharge. The purpose of this study was to identify the incidence of continuation of newly initiated midodrine upon ICU and hospital discharge and identify risk factors associated with its occurrence. Design: Single-center retrospective study. Setting: ICU patients from January 2011 to October 2016 at Mayo Clinic, Rochester. Patients: Adult patients admitted to any ICU who received new midodrine for hypotension and survived to discharge. Interventions: None. Measurements and Main Results: During the study period, 1,010 patients were newly started on midodrine and survived to ICU discharge. Midodrine was continued in 67% (672/1,010) of patients at ICU discharge. Admission to cardiovascular surgery ICU and mixed medical/surgical ICU was a risk factor for midodrine continuation at ICU discharge (odds ratio, 3.94 [2.50–6.21] and 2.03 [1.29–3.20], respectively). At hospital discharge, 34% (311/909) of patients were continued on midodrine therapy. History of congestive heart failure predicted midodrine continuation at hospital discharge (odds ratio, 1.49 [1.05–2.12]). Hypertension and use of mechanical ventilation were associated with a decreased odds of midodrine prescription at both ICU and hospital discharge. Of those discharged from the ICU or hospital on midodrine, 50% were concomitantly prescribed antihypertensives. Discharge from the ICU on midodrine was associated with a significantly shorter ICU length of stay (7.5 ± 8.9 vs 10.6 ± 13.4 d) and reduced risk of in-hospital mortality (hazard ratio, 0.47 [95% CI, 0.32–0.70]; p < 0.001), despite no difference in baseline severity of illness scores. In contrast, patients discharged from the hospital on midodrine had a higher risk of 1-year mortality (hazard ratio, 1.60 [95% CI, 1.26–2.04]; p < 0.001). Conclusions: This study established a high prevalence of midodrine continuation in transitions of care. The risks and benefits of this practice remain unclear. Future studies should explore the impact of this practice on patient outcomes and resource utilization. These insights could be used to model interventions for proper tapering, discontinuation, or follow-up of new start midodrine.

AKI is a global concern with a high incidence among patients across acute care settings. AKI is associated with significant clinical consequences and increased health care costs. Preventive measures, as well as rapid identification of AKI, have been shown to improve outcomes in small studies. Providing high-quality care for patients with AKI or those at risk of AKI occurs across a continuum that starts at the community level and continues in the emergency department, hospital setting, and after discharge from inpatient care. Improving the quality of care provided to these patients, plausibly mitigating the cost of care and improving short- and long-term outcomes, are goals that have not been universally achieved. Therefore, understanding how the management of AKI may be amenable to quality improvement programs is needed. Recognizing this gap in knowledge, the 22nd Acute Disease Quality Initiative meeting was convened to discuss the evidence, provide recommendations, and highlight future directions for AKI-related quality measures and care processes. Using a modified Delphi process, an international group of experts including physicians, a nurse practitioner, and pharmacists provided a framework for current and future quality improvement projects in the area of AKI. Where possible, best practices in the prevention, identification, and care of the patient with AKI were identified and highlighted. This article provides a summary of the key messages and recommendations of the group, with an aim to equip and encourage health care providers to establish quality care delivery for patients with AKI and to measure key quality indicators.