Clinical Outcomes of Weight-Based Norepinephrine Dosing in Underweight and Morbidly Obese Patients: A Propensity-Matched Analysis.

BACKGROUND: Weight-based dosing strategy for norepinephrine in septic shock patients with extremes of body mass index has been lesser studied. METHODS: This historical study of adult septic shock patients was conducted from January 1, 2010, to December 31, 2015, at all intensive care units (ICUs) in Mayo Clinic, Rochester. Patients with documented body mass index were classified into underweight (body mass index <18.5 kg/m2), normal weight (18.5-24.9 kg/m2), and morbidly obese (≥40 kg/m2) patients. Patients with repeat ICU admissions, ICU stay <1 day, and body mass index 25 to 39.9 kg/m2 were excluded. The primary outcome was in-hospital mortality, and secondary outcomes included cumulative norepinephrine exposure acute kidney injury, cardiac arrhythmias, and 1-year mortality. Two-tailed P < .05 was considered statistically significant. RESULTS: From 2010 to 2015, 2016 patients met inclusion-145, 1406, and 466 patients, respectively, in underweight, normal weight, and morbidly obese cohorts. Underweight patients used the highest peak dose and absolute exposure was greatest for morbidly obese patients. In-hospital mortality decreased with increasing log10 body mass index: 41.4% (underweight), 28.4% (normal weight), and 24.7% (morbidly obese), respectively (P < .001); however, this relationship was not noted at 1 year. Unadjusted log10 norepinephrine cumulative exposure (mg) was associated with higher in-hospital mortality, acute kidney injury, cardiac arrhythmias, and 1-year mortality. After adjustment for demographics, body mass index, comorbidity, and illness severity, log10 norepinephrine exposure was an independent predictor of in-hospital mortality (odds ratio 2.4 [95% confidence interval, 2.0-2.8]; P < .001) and 1-year mortality (odds ratio 1.7 [95% confidence interval, 1.5-2.0]; P < .001). In a propensity-matched analysis of 1140 patients, log10 norepinephrine was an independent predictor of in-hospital mortality (odds ratio 2.2 [95% confidence interval, 1.8-2.6]; P < .001). CONCLUSIONS: Morbidly obese patients had lower in-hospital mortality but had higher 1-year mortality compared to normal weight and underweight patients. Cumulative norepinephrine exposure was highest in morbidly obese patients. Total norepinephrine exposure was an independent mortality predictor in septic shock.

Levetiracetam Pharmacokinetics in a Critically Ill Anephric Patient on Intermittent Hemodialysis.

BACKGROUND: In patients requiring hemodialysis, the extracorporeal circuit is expected to remove the majority of serum levetiracetam. The preferred levetiracetam dosing regimen in critically ill patients exhibiting complex pharmacokinetic profiles undergoing hemodialysis is unknown. The objective of this case is to describe levetiracetam pharmacokinetics in a critically ill anephric patient receiving intermittent hemodialysis. METHODS: This is a case report of a single patient. RESULTS: A 43-year-old anephric female was admitted to the intensive care unit for concerns of new onset seizure activity. She was loaded with 2000 mg levetiracetam followed by a 750 mg daily maintenance dose. The levetiracetam volume of distribution was 0.48 L/kg, and the interdialytic elimination half-life was 31 h. Hemodialysis removed nearly 85% of serum levetiracetam, and the patient exhibited slightly higher than expected non-renal elimination. Pharmacokinetic simulations identified 500 mg daily with 750 mg post-dialysis supplements as the regimen most likely to reduce variability in serum levetiracetam concentrations and achieve levels in the therapeutic range. CONCLUSION: Substantial elimination of levetiracetam by hemodialysis occurred in this case, and non-renal clearance was slightly higher than in previous reports. Insufficient intradialytic or post-dialysis levetiracetam concentrations may place patients at risk of breakthrough seizures. This case indicates that dialysis patients on levetiracetam may require higher post-dialysis supplemental doses than currently recommended and tailored therapy supported by therapeutic drug monitoring.

