Protocol and Statistical Analysis Plan for the Mode of Ventilation During Critical Illness (MODE) Trial.

BACKGROUND: For every critically ill adult receiving invasive mechanical ventilation, clinicians must select a mode of ventilation. The mode of ventilation determines whether the ventilator directly controls the tidal volume or the inspiratory pressure. Newer hybrid modes allow clinicians to set a target tidal volume; the ventilator controls and adjusts the inspiratory pressure. A strategy of low tidal volumes and low plateau pressure improves outcomes, but the optimal mode to achieve these targets is not known. RESEARCH QUESTION: Can a cluster-randomized trial design be used to assess whether the mode of mandatory ventilation affects the number of days alive and free of invasive mechanical ventilation among critically ill adults? STUDY DESIGN AND METHODS: The Mode of Ventilation During Critical Illness (MODE) trial is a cluster-randomized, multiple-crossover pilot trial being conducted in the medical ICU at an academic center. The MODE trial compares the use of volume control, pressure control, and adaptive pressure control. The study ICU is assigned to a single-ventilator mode (volume control vs pressure control vs adaptive pressure control) for continuous mandatory ventilation during each 1-month study block. The assigned mode switches every month in a randomly generated sequence. The primary outcome is ventilator-free days to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of mechanical ventilation to 28 days after enrollment. Enrollment began November 1, 2022, and will end on July 31, 2023. RESULTS: This manuscript describes the protocol and statistical analysis plan for the MODE trial of ventilator modes comparing volume control, pressure control, and adaptive pressure control. INTERPRETATION: Prespecifying the full statistical analysis plan prior to completion of enrollment increases rigor, reproducibility, and transparency of the trial results. CLINICAL TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov on October 3, 2022, before initiation of patient enrollment on November 1, 2022 (ClinicalTrials.gov identifier: NCT05563779).

Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes. METHODS: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete. FINDINGS: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo. INTERPRETATION: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults. FUNDING: National Institutes of Health and the US Department of Veterans Affairs.

The road less traveled: Developing pharmacist clinician-scientists through divergent training pathways.

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: Professional organizations have emphasized the growing need for pharmacists to possess advanced research skills; however, there is a scarcity of training programs aimed at nurturing clinician-scientists. This report outlines 3 critical care-focused research programs, each offering a unique approach to training clinician-scientists. SUMMARY: Limited resources and formalized programs are available to bridge the gap between the demand for and availability of skilled clinician-scientists. Several programs have stepped forward to share their experiences in establishing and executing training initiatives aimed at cultivating skilled clinician-scientists in the critical care practice space. CONCLUSION: Enhancing the development of clinician-scientists for clinical and translational research is necessary in the critical care clinical pharmacy community.

Tocilizumab is associated with reduced delirium and coma in critically ill patients with COVID-19.

Recent preclinical studies demonstrate a direct pathological role for the interleukin-6 (IL-6) pathway in mediating structural and functional delirium-like phenotypes in animal models of acute lung injury. Tocilizumab, an IL-6 pathway inhibitor, has shown reduced duration of ventilator dependency and mortality in critically ill patients with COVID-19. In this study, we test the hypothesis that tocilizumab is associated with reduced delirium/coma prevalence in critically ill patients with COVID-19. 253 patients were included in the study cohort, 69 in the tocilizumab group and 184 in the historical control group who did not receive tocilizumab. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with a positive score indicating delirium. Coma was defined as a Richmond Agitation-Sedation Scale score of - 4 or - 5. Tocilizumab was associated with significantly greater number of days alive without delirium/coma (tocilizumab [7 days (IQR: 3-9 days)] vs control [3 days (IQR: 1-8 days)]; p < 0.001). These results remained significant after adjusting for age, sex, sepsis, Charlson Comorbidity Index, Sequential Organ Failure Assessment score, and median daily dose of analgesics/sedatives ( ß ^ = 0.671, p = 0.010). There were no significant differences in mortality ( ß ^ = - 0.204, p = 0.561), ventilator duration ( ß ^ = 0.016, p = 0.956), and ICU or hospital length of stay ( ß ^ = - 0.134, p = 0.603; ß ^ = 0.003, p = 0.991, respectively). Tocilizumab use was associated with significantly increased number of days without delirium/coma. Confirmation of these findings in randomized prospective studies may inform a novel paradigm of pharmacological amelioration of delirium/coma during critical illness.

