Academic Promotions in Medicine: An Appraisal of Fairness.

OBJECTIVE: To investigate whether the process of conferring academic rank or components of the promotion packet contribute to the lack of parity in academic advancement for women and individuals underrepresented in medicine (URMs). PATIENTS AND METHODS: We retrospectively reviewed prospective promotion applications to the position of associate professor or professor at Mayo Clinic from January 2, 2015, through July 1, 2019. Individuals with doctorate degrees who applied for either rank were included in the study. Data collected included demographic characteristics, curriculum vitae at time of application, committee score sheets, and deferral and approval decisions. Deferral rates for women compared with men and for URMs compared with non-URMs was the primary outcome. RESULTS: Of 462 people who applied for associate professor, 10% (n=46) were deferred. Those promoted had worked longer at Mayo Clinic (median, 6 years vs 2 years; P=.01), had more mentees (median, 6 vs 4; P=.02), authored more publications (median [interquartile range (IQR)], 39 [32-52] vs 30 [24-35]; P<.001), and were more likely to be on a National Institutes of Health or institutional grant (P<.05). Of the 320 people who applied for professor, 8.8% (n=28) were deferred. Those promoted had authored more publications (median [IQR], 77 [60-99] vs 56 [44-66]; P<.001) and were less likely to hold an elected office to a professional society (22.6% vs 39.3%; P=.05). There was no significant association between deferral status and sex (P>.4) or race/ethnicity (P>.9) for either rank. CONCLUSION: The process for academic advancement for professorships does not contribute to the gap in promotion rates for women and URMs.

Validation of a Simulation Model for Robotic Myomectomy.

STUDY OBJECTIVE: Several simulation models have been evaluated for gynecologic procedures such as hysterectomy, but there are limited published data for myomectomy. This study aimed to assess the validity of a low-cost robotic myomectomy model for surgical simulation training. DESIGN: Prospective cohort simulation study. SETTING: Surgical simulation laboratory. PARTICIPANTS: Twelve obstetrics and gynecology residents and 4 fellowship-trained minimally invasive gynecologic surgeons were recruited for a 3:1 novice-to-expert ratio. INTERVENTIONS: A robotic myomectomy simulation model was constructed using <$5 worth of materials: a foam cylinder, felt, a stress ball, bandage wrap, and multipurpose sealing wrap. Participants performed a simulation task involving 2 steps: fibroid enucleation and hysterotomy repair. Video-recorded performances were timed and scored by 2 blinded reviewers using the validated Global Evaluative Assessment of Robotic Skills (GEARS) scale (5-25 points) and a modified GEARS scale (5-40 points), which adds 3 novel domains specific to robotic myomectomy. Performance was also scored using predefined task errors. Participants completed a post-task questionnaire assessing the model's realism and utility. MEASUREMENTS AND MAIN RESULTS: Median task completion time was shorter for experts than novices (9.7 vs 24.6 min, p = .001). Experts scored higher than novices on both the GEARS scale (median 23 vs 12, p = .004) and modified GEARS scale (36 vs 20, p = .004). Experts made fewer task errors than novices (median 15.5 vs 37.5, p = .034). For interrater reliability of scoring, the intraclass correlation coefficient was calculated to be 0.91 for the GEARS assessment, 0.93 for the modified GEARS assessment, and 0.60 for task errors. Using the contrasting groups method, the passing mark for the simulation task was set to a minimum modified GEARS score of 28 and a maximum of 28 errors. Most participants agreed that the model was realistic (62.5%) and useful for training (93.8%). CONCLUSION: We have demonstrated evidence supporting the validity of a low-cost robotic myomectomy model. This simulation model and the performance assessments developed in this study provide further educational tools for robotic myomectomy training.

Unresponsiveness of Activated Partial Thromboplastin Time to Bivalirudin in Adults Receiving Extracorporeal Membrane Oxygenation.