Evaluating Muscle Mass by Using Markers of Kidney Function: Development of the Sarcopenia Index.

OBJECTIVES: Sarcopenia is associated with a poor prognosis in the ICU. The purpose of this study was to describe a simple sarcopenia index using routinely available renal biomarkers and evaluate its association with muscle mass and patient outcomes. DESIGN: A retrospective cohort study. SETTING: A tertiary-care medical center. PATIENTS: High-risk adult ICU patients from October 2008 to December 2010. INTERVENTIONS: The gold standard for muscle mass was quantified with the paraspinal muscle surface area at the L4 vertebrae in the subset of individuals with an abdominal CT scan. Using Pearson's correlation coefficient, serum creatinine-to-serum cystatin C ratio was found to be the best performer in the estimation of muscle mass. The relationship between sarcopenia index and hospital and 90-day mortality, and the length of mechanical ventilation was evaluated. MEASUREMENTS AND MAIN RESULTS: Out of 226 enrolled patients, 123 (54%) were female, and 198 (87%) were white. Median (interquartile range) age, body mass index, and body surface area were 68 (57-77) years, 28 (24-34) kg/m, and 1.9 (1.7-2.2) m, respectively. The mean (± SD) Acute Physiology and Chronic Health Evaluation III was 70 (± 22). ICU, hospital, and 90-day mortality rates were 5%, 12%, and 20%, respectively. The correlation (r) between sarcopenia index and muscle mass was 0.62 and coefficient of determination (r) was 0.27 (p < 0.0001). After adjustment for Acute Physiology and Chronic Health Evaluation III, body surface area, and age, sarcopenia index was independently predictive of both hospital (p = 0.001) and 90-day mortality (p < 0.0001). Among the 131 patients on mechanical ventilator, the duration of mechanical ventilation was significantly lower on those with higher sarcopenia index (-1 d for each 10 unit of sarcopenia index [95% CI, -1.4 to -0.2; p = 0.006]). CONCLUSIONS: The sarcopenia index is a fair measure for muscle mass estimation among ICU patients and can modestly predict hospital and 90-day mortality among patients who do not have acute kidney injury at the time of measurement.

Cystatin C-Guided Vancomycin Dosing in Critically Ill Patients: A Quality Improvement Project.

BACKGROUND: The aim of the study was to determine whether a vancomycin dosing algorithm based on estimated glomerular filtration rate from creatinine and cystatin C levels (eGFRcr-cys) improves target trough concentration achievement compared to an algorithm based on estimated creatinine clearance (eCLcr) in critically ill patients. STUDY DESIGN: This prospective quality improvement project evaluated intensive care unit (ICU) patients started on intravenous vancomycin using one of 2 different strategies. Dosing regimens were selected and implemented after an individualized goal trough range was established (10-15 or 15-20mg/L). Steady-state goal trough achievement was compared between treatment arms with and without adjustment for potential confounders. SETTING & PARTICIPANTS: 3 medical and surgical ICUs at a single tertiary medical center. QUALITY IMPROVEMENT PLAN: During January 2012 to October 2013, vancomycin was dosed according to eCLcr using the Cockcroft-Gault formula (control arm). During December 2013 to May 2015, a multidisciplinary quality improvement team implemented a novel vancomycin dosing algorithm according to eGFRcr-cys using the CKD-EPI equation (intervention arm). OUTCOME: Steady-state initial goal vancomycin trough concentration achievement. MEASUREMENTS & RESULTS: More patients in the intervention arm (67 of 135 [50%]) achieved therapeutic trough vancomycin levels than in the control arm (74 of 264 [28%]; OR, 2.53; 95% CI, 1.65-3.90; P<0.001). Improved trough achievement was maintained even after adjustment for age, sex, APACHE (Acute Physiology and Chronic Health Evaluation) III score, fluid balance, baseline CLcr, surgical admission diagnosis, presence of sepsis, and goal trough concentration range (adjusted OR, 2.79; 95% CI, 1.76-4.44; P<0.001). Clinical outcomes were similar between groups. LIMITATIONS: Nonrandomized, incomplete algorithm compliance. CONCLUSIONS: A vancomycin dosing nomogram based on eGFRcr-cys significantly improved goal trough achievement compared to eCLcr among ICU patients with stable kidney function. Further studies are warranted to characterize the relationship between use of cystatin C-guided dosing and clinical outcomes.

