Heterogeneity, Bayesian thinking, and phenotyping in critical care: A primer.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To familiarize clinicians with the emerging concepts in critical care research of Bayesian thinking and personalized medicine through phenotyping and explain their clinical relevance by highlighting how they address the issues of frequent negative trials and heterogeneity of treatment effect. SUMMARY: The past decades have seen many negative (effect-neutral) critical care trials of promising interventions, culminating in calls to improve the field's research through adopting Bayesian thinking and increasing personalization of critical care medicine through phenotyping. Bayesian analyses add interpretive power for clinicians as they summarize treatment effects based on probabilities of benefit or harm, contrasting with conventional frequentist statistics that either affirm or reject a null hypothesis. Critical care trials are beginning to include prospective Bayesian analyses, and many trials have undergone reanalysis with Bayesian methods. Phenotyping seeks to identify treatable traits to target interventions to patients expected to derive benefit. Phenotyping and subphenotyping have gained prominence in the most syndromic and heterogenous critical care disease states, acute respiratory distress syndrome and sepsis. Grouping of patients has been informative across a spectrum of clinically observable physiological parameters, biomarkers, and genomic data. Bayesian thinking and phenotyping are emerging as elements of adaptive clinical trials and predictive enrichment, paving the way for a new era of high-quality evidence. These concepts share a common goal, sifting through the noise of heterogeneity in critical care to increase the value of existing and future research. CONCLUSION: The future of critical care medicine will inevitably involve modification of statistical methods through Bayesian analyses and targeted therapeutics via phenotyping. Clinicians must be familiar with these systems that support recommendations to improve decision-making in the gray areas of critical care practice.

Evaluation of Critical Care Pharmacist Evening Services at an Academic Medical Center.

Purpose: Critical care pharmacists are considered essential members of the healthcare team; however, justification and recruitment of new positions, especially in the evening or weekend shifts, remains a significant challenge. The purpose of this study was to investigate the number of interventions, type of interventions, and associated cost savings with the addition of 1 board certified critical care clinical pharmacist to evening shift. Methods: This was a prospective collection and characterization of 1 evening shift critical care pharmacist's clinical interventions over a 12-week period. Interventions were collected and categorized daily from 13:00 to 22:00 Monday through Friday. After collection was complete, cost savings estimates were calculated using pharmacy wholesaler acquisition cost. Results: Interventions were collected on 52 of 60 weekdays. A total of 510 interventions were collected with an average of 9.8 interventions accepted per day. The most common interventions included transitions of care, medication dose adjustment, and antibiotic de-escalation and the highest proportion of interventions occurred in the medical intensive care unit. An estimated associated cost avoidance of $66 537.80 was calculated for an average of $1279.57 saved per day. Additionally, 22 (4.1%) of interventions were considered high yield interventions upon independent review by 2 pharmacists. Conclusion: The addition of 1 board-certified critical care pharmacist to evening shift resulted in multiple interventions across several categories and a significant cost avoidance when calculated using conservative measures.

Evaluation of Short Versus Long Courses of Antibiotics in Critically Ill Patients With Gram-Negative Bloodstream Infections.

BACKGROUND: Short courses of antibiotics (7-10 days) are effective for uncomplicated gram-negative bloodstream infections (GN-BSI). However, prior studies have been limited to small cohorts of critically ill patients. OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of short courses of therapy compared with longer courses in patients admitted to the intensive care unit (ICU) with GN-BSI. METHODS: Propensity-matched, retrospective cohort study of critically ill patients with GN-BSI. The primary outcome was a composite of 30-day mortality or 60-day relapse. Secondary endpoints were components of the composite, 30-day relapse, cure with or without adverse drug events (ADE), and ADEs. Regression analysis was performed to identify factors predictive of the composite outcome. RESULTS: 225 patients were included in the propensity analysis, 145 in the long cohort and 80 in the short cohort. The primary outcome occurred in 3.8% of patients in the short group and 9.0% of patients in the long group (P = 0.24). There was no difference in 30-day mortality (3.8% vs 5.5%, P = 0.79), 60-day relapse (0% vs 3.4%, P = 0.23), or 30-day readmission (20% vs 22.8%, P = 0.76). ADEs were more common in the long group (47.2% vs 34.1%, OR 1.7, 95% CI 1.04-2.9), primarily attributable to diarrhea. CONCLUSION AND RELEVANCE: In critically ill patients with GN-BSI, there were no efficacy outcome differences in patients treated with a short course of antibiotics compared with longer. However, patients in the short group were less likely to experience ADE. These findings suggest that short courses of antibiotics are effective for GN-BSI in critically ill patients.

