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OBJECTIVE: : Doripenem is a valuable broad-spectrum antibiotic for empirical therapy in critically ill patients, although little data exist to guide effective dosing. We sought to describe the population pharmacokinetics of doripenem in critically ill patients with nosocomial pneumonia and then to use Monte Carlo dosing simulations to procure clinically relevant dosing recommendations for that population. DESIGN: : Pharmacokinetic analysis of Phase III Trial data. SETTING: : Critical care units at multiple centers. PATIENTS: : Thirty-one critically ill adult patients with nosocomial pneumonia. INTERVENTIONS: : Serial blood samples were taken on day 2 or 3 of treatment and used for population pharmacokinetic analysis with nonlinear mixed effects modelling and Monte Carlo simulation. MEASUREMENTS AND MAIN RESULTS: : A two-compartment linear model was most appropriate. The mean values for doripenem clearance (20.4 ± 14.2 L/hr) and volume of distribution (45.9 ± 36.3 L) were larger than that observed in previous studies in noncritically ill patients. Doripenem clearance was correlated with creatinine clearance and peripheral volume of distribution with patient body weight. Administration by extended infusion negated much of the pharmacokinetic variability caused by different patient body weight and renal function and enabled achievement of concentrations associated with maximal bacterial killing. CONCLUSIONS: : This is the first article describing the pharmacokinetics/pharmacodynamics of doripenem solely in critically ill patients and emphasizes the effect of patient weight and creatinine clearance on pharmacokinetics. Use of extended infusions with this antibiotic should be encouraged as it maximizes the likelihood of achieving target blood concentrations. [ABSTRACT FROM AUTHOR]

Polyethylene tibial post wear in posterior-stabilized knee designs is a major problem. The Insall-Burstein II (IB PS II) reportedly has severe anterior wear of the post in retrieved implants. We hypothesized the more anterior placement in the IB PS II would be reflected in greater wear at the anterior face than the IB PS I. We examined 234 retrieved inserts using subjective scales to grade post damage and wear. Of the IB PS II inserts, 38% demonstrated severe wear compared with only 25% of IB PS I inserts. The most prevalent damage location for the IB PS II was the anterior face, whereas the IB PS I sustained wear mainly on the medial face. While the IB PS post was not designed to constrain posterior femoral displacement, our observations confirm contact in hyperextension or other paradoxic anterior tibial translation is common and design-dependent. Minimizing wear and damage through proper post placement and changes in implant design to anticipate contact on the anterior post should be considered for future posterior stabilized knee replacements. These changes cannot occur in isolation, however, because changes in post placement and design also depend on their relation to the shape and location of the tibial bearing surfaces. [ABSTRACT FROM AUTHOR]

Drug treatments for coronavirus disease 2019 (COVID-19) dramatically improve patient outcomes, and although extracorporeal membrane oxygenation (ECMO) has significant use in these patients, it is unknown whether ECMO affects drug dosing. We used an ex vivo adult ECMO model to measure ECMO circuit effects on concentrations of specific COVID-19 drug treatments. Three identical ECMO circuits used in adult patients were set up. Circuits were primed with fresh human blood (temperature and pH maintained within normal limits). Three polystyrene jars with 75 ml fresh human blood were used as controls. Remdesivir, GS-441524, nafamostat, and tocilizumab were injected in the circuit and control jars at therapeutic concentrations. Samples were taken from circuit and control jars at predefined time points over 6 h and drug concentrations were measured using validated assays. Relative to baseline, mean (± standard deviation [SD]) study drug recoveries in both controls and circuits at 6 h were significantly lower for remdesivir (32.2% [±2.7] and 12.4% [±2.1], p < 0.001), nafamostat (21.4% [±5.0] and 0.0% [±0.0], p = 0.018). Reduced concentrations of COVID-19 drug treatments in ECMO circuits is a clinical concern. Remdesivir and nafamostat may need dose adjustments. Clinical pharmacokinetic studies are suggested to guide optimized COVID-19 drug treatment dosing during ECMO., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Objective: This study aims to define an effective senior resident and understand the process of leadership and nontechnical skill development in the transition from junior to senior surgery resident., Summary Background: General surgery residents are responsible for patient care, technically demanding operations, and diverse care team management. However, leadership skill development for the transition from junior to senior resident roles is often overlooked., Methods: We conducted 15 semi-structured focus groups with surgery residents from an urban, academic institution. Focus group transcripts were inductively coded. Using content analysis and constant comparative methodology, primary codes were refined into categories and organized into higher-level themes., Results: Thirty-three general surgery residents completed fifteen focus groups. Six themes were identified. Three themes describe the process of becoming an effective senior resident: how to define a senior resident's scope of practice, the transition process, and the importance of personal investment. Three themes were identified regarding effective