Drug Class Combination-Associated Acute Kidney Injury.

OBJECTIVE: To evaluate the quality of available evidence of drug class combinations and their association with the development of acute kidney injury (AKI). DATA SOURCES: A search of MEDLINE and Embase databases was completed using the following terms: "risk factor AND (acute kidney injury or acute kidney failure) AND (drug or medication)." STUDY SELECTION AND DATA EXTRACTION: Inclusion criteria were the following: English language, full-text availability, and at least 1 drug-combination. Each citation was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. The literature was evaluated using the quality of evidence component of GRADE. No standardized definition of AKI was applied throughout.. DATA SYNTHESIS: Out of 2139 total citations, 151 were assessed for full-text review, with 121 citations (6%) meeting inclusion criteria, producing76 unique drug class combinations. Overall, 56 combinations (73.7%) were considered very low quality; 12 (15.8%) were considered low quality. There were 8 (10.5%) of moderate quality, and no combination was considered high quality. 58 (76%) combinations that had a single citation,with a mean of 1.6 citations per drug class combination. The combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics was reported in 10 citations, the largest number of citations. CONCLUSIONS: Our study demonstrates a lack of well-designed studies addressing drug class combination-associated AKI. The combination of NSAIDs and diuretics with or without additional renin-angiotensin aldosterone agents had the strongest level of evidence. Despite limitations, the information included in this review may result in additional scrutiny about combining certain individual nephrotoxic drugs.

Risk Factors for Dexmedetomidine-Associated Hemodynamic Instability in Noncardiac Intensive Care Unit Patients.

BACKGROUND: The reported incidence of hypotension and bradycardia in patients receiving dexmedetomidine for sedation commonly exceeds 50%. In this study, we describe the incidence of, patient- and treatment-specific risk factors for, and clinical significance of dexmedetomidine-associated hemodynamic instability. METHODS: This retrospective cohort study was conducted in critically ill adults receiving dexmedetomidine for sedation at Mayo Clinic Hospital in Rochester, MN, during a 1-year period. The primary end point was hemodynamic instability: a composite of hypotension and/or bradycardia, defined as systolic blood pressure <80 mm Hg, diastolic blood pressure <50 mm Hg, or heart rate <50 beats per minute during dexmedetomidine therapy. Cox proportional hazards models were constructed to determine hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk factors of hemodynamic instability. RESULTS: Hemodynamic instability occurred in 197 of the analyzed 300 patients receiving dexmedetomidine, resulting in a cumulative incidence of 71% at 24 hours via Kaplan-Meier estimation. In addition to dexmedetomidine, univariate analysis identified age, vasopressor use, low baseline arterial blood pressure, and concomitant sedatives as associated with increased risk of hemodynamic instability. Multivariable analysis demonstrated associations between age (HR, 1.23 per 10 years, 95% CI, 1.10-1.38) and low baseline blood pressure (HR, 2.42 at dexmedetomidine initiation, 95% CI, 1.68-3.49) and risk of hemodynamic instability. Variables such as concomitantly administered cardiac medications or sedative therapies and dexmedetomidine infusion rates >0.7 µg/kg/h were not found to be predictors of hemodynamic instability among the analyzed sample. CONCLUSIONS: Hemodynamic instability commonly occurs in critically ill adults receiving dexmedetomidine, with more than two thirds of this cohort experiencing hypotension and/or bradycardia within 24 hours of initiation. Increasing age and low baseline arterial blood pressure were associated with the development of hemodynamic instability. These findings suggest that clinicians should be aware of the potential risk of hemodynamic instability when using dexmedetomidine in patients with advanced age or low baseline arterial blood pressure.