Prescription of potentially inappropriate medications after an intensive care unit stay for acute respiratory failure.

BACKGROUND: Among survivors of critical illness, prescription of potentially inappropriate medications (PIM) at hospital discharge is thought to be an important, modifiable patient safety concern. To date, there are little empirical data evaluating this issue. RESEARCH QUESTION: The objective of this study was to determine the frequency of PIM prescribed to survivors of acute respiratory failure (ARF) at hospital discharge and explore their association with readmissions or death within 90 days of hospital discharge. STUDY DESIGN AND METHODS: Prospective multicenter cohort study of ARF survivors admitted to ICUs and discharged home. Prospective of new PIMs with a high-adverse-effect profile ("high impact") at discharge was the primary exposure. Potential inappropriateness was determined by a structured consensus process using Screening Tool of Older Persons' Prescriptions-Screening Tool to Alert to Right Treatment, Beers' criteria, and clinical context of prescriptions by a multidisciplinary team. Covariate balancing propensity score was used for the primary analysis. RESULTS: Of the 195 Addressing Post Intensive Care Syndrome-01 (APICS-01) patients, 169 (87%) had ≥1 new medications prescribed at discharge, with 154 (91.1%) prescribed with one or more high-impact (HI) medications. Patients were prescribed a median of 5 [3-7] medications, of which 3 [1-4] were HI. Twenty percent of HI medications were potentially inappropriate. Medications with significant central nervous system side-effects were most prescribed potentially inappropriately. Forty-six (30%) patients experienced readmission or death within 90 days of hospital discharge. After adjusting for prespecified covariates, the association between prescription of potentially inappropriate HI medications and the composite primary outcome did not meet the prespecified threshold for statistical significance (risk ratio: 0.54; 0.26-1.13; p = 0.095) or with the constituent endpoints: readmission (risk ratio: 0.57, 0.27-1.11) or death (0.7, 0.05-9.32). CONCLUSION: At hospital discharge, most ARF survivors are prescribed medications with a high-adverse-effect profile and approximately one-fifth are potentially inappropriate. Although prescription of such medications was not associated with 90-day readmissions and mortality, these results highlight an area for additional investigation.

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. Objective: To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. Design, Setting, and Participants: An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Interventions: Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Main Outcomes and Measures: Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. Results: A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. Conclusions and Relevance: The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. Trial Registration: ClinicalTrials.gov Identifier: NCT01211522.

Physical and Chemical Compatibility of Medications Commonly Used in Critically Ill Patients With Balanced Crystalloids: A Systematic Review.

OBJECTIVE: Evaluate available evidence of physical and/or chemical compatibility of commonly used medications in critically ill patients with balanced crystalloids. DATA SOURCES: Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews were queried from inception to September 2022. STUDY SELECTION AND DATA EXTRACTION: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English-language studies reporting physical and/or chemical compatibility data between 50 selected medications and balanced crystalloids were included. A previously designed tool to assess risk of bias was adapted for use. DATA SYNTHESIS: Twenty-nine studies encompassing 39 (78%) medications and 188 unique combinations with balanced crystalloids were included. Combinations included 35 (70%) medications with lactated Ringer's, 26 (52%) medications with Plasma-Lyte, 10 (20%) medications with Normosol, and one (2%) medication with Isolyte. Studies commonly evaluated physical and chemical compatibility (55.2%). More medications were evaluated via Y-site than admixture. Incompatibilities were identified in 18% of combinations comprising 13 individual drugs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This systematic review evaluates the compatibility of select critical care medications with balanced crystalloid solutions. Results may be used as a tool to guide clinicians on balanced crystalloid compatibility, potentially increasing ubiquitous use and reducing patient exposure to normal saline. CONCLUSION AND RELEVANCE: Data are limited regarding chemical/physical compatibility of commonly used medications in critically ill patients with balanced crystalloids. Additional compatibility studies are warranted, particularly methodologically rigorous studies assessing Plasma-Lyte, Normosol, and Isolyte. Of the evaluated medications, there was a low frequency of incompatibilities with balanced crystalloids.