Plasma matrix metalloproteinase-3 predicts mortality in acute respiratory distress syndrome: a biomarker analysis of a randomized controlled trial.

BACKGROUND: Matrix metalloproteinase-3 (MMP-3) is a proteolytic enzyme involved in acute respiratory distress syndrome (ARDS) pathophysiology that may serve as a lung-specific biomarker in ARDS. METHODS: This study was a secondary biomarker analysis of a subset of Albuterol for the Treatment of Acute Lung Injury (ALTA) trial patients to determine the prognostic value of MMP-3. Plasma sample MMP-3 was measured by enzyme-linked immunosorbent assay. The primary outcome was the area under the receiver operating characteristic (AUROC) of MMP-3 at day 3 for the prediction of 90-day mortality. RESULTS: A total of 100 unique patient samples were evaluated and the AUROC analysis of day three MMP-3 showed an AUROC of 0.77 for the prediction of 90-day mortality (95% confidence interval: 0.67-0.87), corresponding to a sensitivity of 92% and specificity of 63% and an optimal cutoff value of 18.4 ng/mL. Patients in the high MMP-3 group (≥ 18.4 ng/mL) showed higher mortality compared to the non-elevated MMP-3 group (< 18.4 ng/mL) (47% vs. 4%, p < 0.001). A positive difference in day zero and day three MMP-3 concentration was predictive of mortality with an AUROC of 0.74 correlating to 73% sensitivity, 81% specificity, and an optimal cutoff value of + 9.5 ng/mL. CONCLUSIONS: Day three MMP-3 concentration and difference in day zero and three MMP-3 concentrations demonstrated acceptable AUROCs for predicting 90-day mortality with a cut-point of 18.4 ng/mL and + 9.5 ng/mL, respectively. These results suggest a prognostic role of MMP-3 in ARDS.

Validation of Prognostic Club Cell Secretory Protein (CC16) Cut-point in an Independent ALTA Cohort.

Background: Club cell secretory protein (CC16) has demonstrated utility as a lung-specific biomarker in predicting mortality in acute respiratory distress syndrome (ARDS). These findings have been observed in pre-clinical trials and a re-analysis of a large, randomized controlled trial of ARDS (Fluid and Catheter Treatment Trial (FACTT)). Objectives: The purpose of this study was to validate previous findings by evaluating CC16 level as a mortality predictor in patients from the albuterol to treat acute lung injury (ALTA) trial. Design and Method: In this secondary biomarker analysis, plasma CC16 level was measured from 100 ALTA subjects using enzyme-linked immunosorbent assay (ELISA). The rate of mortality was assessed in patients with high (⩾45 ng/mL) versus low CC16 (<45 ng/mL) levels. This cut-off level was applied based on our previous analysis from FACTT trial. Significance was assessed using Kaplan-Meier curves and a log-rank test. Results: Subjects were an average of 50 years old and 46% of them were females. Patients with high CC16 levels had higher 90-day mortality compared to those with low CC16 levels, (37.73% vs 8.95%, P < .001). Other clinical outcomes including ICU-free days, ventilator-free days, and organ failure free days were significantly different between the groups (All P < .05). Conclusion: In this validation study, we demonstrated that ARDS patients with high plasma CC16 concentration had a higher mortality rate than those with low CC16 levels, confirming previous findings that CC16 levels are associated with ARDS mortality.

The Potential Synergistic Risk of Albuterol and Vasoactives in Acute Lung Injury Trials.