Levetiracetam Pharmacokinetics During Continuous Venovenous Hemofiltration and Acute Liver Dysfunction.

BACKGROUND: Levetiracetam clearance is dependent on renal (major) and hepatic (minor) elimination pathways. In the setting of organ dysfunction, dose reductions are recommended to prevent accumulation. Continuous venovenous hemofiltration (CVVH) has been shown to eliminate levetiracetam, but the preferred dosing regimen when a patient is on CVVH and has concomitant acute liver dysfunction is unknown. The objective of this case is to describe levetiracetam dosing and pharmacokinetics in the setting of CVVH and acute liver dysfunction. METHODS: This is a case report of a single patient. RESULTS: A 59-year-old male was admitted to the intensive care unit for acute onset multiorgan dysfunction associated with a hematologic disorder. His hospital course was complicated by persistent liver dysfunction with a model for end-stage liver disease score of 47 and renal failure which necessitated initiation of CVVH. On hospital day two, the patient developed new-onset focal seizures secondary to metabolic abnormalities that resulted in the initiation of levetiracetam 1000 mg intravenously twice daily. The peak concentration at steady state was 32.2 mcg/mL, and the trough concentration was 16.1 mcg/mL (goal 12-46 mcg/mL). The volume of distribution was 0.65 L/kg, and the elimination half-life was 11.4 h. CONCLUSION: Levetiracetam pharmacokinetics observed in this case approximated those seen in a normal healthy patient and a regimen of 1000 mg twice daily achieved serum trough concentrations at the lower limit of the target range. This case indicates that in a patient with acute liver dysfunction on CVVH, 1000 mg twice daily may be considered as an empiric levetiracetam regimen.

Key Controversies in Colloid and Crystalloid Fluid Utilization.

Nearly 2 centuries have passed since the use of intravenous fluid became a foundational component of clinical practice. Despite a steady stream of published investigations on the topic, questions surrounding the choice, dose, timing, targets, and cost-effectiveness of various fluid options remain insufficiently answered. In recent years, 2 of the most debated topics reference the role of albumin in acute care and the safety of normal saline. Although albumin has a place in therapy for specific patient populations, its high cost relative to other fluids makes it a less desirable option for hospitals and health systems with escalating formulary scrutiny. Pharmacists bear responsibility for reconciling this disparity and supporting the rational use of albumin in acute care through a careful evaluation of recently published literature. In parallel, it has become clear that crystalloids should no longer be considered a homogenous class of fluids. The past reliance on normal saline has been questioned due to recent findings of renal dysfunction attributable to the solution's supraphysiologic chloride concentration. These safety concerns with 0.9% sodium chloride may result in a practice shift toward more routine use of "balanced crystalloids," such as lactated Ringer's or Plasma-Lyte, that mimic the composition of extracellular fluid. The purpose of this review is to summarize the evidence regarding these 2 important fluid controversies that are likely to affect hospital pharmacists in the coming decades - the evidence-based use of human albumin and the rising role of balanced salt solutions in clinical practice.

Serum cystatin C predicts vancomycin trough levels better than serum creatinine in hospitalized patients: a cohort study.