seniors: ideal traits, teachable skills, and the team and patient impact., Conclusions: Surgery residents define an effective senior resident as the team member with the highest level of experience who manages the big picture of patient care. The transition is improved by personal engagement and acknowledgement of the transition. Ideal traits of effective seniors, including emotional intelligence and inherent personality traits, allow a resident to more naturally assume this role; however, teachable skills, such as communication, expectation setting and competence, can be taught to improve one's effectiveness. The actions of a senior resident impact the team and patient care, underscoring the importance of understanding this role., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In this study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous venovenous hemofiltration (CVVH, 30 mL·kg-1·h-1) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL·kg-1·h-1 + 15 mL·kg-1·h-1) and determine the optimal dosing regimen using the developed model., Methods: Patients with septic shock undergoing continuous renal replacement therapy and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from 8 CVVH sessions and 8 CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 hours to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma., Results: The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a 2-compartmental PK model. No covariates, including continuous renal replacement therapy modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (SD) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis., Conclusions: No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy., Competing Interests: E. Maseda received consultancy fees and payment for lectures from Astellas Pharma, Pfizer, and Novartis. J. Lipman received honoraria from MSD and Pfizer and received institutional support from MSD. C. Roger received consultancy fees from MSD, Pfizer, and Fresenius Medical Care. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: A dysfunctional microcirculation is universal in shock and is often dissociated from global hemodynamic parameters. Persistent microcirculatory derangements reflect ongoing tissue hypoperfusion and organ injury. The initial microcirculatory dysfunction and subsequent resolution could potentially guide therapy and predict outcomes. We evaluated the microcirculation early in a heterogenous shocked population. Microcirculatory resolution was correlated with measures of tissue perfusion and global hemodynamics. The relationship between the microcirculation over 24 h and outcome were evaluated., Design: We prospectively recruited patients with all forms of shock, based on global hemodynamics and evidence of organ hypoperfusion., Setting: A 30-bed adult intensive care unit (ICU)., Patients: Eighty-two shocked patients., Measurements and Main Results: Following the diagnosis of shock, patients underwent a sublingual microcirculation examination using Sidestream Dark Field Imaging. The median age of patients was 66 years old (interquartile range [IQR] 54-71), with an Acute Physiology and Chronic Health Evaluation II of 27 (IQR 20-32). Microcirculatory parameters included Percentage Perfused Vessels (PPV), De Backer Score, and a heterogeneity index in patients with septic shock, according to the second consensus guidelines Additional parameters collected: temperature, heart rate and arterial pressure, cumulative fluid balance, and vasopressor use. Arterial blood samples were taken at the time of microcirculatory assessments, providing HCO3, lactate concentrations, PaO2, and PaCO2 measurements. A statistically significant improvement in PPV and the heterogeneity index was demonstrated. This improvement was mirrored by biomarkers of perfusion; however, the global hemodynamic parameter changes were not significantly different over the 24-h period. The early microcirculatory improvement was not predictive of an improvement in acute kidney injury, length of stay, ICU, or hospital mortality., Conclusions: Early sequential evaluation of the microcirculation in shocked patients, demonstrated statistically significant improvement in the PPV and microvascular heterogeneity with standard care. These improvements were mirrored by biomarkers of organ perfusion; however, the changes in global hemodynamics were not as pronounced in this early phase. Early improvement in the microcirculation did not predict clinical outcome., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Purpose of Review: Antibiotics are an essential treatment for septic shock. This review provides an overview of the key issues in antimicrobial therapy for septic shock. We include a summary of available evidence with an emphasis on data published in the last few years., Recent Findings: We examine apparently contradictory data supporting the importance of minimizing time to antimicrobial therapy in sepsis, discuss approaches to choosing appropriate antibiotics, and review the importance and challenges presented by antimicrobial dosing. Lastly, we evaluate the evolving concepts of de-escalation, and optimization of the duration of antimicrobials., Summary: The topics discussed in this review provide background to key clinical decisions in antimicrobial therapy for septic shock: timing, antibiotic choice, dosage, de-escalation, and duration. Although acknowledging some controversy, antimicrobial therapy in septic shock should be delivered early, be of the adequate spectrum, appropriately and individually dosed, rationalized when possible, and of minimal effective duration., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.