Activated partial thromboplastin time (aPTT) is the standard for monitoring bivalirudin but demonstrates a nonlinear response at higher drug concentrations. The objective of this study was to assess the relationship between bivalirudin dose and aPTT in patients receiving extracorporeal membrane oxygenation (ECMO) to determine a threshold where aPTT unresponsiveness occurs. Two hundred fourteen adults receiving bivalirudin during ECMO between 2018 and 2022 were included. Piecewise regression in a linear mixed effects model was used to determine a bivalirudin dose threshold of 0.21 mg/kg/hr for aPTT unresponsiveness. For doses of less than 0.21 mg/kg/hr (n = 135), every 0.1 mg/kg/hr dose increase led to an aPTT increase of 11.53 (95% confidence interval [CI] = 9.85-13.20) seconds compared to only a 3.81 (95% CI = 1.55-6.06) seconds increase when dose was greater than or equal to 0.21 mg/kg/hr (n = 79) (pinteraction < 0.001). In multivariable logistic regression, venovenous configuration (odds ratio [OR] = 2.83, 95% CI = 1.38-5.77) and higher fibrinogen concentration (OR = 1.22, 95% CI = 1.05-1.42) were associated with greater odds of unresponsiveness, whereas older age (OR = 0.79, 95% CI = 0.63-0.98), kidney dysfunction (OR = 0.48, 95% CI = 0.25-0.92), and a higher baseline aPTT (OR = 0.89, 95% CI = 0.82-0.97) were associated with lower odds. Alternative methods are necessary to ascertain bivalirudin's hemostatic impact when doses exceed 0.21 mg/kg/hr during ECMO.

Association of resilience with female sexual dysfunction.

OBJECTIVES: Female sexual dysfunction (FSD), a common concern affecting women of all ages, is often mediated by important psychological factors. Resilience has been shown to correlate with psychological well-being across different groups of people. The aim of this study was to assess if there is an association between resilience and FSD. STUDY DESIGN: This cross-sectional study included 4,366 women (mean [SD] age, 51.7 [11]) seen in women's health clinics at 1 of 3 geographic Mayo Clinic locations. Participants completed the Brief Resilience Scale, the Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale-Revised (FSDS-R). MAIN OUTCOME MEASURES: We used univariate and multivariable logistic regression analyses to assess associations between resilience, sexual function, and sexual distress, adjusting for potential confounding variables. RESULTS: FSD criteria (FSFI ≤26.55 and FSDS-R ≥ 11) were met by 55.8 % of women. Low, normal, and high levels of resilience were reported by 17.3 %, 57.1 %, and 25.6 % of participants, respectively. The univariate analysis showed that higher resilience was associated with lower sexual distress, lower odds of FSD, and better sexual function. Multivariable analysis adjusted for potential confounders showed that the association persisted and that higher resilience correlated with better sexual function and lower odds of FSD. CONCLUSIONS: In this large cross-sectional study, women with higher resilience scores had better sexual function and lower odds of FSD. Additional studies with diverse women are needed to confirm this association and to determine whether women with FSD could benefit from enhancing resilience as a therapeutic strategy.

De novo hepatitis B infection following liver transplantation with core antibody positive grafts: The role of surface antibody status in guiding long-term prophylaxis.

Liver transplantation (LT) with hepatitis B core antibody (anti-HBc) positive grafts to hepatitis B surface-antigen (HBsAg) negative recipients is safe and has likely contributed to improvements in organ access over the years. The incidence of de novo hepatitis B infection (HBV) in these instances is low with appropriate prophylaxis and is affected by recipient immunologic status. There is debate as to whether hepatitis B surface antibody (anti-HBs) positivity may safely inform prophylaxis discontinuation post-LT. In this retrospective study of all hepatitis B surface antigen (HBsAg) negative recipients of anti-HBc positive organs at three large academic centers between January 2014 and December 2019, nine LT recipients discontinued prophylaxis after developing anti-HBs antibodies 1 year or later post-LT. Three of the nine patients (33%) developed de novo HBV, defined by positive HBsAg or hepatitis B virus (HBV) DNA, during the study period. The remaining six patients had no evidence of HBV infection after a mean follow-up of 37 months. The patients without de novo HBV had higher anti-HBs titers at the time of prophylaxis discontinuation and were less likely to have negative anti-HBs at the time of transplant or negative anti-HBc at any time point. These results suggest that quantitative anti-HBs titer thresholds rather than qualitative anti-HBs positivity at 1 year or later after LT should be used to identify patients at decreased risk of de novo infection and help guide prophylaxis duration.

Rechallenge With High-Dose Methotrexate After Treatment With Glucarpidase in Adult Patients With Lymphoma.

