Frazee, Erin N.

AbstractBackgroundReliable and valid tools to screen for malnutrition in the intensive care unit (ICU) remain elusive. The sarcopenia index (SI) [(serum creatinine/serum cystatin C) × 100], could be an inexpensive, objective tool to predict malnutrition. We evaluated the SI as a screening tool for malnutrition in the ICU and compared it with the modified‐NUTRIC score.Materials and MethodsThis was a historical cohort study of ICU patients with stable kidney function admitted to Mayo Clinic ICUs between 2008 and 2015. Malnutrition was defined by the Subjective Global Assessment. Diagnostic performance was evaluated with the area under the receiver operating characteristic curve (AUC) and multivariable logistic regression.ResultsOf the 398 included patients, 181 (45%) had malnutrition, with 34 (9%) scored as severely malnourished. The SI was significantly lower in malnourished patients than in well‐nourished patients (64 ± 27 vs 72 ± 25; P = 0.002), and reductions in SI corresponded to increased malnutrition severity (P = 0.001). As a screening tool, the SI was an indicator of malnutrition risk (AUC 0.61) and performed slightly better than the more complex modified‐NUTRIC score (AUC = 0.57). SI cutoffs of 101 and 43 had >90% sensitivity and >90% specificity, respectively, for the prediction of malnutrition. Patients with a low SI (≤43) had a significantly higher risk of mortality (HR = 2.61, 95% CI 1.06–6.48, P = 0.038).ConclusionThe frequency of malnutrition was high in this critically ill population, and it was associated with a poor prognosis. The SI could be used to assess nutrition risk in ICU patients.

The incidence and severity of Clostridium difficile infection (CDI) remain high across intensive care units in the United States despite national efforts to decrease this escalating health care burden. Most published literature and guidelines address treatment rather than prevention, yet this approach may be too downstream to limit morbidity and mortality from the disease and its complications. Mechanisms to prevent CDI successfully include reducing modifiable risk factors and minimizing horizontal transmission of C. difficile spores between patients and the health care environment. Because CDI prevention is characterized by a bundled approach, it is difficult to quantify the individual impact of any one element; however, a number of patient‐ and facility‐level strategies can be considered for CDI prevention. Robust hygiene strategies, diagnostic and antimicrobial stewardship, and particular prophylaxis maneuvers such as continuation of oral vancomycin or fidaxomicin in the setting of systemic antibiotics have all demonstrated benefit. The preventive roles of deprescribing acid suppressants, routine use of probiotics, or early fecal microbiota transplantation remain unclear. The focus of this review is to summarize the evidence related to primary and secondary CDI prevention in critically ill adults and provide a concise implementation pathway for clinicians and policymakers.

The objective of this study is to describe the pharmacokinetics of lacosamide in a critically ill adult during continuous venovenous hemofiltration (CVVH). A 78-year-old male developed sepsis and acute kidney injury following cardiac surgery. He was initially treated with intermittent hemodialysis but developed nonconvulsive status epilepticus at the end of the first session and was subsequently initiated on CVVH. In addition to lorazepam boluses, levetiracetam, and midazolam infusion, he was loaded with lacosamide 400 mg intravenously and started on 200 mg intravenously twice daily as maintenance therapy. Noncompartmental modeling of lacosamide pharmacokinetics revealed significant extracorporeal removal, a volume of distribution of 0.69 L/kg, elimination half-life of 13.6 hours, and peak and trough concentrations of 7.4 and 3.7 mg/L, respectively (goal trough, 5-10 mg/L). We found significant extracorporeal removal of serum lacosamide during CVVH, which was higher than previously reported. This led to subtherapeutic concentrations and decreased overall antiepileptic drug exposure. The relationship between serum lacosamide concentrations and clinical efficacy is not well understood; thus, therapeutic drug monitoring is not routinely recommended. Yet, we demonstrated that measuring serum lacosamide concentrations in the critically ill population during continuous renal replacement therapy may be useful to individualize dosing programs. Further pharmacokinetic studies of lacosamide may be necessary to generate widespread dosing recommendations.

AbstractBackgroundNephrotoxins contribute to 20%–40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations.MethodsThe study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups.ResultsThe overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85–1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71–1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09).ConclusionShort courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.

Study Objective Serum creatinine ( S c r ) concentration is used to calculate estimated glomerular filtration rate (e GFR ) for medication dosing. Serum cystatin C (CysC) concentration has been proposed as an adjunct or alternative to S cr . This study sought to evaluate the possible impact of using CysC in eGFR equations on drug dose recommendations in hospitalized patients with infections. Design Retrospective analysis of prospectively collected data. Setting Large academic tertiary care medical center. Patients A total of 308 adults with suspected or documented infections and stable kidney function who were hospitalized between 2012 and 2015. Measurements and Main Results Standardized S c r and CysC measured at the time of antibiotic dosing were used to estimate GFR from the three Chronic Kidney Disease Epidemiology Collaborative ( CKD ‐ EPI ) equations using S c r (eGFR Cr ), CysC( eGFR CysC ), or a combination of S c r and CysC (eGFR Cr‐CysC ), and these values were compared with estimated creatinine clearance (eCl cr ) from the Cockcroft‐Gault equation (standard of care for drug dosage adjustments). The eGFR s were categorized into five common dosage adjustment strata (lower than 20, 20–49, 50–79, 80–130, and higher than 130 ml/min), and agreement between equations was tested with the weighted κ statistic. Recommended drug doses varied considerably between the eC l cr and the CKD ‐ EPI equations (weighted κ [95% confidence interval]: eGFR Cr 0.73 [0.68–0.79], eGFR CysC 0.42 [0.35–0.5], eGFR Cr‐CysC 0.65 [0.6–0.71]). If eGFR Cr, eGFR CysC , or eGFR Cr‐CysC were used instead of eC l cr to dose drugs, 11%, 12%, and 8% of doses, respectively, would be higher, and 12%, 38%, and 24% of doses, respectively, would be lower. Conclusion Significant discordance in drug doses was observed when the CKD ‐ EPI equations were used in place of eCl cr . When CysC was included in eGFR equations, recommended doses were often lower. Further study is needed to develop and test drug‐specific dosing guidelines that incorporate alternate renal biomarkers and/or more contemporary eGFR equations.