INTRODUCTION: Serum cystatin C can improve glomerular filtration rate (GFR) estimation over creatinine alone, but whether this translates into clinically relevant improvements in drug dosing is unclear. METHODS: This prospective cohort study enrolled adults receiving scheduled intravenous vancomycin while hospitalized at the Mayo Clinic in 2012. Vancomycin dosing was based on weight, serum creatinine with the Cockcroft-Gault equation, and clinical judgment. Cystatin C was later assayed from the stored serum used for the creatinine-based dosing. Vancomycin trough prediction models were developed by using factors available at therapy initiation. Residuals from each model were used to predict the proportion of patients who would have achieved the target trough with the model compared with that observed with usual care. RESULTS: Of 173 patients enrolled, only 35 (20%) had a trough vancomycin level within their target range (10 to 15 mg/L or 15 to 20 mg/L). Cystatin C-inclusive models better predicted vancomycin troughs than models based upon serum creatinine alone, although both were an improvement over usual care. The optimal model used estimated GFR by the Chronic Kidney Disease Epidemiology Collaborative (CKD-EPI) creatinine-cystatin C equation (R(2) = 0.580). This model is expected to yield 54% (95% confidence interval 45% to 61%) target trough attainment (P <0.001 compared with the 20% with usual care). CONCLUSIONS: Vancomycin dosing based on standard care with Cockcroft-Gault creatinine clearance yielded poor trough achievement. The developed dosing model with estimated GFR from CKD-EPIcreatinine-cystatin C could yield a 2.5-fold increase in target trough achievement compared with current clinical practice. Although this study is promising, prospective validation of this or similar cystatin C-inclusive dosing models is warranted.

Clostridium difficile infection: a multicenter study of epidemiology and outcomes in mechanically ventilated patients.

OBJECTIVES: Clostridium difficile is a leading cause of hospital-associated infection in the United States. The purpose of this study is to assess the prevalence of C. difficile infection among mechanically ventilated patients within the ICUs of three academic hospitals and secondarily describe the influence of C. difficile infection on the outcomes of these patients. DESIGN: A retrospective cohort study. SETTING: ICUs at three teaching hospitals: Barnes-Jewish Hospital, Mayo Clinic, and Creighton University Medical Center over a 2-year period. PATIENTS: All hospitalized patients requiring mechanical ventilation for greater than 48 hours within an ICU were eligible for inclusion. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 5,852 consecutive patients admitted to the ICU were included. Three hundred eighty-six (6.6%) patients with development of C. difficile infection while in the hospital (5.39 cases/1,000 patient days). Septic shock complicating C. difficile infection occurred in 34.7% of patients. Compared with patients without C. difficile infection (n = 5,466), patients with C. difficile infection had a similar hospital mortality rate (25.1% vs 26.3%, p = 0.638). Patients with C. difficile infection were significantly more likely to be discharged to a skilled nursing or rehabilitation facility (42.4% vs 31.9%, p < 0.001), and the median hospital (23 d vs 15 d, p < 0.001) and ICU length of stay (12 d vs 8 d, p < 0.001) were found to be significantly longer in patients with C. difficile infection. CONCLUSIONS: Clostridium difficile infection is a relatively common nosocomial infection in mechanically ventilated patients and is associated with prolonged length of hospital and ICU stay, and increased need for skilled nursing care or rehabilitation following hospital discharge.

Adjunctive aerosolized colistin for multi-drug resistant gram-negative pneumonia in the critically ill: a retrospective study.