Background: Obesity is a risk factor for surgical site infection after cesarean delivery. There is inadequate pharmacokinetic data available regarding prophylactic cefazolin dosing in obese pregnant women. We aimed to describe the plasma and interstitial fluid (ISF) pharmacokinetics of cefazolin in obese women undergoing elective cesarean delivery and use dosing simulations to predict optimal dosing regimens., Methods: Eligible women were scheduled for elective cesarean delivery at term, with a body mass index (BMI) of >35 kg·m. Plasma and ISF samples were collected following 2 g of intravenous cefazolin. Concentrations were determined using liquid chromatography-mass spectrometry. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. Total and unbound cefazolin concentrations in plasma and ISF were compared with the minimum inhibitory concentration at which 90% of isolates are inhibited (MIC90) of cefazolin for Staphylococcus aureus, 2 mg·L. The fractional target attainment (FTA) of dosing regimens to achieve a pre-established target of 95% unbound ISF concentrations >2 mg·L throughout a 3-hour duration of the surgery was calculated., Results: The 12 women recruited had a median (interquartile range [IQR]) BMI of 41.5 (39.7-46.6) kg·m and a median (IQR) gestation of 38.7 weeks (37.9-39.0). For each timepoint up to 180 minutes, the median across subjects of total and unbound plasma concentration of cefazolin remained above 2 mg·L. The minimum observed total plasma concentration was 31.7 mg·L and plasma unbound concentration was 7.7 mg·L (observed in the same participant). For each timepoint up to 150 minutes, the median across subjects of unbound ISF concentrations remained above 2 mg·L. The minimum observed unbound ISF concentration was 0.7 mg·L (observed in 1 participant). In 2 participants, the ISF concentration of cefazolin was not maintained above 2 mg·L. The mean (± standard error [SE]) penetration of cefazolin (calculated as area under the concentration-time curve for the unbound fraction of drug [fAUC]tissue/fAUCplasma) into the ISF was 0.884 ± 1.11. Simulations demonstrated that FTA >95% was achieved in patients weighing 90-150 kg by an initial 2 g dose with redosing of 2 g at 2 hours. FTA was improved to >99% when an initial 3 g dose was repeated at 2 hours., Conclusions: To maintain adequate ISF antibiotic concentrations in obese pregnant women, our results suggest that redosing of cefazolin may be required. When wound closure has not occurred within 2 hours, redosing is suggested, following either a 2 or 3 g initial bolus. These preliminary results require validation in a larger population.