PURPOSE: Limited evidence exists regarding methotrexate (MTX) resumption after patients with lymphoma receive glucarpidase for toxic MTX levels and acute kidney injury (AKI). METHODS: This retrospective review included adults with lymphoma treated with glucarpidase after MTX at Mayo Clinic between January 31, 2020, and October 10, 2022. Descriptive statistics summarize patient characteristics and clinical outcomes. RESULTS: Of 11 patients treated with glucarpidase after MTX, seven (64%) were rechallenged with MTX. Indications for MTX rechallenge included confirmed CNS disease (n = 6, 86%) and intravascular lymphoma (n = 1, 14%). Compared with the nonrechallenged subgroup, before receiving MTX that required glucarpidase rescue, the rechallenged patients had lower median pretreatment serum creatinine (Scr; 0.7 v 1.2 mg/dL), and none had AKI with previous MTX doses, n = 0 (0%) versus n = 2 (50%). During the MTX dose requiring glucarpidase rescue, the rechallenged group had lower median peak Scr (1.26 v 3.32 mg/dL) and lower incidence of AKI stage III (n = 1 [14%] v n = 3 [75%]), and none of the rechallenged patients required renal replacement therapy (RRT; n = 0 [0%] v n = 1 [25%]). At the first rechallenge after glucarpidase administration, the median MTX dose reduction was 56% (range, 46%-75%), and the lowest used dose when prescribed according to each treatment protocol schedule was 1.5 g/m2. Two (29%) patients experienced AKI (n = 1 stage I, n = 1 stage II) after MTX rechallenge. Zero patients required RRT, and zero required another glucarpidase administration. Six (86%) patients completed all recommended MTX doses. CONCLUSION: In selected adults with lymphoma who required glucarpidase for toxic MTX levels after administration of high-dose MTX, resumption of MTX therapy at lower doses is safe. Patients selected for MTX resumption had experienced less severe AKI during the previous cycle compared with those not selected for MTX resumption.

Assessment of Dofetilide or Sotalol Tolerability in the Elderly.

Background: Dofetilide and sotalol are potassium channel antagonists that require inpatient QTc monitoring during initiation, due to increased risk of fatal arrhythmias. Elderly patients are especially subject to an increased risk of fatal arrhythmias due to polypharmacy, comorbidities, and physiologic cardiac changes with aging. This study will describe the tolerability and risk factors associated with the initiation of sotalol or dofetilide in patients ≥80 years of age. Methodology: This is a multicenter, retrospective, descriptive study of patients ≥80 years old who were initiated on either dofetilide or sotalol between May 8, 2018 and July 31, 2021 at institutions within the Mayo Clinic Health System. The percentage of patients who received nonpackage insert recommended doses was identified. Incidence of and reasons for dose reductions or discontinuations due to safety-related events or clinical concerns during the initial loading period were collected. Results: The final analysis included 104 patients. The majority of patients (75%) received nonstandard initial doses of dofetilide or sotalol based on baseline estimated creatinine clearance or QTc. Overall, 39% (N = 41) of patients experienced a dose reduction or discontinuation due to a safety-related event or concern. Patients who received nonstandard initial doses of dofetilide or sotalol had 4.7 times greater odds of experiencing a safety-related event requiring dose reduction or discontinuation. Conclusion: Following package insert dosing in elderly patients increases safety and tolerability relative to more aggressive dosing of dofetilide or sotalol.

Safety and Efficacy of Reduced-Dose Versus Full-Dose Alteplase for Acute Pulmonary Embolism: A Multicenter Observational Comparative Effectiveness Study.

