Evaluation of Hospitalized Patients Receiving High versus Low-Dose Opioids for Non-Cancer Pain.

Limited studies suggest that opioid-related adverse effects (ORAEs) may worsen hospitalized patient outcomes, but there is insufficient data related to the impact of high-dose opioids compared to low-dose on adverse patient events. Given the paucity of data, our study aims to evaluate these ORAEs in the general hospitalized patient with non-cancer pain. A retrospective study of adult patients receiving opioids with a primary diagnoses of myocardial infarction, chronic obstructive pulmonary disease, heart failure, pneumonia, sepsis, or diabetes was conducted. Average oral morphine milligram equivalents (MMEs) administered over the entire LOS was collected, and patients were categorized as high-dose (≥50 MMEs/day) or low-dose (<50 MMEs/day). The primary composite endpoint was the incidence of ORAEs (naloxone use, decreased oxygen saturations, nausea/vomiting). Secondary outcomes included LOS, 30-day readmission, ORAEs with >100 MMEs/day. A total of 100 patients were included (n = 58 low-dose group; n = 42 high-dose group). For the primary outcome, more patients in the high-dose group experienced ORAEs (50% high-dose vs. 22.4% low-dose; p < 0.006). No statistically significant differences in LOS or 30-day readmission rates were identified between the groups. For patients receiving >100 MMEs/day, ORAEs occurred in 61% of patients. Hospitalized patients receiving high-dose opioids for non-cancer pain may have an increased incidence of ORAEs.

Levetiracetam pharmacokinetics in critically ill patients undergoing renal replacement therapy.

PURPOSE: To determine clearance of levetiracetam in patients requiring continuous renal replacement therapy (CRRT) or sustained low efficiency dialysis (SLED). MATERIALS AND METHODS: Adult patients with acute kidney injury or end stage renal disease requiring either CRRT or SLED and levetiracetam were eligible for inclusion. Simultaneous arterial, venous, and effluent samples for analysis of levetiracetam concentrations were collected every two hours for up to 6-8 h. Levetiracetam clearance (CL) and half-life (t1/2) were calculated for each modality. RESULTS: Eight CRRT patients and 4 SLED patients completed the study: 67% male, mean age 50 ± 13 years, and 83% had AKI. Seven CRRT patients received continuous venovenous hemodiafiltration (CVVHDF) [median pre-replacement rate 700 mL/h (range 500-1000), post-replacement rate 500 mL/h (range 200-1000), effluent rate 2500 mL/h (range 1700-3650) and delivered CRRT dose 27 mL/kg/h (range 19-54)] and one patient received CVV hemofiltration (CVVH). The mm mean levetiracetam CL during CVVHDF was 31.2 ± 8.5 mL/min, and the and the mean t1/2 was 10.4 ± 2.2 h. For the patient requiring CVVH, clearance and t1/2 were 22.5 mL/min and 9.5 h, respectively. Mean levetiracetam CL during SLED performed at a blood flow rate of 250 mL/min and a dialysate flow rate of 100 mL/min was 74.0 ± 25.3 mL/min and t1/2 was 4.8 ± 2.3 h. CONCLUSIONS: Levetiracetam clearance was substantial with both modalities under the operating conditions reported. There is the potential for subtherapeutic concentrations with current recommended dosing strategies that account only for kidney function and not these extracorporeal routes of elimination.

Pragmatic Use of Kidney Function Estimates for Drug Dosing: The Tide Is Turning.

Creatinine clearance has been the most common method of estimating kidney function for the purpose of drug dosing for decades. The availability and extensive clinical use of estimated glomerular filtration rate (eGFR) now provides clinicians a potential alternative. Currently, data demonstrating the validity of eGFR-based drug dosing is limited, but proof of principle has been established and the tide related to use of eGFR for drug dosing appears to be turning. Use of the same kidney function estimate for management of kidney disease, drug development and dosing, and harmonization in all clinical arenas would be ideal. Use of multiple equations can lead to differences in kidney function estimates and corresponding drug dosing regimens, which necessitates clinical judgment and a pragmatic approach when rendering drug dosing decisions. Careful consideration of the risk-benefit ratio of individual drugs and dosing regimens within each patient is warranted. Going forward, FDA guidance will likely incentivize pharmaceutical manufacturers to generate eGFR-based dosing recommendations in addition to creatinine clearance for inclusion in the label of newly approved drugs. However, dosing information for currently approved drugs will continue to be based on creatinine clearance alone, so clinicians must be vigilant in the assessment of kidney function in order to provide optimal pharmacotherapy.