Background: Mycophenolate mofetil or enteric-coated mycophenolate sodium (EC-MPS) and steroids are used for induction and maintenance therapy in severe lupus nephritis. Blood concentrations of mycophenolic acid (MPA), the active metabolite of these drugs, vary among patients with lupus nephritis. The objective of this study was to examine whether concentration-controlled (CC) dosing (through therapeutic drug monitoring) of EC-MPS results in a higher proportion of participants achieving target exposure of MPA compared with fixed-dosing (FD). An additional aim of the study was to evaluate the influence of CC dosing on clinical outcomes., Methods: Nineteen participants were randomly assigned either to the FD or CC group. All the participants were eligible to have free and total measurements of MPA over a period of 8-12 hours on 3 different occasions. Area under the concentration-time curve between 0 and 12 hours (AUC0-12) was calculated using noncompartmental methods. Dose of EC-MPS was titrated according to AUC0-12 in the CC group., Results: Thirty-two AUC0-12 measurements were obtained from 9 FD and 9 CC participants. Large inter-patient variability was observed in both groups but was more pronounced in the FD group. There were no significant differences between FD and CC participants in any pharmacokinetic parameters across the study visits, except for total C0 (FD 2.0 ± 0.3 mg/L versus CC 1.1 ± 0.3; P = 0.01) and dose-normalized C0 (FD 2.9 ± 0.2 mg/L/g versus CC 2.1 ± 0.7 mg/L/g; P = 0.04) at the second visit and total AUC0-12 (FD 66.6 ± 6.0 mg·h/L versus CC 35.2 ± 11.4 mg·h/L; P = 0.03) at the third visit. At the first study visit, 33.3% of the FD and 11.1% of the CC participants achieved the target area under the concentration-time curve (P = 0.58). From the second visit, none of the FD participants, compared with all the CC participants, achieved target AUC0-12 (P = 0.01). More CC participants achieved remission compared with FD participants (absolute difference of -22.2, 95% confidence interval (Equation is included in full-text article.)0.19 to 0.55; P = 0.62). The mean free MPA AUC0-12 was significantly lower in those who had complete remission., Conclusions: CC participants reached target AUC0-12 quicker. Larger studies are required to test clinical efficacy.

Objectives: Incomplete biostatistical knowledge among clinicians is widely described. This study aimed to categorize and summarize the statistical methodology within recent critical care randomized controlled trials., Design: Descriptive analysis, with comparison of findings to previous work., Setting: Ten high-impact clinical journals publishing trials in critical illness., Subjects: Randomized controlled trials published between 2011 and 2015 inclusive., Interventions: Data extraction from published reports., Measurements and Main Results: The frequency and overall proportion of each statistical method encountered, grouped according to those used to generate each trial's primary outcome and separately according to underlying statistical methodology. Subsequent analysis compared these proportions with previously published reports. A total of 580 statistical tests or methods were identified within 116 original randomized controlled trials published between 2011 and 2015. Overall, the chi-square test was the most commonly encountered (70/116; 60%), followed by the Cox proportional hazards model (63/116; 54%) and logistic regression (53/116; 46%). When classified according to underlying statistical assumptions, the most common types of analyses were tests of 2 × 2 contingency tables and nonparametric tests of rank order. A greater proportion of more complex methodology was observed compared with trial reports from previous work., Conclusions: Physicians assessing recent randomized controlled trials in critical illness encounter results derived from a substantial and potentially expanding range of biostatistical methods. In-depth training in the assumptions and limitations of these current and emerging biostatistical methods may not be practically achievable for most clinicians, making accessible specialist biostatistical support an asset to evidence-based clinical practice.