Correlation of the Critical Care Pain Observation Tool and Numeric Rating Scale in Intensive Care Unit Patients.

PURPOSE: We sought to determine the correlation between the Numeric Rating Scale (NRS) and Critical-Care Pain Observation Tool (CPOT) to determine whether clinical factors modified the relationship between NRS and CPOT assessments. MATERIALS AND METHODS: We included nonventilated adults admitted to the MICU or SICU who could self-report pain and had at least 3 paired NRS and CPOT assessments. We performed Spearman correlation to assess overall correlation and performed proportional odds logistic regression to evaluate whether the relationship between NRS and CPOT assessments was modified by clinical factors. RESULTS: Nursing staff performed NRS and CPOT assessments every 4 h in 1302 patients, leading to 61,142 matched assessments. We found that the NRS and CPOT have a Spearman correlation coefficient of 0.56 and an intraclass correlation coefficient of 0.32 in intensive care unit patients. Factors that modified the relationship between the NRS and CPOT included the presence of delirium (P < .001) and lower mean daily Richmond Agitation Sedation Scale (<0.001). CONCLUSIONS: The correlation coefficient between the NRS and the CPOT was found to be 0.56. The presence of delirium, decreased level of arousal, modified the relationship between the NRS and CPOT. Self-reported and behavioral pain assessments cannot be used interchangeably in critically ill adults.

Recurrent delirium episodes within the intensive care unit: Incidence and associated factors.

PURPOSE: Describe the incidence and factors associated with recurrent delirium in the intensive care unit (ICU). MATERIALS AND METHODS: Retrospective study of ICU patients diagnosed with delirium. Delirium clearance defined as 48 h of negative delirium assessments following initial episode and recurrent delirium as any positive delirium assessment following clearance. Multivariable logistic regression model assessed independent association of patient and hospital factors on development of recurrent delirium, adjusting for pre-defined covariates. RESULTS: Among 8591 ICU admissions identified with delirium, 1067 (12.4%) had recurrent symptoms. Factors associated with increased odds of recurrent delirium were age (nonlinear; p = 0.02), shock (OR 1.45, 95% CI [1.20, 1.75]), admission to medical (OR 3.25, 95% CI [2.42, 4.37]), surgical (OR 3.00, 95% CI [2.21, 4.06]), or trauma (OR 2.17, 95% CI [1.58, 3.00]) ICU vs. cardiovascular ICU, increased duration of mechanical ventilation (OR 2.43, 95% CI [2.22, 2.65]), propofol use (OR 1.35, 95% CI [1.02, 1.80]), and antipsychotic medications (haloperidol OR 1.53, 95% CI [1.26, 1.86]; quetiapine OR 2.45, 95% CI [1.98, 3.02]; and olanzapine OR 1.54, 95% CI [1.25, 1.88]). CONCLUSIONS: Over 10% of delirious ICU patients had recurrent symptoms. Factors associated with recurrence included age, duration of mechanical ventilation and medication exposure. CLINICAL TRIAL NUMBER: Not applicable.

Comparison of SAT and SBT Conduct During the ABC Trial and PILOT Trial.