Predictors of adherence to a new erythropoiesis-stimulating agent inpatient ordering policy: A cross-sectional study.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are recommended for treating anemia in patients with chronic kidney disease and end-stage renal disease. However, misappropriate and over-use of these agents can be costly and unnecessary in some settings. OBJECTIVE: The primary aim was to identify predictors of adherence to a newly approved ESA inpatient ordering policy. The secondary aims were to evaluate the impact of a 5-day delay in the initiation of ESA therapy on ESA usage, hemoglobin (Hb) levels, and costs. METHODS: This retrospective observational record review included a sample of adult patients admitted to four tertiary care hospitals from November 1, 2013 to August 31, 2014. Multivariable logistic and linear regression analyses were used to calculate the odds of adherence to the new ESA inpatient ordering policy and the impact of this policy on discharge Hb level, respectively. RESULTS: A total of 242 patients were included. The majority of the prescribers (77%) adhered to the new ESA ordering policy. Hemoglobin (OR = 1.306; 95% CI: 1.03-1.65) and ferritin (OR = 3.91; 95% CI: 1.23-12.51) levels at admission and length of hospital stay were positively correlated with the odds of patients receiving ESAs after day 5 (OR = 1.12; 95% CI:1.05-1.20). Furthermore, adherence to the new policy did not have a significant impact on discharge Hb level (ß = 0.02349; P = 0.895). CONCLUSIONS: Prescribers were adherent to a 5-day delay in the initiation of ESA therapy policy which resulted in a reduction in ESA usage, did not impact the discharge Hb levels, and was proven to be cost effective.

Effect of α -Lipoic Acid on Oxidative Stress in End-Stage Renal Disease Patients Receiving Intravenous Iron.

Oxidative stress is associated with increased risk of cardiovascular disease in end-stage renal disease (ESRD) patients. Intravenous (IV) iron has been shown to increase oxidative stress. The aim of the study was to evaluate changes in oxidative stress markers following administration of IV sodium ferric gluconate (SFG) to ESRD patients with and without administration of the antioxidant, α -lipoic acid. This is an open-label, crossover study. 125 mg of IV SFG was administered during control (C) and intervention (I) visits. During the I visit, 600 mg of α -lipoic acid was given orally prior to IV SFG. Blood samples were collected at defined time periods for F2-isoprostane (FIP), lipid hydroperoxide (LHP), malondialdehyde (MDA), and iron indices. We recruited ten African-American ESRD subjects: 50% male; mean age 45 ± 9 years; mean hemoglobin 13 ± 1 g/dL; ferritin 449 ± 145 ng/mL; transferrin saturation 27 ± 4%. There were no significant differences in iron indices between the two visits after IV SFG. MDA, FIP, and LHP increased significantly for both C and I visits with a greater increase in the I group. Administration of IV SFG results in an acute rise in oxidative stress in ESRD patients. In contrast to previous studies, administration of α -lipoic acid was associated with a greater increase in oxidative stress.

Evaluation of warfarin dose requirements in patients with chronic kidney disease and end-stage renal disease.