OBJECTIVES: Systemic thrombolysis improves outcomes in patients with pulmonary embolism (PE) but is associated with the risk of hemorrhage. The data on efficacy and safety of reduced-dose alteplase are limited. The study objective was to compare the characteristics, outcomes, and complications of patients with PE treated with full- or reduced-dose alteplase regimens. DESIGN: Multicenter retrospective observational study. SETTING: Tertiary care hospital and 15 community and academic centers of a large healthcare system. PATIENTS: Hospitalized patients with PE treated with systemic alteplase. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pre- and post-alteplase hemodynamic and respiratory variables, patient outcomes, and complications were compared. Propensity score (PS) weighting was used to adjust for imbalances of baseline characteristics between reduced- and full-dose patients. Separate analyses were performed using the unweighted and weighted cohorts. Ninety-eight patients were treated with full-dose (100 mg) and 186 with reduced-dose (50 mg) regimens. Following alteplase, significant improvements in shock index, blood pressure, heart rate, respiratory rate, and supplemental oxygen requirements were observed in both groups. Hemorrhagic complications were lower with the reduced-dose compared with the full-dose regimen (13% vs. 24.5%, p = 0.014), and most were minor. Major extracranial hemorrhage occurred in 1.1% versus 6.1%, respectively ( p = 0.022). Complications were associated with supratherapeutic levels of heparin anticoagulation in 37.5% of cases and invasive procedures in 31.3% of cases. The differences in complications persisted after PS weighting (15.4% vs. 24.7%, p = 0.12 and 1.3% vs. 7.1%, p = 0.067), but did not reach statistical significance. There were no significant differences in mortality, discharge destination, ICU or hospital length of stay, or readmission after PS weighting. CONCLUSIONS: In a retrospective, PS-weighted observational study, when compared with the full-dose, reduced-dose alteplase results in similar outcomes but fewer hemorrhagic complications. Avoidance of excessive levels of anticoagulation or invasive procedures should be considered to further reduce complications.

Design and evaluation of an electronic prospective medication order review system for medication orders in the inpatient setting.

Objectives: Since the 1970s, a plethora of tools have been introduced to support the medication use process. However, automation initiatives to assist pharmacists in prospectively reviewing medication orders are lacking. The review of many medications may be protocolized and implemented in an algorithmic fashion utilizing discrete data from the electronic health record (EHR). This research serves as a proof of concept to evaluate the capability and effectiveness of an electronic prospective medication order review (EPMOR) system compared to pharmacists' review. Materials and methods: A subset of the most frequently verified medication orders were identified for inclusion. A team of clinical pharmacist experts developed best-practice EPMOR criteria. The established criteria were incorporated into conditional logic built within the EHR. Verification outcomes from the pharmacist (human) and EPMOR (automation) were compared. Results: Overall, 13 404 medication orders were included. Of those orders, 13 133 passed pharmacist review, 7388 of which passed EPMOR. A total of 271 medication orders failed pharmacist review due to order modification or discontinuation, 105 of which passed EPMOR. Of the 105 orders, 19 were duplicate orders correctly caught by both EPMOR and pharmacists, but the opposite duplicate order was rejected, 51 orders failed due to scheduling changes. Discussion: This simulation was capable of effectively discriminating and triaging orders. Protocolization and automation of the prospective medication order review process in the EHR appear possible using clinically driven algorithms. Conclusion: Further research is necessary to refine such algorithms to maximize value, improve efficiency, and minimize safety risks in preparation for the implementation of fully automated systems.

Ketamine for Primary Analgosedation in Critically Ill Surgery and Trauma Patients Requiring Mechanical Ventilation.

OBJECTIVES: Evaluate effectiveness and safety outcomes associated with the use of ketamine for primary analgosedation in the surgical/trauma ICU setting. DESIGN: Retrospective cohort study. SETTING: Academic medical center in Minnesota. PATIENTS: Patients admitted to the surgical ICU between 2015 and 2019 requiring mechanical ventilation and meeting one of three definitions for ketamine primary analgosedation were included: 1) no concomitant opioid infusion, 2) ketamine monotherapy for greater than or equal to 6 hours with subsequent opioid infusion, or 3) ketamine initiated concomitantly or within 4 hours of opioid and total opioid duration less than 4 hours. INTERVENTIONS: None. MEASUREMENTS: Use of ketamine, analgesics, and sedatives were evaluated. Pain, sedation, and delirium assessments immediately before and during ketamine infusion were collected and compared with reported goals. Concomitant analgesics, sedatives, and psychotropics were recorded. Reported failures due to ineffectiveness and toxicity were collected. MAIN RESULTS: Of 164 included patients, 88% never received a concomitant opioid infusion (primary analgosedation definition 1), 12% met alternative criteria for primary analgosedation (definitions 2 and 3). A majority, 68%, were surgical admissions and mean Acute Physiology and Chronic Health Evaluation III score was 90 (± 30). Median mechanical ventilation duration was 2.5 days (1.1-4.5) and ICU length of stay of 4.9 days (3-8). The median ketamine infusion dose and duration were 0.18 mg/kg/hr (0.1-0.3) and 30 hours (15.1-51.8). Concomitant infusions of propofol and dexmedetomidine were administered in 49% and 29% of patients, respectively. During ketamine infusion, the median percent of total pain scores at goal was 62% (33-96%), while 64% (37-91%) of Richmond Agitation Sedation Scale scores were at goal, and 47% of patients were Confusion Assessment Method-ICU positive during the ketamine infusion. Hallucinations were documented in 14% of patients and ketamine failure occurred in 11% of patients. CONCLUSIONS: Ketamine may be an effective primary analgosedation option in intubated surgical ICU patients, but prospective randomized studies are needed to evaluate this strategy.

