Erin F. Barreto

Innovative Use of Novel Biomarkers to Improve the Safety of Renally Eliminated and Nephrotoxic Medications

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.

Impact of Serum Cystatin C-Based Glomerular Filtration Rate Estimates on Drug Dose Selection in Hospitalized Patients

Serum creatinine (Scr) concentration is used to calculate estimated glomerular filtration rate (eGFR) for medication dosing. Serum cystatin C (CysC) concentration has been proposed as an adjunct or alternative to Scr. This study sought to evaluate the possible impact of using CysC in eGFR equations on drug dose recommendations in hospitalized patients with infections.

Lacosamide Pharmacokinetics in a Critically Ill Patient During Continuous Renal Replacement Therapy

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.

It's What’s Inside that Counts: Body Composition and Lung Transplantation

Purpose of ReviewFactors such as weight, body composition, and functional status appear to influence lung transplant outcomes. Body mass index (BMI) is incorporated into the International Society for Heart and Lung Transplantation’s (ISHLT) recipient selection guidelines. Data suggests BMI does not effectively differentiate patients with high body fat percentage or low lean muscle mass, leading to both over and under estimates of candidates’ risks.Recent FindingsRecent research has focused on alternate measures and estimates of body composition and their associations with important lung transplant outcomes. Herein, we review the current literature on body composition in lung transplantation, including the variety of measurements used and the concepts of obesity, low muscle mass, and frailty.SummaryThe concept of body composition is evolving beyond the relationship between weight and height as represented by a calculated body mass index. Radiographic assessments and serum markers allow for a more precise and representative measurement of body composition which takes into consideration fat percentage and muscle mass.

1366: EXTRACORPOREAL ELIMINATION OF BUTALBITAL IN ACUTE ASPIRIN- BUTALBITAL-CAFFEINE-CODEINE POISONING

www.ccmjournal.org Critical Care Medicine • Volume 46 • Number 1 (Supplement) Learning Objectives: Butalbital is a small molecule (approximately 220 Daltons), with 26% protein binding, a 0.8 L/kg volume of distribution, and is eliminated nearly 80% unchanged in the urine. Although hemodialysis (HD) has been used to treat overdoses of other barbiturates, the extracorporeal clearance of butalbital is unknown. The objective of this case is to describe the use of extracorporeal therapy to augment elimination of butalbital after overdose of aspirin-butalbitalcaffeine with codeine (Fiorinal with Codeine). Methods: A 67 year old female was admitted to the medical intensive care unit approximately three hours after ingestion of 40 tablets of Fiorinal with Codeine. Her presentation was notable for a decline in mental status, preserved renal function, and a relatively low peak aspirin concentration at 46.4 mg/dL. Approximately 8-hours after ingestion of nearly 1600mg of butalbital, our patient’s serum concentration was 26.9 mg/L (normal < 10 mg/L). At the end of a four-hour hemodialysis session, the total body elimination of butalbital was approximately 60% which corresponded to an intradialytic clearance of 14-18L/hr. Results: Extracorporeal removal of drug likely explains the majority of this total clearance based on the observed butalbital dialysate concentrations. We believe that timely initiation of intermittent HD in this case averted further cognitive and respiratory depression associated with barbiturate intoxication. Rapid reversal of the patient’s depressed mental status mitigated the respiratory failure risks quite quickly in this case and likely spared a protracted ICU course while intrinsic elimination of the drug occurred. While the inherent risks of the placement of temporary central venous access must be balanced, and the ready availability of dialysis team support must be considered; this objective experience supports the benefit of hemodialysis provision in severe overdoses of Fiorinal with Codeine that fail to respond to standard measures.

Extracorporeal elimination of butalbital in acute aspirin–butalbital–caffeine–codeine (Fiorinal with Codeine) poisoning

Abstract Background: Butalbital is a small molecule (approximately 220u2009Da), with 26% protein binding, a 0.8u2009L/kg volume of distribution, and is eliminated nearly 80% unchanged in the urine. Although hemodialysis has been used to treat overdoses of other barbiturates, the extracorporeal clearance of butalbital is unknown. The objective of this case is to describe the use of extracorporeal therapy to augment elimination of butalbital after an overdose of aspirin 325u2009mg–butalbital 50u2009mg–caffeine 40u2009mg with codeine 30u2009mg (Fiorinal with Codeine). Methods: This is a case report of a single patient. Results: A 67-year-old female was admitted to the medical intensive care unit approximately 3u2009h after ingestion of 40 tablets of Fiorinal with Codeine. Her presentation was notable for a decline in mental status, preserved renal function and a relatively low peak salicylate concentration at 46.4u2009mg/dL (3.4u2009mmol/L). Approximately 8u2009h after ingestion of 2000u2009mg of butalbital, our patient’s serum concentration was 26.9u2009mg/L (normal <10u2009mg/L). At the end of a four-hour hemodialysis session, the total body elimination of butalbital was approximately 60% which corresponded to an intradialytic clearance of 233–300u2009mL/min. Conclusions: The extracorporeal clearance of butalbital observed in this case demonstrates the utility of dialysis to augment drug elimination in a Fiorinal with Codeine overdose.