BACKGROUND: Implementation of the "B" element-both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs)-of the ABCDEF bundle improves the outcomes for mechanically ventilated patients. In 2021, the Pragmatic Investigation of optimal Oxygen Targets (PILOT) trial investigating optimal oxygenation targets in patients on mechanical ventilation was completed. OBJECTIVES: To compare SAT and SBT conduct between a randomized controlled trial and current clinical care. METHODS: The 2008 Awakening and Breathing Controlled (ABC) Trial (2003-2006) randomized mechanically ventilated patients to paired SATs and SBTs versus sedation per usual care plus SBTs. The PILOT trial (2018-2021) enrolled patients years later where SAT + SBT conduct was observed. We compared SAT and SBT conduct in ABC's interventional group (SAT + SBT; n = 167, 1140 patient days) to that in PILOT (n = 2083, 8355 patient days). RESULTS: Spontaneous awakening trial safety screens were done in all 1140 ABC patient-days on sedation and/or analgesia and in 3889 of 4228 (92%) in PILOT. Spontaneous awakening trial safety screens were passed in 939 of 1140 (82%) instances in ABC versus only 1897 of 3889 (49%) in PILOT. Interestingly, SAT was performed in ≥95% of passed SAT safety screens in both trials and was passed in 837 of 895 (94%) in ABC versus 1145 of 1867 (61%) in PILOT. SBT safety screens were performed in all 983 ABC instances and 8031 of 8370 (96%) in PILOT. SBT safety screens were passed in 647 of 983 (66%) in ABC versus 4475 of 8031 (56%) in PILOT. Spontaneous breathing trial was performed in ≥93% of passed SBT safety screens in both trials and was passed in 319 of 603 (53%) in ABC versus 3337 of 4454 (75%) in PILOT. CONCLUSION: This study compared SAT/SBT conduction in an ideal setting to real-world practice, 13 years later. Performance of SAT/SBT safety screens, SATs, and SBTs between a definitive clinical trial (ABC) as compared to current clinical care (PILOT) remained high.

Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial.

Importance: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial. Objective: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. Design, Setting, and Participants: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022. Interventions: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. Main Outcomes and Measures: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days. Results: There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95]). Conclusions and Relevance: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction. Trial Registration: ClinicalTrials.gov Identifier: NCT05094154.

Protocol and statistical analysis plan for the Mode of Ventilation During Critical IllnEss (MODE) trial.

Introduction: For every critically ill adult receiving invasive mechanical ventilation, clinicians must select a mode of ventilation. The mode of ventilation determines whether the ventilator directly controls the tidal volume or the inspiratory pressure. Newer hybrid modes allow clinicians to set a target tidal volume, for which the ventilator controls and adjusts the inspiratory pressure. A strategy of low tidal volumes and low plateau pressure improves outcomes, but the optimal mode to achieve these targets is not known. Methods and analysis: The Mode of Ventilation During Critical Illness (MODE) trial is a cluster-randomized, multiple-crossover pilot trial being conducted in the medical intensive care unit (ICU) at an academic center. The MODE trial compares the use of volume control, pressure control, and adaptive pressure control. The study ICU is assigned to a single ventilator mode (volume control versus pressure control versus adaptive pressure control) for continuous mandatory ventilation during each 1-month study block. The assigned mode switches every month in a randomly generated sequence. The primary outcome is ventilator-free days (VFDs) to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of mechanical ventilation to 28 days after enrollment. Enrollment began November 1, 2022 and will end on July 31, 2023. Ethics and dissemination: The trial was approved by the Vanderbilt University Medical Center institutional review board (IRB# 220446). Results of this study will be submitted to a peer-reviewed journal and presented at scientific conferences. Trial registration number: The trial was registered with clinicaltrials.gov on October 3, 2022, prior to initiation of patient enrollment on November 1, 2022 (ClinicalTrials.gov identifier: NCT05563779).

Piperacillin-Tazobactam Versus Anti-Pseudomonal Cephalosporins and Renal and Neurologic Outcomes in Critically Ill Adults: A Secondary Analysis of the SMART Trial.