Development and validation of a model to predict acute kidney injury following high-dose methotrexate in patients with lymphoma.

STUDY OBJECTIVE: To develop and validate a model for predicting acute kidney injury (AKI) after high-dose methotrexate (HDMTX) exposure. DESIGN: Retrospective analysis. SETTING: Multisite integrated health system throughout Minnesota and Wisconsin. PATIENTS: Adult patients with lymphoma who received HDMTX as a 4-h infusion. MEASUREMENTS AND MAIN RESULTS: LASSO methodology was used to identify factors available at the outset of therapy that predicted incident AKI within 7 days following HDMTX. The model was then validated in an independent cohort. The incidence of AKI within 7 days following HDMTX was 21.6% (95% confidence interval (CI) 18.4%-24.8%) in the derivation cohort (435 unique patients who received a total of 1642 doses of HDMTX) and 15.6% (95% CI 5.3%-24.8%) in the validation cohort (55 unique patients who received a total of 247 doses of HDMTX). Factors significantly associated with AKI after HDMTX in the multivariable model included age ≥ 55 years, male sex, and lower HDMTX dose number. Other factors that were not found to be significantly associated with AKI on multivariable analysis, but were included in the final model, were body surface area, Charlson Comorbidity Index, and estimated glomerular filtration rate. The c-statistic of the model was 0.72 (95% CI 0.69-0.75) in the derivation cohort and 0.72 (95% CI 0.60-0.84) in the validation cohort. CONCLUSION: This model utilizing identified sociodemographic and clinical factors is predictive of AKI following HDMTX administration in adult patients with lymphoma.

Remimazolam: A Retrospective Study of Initial Safety and Recovery Data in Diverse Procedural Sedation.

PURPOSE: The new ultra-short-acting benzodiazepine, remimazolam, offers a pharmacokinetic and pharmacodynamic advantage over commonly used procedural sedation medication. This retrospective study explored the real-world utilization of remimazolam during procedural sedation to support the development of a nurse sedation protocol. The primary outcome was to identify associations between recovery time, adverse reactions, and dose-response in expanded patient populations. METHODS: This study reviewed charts of 292 adult patients from 3 hospitals within one institution who received remimazolam during procedural sedation between June 1, 2021 and December 31, 2021. Data were analyzed using logistic and linear regression. FINDINGS: The median time to alert in patients receiving remimazolam alone was 12 minutes (interquartile range 10, 17) and increased when additional sedation medications were utilized. Receiving additional sedative medication significantly increased the odds of hypoxia (OR 2.77, 95% CI 1.30-5.91, P = 0.008) after adjusting for body mass index (BMI), American Society of Anesthesiologists physical status (ASA-PS), and total remimazolam dose. There was a 25% increase in odds of experiencing hypoxia for every 5 kg/m2 increase in BMI (95% CI 1.01-1.54, P = 0.037). IMPLICATIONS: Remimazolam presents as a promising option for nurse procedural sedation, offering minimal impact on hemodynamics and respirations, quick recovery, and no residual sedative effects.

Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1. METHODS: For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6). RESULTS: Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups. CONCLUSIONS: Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Risk of arrhythmia in post-resuscitative shock after out-of-hospital cardiac arrest with epinephrine versus norepinephrine.