BACKGROUND: Critically ill patients are often prescribed both inhaled beta-agonists and intravenous vasoactive; however, the interaction of the additive beta-agonist effects of these 2 agents remains largely uncharacterized. OBJECTIVE: The purpose of this study was to evaluate how concomitant use of albuterol and vasoactive or inotropes affected ventilator-free days (VFDs) by re-analyzing the data from the Albuterol to Treat Acute Lung Injury (ALTA) trial. METHODS: In this study, subjects were grouped to albuterol-vasoactive (n = 84) versus (vs) placebo-vasoactive (n = 62). Ventilator-free days, intensive care unit (ICU)-free days, organ failure-free days, cardiovascular adverse events, and 90-day mortality were compared. The primary outcome was VFDs. RESULTS: Patients in the albuterol-vasoactive group had significantly fewer VFDs than patients in the placebo-vasoactive group (11 vs 19, P = 0.05). Patients in the albuterol-vasoactive group also had significantly fewer ICU-free days (9.5 vs 18.5, P = .006). The 90-day mortality was similar between groups (36.9% vs 27.4%, P = .20). Similarly, no significant difference in cardiac adverse events between the groups (14.3% vs 11.3%, P = 0.59). CONCLUSION AND RELEVANCE: This study has shown fewer VFDs for patients who received both vasoactive and albuterol. There were also fewer ICU-free days when compared to those on vasoactive only. Given the common use of both agents, a prospective evaluation of the additive adverse effects of beta-agonism is warranted.

Medication regimen complexity (MRC-ICU) for in-hospital mortality prediction in COVID-19 patients.

Purpose: The medication regimen complexity-intensive care unit (MRC-ICU) score was developed prior to the existence of COVID-19. The purpose of this study was to assess if MRC-ICU could predict in-hospital mortality in patients with COVID-19. Methods: A single-center, observational study was conducted from August 2020 to January 2021. The primary outcome of this study was the area under the receiver operating characteristic (AUROC) for in-hospital mortality for the 48-hour MRC-ICU. Age, sequential organ failure assessment (SOFA), and World Health Organization (WHO) COVID-19 Severity Classification were assessed. Logistic regression was performed to predict in-hospital mortality as well as WHO Severity Classification at 7 days. Results: A total of 149 patients were included. The median SOFA score was 8 (IQR 5-11) and median MRC-ICU score at 48 hours was 15 (IQR 7-21). The in-hospital mortality rate was 36% (n = 54). The AUROC for MRC-ICU was 0.71 (95% Confidence Interval (CI), 0.62-0.78) compared to 0.66 for age, 0.81 SOFA, and 0.72 for the WHO Severity Classification. In univariate analysis, age, SOFA, MRC-ICU, and WHO Severity Classification all demonstrated significant association with in-hospital mortality, while SOFA, MRC-ICU, and WHO Severity Classification demonstrated significant association with WHO Severity Classification at 7 days. In univariate analysis, all 4 characteristics showed significant association with mortality; however, only age and SOFA remained significant following multivariate analysis. Conclusion: In the first analysis of medication-related variables as a predictor of severity and in-hospital mortality in COVID-19, MRC-ICU demonstrated acceptable predictive ability as represented by AUROC; however, SOFA was the strongest predictor in both AUROC and regression analysis.

An Evaluation of the Relationship Between Medication Regimen Complexity as Measured by the MRC-ICU to Medication Errors in Critically Ill Patients.

Purpose: The purpose of this study was to determine the relationship between medication regimen complexity-intensive care unit (MRC-ICU) score at 24 hours and medication errors identified throughout the ICU. Methods: A single-center, observational study was conducted from August to October 2021. The primary outcome was the association between MRC-ICU at 24 hours and total medication errors identified. During the prospective component, ICU pharmacists recorded medication errors identified over an 8-week period. During the retrospective component, the electronic medical record was reviewed to collect patient demographics, outcomes, and MRC-ICU score at 24 hours. The primary outcome of the relationship of MRC-ICU at 24 hours to medication errors was assessed using Pearson correlation. Results: A total of 150 patients were included. There were 2 pharmacists who recorded 634 errors during the 8-week study period. No significant relationship between MRC-ICU and medication errors was observed (r2 = .13, P = .11). Exploratory analyses of MRC-ICU relationship to major interventions and harm scores showed that MRC-ICU scores >10 had more major interventions (27 vs 14, P = .27) and higher harm scores (15 vs 7, P = .33), although these values were not statistically significant. Conclusion: Medication errors appear to occur independently of medication regimen complexity. Critical care pharmacists were responsible for mitigating a large number of medication errors.

Identification of circulating microvesicle-encapsulated miR-223 as a potential novel biomarker for ARDS.