BACKGROUND: The incidence of multi-drug resistant (MDR) gram-negative (GN) organisms including Pseudomonas and Acinetobacter spp has increased in the last decade, prompting re-evaluation of colistin for the management of these infections. Aerosolized colistin as an adjunct to intravenous therapy is a current option for the management of MDR-GN pneumonia, although data supporting this practice is limited. This study evaluates the efficacy of adjunctive aerosolized colistin in combination with intravenous colistin in critically ill patients with MDR-GN pneumonia. METHODS: A retrospective multi-center cohort analysis comparing critically ill patients with MDR-GN pneumonia who received intravenous colistin (IV) alone or in combination with adjunctive aerosolized colistin (IV/AER) with a primary endpoint of clinical cure at the end of colistin therapy. Secondary endpoints included microbiologic cure, duration of mechanical ventilation, length of stay, and hospital mortality. A post-hoc subgroup analysis was performed for patients with high quality cultures used for diagnosis of MDR-GN pneumonia. Dichotomous data were compared using Fisher's exact test while the student's t-test or Mann-Whitney U test were used for continuous variables. RESULTS: Ninety-five patients met criteria for evaluation with 51 patients receiving IV and 44 receiving IV/AER. Baseline characteristics were similar between the two groups. Twenty patients (39.2%) receiving IV and 24 (54.5%) receiving IV/AER achieved clinical cure (p = 0.135). There was no difference in microbiologic cure rates between the IV and IV/AER colistin groups (40.7vs. 44.4%, p = 0.805). The IV group demonstrated a trend towards higher pneumonia attributable mortality (70.4 vs. 40%, p = 0.055). In the subgroup analysis of patients with high quality respiratory cultures, there was a significantly lower clinical cure rate for those in the IV group as compared to the IV/AER group (31.3 vs. 57.1%, p = 0.033). CONCLUSIONS: Addition of aerosolized colistin to IV colistin may improve clinical cure and mortality for patients with MDR-GN pneumonia. Larger, prospective trials are warranted to confirm the benefit of adjunctive aerosolized colistin in critically ill patients with MDR-GN pneumonia.

Effect of continuous venovenous hemofiltration dose on achievement of adequate vancomycin trough concentrations.

The vancomycin dose necessary for the achievement of target serum trough concentrations during continuous venovenous hemofiltration (CVVH) remains to be elucidated. This was a retrospective cohort study of critically ill adults at a tertiary medical center on concurrent CVVH and vancomycin between 2006 and 2010 with a steady-state vancomycin trough concentration. The 87 included patients were grouped according to low (≤30 ml/kg/h; n = 10) or high (>30 ml/kg/h; n = 77) CVVH hemofiltration rate (HFR) for analysis. Vancomycin goal trough achievement occurred in only 32 (37%) patients. The primary endpoint of trough attainment significantly differed between HFR subgroups: 90% versus 30% in low- and high-HFR individuals, respectively (P < 0.001). Patients with subtherapeutic trough concentrations had a median (interquartile range) HFR of 40 ml/kg/h (range, 37 to 47 ml/kg/h) compared to 36 ml/kg/h (range, 30 to 39 ml/kg/h) in those who achieved the trough goal. Irrespective of goal trough, an inverse correlation existed between HFR and serum vancomycin concentration (r = -0.423; P < 0.001). In the subgroup of 14 methicillin-resistant Staphylococcus aureus (MRSA) patients, trough achievement was similar to the aggregate cohort (36%). Mortality at 28 days was unrelated to trough achievement in both the overall sample (P = 0.516) and in culture-positive MRSA patients (P = 0.396). Critically ill patients undergoing CVVH therapy may experience clinically significant reductions in goal vancomycin troughs. The results of the present study justify prospective evaluations in this population to determine the optimal vancomycin dosing strategy for attainment of goal trough concentrations.

Baseline Thromboelastogram as a Predictor of Left Ventricular Assist Device Thrombosis.

Left ventricular assist device (LVAD) pump thrombosis occurs in up to 8.4% of patients within 3-months postimplantation. Thromboelastography (TEG) could be used to signal hypercoagulability at LVAD implantation to predict patients at high risk for thrombosis. We sought to evaluate whether TEG maximum amplitude (MA) hypercoagulability (MA ≥69 mm) at the time of LVAD implantation predicts pump thrombosis. A single center, retrospective, nested case-control study was conducted using patients from January 1, 2005, to March 31, 2015. Each pump thrombosis case was matched to two control subjects based on age ± 5 years, sex, and duration of follow-up. A multivariable logistic regression analysis was performed on the matched sets; the odds ratio with 95% confidence interval (CI) was calculated to estimate the relative risk. Thirty-seven age- and sex-matched case-control sets were included for a total of 111 study participants. TEG-MA hypercoagulability occurred in 10.8% of the case group versus 6.8% of controls. There was no association between TEG-MA hypercoagulability and device thrombosis (odds ratio 1.71, 95% confidence interval 0.42-7.05, p = 0.46). Utilization of baseline TEG-MA hypercoagulability to detect individuals at risk for LVAD thrombosis is a novel concept. This study found no significant association between TEG-MA and LVAD thrombosis.