OBJECTIVE: To determine the rates of clinically significant tachyarrhythmias and mortality in the management of post-resuscitative shock after return of spontaneous circulation (ROSC) in patients with out-of-hospital cardiac arrest (OHCA) who receive a continuous epinephrine versus norepinephrine infusion. DESIGN: Retrospective cohort study. SETTING: A large multi-site health system with hospitals across the United States. PATIENTS: Adult patients admitted for OHCA with post-resuscitative shock managed with either epinephrine or norepinephrine infusions within 6 h of ROSC. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between May 5th, 2018, to January 31st, 2022, there were 221 patients admitted for OHCA who received post-resuscitative epinephrine or norepinephrine infusions. There was no difference in the rate of tachyarrhythmias between epinephrine and norepinephrine infusion in univariate (47.1% vs 41.7%, OR 1.24, 95% CI 0.71-2.20) or multivariable analysis (OR 1.34, 95% CI 0.68-2.62). Patients treated with epinephrine were more likely to die during hospitalization than those treated with norepinephrine (90.0% vs 54.3%, OR 6.21, 95% CI 2.37-16.25, p < 0.001). Epinephrine treated patients were more likely to have re-arrest during hospital admission (55.7% vs 14.6%, OR 5.77, 95% CI 2.74-12.18, p < 0.001). CONCLUSION: There was no statistically significant difference in clinically significant cardiac tachyarrhythmias in post-OHCA patients treated with epinephrine versus norepinephrine infusions after ROSC. Re-arrest rates and in-hospital mortality were higher in patients who received epinephrine infusions in the first 6 h post-ROSC. Results of this study add to the literature suggesting norepinephrine may be the vasopressor of choice in post-OHCA patients with post-resuscitative shock after ROSC.

Impact of Various Estimated Glomerular Filtration Rate Equations on the Pharmacokinetics of Meropenem in Critically Ill Adults.

IMPORTANCE: Meropenem dosing is typically guided by creatinine-based estimated glomerular filtration rate (eGFR), but creatinine is a suboptimal GFR marker in the critically ill. OBJECTIVES: This study aimed to develop and qualify a population pharmacokinetic model for meropenem in critically ill adults and to determine which eGFR equation based on creatinine, cystatin C, or both biomarkers best improves model performance. DESIGN SETTING AND PARTICIPANTS: This single-center study evaluated adults hospitalized in an ICU who received IV meropenem from 2018 to 2022. Patients were excluded if they had acute kidney injury, were on kidney replacement therapy, or were treated with extracorporeal membrane oxygenation. Two cohorts were used for population pharmacokinetic modeling: a richly sampled development cohort (n = 19) and an opportunistically sampled qualification cohort (n = 32). MAIN OUTCOMES AND MEASURES: A nonlinear mixed-effects model was developed using parametric methods to estimate meropenem serum concentrations. RESULTS: The best-fit structural model in the richly sampled development cohort was a two-compartment model with first-order elimination. The final model included time-dependent weight normalized to a 70-kg adult as a covariate for volume of distribution (Vd) and time-dependent eGFR for clearance. Among the eGFR equations evaluated, eGFR based on creatinine and cystatin C expressed in mL/min best-predicted meropenem clearance. The mean (se) Vd in the final model was 18.2 (3.5) liters and clearance was 11.5 (1.3) L/hr. Using the development cohort as the Bayesian prior, the opportunistically sampled cohort demonstrated good accuracy and low bias. CONCLUSIONS AND RELEVANCE: Contemporary eGFR equations that use both creatinine and cystatin C improved meropenem population pharmacokinetic model performance compared with creatinine-only or cystatin C-only eGFR equations in adult critically ill patients.

Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients.

IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Doré (-2.0 [-16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

Population pharmacokinetic model of cefepime for critically ill adults: a comparative assessment of eGFR equations.

Cefepime exhibits highly variable pharmacokinetics in critically ill patients. The purpose of this study was to develop and qualify a population pharmacokinetic model for use in the critically ill and investigate the impact of various estimated glomerular filtration rate (eGFR) equations using creatinine, cystatin C, or both on model parameters. This was a prospective study of critically ill adults hospitalized at an academic medical center treated with intravenous cefepime. Individuals with acute kidney injury or on kidney replacement therapy or extracorporeal membrane oxygenation were excluded. A nonlinear mixed-effects population pharmacokinetic model was developed using data collected from 2018 to 2022. The 120 included individuals contributed 379 serum samples for analysis. A two-compartment pharmacokinetic model with first-order elimination best described the data. The population mean parameters (standard error) in the final model were 7.84 (0.24) L/h for CL1 and 15.6 (1.45) L for V1. Q was fixed at 7.09 L/h and V2 was fixed at 10.6 L, due to low observed interindividual variation in these parameters. The final model included weight as a covariate for volume of distribution and the eGFRcr-cysC (mL/min) as a predictor of drug clearance. In summary, a population pharmacokinetic model for cefepime was created for critically ill adults. The study demonstrated the importance of cystatin C to prediction of cefepime clearance. Cefepime dosing models which use an eGFR equation inclusive of cystatin C are likely to exhibit improved accuracy and precision compared to dosing models which incorporate an eGFR equation with only creatinine.