STUDY OBJECTIVES: The effect of chronic kidney disease (CKD) on warfarin has gained attention because of an increased risk of thromboembolism and an increased risk of bleeding associated with warfarin treatment in these patients. Data suggest that patients with reduced kidney function require lower warfarin doses; however, relatively few patients with end-stage renal disease (ESRD) were included in previous studies. The goal of this study was to evaluate warfarin dosing requirements and time to reach therapeutic international normalized ratio (INR) in patients with CKD stages 3-5 and ESRD compared with patients with normal kidney function (NKF). METHODS: A historical cohort was identified to evaluate warfarin response in 210 hospitalized adults with varying degrees of kidney function initiated or maintained on warfarin for 4 or more consecutive days including 49 patients with NKF (glomerular filtration rate [GFR] higher than 60 ml/min/1.73 m(2) ), 44 with CKD stage 3, 27 with CKD stage 4/5, and 90 with ESRD. The average daily dose (ADD), time to achieve a therapeutic INR, and adverse effects were compared. MEASUREMENTS AND MAIN RESULTS: The ADD to maintain a therapeutic INR was 5.6 ± 1.7 mg in the NKF group, 4.3 ± 1.6 mg in CKD stage 3, 4.6 ± 1.9 mg in CKD stage 4/5, and 4.8 ± 1.9 mg in ESRD. The ADD was lower in CKD/ESRD patients compared with NKF patients (p=0.001), especially among whites. The time to reach a therapeutic INR in patients newly initiated on warfarin was significantly lower in the CKD/ESRD group when compared with the NKF group (p=0.02). No differences in bleeding episodes were observed during hospitalization or within 30 days of discharge in patients with CKD stage 3 or higher compared with patients with NKF. CONCLUSIONS: Our findings suggest that CKD and ESRD patients require ~20% lower warfarin doses to maintain a therapeutic INR and may require less time to achieve a therapeutic INR compared with patients with NKF.

Performance of methods to assess kidney function in a predominantly overweight sample of patients with liver disease.

The assessment of glomerular filtration rate (GFR) in patients with liver disease is necessary to make decisions about organ allocation. Creatinine is widely used as a marker of GFR; however, it is not reliable in patients with liver disease. The aims of this study were to (1) determine if iodine 125-labeled iothalamate ((125)I-iothalamate) clearance calculated using the plasma decay method is equal to renal clearance of (125)I-iothalamate and (2) estimate kidney function using the creatinine-based Cockcroft-Gault and the Modification of Diet in Renal Disease equations, a cystatin C-based equation, the urine collection method for creatinine clearance, and plasma clearance of vancomycin (V) and compare these estimates to renal clearance of (125)I-iothalamate in adult patients with liver disease. Adults with liver disease received (125)I-iothalamate and V and had a catheter placed for urine collection. Blood and urine samples were collected over 8 h for analysis of (125)I-iothalamate, creatinine, and V to determine kidney function. Estimates were compared to renal (125)I-iothalamate clearance. Eight patients classified as Child-Pugh class B were enrolled: age was 52 ± 6 years; body mass index was 36.5 ± 19 kg/m(2); and Model for End-Stage Liver Disease score was 13 ± 3. Mean estimates of kidney function did not differ significantly from mean renal (125)I-iothalamate clearance (74 ± 38 mL/min/1.73 m(2)). Other methods overestimated kidney function at lower levels of GFR (<60 mL/min/1.73 m(2)) and underestimated kidney function at higher GFR levels. Given the variability in performance of methods to assess kidney function in this population, direct measurement of GFR may be preferable to indirect estimates based on marker compounds such as creatinine and cystatin C until more accurate methods are developed.

Vancomycin-resistant Enterococcus bacteremia: an evaluation of treatment with linezolid or daptomycin.

BACKGROUND: Due to high rates of resistance and a limited number of efficacious antimicrobials for vancomycin-resistant Enterococcus (VRE), appropriate antibiotic selection is vital to treatment success. The purpose of this study was to assess clinical and microbiologic outcomes associated with the use of linezolid or daptomycin in the treatment of VRE bacteremia. METHODS: A retrospective analysis of adult patients with VRE bacteremia between January 2004 and July 2009 was conducted at a tertiary care hospital in the United States. Clinical and microbiologic outcomes for both therapies were evaluated using multiple criteria. RESULTS: Of the 361 patients with VRE bacteremia identified, 201 were included in the study (linezolid group, n = 138; daptomycin group, n = 63). More patients in the daptomycin group had hematologic malignancies (33% vs 14%) or received liver transplants (13% vs 4%). There was no difference in clinical or microbiologic cure between the linezolid and daptomycin groups (74% vs 75% and 94% vs 94%, respectively). Recurrence was documented in 3% of linezolid patients vs 12% of daptomycin patients (P = 0.0321). Reinfection was noted in 1% of patients in the linezolid group vs 6% of patients in the daptomycin group (P not significant). The average length of stay (LOS) was 37 days for the linezolid group vs 40 days for the daptomycin group (P not significant). Overall mortality was 20%, occurring in 25/138 linezolid patients vs 15/63 daptomycin patients (P not significant). CONCLUSIONS: No differences in clinical or microbiologic cure rates, LOS, or mortality were identified between the groups. Various factors may have contributed to the significantly higher recurrence of VRE bacteremia in daptomycin patients. This study suggests that linezolid and daptomycin appear equally efficacious in the treatment of VRE bacteremia.