Road Map for Research Training in the Residency Learning Experience.

The American Society of Health-System Pharmacists residency accreditation standards require all postgraduate residency training programs to teach and evaluate a resident's ability to advance practice through project development and presentation, underscoring the importance of conducting research in today's professional climate. Although many residents express strong interest in research participation and contributing to the medical literature, many obstacles to publication have been identified. We aim to illustrate a deliberate approach to teaching this material and structuring the longitudinal experience in a way that maximizes resources to overcome these barriers. Such efforts should aid residents, advisors, and program directors in establishing curriculum which leads to successful completion and publication of pharmacy resident's research projects.

Incorporating Cystatin C to Predict Methotrexate Elimination in Patients with CNS Lymphoma and Suspicious Renal Function.

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.

Early Corticosteroids for Pneumocystis Pneumonia in Adults Without HIV Are Not Associated With Better Outcome.

BACKGROUND: Evidence supporting adjunctive corticosteroids during the treatment of Pneumocystis jirovecii pneumonia (PcP) in adults without HIV is minimal and controversial. METHODS: This retrospective cohort study included P jirovecii pneumonia-positive, hospitalized patients without HIV admitted to the Mayo Clinic from 2006 to 2016. Change from baseline in the respiratory component of the Sequential Organ Failure Assessment score (SOFAresp) at day 5 was compared between early (within 48 h) steroid recipients and nonrecipients by using multivariable logistic regression and in a propensity-matched analysis. RESULTS: Among the 323 included patients (early steroids, n = 258; no steroids, n = 65), the median (interquartile range) age was 65 (53, 73) years, 63% were male, and 92% were white. Severity-adjusted regression and propensity-matched analyses found that early administration of steroids was associated with less improvement in SOFAresp at day 5 compared with no steroids (P = .001 and P = .017, respectively). No differences were observed in the odds of having at least a one-point improvement in SOFAresp at day 5 compared with baseline between groups (adjusted OR, 0.76 [95% CI, 0.24-2.28]; P = .61). Overall 30-day mortality was 22.9% (95% CI, 18.2-27.4). No differences in mortality, length of stay, admission to the ICU, or need for mechanical ventilation were found between early steroid recipients and nonrecipients. CONCLUSIONS: The addition of early corticosteroids to anti-Pneumocystis therapy in patients without HIV was not associated with improved respiratory outcomes.

Continuous renal replacement therapy: a potential source of calories in the critically ill.

Background: Overfeeding can lead to multiple metabolic and clinical complications and has been associated with increased mortality in the critically ill. Continuous venovenous hemofiltration (CVVH) represents a potential source of calories that is poorly recognized and may contribute to overfeeding complications.Objective: We aimed to quantify the systemic caloric contribution of acid-citrate-dextrose regional anticoagulation and dextrose-containing replacement fluids in the CVVH circuit.Design: This was a prospective study in 10 critically ill adult patients who received CVVH from April 2014 to June 2014. Serial pre- and postfilter blood samples (n = 4 each) were drawn and analyzed for glucose and citrate concentrations on each of 2 consecutive days.Results: Participants included 5 men and 5 women with a mean ± SEM age of 61 ± 4 y (range: 42-84 y) and body mass index (in kg/m2) of 28 ± 2 (range: 18.3-36.2). There was generally good agreement between data on the 2 study days (CV: 7-11%). Mean ± SEM pre- and postfilter venous plasma glucose concentrations in the aggregate group were 152 ± 10 and 178 ± 9 mg/dL, respectively. Net glucose uptake from the CVVH circuit was 54 ± 5 mg/min and provided 295 ± 28 kcal/d. Prefilter plasma glucose concentrations were higher in patients with diabetes (n = 5) than in those without diabetes (168 ± 12 compared with 140 ± 14 mg/dL; P < 0.05); however, net glucose uptake was similar (46 ± 8 compared with 61 ± 6 mg/min; P = 0.15). Mean ± SEM pre- and postfilter venous plasma citrate concentrations were 1 ± 0.1 and 3.1 ± 0.2 mmol/L, respectively. Net citrate uptake from the CVVH circuit was 60 ± 2 mg/min and provided 218 ± 8 kcal/d.Conclusions: During CVVH there was a substantial net uptake of both glucose and citrate that delivered exogenous energy and provided ∼512 kcal/d. Failure to account for this source of calories in critically ill patients receiving nutrition on CVVH may result in overfeeding.