Intraoperative Versus Postoperative Hydroxocobalamin for Vasoplegic Shock in Cardiothoracic Surgery.

OBJECTIVES: Hydroxocobalamin inhibits nitric oxide pathways contributing to vasoplegic shock in patients undergoing cardiopulmonary bypass (CPB). The objective of this study was to evaluate the effect of intraoperative versus postoperative application of hydroxocobalamin for vasoplegic shock in patients undergoing CPB. DESIGN: This was a historic cohort study. SETTING: The study was conducted at a quaternary academic cardiovascular surgery program. PARTICIPANTS: Adults undergoing cardiac surgery using CPB were participants in the study. INTERVENTIONS: Hydroxocobalamin (5 g) intravenously over 15 minutes. MEASUREMENTS AND MAIN RESULTS: The treatment groups were assigned based on the receipt location of hydroxocobalamin (ie, intensive care unit [ICU] versus operating room [OR]). The primary outcome was vasopressor-free days in the first 14 days after CPB. Of the 112 patients included, 37 patients received hydroxocobalamin in the OR and 75 in the ICU. Patients in the OR group were younger than those in the ICU group (57.5 v 63.9 years, p = 0.007), with statistically similar American Society of Anesthesiologists scores. The mean CPB duration was 3.4 hours in the OR group and 2.9 hours in the ICU group (p = 0.09). In both groups, the norepinephrine-equivalent dose of vasopressors at hydroxocobalamin was 0.27 µg/kg/min. Days alive and free of vasopressors were not different between the OR and ICU groups (estimated difference 0.48 [95% CI -1.76-2.72], p = 0.67). The odds of postoperative renal failure, mesenteric ischemia, ICU, hospital length of stay, and in-hospital mortality were also similar between groups. CONCLUSIONS: A difference in vasopressor-free days after CPB was not found between patients who received hydroxocobalamin intraoperatively versus postoperatively for vasoplegic shock.

A Pharmacovigilance Analysis of Daptomycin Use Based on CLSI Susceptible Dose-Dependent Category.

INTRODUCTION: Daptomycin doses 8-12 mg/kg are recommended for susceptible dose-dependent Enterococcus species. However, data remain limited on safety outcomes of such dosing, compared to standard 4-6 mg/kg dosing. METHODS: In this retrospective cohort study, patients were stratified into daptomycin standard-dose (≤ 6.5 mg/kg) versus high-dose (≥ 7.5 mg/kg) groups. The primary outcome was daptomycin safety based on a composite of creatine kinase elevation, daptomycin-related peripheral blood eosinophilia, eosinophilic pneumonitis, alanine aminotransferase elevation, and alkaline phosphatase elevation. A secondary aim was to identify risk factors for daptomycin adverse effects. Inclusion criteria were age ≥ 18 years old, daptomycin receipt for ≥ 48 h, and Enterococcus cultures with a daptomycin minimal inhibitory concentration 2-4 mg/L. RESULTS: A total of 119 patients were included for analysis. Median daptomycin doses were 6.0 mg/kg (IQR 5.4, 6.1) and 8.1 mg/kg (IQR 7.9, 9.6) in the standard- and high-dose cohorts, respectively. Median durations were 13.5 days (standard-dose) and 16 days (high-dose) (p = 0.02). The composite safety endpoint occurred in 32.0% of the standard-dose group and 32.5% of the high-dose group (p = 0.96). Daptomycin was dose-reduced or held in 8.1% of patients experiencing an adverse effect. Concurrent antihistamine usage was associated with the composite outcome; however, there was no association with daptomycin dose or concurrent statin use. CONCLUSION: High-dose daptomycin was not associated with increased laboratory abnormalities or adverse drug reactions compared to standard-dose daptomycin.