Acute respiratory distress syndrome (ARDS) is a lethal disease with severe forms conferring a mortality rate approaching 40%. The initial phase of ARDS results in acute lung injury (ALI) characterized by a severe inflammatory response and exudative alveolar flooding due to pulmonary capillary leak. Timely therapies to reduce ARDS mortality are limited by the lack of laboratory-guided diagnostic biomarkers for ARDS. The purpose of this study was to evaluate the prognostic role of circulating microvesicles (MVs)-containing miR-223 (MV-miR-223) if indicate more severe lung injury and worse outcomes in ARDS patients. Human plasma samples from one hundred ARDS patients enrolled in Albuterol to Treat Acute Lung Injury (ALTA) trial were compared to a control group of twenty normal human plasma specimens. The amount of MV-miR-223 was measured using absolute real-time polymerase chain reaction (PCR) with a standard curve. Mann-Whitney-Wilcoxon, Spearman correlation, Chi-squared tests, and Kaplan-Meier curves were computed to assess different variables and survival. Plasma levels of MV-miR-223 were significantly higher in ARDS patients compared to normal control subjects. Upon receiver operator characteristic (ROC) analysis of MV-miR-223 in relation to 30-day mortality, MV-miR-223 had an area under the curve (AUC) of 0.7021 with an optimal cut-off value of 2.413 pg/ml. Patients with high MV-miR-223 had higher 30-day mortality than subjects with low MV-miR-223 levels. MV-miR-223 was negatively correlated with ICU-free days, ventilator-free days, and organ failure-free days. Patients with high MV-miR-223 levels had higher 30 and 90-day mortality. MV-miR-223 was associated with 28-day clinical outcomes of ALTA trial including ICU-free days, ventilator-free days, and organ failure-free days. Thus, circulating MV-miR-223 may be a potential biomarker in prognosticating patient-centered outcomes and predicting mortality in ARDS.

Club Cell Secretory Protein-Derived Acute Respiratory Distress Syndrome Phenotypes Predict 90-Day Mortality: A Reanalysis of the Fluids and Catheter Treatment Trial.

Club cell secretory protein (CC16) is a protein with potential utility as a lung-specific biomarker for acute respiratory distress syndrome. The purpose of this study was to characterize CC16 in plasma from patients enrolled in the Fluid and Catheter Treatment Trial (FACTT) to determine the prognostic value for patient outcomes in our subgroup of FACTT patients. DESIGN: A secondary biomarker analysis of a prospective randomized-controlled trial. The primary outcome was area under the receiver operating characteristic (AUROC) of CC16 for prediction of 90-day mortality. Secondary outcomes included differences in mortality, length of stay, and ventilator-free days (VFDs) between patients with high and low CC16. Statistical analyses were performed with IBM SPSS Statistics. SETTING: Single-center laboratory analysis. SUBJECTS: Plasma samples from 68 FACTT subjects and 20 healthy controls. INTERVENTIONS: CC16 was measured in patient plasma samples by enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS: Subjects were an average of 48 years old (sd, 16.7 yr old) and 51.5% male. AUROC analysis of CC16 on day 1 showed an area under the ROC curve of 0.78 for prediction of mortality (odds ratio, 1.011; 95% CI, 1.003-1.021) with an optimal cutoff value of 45 ng/mL. Patients in the low CC16 group (<45 ng/mL) had lower mortality (7.5 vs 50.0%; p < 0.001) and similar VFD (11.9 vs 13.2; p = 0.638). When stratified by CC16 concentration, there was no difference between mortality in the fluid liberal (36.4 vs 58.8%; p = 0.256) or conservative (4.3 vs 11.8%; p = 0.366) groups. CONCLUSIONS: CC16 demonstrated an acceptable AUROC for prediction of patient mortality with a cut point of 45 ng/mL. Patients with high CC16 on day 1 had worse outcomes compared with those with low CC16, suggesting a prognostic role for this lung-specific biomarker.

Productivity Tracking: A Survey of Critical Care Pharmacist Practices and Satisfaction.