Clinical Relevance and Predictive Value of Damage Biomarkers of Drug-Induced Kidney Injury.

Nephrotoxin exposure accounts for up to one-fourth of acute kidney injury episodes in hospitalized patients, and the associated consequences are as severe as acute kidney injury due to other etiologies. As the use of nephrotoxic agents represents one of the few modifiable risk factors for acute kidney injury, clinicians must be able to identify patients at high risk for drug-induced kidney injury rapidly. Recently, significant advancements have been made in the field of biomarker utilization for the prediction and detection of acute kidney injury. Such biomarkers may have a role both for detection of drug-induced kidney disease and implementation of preventative and therapeutic strategies designed to mitigate injury. In this article, basic principles of renal biomarker use in practice are summarized, and the existing evidence for six markers specifically used to detect drug-induced kidney injury are outlined, including liver-type fatty acid binding protein, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase-2 times insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]), kidney injury molecule-1 and N-acetyl-ß-D-glucosaminidase. The results of the literature search for these six kidney damage biomarkers identified 29 unique articles with none detected for liver-type fatty acid binding protein and [TIMP-2]·[IGFBP7]. For three biomarkers, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and N-acetyl-ß-D-glucosaminidase, the majority of the studies suggest utility in clinical practice. While many questions need to be answered to clearly articulate the use of biomarkers to predict drug-induced kidney disease, current data are promising.

Perceived safety and efficacy of neuromuscular blockers for acute respiratory distress syndrome among medical intensive care unit practitioners: A multicenter survey.

PURPOSE: Neuromuscular blocking agents (NMBAs) are frequently used in patients with acute respiratory distress syndrome (ARDS). The purpose of this survey is to describe providers' knowledge and perceived efficacy and safety of NMBAs in patients with ARDS. MATERIALS AND METHODS: We performed a prospective, multicenter survey of medical intensive care unit intensivists, fellows, nurse practitioners (NPs), physician's assistants (PAs), and pharmacists at 5 tertiary care centers between July 2012 and May 2013. RESULTS: A total of 335 surveys were sent to providers, with a 47% response rate. Ninety-eight percent of providers correctly identified that NMBAs lack anxiolytic and analgesic properties. The effect of end-organ damage on NMBA clearance was less commonly identified by NPs/PAs for both hepatic (P=.0077) and renal (P=.0272) dysfunction compared with physicians. More NP/PAs identified the association of consciousness with the use of NMBAs than physicians (P=.047). Forty-two percent of prescribers reported always or frequently using continuous-infusion NMBAs in patients with severe ARDS, with 89% initiating NMBAs because of ventilator dyssynchrony. Prescribers perceived continuous NMBAs to be more effective than inhaled prostaglandins (74% vs 56%) in severe ARDS but less safe (45% vs 84%). Train of 4 was identified by 54% of prescribers as their primary method for titration. CONCLUSION: Providers are knowledgeable about NMBAs, but educational opportunities exist. Perceptions about the efficacy and safety of NMBAs varied among prescribers, and inconsistencies existed in the prioritization of management strategies for ARDS.