Over the last decade, the discovery of novel renal biomarkers and research on their use to improve medication effectiveness and safety has expanded considerably. Pharmacists are uniquely positioned to leverage this new technology for renal assessment to improve medication dosing and monitoring. Serum cystatin C is a relatively new, inexpensive, functional renal biomarker that responds more quickly to changing renal function than creatinine and is not meaningfully affected by age, sex, skeletal muscle mass, dietary intake, or deconditioning. Cystatin C has been proposed as an adjunct or alternative to creatinine for glomerular filtration rate assessment and estimation of drug clearance. Tissue inhibitor of metalloproteinase‐2·insulin‐like growth factor‐binding protein 7 ([TIMP‐2]·[IGFBP7]) is a composite of two damage biomarkers released into the urine at a checkpoint in mitosis when renal cells undergo stress or sense a future risk of damage. Concentrations of [TIMP‐2]·[IGFBP7] increase before a rise in serum creatinine is evident, thus providing insightful information for evaluation in the context of other patient data to predict the risk for impending kidney injury. This article provides a brief overview of novel renal biomarkers being used as a mechanism to improve medication safety including a discussion of cystatin C, as part of drug‐dosing algorithms and specifically for vancomycin dosing, and the use of [TIMP‐2]·[IGFBP7] for risk prediction in acute kidney injury and drug‐induced kidney disease. Select cases of clinical experience with novel renal biomarkers are outlined, and lessons learned and future applications are described.

High-dose methotrexate (MTX; ≥1 g/m2) is a renally eliminated and nephrotoxic first-line therapy for central nervous system (CNS) lymphoma. Creatinine-based estimation of renal function is the recommended approach to dosing MTX in these cases, but nonrenal determinants of creatinine production and elimination in cancer patients such as malnutrition and cachexia lead to overestimation of glomerular filtration rate (GFR) by this method and a heightened risk for drug toxicity. Serum cystatin C is one of the first readily available, relatively inexpensive, endogenous biomarkers to emerge as a practical adjunct to creatinine for estimation of renal function for drug dosing. In this report, we describe two cases where cystatin C was used in conjunction with creatinine to inform MTX dosing for CNS lymphoma. In both cases, the estimated GFR was nearly 40% lower with the combination of the two biomarkers compared to creatinine-only estimates. Empiric MTX dose reductions as a product of these results likely spared the patients sustained exposure to toxic drug concentrations and facilitated earlier administration of supportive care interventions. Further prospective investigations with validated dosing regimens including cystatin C are warranted for high-dose MTX.

AbstractBackgroundFrailty, including low muscle mass, is an emerging risk factor for poor outcomes after lung transplant. The sarcopenia index (SI)—(serum creatinine value/cystatin C value) × 100—is a novel blood test to approximate muscle mass. We sought to validate SI among lung transplant patients.MethodsWe retrospectively identified adult lung transplant recipients from 2000 through 2012 at our institution who underwent computed tomography within 1 year before transplant and had preserved blood samples. Creatinine and cystatin C values were measured using the samples and used to calculate SI. Muscle mass was estimated by computed tomographic measurement of skeletal muscle cross‐sectional surface area (SA) at the L1 to L3 vertebral levels. Correlation between SI and SA was evaluated.ResultsOf 28 patients meeting eligibility criteria, most were white (96%) and men (54%). Median (interquartile range) body mass index, SI, and SA were 25.9 (22‐30) kg/m2, 106 (91‐119), and 157 (113‐195) cm2, respectively. The Pearson correlation coefficient between SI and SA was significant at L2 (0.43; P = .02) and L3 (0.41; P = .03).ConclusionSarcopenia index is a potentially objective measure for estimating muscle mass that is noninvasive and less expensive. Sarcopenia index could be considered in lung transplant candidate selection following prospective validation in larger cohorts.

Cystatin C has been suggested to be a more accurate glomerular filtration rate (GFR) surrogate than creatinine in patients with acquired immunodeficiency syndrome (AIDS) because it is unaffected by skeletal muscle mass and dietary influences. However, little is known about the utility of this marker for monitoring medications in the critically ill. We describe the case of a 64-year-old female with opportunistic infections associated with a new diagnosis of AIDS. During her course, she experienced neurologic, cardiac, and respiratory failure; yet her renal function remained preserved as indicated by an eGFR ≥ 120 mL/min and a urine output > 1 mL/kg/hr without diuresis. The patient was treated with nephrotoxic agents; therefore cystatin C was assessed to determine if cachexia was resulting in a falsely low serum creatinine. Cystatin C measured 1.50 mg/L which corresponded to an eGFR of 36 mL/min. Given the >60 mL/min discrepancy, serial 8-hour urine samples were collected and a GFR > 120 mL/min was confirmed. It is unclear why cystatin C was falsely elevated, but we hypothesize that it relates to the proinflammatory state with AIDS, opportunistic infections, and corticosteroids. More research is needed before routine use of cystatin C in this setting can be recommended.