Assessment of eptifibatide clearance by hemodialysis using an in vitro system.

BACKGROUND/AIMS: Eptifibatide is a parenteral glycoprotein IIb-IIIa inhibitor that prevents platelet aggregation. Although contraindicated in dialysis patients due to limited safety and dialysis data, eptifibatide is prescribed in this population and is associated with bleeding complications. This study was done to determine dialysis clearance (CL(D)) of eptifibatide using an in vitro system. METHODS: Three common dialyzers were tested. In vitro dialysis was performed at a dialysate flow rate of 500 ml/min, 'blood' flow rate (Q(B)) of 200 and 400 ml/min, and the minimal ultrafiltration rate. Eptifibatide CL(D) and fraction removed were calculated for each condition. RESULTS: CL(D) ranged from 122 to 225 ml/min and was not significantly different among the dialyzers tested. CL(D) was flow dependent with higher clearances observed at higher Q(B). The estimated fraction of eptifibatide removed was 73-83%. CONCLUSIONS: These data suggest that hemodialysis is an effective method to decrease the effects of eptifibatide in patients with impaired kidney function.

Pharmacokinetics of 2-chlorodeoxyadenosine in a child undergoing hemofiltration and hemodialysis for acute renal failure.

The clearance of 2-chlorodeoxyadenosine (2-CdA) in patients with renal insufficiency has not been characterized previously. The authors describe the clinical course and the pharmacokinetics of 2-CdA in a child with acute monoblastic leukemia who experienced acute renal failure during treatment with cytarabine and 2-CdA. 2-CdA (9 mg/m per day) was infused over 30 minutes daily for 5 days. Plasma and dialysate concentrations of 2-CdA were measured by high-performance liquid chromatography. The rate of this patient's 2-CdA clearance was lower than the rates reported for children with normal renal function. The average clearance rate, reflecting systemic clearance and clearance by continuous venovenous hemofiltration and hemodialysis, was 12.4 L/hour per m for the first 3 days of 2-CdA therapy. He did not experience untoward hematologic toxicity. Because high 2-CdA plasma concentrations were observed in this patient, clinicians are advised to exercise caution when using this drug in patients with renal dysfunction. More experience in the administration of 2-CdA to patients with renal insufficiency will be necessary to determine the need for dosage adjustment.

Darbepoetin alfa, a new therapy for the management of anemia of chronic kidney disease.

Anemia of chronic kidney disease (CKD) results primarily from a deficiency of the hormone erythropoietin. Treatment of anemia in the early stages of CKD is essential to reduce the risk of developing anemia-associated complications and to improve health-related quality of life. Treatment with recombinant human erythropoietin (r-HuEPO, epoetin alfa) can correct erythropoietin deficiency and increase red blood cell production, but the short half-life of r-HuEPO necessitates frequent injections. Reducing the frequency of administration has potential benefits for both patients and health care providers. Darbepoetin alfa is a new erythropoietic protein with greater biologic activity and a longer dosing interval than those of r-HuEPO. It has been shown to be effective when administered once/week and once every 2, 3, or 4 weeks, and is well tolerated. With the ability to simplify anemia management by allowing less frequent dosing, darbepoetin alfa offers an effective alternative to r-HuEPO for the treatment of anemia of CKD.