Objective: Most published data on emergency department (ED) patients with septic shock have been generated from studies examining the effect of early protocolised resuscitation in selected cohorts. Consequently, these data do not generally represent patients falling outside trial inclusion criteria or judged unsuitable for aggressive treatment. Our aim was to determine the characteristics, treatment and outcomes for all ED patients fulfilling the criteria for septic shock., Methods: Septic shock patients were identified from a prospective database of consecutive ED patients admitted with infection. Descriptive data were compared with those from previous studies and associations between ED processes of care and mortality were determined., Results: A total of 399 septic shock patients were identified, with a 30-day mortality of 19.5%. The median ED length of stay was 9.2 h. Rates of vasopressor use (22.6%) and ICU admission (37.3%) were low. Subgroups fulfilling the lactate criteria alone, hypotension criteria alone and both criteria represented distinct shock phenotypes with increasing severity of illness and mortality. Mortality for patients with limitations to treatment determined in the ED was 65.6% and 6.1% for those without limitations. Greater volumes of intravenous fluid and early vasopressor therapy for appropriate patients were associated with survival., Conclusion: Median length of stay over 9 hours may have enhanced identification of patients with limitations to treatment and fluid responders, reducing invasive therapies and ICU admissions. Distinct shock phenotypes were apparent, with implications for revision of septic shock definitions and future trial design. Liberal fluids and early vasopressor use in appropriate patients were associated with survival.

Objective: Piperacillin-tazobactam is a commonly used antibiotic in critically ill patients; however, controversy exists as to whether mortality in serious infections can be decreased through administration by prolonged infusion compared with intermittent infusion. The purpose of this systematic review and meta-analysis was to describe the impact of prolonged infusion piperacillin-tazobactam schemes on clinical endpoints in severely ill patients., Design: We conducted a systematic literature review and meta-analysis searching MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to April 1, 2017, for studies., Interventions: Mortality rates were compared between severely ill patients receiving piperacillin-tazobactam via prolonged infusion or intermittent infusion. Included studies must have reported severity of illness scores, which were transformed into average study-level mortality probabilities., Measurements and Main Results: Two investigators independently screened titles, abstracts, and full texts of studies meeting inclusion criteria for this systematic review and meta-analysis. Variables included author name, publication year, study design, demographics, total daily dose(s), average estimated creatinine clearance, type of prolonged infusion, prevalence of combination therapy, severity of illness scores, infectious sources, all-cause mortality, clinical cure, microbiological cure, and hospital and ICU length of stay. The review identified 18 studies including 3,401 patients who received piperacillin-tazobactam, 56.7% via prolonged infusion. Across all studies, the majority of patients had an identified primary infectious source. Receipt of prolonged infusion was associated with a 1.46-fold lower odds of mortality (95% CI, 1.20-1.77) in the pooled analysis. Patients receiving prolonged infusion had a 1.77-fold higher odds of clinical cure (95% CI, 1.24-2.54) and a 1.22-fold higher odds of microbiological cure (95% CI, 0.84-1.77). Subanalyses were conducted according to high (≥ 20%) and low (< 20%) average study-level mortality probabilities. In studies reporting higher mortality probabilities, effect sizes were variable but similar to the pooled results., Conclusions: Receipt of prolonged infusion of piperacillin-tazobactam was associated with reduced mortality and improved clinical cure rates across diverse cohorts of severely ill patients.

Purpose of Review: Nosocomial pneumonia caused by multidrug-resistant pathogens is increasing in the ICU, and these infections are negatively associated with patient outcomes. Optimization of antibiotic dosing has been suggested as a key intervention to improve clinical outcomes in patients with nosocomial pneumonia. This review describes the recent pharmacokinetic/pharmacodynamic data relevant to antibiotic dosing for nosocomial pneumonia caused by multidrug-resistant pathogens., Recent Findings: Optimal antibiotic treatment is challenging in critically ill patients with nosocomial pneumonia; most dosing guidelines do not consider the altered physiology and illness severity associated with severe lung infections. Antibiotic dosing can be guided by plasma drug concentrations, which do not reflect the concentrations at the site of infection. The application of aggressive dosing regimens, in accordance to the antibiotic's pharmacokinetic/pharmacodynamic characteristics, may be required to ensure rapid and effective drug exposure in infected lung tissues., Summary: Conventional antibiotic dosing increases the likelihood of therapeutic failure in critically ill patients with nosocomial pneumonia. Alternative dosing strategies, which exploit the pharmacokinetic/pharmacodynamic properties of an antibiotic, should be strongly considered to ensure optimal antibiotic exposure and better therapeutic outcomes in these patients.