Introduction: The position paper on critical care pharmacy services describes two tiers of responsibilities: essential and desirable activities. Activities are categorized into five domains: patient care, quality improvement, research and scholarship, training and education, and professional development. Documentation of these activities can be important for justifying pharmacist positions, comparing pharmacy practice models, conducting performance evaluations, and tracking individual workload; however, limited recommendations are provided for standardized productivity tracking, and national practices remain largely uncharacterized. Objectives: The purpose of this survey was to describe documentation practices of critical care pharmacist activities. Methods: A cross-sectional survey was distributed via email to 1694 members of the ACCP critical care practice research network. The survey asked respondents to describe the methods used to document productivity as it relates to the 5 domains. Results: Seventy-nine (4.7%) critical care pharmacists from 63 institutions completed the survey. Intervention documentation was used for position justification and annual reviews among 54.4% and 44.1% of pharmacists, respectively. Pharmacists were routinely expected to perform additional responsibilities beyond patient care that contribute to overall productivity, but the percentage of institutions that track these activities as a measure of pharmacist productivity was relatively low: quality improvement (46%), research/scholarship (29%), training/education (38%), and professional development (27%). Documentation of these additional responsibilities and activities was primarily used for annual evaluations, but the majority of respondents answered that no standardized method for tracking activities existed. In multivariate regression, dedicated ICU pharmacists was a significant predictor for increased satisfaction (Exp(ß) 4.498, 95% CI 1.054-19.187, P = .042). Conclusion: Practice variation exists in how and for what intent critical care pharmacists track productivity. Further evaluation and standardization of productivity tracking may aid in position justification and practice model evaluation for dedicated ICU pharmacists in today's value-based era.

Early Diuretics for De-resuscitation in Septic Patients With Left Ventricular Dysfunction.

Introduction: De-resuscitation practices in septic patients with heart failure (HF) are not well characterized. This study aimed to determine if diuretic initiation within 48 hours of intensive care unit (ICU) admission was associated with a positive fluid balance and patient outcomes. Methods: This single-center, retrospective cohort study included adult patients with an established diagnosis of HF admitted to the ICU with sepsis or septic shock. The primary outcome was the incidence of positive fluid balance in patients receiving early (<48 hours) versus late (>48 hours) initiation of diuresis. Secondary outcomes included hospital mortality, ventilator-free days, and hospital and ICU length of stay. Continuous variables were assessed using independent t-test or Mann-Whitney U, while categorical variables were evaluated using the Pearson Chi-squared test. Results: A total of 101 patients were included. Positive fluid balance was significantly reduced at 72 hours (-139 mL vs 4370 mL, P < .001). The duration of mechanical ventilation (4 vs 5 days, P = .129), ventilator-free days (22 vs 18.5 days, P = .129), and in-hospital mortality (28 (38%) vs 12 (43%), P = .821) were similar between groups. In a subgroup analysis excluding patients not receiving renal replacement therap (RRT) (n = 76), early diuretics was associated with lower incidence of mechanical ventilation (41 [73.2%] vs 20 (100%), P = .01) and reduced duration of mechanical ventilation (4 vs 8 days, P = .018). Conclusions: Diuretic use within 48 hours of ICU admission in septic patients with HF resulted in less incidence of positive fluid balance. Early diuresis in this unique patient population warrants further investigation.

Effects of Epidiolex® (Cannabidiol) on seizure-related emergency department visits and hospital admissions: A retrospective cohort study.

AIM: The aim of this study was to evaluate the potential impact of cannabidiol (CBD) on healthcare resource utilization and determine the effect of CBD on seizure-related emergency departments (ED) and hospital admissions in patients with epilepsy. METHODS: This single-center, retrospective longitudinal cohort study included patients ≥1 year on CBD, excluding participants in CBD clinical trials or on <6 months of CBD therapy. Demographics, antiseizure medications (ASM), ED and hospital admissions were collected from the electronic medical record. Co-primary outcomes included change in seizure-related ED and hospital admissions. Secondary outcomes included change in ASMs and total ED or hospital admissions. Co-primary outcomes were assessed using generalized linear modeling. Descriptive statistics were used to analyze all other variables. RESULTS: In the one-hundred total patients, there was no difference in either seizure-related ED visits (0.012 vs 0.011, p = 0.85) or hospital admissions per month (0.019 vs 0.021, p = 0.7). However, given the low percentage of the total cohort (n = 100) with either a seizure-related ED visits and hospital admissions (9% and 18%, respectively), a subgroup analysis was conducted. Those with seizure-related hospital admissions prior to CBD (n = 18) had significantly less seizure-related hospital admissions after initiation of CBD (23 admissions [0.104 per month] vs 15 admissions [0.055 per month], p = 0.007). CONCLUSION: Despite the lack of statistically significant difference in primary outcomes for the total cohort, CBD may have a potential for a clinically beneficial impact in real-world settings on those patients with prior seizure-related admissions, who are the highest utilizers of healthcare resources.