Background: Prior studies suggest associations between receipt of piperacillin-tazobactam and development of acute kidney injury and receipt of anti-pseudomonal cephalosporins and neurotoxicity. We compared clinically-relevant renal and neurologic outcomes in critically ill patients who received piperacillin-tazobactam versus anti-pseudomonal cephalosporins. Methods: We conducted a secondary analysis of data from the Isotonic Solutions and Major Adverse Renal Events Trial examining patients who received piperacillin-tazobactam or an anti-pseudomonal cephalosporin within 24 h of intensive care unit admission. We performed multivariable analysis using a proportional odds model to examine the association between the first antibiotic received and the outcomes of Major Adverse Kidney Events within 30 days (MAKE30) and days alive and free of delirium and coma to day 28. Results: 3199 were included in the study; 2375 (74%) receiving piperacillin-tazobactam and 824 (26%) receiving anti-pseudomonal cephalosporin. After adjustment for prespecified confounders, initial receipt of piperacillin-tazobactam, compared to anti-pseudomonal cephalosporins, was not associated with higher incidence of MAKE30 (adjusted odds ratio, 1.03; 95% CI, 0.83-1.27; P = .80) but was associated with a greater number of days alive and free of delirium and coma (adjusted odds ratio, 1.18; 95% CI, 1.00-1.38; P = .04). In a sensitivity analysis adjusting for baseline receipt of medications which may impact neuro function, this finding was not significant. Conclusion: Among critically ill adults, receipt of piperacillin-tazobactam was not associated with an increased incidence of death, renal replacement therapy, or persistent renal dysfunction or a greater number of days alive and free of delirium and coma. Randomized trials are needed to inform the choice of antibiotics for empiric treatment infection in critically ill adults.

An International, Multicenter Evaluation of Comprehensive Medication Management by Pharmacists in ICU Recovery Centers.

BACKGROUND: Post-intensive care syndrome (PICS) is defined as a new or worsening impairment in physical, cognitive, or mental health following critical illness. Intensive care unit recovery centers (ICU-RC) are one means to treat patients who have PICS. The purpose of this study is to describe the role of pharmacists in ICU-RCs. RESEARCH QUESTION: What is the number and type of medication interventions made by a pharmacist at an ICU-RC at 12 different centers? STUDY DESIGN AND METHODS: This prospective, observational study was conducted in 12 intensive care units (ICUs)/ICU-RCs between September 2019 and July 2021. A full medication review was conducted by a pharmacist on patients seen at the ICU-RC. RESULTS: 507 patients were referred to the ICU-RC. Of these patients, 474 attended the ICU-RC and 472 had a full medication review performed by a pharmacist. Baseline demographic and hospital course data were obtained from the electronic health record and at the ICU-RC appointment. Pharmacy interventions were made in 397 (84%) patients. The median number of pharmacy interventions per patient was 2 (interquartile range [IQR] = 1,3). Medications were stopped and started in 124 (26%) and 91 (19%) patients, respectively. The number of patients that had a dose decreased and a dose increased was 51 (11%) and 43 (9%), respectively. There was no difference in the median total number of medications that the patient was prescribed at the start and end of the patient visit (10, IQR = 5, 15). Adverse drug event (ADE) preventive measures were implemented in 115 (24%) patients. ADE events were identified in 69 (15%) patients. Medication interactions were identified in 30 (6%) patients. INTERPRETATION: A pharmacist plays an integral role in an ICU-RC resulting in the identification, prevention, and treatment of medication-related problems. This paper should serve as a call to action on the importance of the inclusion of a pharmacist in ICU-RC clinics.

Protocol and statistical analysis plan for the Antibiotic Choice On ReNal outcomes (ACORN) randomised clinical trial.