Validation of the sarcopenia index to assess muscle mass in the critically ill: A novel application of kidney function markers

BACKGROUND & AIMSnAdverse outcomes for hospitalized patients with sarcopenia are well documented, and identification of patients at risk remains challenging. The sarcopenia index (SI), previously defined as (serum creatinine/serum cystatin C)xa0×xa0100, could be an inexpensive, readily accessible, objective tool to predict muscle mass and risk for adverse clinical outcomes. The aim of this study was to assess the validity of the SI as a predictor of muscle mass.nnnMETHODSnRetrospective study of critically ill adults admitted to Mayo Clinic from 2012 to 2015 with suspected sepsis and an available creatinine and serum cystatin C. Muscle surface area was quantified at the L3/4 vertebral level in patients with an abdominal CT scan (CTMSA). Multivariable regression modeling was used to assess the relationship between SI and CTMSA, as well as short-term clinical outcomes.nnnRESULTSnThe 171 included had a mean weight and body mass index (BMI) of 75.2xa0±xa016.4xa0kg and 26.0xa0±xa04.6xa0kg/m2 and abdominal CT scans were available for 81 (47%) patients. The SI correlated with CTMSA (rxa0=xa00.40). After adjustment for age, sex, severity of illness, and BMI, SI was independently associated with muscle mass (Pxa0=xa00.001). A decrease in the SI (indicative of lower muscle mass) was also associated with frailty and worse short-term clinical outcomes.nnnCONCLUSIONnThe SI, a simple calculation from kidney function markers, is a significant predictor of muscle mass in this validation cohort of ICU patients. A low SI was associated with longer hospital length of stay and frailty. Future studies could explore whether the use of SI assists with identifying patients likely to benefit from pharmacotherapy-, nutrition-, or physical therapy-based interventions.

Incidence of acute kidney injury among critically ill patients with brief empiric use of anti-pseudomonal beta-lactams with vancomycin

BACKGROUNDnNephrotoxins 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.nnnMETHODSnThe 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.nnnRESULTSnThe 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).nnnCONCLUSIONnShort 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.

β-Lactams: The Competing Priorities of Nephrotoxicity, Neurotoxicity, and Stewardship

Antipseudomonal β-lactams are widely used in hospitalized patients, particularly in the critically ill. Notwithstanding slight differences in spectrum of activity, several other factors may inform the choice between agents. The combination of piperacillin/tazobactam with vancomycin has been associated with a heightened risk of nephrotoxicity relative to other similar antibiotic combinations. The biological mechanisms underlying the toxicity of this combination are poorly understood, and the attributed risk in sensitized populations, such as those with baseline kidney dysfunction or critical illness, has been incompletely characterized. These data are often used to justify early deescalation of vancomycin, which although important, is intuitive and has long been called for. Unfortunately, this is not the only consequence of this growing body of evidence because we have also seen a reflexive shift away from piperacillin/tazobactam in the empirical setting toward alternative agents that carry their own risks. Neurotoxicity, for example, has been noted with βlactams, most commonly cefepime when used in patients with kidney dysfunction. This dose-dependent toxicity, which manifests as encephalopathy, delirium, seizures, myoclonus, nonconvulsive status epilepticus, and coma, leading to death, may be irreversible in up to 10% of patients. In critically ill patients where the differential diagnosis of altered mental status is broad, the incidence of β-lactam neurotoxicity is likely underestimated and the manifestations often ascribed to alternative explanations. Carbapenems may have a lower incidence of both nephrotoxicity and neurotoxicity than the aforementioned agents. Yet favoring carbapenem use for routine empiricism would be undoubtedly at the expense of some antibiotic stewardship metrics. As one of the few classes of medications available to treat multidrug-resistant infections, development of drug resistance to carbapenems leaves clinicians with few options that are typically less effective and more toxic. This is especially concerning given the relatively limited number of antibiotics in the drug development pipeline. The observational data that underlie many of these associations are of modest quality. As we have demonstrated above, shelving any one of these antibiotics in favor of another simply shifts the balance toward a different problem. Depending on whether you practice in infectious diseases, nephrology, neurology, critical care, or pharmacy, you may inherently prioritize each of these elements differently. Antibiotic stewardship cannot be at the expense of nephrotoxic stewardship or neurotoxic stewardship, which too are independently associated with worsened morbidity, mortality, and resource utilization in the critically ill. Antibiotic stewardship programs should integrate feedback from these essential stakeholders when developing protocols and guidelines. Treatment individualization according to baseline risk factors, early de-escalation using rapid diagnostics, minimization of nonantimicrobial nephrotoxins, kidney biomarker testing, drug level monitoring, and electronic tools for adverse drug event surveillance are all promising innovations to optimize the safe and effective use of β-lactams. In summary, we challenge clinicians to consider a more holistic approach to measuring the success of antimicrobial stewardship efforts. Defined daily doses of antibiotics, days of therapy, standardized antimicrobial administration ratio, incidences of hospital-acquired infections, and antimicrobial resistance should be considered in conjunction with the potential end-organ dysfunction attributed to these therapies.