Medication Regimen Complexity Score as an Indicator of Fluid Balance in Critically Ill Patients.

BACKGROUND: Critically ill patients are at increased risk for fluid overload, but objective prediction tools to guide clinical decision-making are lacking. The MRC-ICU scoring tool is an objective tool for measuring medication regimen complexity. OBJECTIVE: To evaluate the relationship between MRC-ICU score and fluid overload in critically ill patients. METHODS: In this multi-center, retrospective, observational study, the relationship between MRC-ICU and the risk of fluid overload was examined. Patient demographics, fluid balance at day 3 of ICU admission, MRC-ICU score at 24 hours, and clinical outcomes were collected from the medical record. The primary outcome was relationship between MRC-ICU and fluid overload. To analyze this, MRC-ICU scores were divided into tertiles (low, moderate, high), and binary logistic regression was performed. Linear regression was performed to determine variables associated with positive fluid balance. RESULTS: A total of 125 patients were included. The median MRC-ICU score at 24 hours of ICU admission for low, moderate, and high tertiles were 9, 15, and 21, respectively. For each point increase in MRC-ICU, a 13% increase in the likelihood of fluid overload was observed (OR 1.128, 95% CI 1.028-1.238, p = 0.011). The MRC-ICU score was positively associated with fluid balance at day 3 (ß-coefficient 218.455, 95% CI 94.693-342.217, p = 0.001) when controlling for age, gender, and SOFA score. CONCLUSIONS: Medication regimen complexity demonstrated a weakly positive correlation with fluid overload in critically ill patients. Future studies are necessary to establish the MRC-ICU as a predictor to identify patients at risk of fluid overload.

Assessing the impact of adding acetazolamide to oral or intravenous sodium bicarbonate as compared with intravenous bicarbonate monotherapy as urinary alkalinization in adults receiving high-dose methotrexate.

PURPOSE: High-dose methotrexate (HD-MTX) requires urine alkalinization to pH ≥ 7 for adequate excretion to prevent toxicity. Due to shortages of IV sodium bicarbonate (IV-NaHCO3), few reports have demonstrated utility of oral bicarbonate (PO-NaHCO3); however, the addition of acetazolamide (Acet) has not been well described. Our study compares outcomes between alkalinization methods of IV-NaHCO3 monotherapy versus IV-NaHCO2 + Acet and PO-NaHCO3 + Acet. METHODS: A single-center, IRB exempt, retrospective review was conducted from Jan 2016 to Sept 2019 of adults receiving HD-MTX ≥ 500 mg/m2. The primary outcome was time from start of alkalinization to pH ≥ 7. Secondary outcomes included time from start of alkalinization to initiation of HD-MTX, time to MTX clearance, length of stay (LOS), percentage of urine pH assessments < 7, and incidence of MTX toxicity. Statistical analysis was performed using SAS9.4 with alpha 0.05. RESULTS: Overall demographics (n = 196 HD-MTX cycles for 55 patients) include a mean age 55 years, HD-MTX dose ~ 5400 mg/m2, and 69% with a diagnosis of lymphoma. Adjusting for baseline demographic differences among groups, median time from first dose alkalinization to pH ≥ 7 and to start of HD-MTX was longer for those receiving IV-NaHCO3 (n = 41) vs either IV-NaHCO3 + Acet (n = 70) or PO-NaHCO3 + Acet (n = 76) (p = 0.0001). HD-MTX clearance to a level < 0.1 µmol/L was not improved with the addition of Acet. No difference existed among groups for pH results < 7, LOS, or incidence of MTX toxicity (p > 0.05). CONCLUSIONS: Addition of Acet to NaHCO3 reduces time to pH ≥ 7 and initiation of HD-MTX but does not appear to improve LOS, MTX toxicities, or time to MTX clearance.