INTRODUCTION: Antibiotics are time-critical in the management of sepsis. When infectious organisms are unknown, patients are treated with empiric antibiotics to include coverage for gram-negative organisms, such as antipseudomonal cephalosporins and penicillins. However, in observational studies, some antipseudomonal cephalosporins (eg, cefepime) are associated with neurologic dysfunction while the most common antipseudomonal penicillin (piperacillin-tazobactam) is associated with acute kidney injury (AKI). No randomised control trials have compared these regimens. This manuscript describes the protocol and analysis plan for a trial designed to compare the effects of antipseudomonal cephalosporins and antipseudomonal penicillins among acutely ill patients receiving empiric antibiotics. METHODS AND ANALYSIS: The Antibiotic Choice On ReNal outcomes trial is a prospective, single-centre, non-blinded randomised trial being conducted at Vanderbilt University Medical Center. The trial will enrol 2500 acutely ill adults receiving gram-negative coverage for treatment of infection. Eligible patients are randomised 1:1 to receive cefepime or piperacillin-tazobactam on first order entry of a broad-spectrum antibiotic covering gram-negative organisms. The primary outcome is the highest stage of AKI and death occurring between enrolment and 14 days after enrolment. This will be compared between patients randomised to cefepime and randomised to piperacillin-tazobactam using an unadjusted proportional odds regression model. The secondary outcomes are major adverse kidney events through day 14 and number of days alive and free of delirium and coma in 14 days after enrolment. Enrolment began on 10 November 2021 and is expected to be completed in December 2022. ETHICS AND DISSEMINATION: The trial was approved by the Vanderbilt University Medical Center institutional review board (IRB#210591) with a waiver of informed consent. Results will be submitted to a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT05094154.

Quantifying Critical Care Pharmacist Interventions in COVID-19.

Purpose/Background: Pharmacists have been shown to play an important role in the medication management of critically ill patients. Pharmacist interventions in the care of critically ill patients with coronavirus disease 2019 (COVID-19) have not been quantitatively described. Methodology: A single center, retrospective, observational study was conducted at Vanderbilt University Medical Center in Nashville, Tennessee. All adult patients admitted to the COVID-19 intensive care unit (ICU) or Medical ICU with a COVID-19 diagnosis between March 1, 2020, and June 30, 2021, were included. All interventions made by pharmacists were documented electronically, collected, categorized, and analyzed. The primary outcome of this study was the median number of interventions by pharmacists per patient. The secondary outcome was the number of different types of interventions performed. Results: A total of 768 patients were included in the analysis. The median age was 63 years old; 63% of patients were male and 71% were Caucasian. Median hospital length of stay (LOS) was 12 days (interquartile range (IQR) 7-21) and ICU LOS was 5 days (IQR 1-11). The median Sequential Organ Failure Assessment score was 4 (IQR 2-7) and Charlson Comorbidity Index was 3 (IQR 2-5). Mortality at 60 days occurred in 352 patients (46%). Pharmacists performed a total of 7027 interventions for 655 patients with a median number of pharmacist interventions per patient of 6 (IQR 3-14). The most common pharmacist interventions were medication discontinuation (24%), completion of components of the ICU liberation bundle (19%), medication dose adjustment (18%), therapeutic drug monitoring (15%), and medication initiation (10%). Conclusions: Pharmacists made multiple interventions related to medication use and management in critically ill patients with COVID-19. This study adds important information of the evolving role clinical pharmacists play in the care of critical illness, specifically during the COVID-19 pandemic.

Identifying Predictors of Extubation on the day of Passing an SBT in Critically ill Adults.

INTRODUCTION: Many patients who pass a spontaneous awakening trial (SAT) and spontaneous breathing trial (SBT) do not undergo extubation that day. We aimed to identify predictors of extubation on the day of passing an SBT and to develop prediction models for extubation among mechanically ventilated patients. METHODS: In a cohort of mechanically ventilated patients who had passed an SBT in a single, academic medical intensive care unit (ICU) from 2018 to 2019, we developed a logistic regression model for identifying predictors of extubation. RESULTS: Of 745 patients in our study, 77% were extubated the day they passed a SBT. Independent predictors of extubation included higher Richmond Agitation Sedation Scale (RASS) (-2 compared to -4: odds ratio (OR) 1.83, 95% confidence interval (CI) 1.56 to 2.14), receipt of sedation on the day prior (OR 2.12, 95% CI 1.63 to 2.74), absence of diagnosis of sepsis or septic shock (OR 0.77, 95% CI 0.59 to 1), absence of neurological illness (OR 0.59, 95% CI 0.37 to 0.96), indication for intubation of altered mental status, seizure, or agitation (OR 1.67, 95% CI 1.05 to 2.65), and absence of hemodynamic instability or cardiac arrest (OR 0.67, 95% CI 0.47 to 0.95). CONCLUSION AND RELEVANCE: Patients on mechanical ventilation were more likely to be extubated on the day they passed an SBT if they had higher RASS scores, received sedation the day prior, or did not have diagnosis of sepsis, neurological illness, or hemodynamic instability. Future research should attempt to identify and address modifiable risk factors for failure to extubate after passing an SBT.

A pharmacogenetic precision medicine approach to analgesia and sedation optimization in critically ill adults.

Precision medicine is a growing field in critical care. Research increasingly demonstrated pharmacogenomic variability to be an important determinant of analgesic and sedative drug response in the intensive care unit (ICU). Genome-wide association and candidate gene finding studies suggest analgesic and sedatives tailored to an individual's genetic makeup, environmental adaptations, in addition to several other patient- and drug-related factors, will maximize effectiveness and help mitigate harm. However, the number of pharmacogenetic studies in ICU patients remains small and no prospective studies have been published using pharmacogenomic data to optimize analgesic or sedative therapy in critically ill patients. Current recommendations for treating ICU pain and agitation are based on controlled studies having low external validity, including the failure to consider pharmacogenomic factors affecting response. Use of a precision medicine approach to individualize pharmacotherapy focused on optimizing ICU patient comfort and safety may improve the outcomes of critically ill adults. Additionally, benefits and risks of analgesic and/or sedative therapy in an individual may be informed with large, standardized datasets. The purpose of this review was to describe a precision medicine approach focused on optimizing analgesic and sedative therapy in individual ICU patients to optimize clinical outcomes and reduce safety concerns.

Patient and caregiver experiences with a telemedicine intensive care unit recovery clinic.

BACKGROUND: Intensive Care Unit Recovery Clinics (ICU-RCs) were founded to address post-intensive care syndrome among ICU survivors. Telemedicine ICU-RCs may facilitate access for more ICU survivors, however, patient and caregiver experiences with telemedicine ICU-RCs have not been explored qualitatively. OBJECTIVE: To explore patient and informal caregiver experiences with a telemedicine ICU-RC. METHODS: Our qualitative exploratory cross-sectional study was guided by qualitative description methodology. Telemedicine ICU-RC visits were conducted at 3- and 12-weeks post-discharge following critical illness. Patients, and caregivers when available, met with an ICU pharmacist, ICU physician, and a neuropsychologist via Zoom. Thereafter, we conducted qualitative (1:1) telephone interviews with 14 patients and 12 caregivers recruited purposefully. Data were analyzed using conventional content analysis. RESULTS: Five themes were identified: (1) general impressions of the intervention; (2) intervention organization and delivery; (3) intervention substance; (4) caregiver participation; and (5) ways to improve the intervention. Participants found the telemedicine delivery acceptable, convenient, time-saving, and conducive to thorough discussions. Participants appreciated the information, reassurance, and validation. Attention to mental health during the visits was strongly endorsed. Caregiver involvement depended on patient self-management and technical ability. Suggestions included scheduling a 1-week post-discharge visit, more follow-up visits, and individualizing content for in-depth discussions, including mental health evaluation. CONCLUSIONS: The study results enhance the understanding of patient and caregiver experiences with a telemedicine ICU-RC. Participants' narratives helped to formulate recommendations to improve telemedicine ICU-RC delivery and content. Acceptability of this intervention indicates the potential for wider implementation of telemedicine ICU-RCs to reach more ICU survivors.