Comparative efficacy of later-line therapies for metastatic colorectal cancer: a network meta-analysis of survival curves.

INTRODUCTION: We evaluated the comparative efficacy of 6 later-line (≥3) therapies for metastatic colorectal cancer (mCRC) over placebo. We applied a novel statistical method of reconstructing pseudo patient-level data (pseudo-IPD) to inform a network meta-analysis of survival curves that considers shape in addition to scale parameters. METHODS: A literature search yielded 10 phase II/III trials. We digitized all survival curves and applied a novel method incorporating curve coordinates, patients-at-risk, and events reported to generate pseudo-IPD. Using fitted random effects lognormal distributions, we estimated the survival proportions and HRs(95CrI) of progression-free (PFS) and overall survival(OS) over 12 months of follow-up. RESULTS: Compared to placebo, in ascending order, 12-month OS HRs were 0.50(95%CrI = 0.35, 0.69; PFS = 0.11(95%CrI = 0.06, 0.14)) for TAS+bevacizumab; 0.71(95%CrI = 0.51, 0.97; PFS = 0.26(95%CrI = 0.16, 0.41)) for regorafenib; 0.75(95%CrI = 0.61, 0.91; (PFS = 0.24(95%CrI = 0.17, 0.31)) for TAS-102; 0.80(95%CrI = 0.79, 0.90; PFS = 0.18(95%CrI = 0.13, 0.24)) for fruquintinib; 0.83(95%CrI = 0.50, 0.99; PFS = 0.42(95%CrI = 0.20, 0.75)) for atezolizumab+cobimetinib; and 1.03(95%CrI = 0.55, 1.65; PFS = 0.67(95%CrI = 0.29, 1.01)) for atezolizumab. CONCLUSION: In this independent NMA of survival data all later-line mCRC therapies but atezolizumab monotherapy exhibited superiority in 12-month PFS and OS over placebo. TAS+bevacizumab emerged as the most dominant option and may be the preferred choice; with fruquintinib, regorafenib and TAS-102 monotherapy showing statistically significant but lower PFS and OS benefits. REGISTRATION: PROSPERO: CRD42022371953.

Buprenorphine in the Intensive Care Unit: Commentary on the Unanswered Questions.

The removal of the X-waiver in the Mainstreaming Addiction Treatment (MAT) Act of 2023 has substantial implications for buprenorphine prescribing as one of the options to treat opioid use disorder. The purpose of this commentary is to discuss the unanswered questions regarding buprenorphine in the intensive care unit (ICU) including how the passage of the MAT Act will affect ICU providers, which patients should receive buprenorphine, what is the most appropriate route of administration and dose of buprenorphine, what medications interact with buprenorphine, and how can transitions of care be optimized for these patients.

Accuracy of a Chatbot in Answering Questions that Patients Should Ask Before Taking a New Medication.

BACKGROUND: The potential uses of artificial intelligence have extended into the fields of healthcare delivery and education. However, challenges are associated with introducing innovative technologies into healthcare, particularly with respect to information quality. OBJECTIVE: To evaluate the accuracy of answers provided by a chatbot in response to questions that patients should ask before taking a new medication. METHODS: Twelve questions obtained from the Agency for Healthcare Research and Quality were asked to a chatbot for the top 20 drugs. Two reviewers independently evaluated and rated each response on a 6-point scale for accuracy and a 3-point scale for completeness with a score of 2 considered adequate. Accuracy was determined using clinical expertise and a drug information database. After the independent reviews, answers were compared, and discrepancies were assigned a consensus score. RESULTS: Out of 240 responses, 222 (92.5%) were assessed as completely accurate. Of the inaccurate responses, 10 (4.2%) were mostly accurate, 5 (2.1%) more accurate than inaccurate, 2 (0.8%) were equal parts accurate and inaccurate, and 1(0.4%) was more inaccurate than accurate. Of the 240 responses, 194 (80.8%) were comprehensively complete. There were 235 (97.9%) responses that scored 2 or higher. Five responses (2.1%) were considered incomplete. CONCLUSION: Utilizing a chatbot to answer questions commonly asked by patients is mostly accurate but may include inaccurate information or lack valuable information for patients.

Evaluation of a Generative Language Model Tool for Writing Examination Questions.

OBJECTIVE: To describe an evaluation of a generative language model tool to write examination questions for a new elective course focused on the interpretation of common clinical laboratory results being developed as an elective for students in a Bachelor of Science in Pharmaceutical Sciences program. METHODS: A total of 100 multiple-choice questions were generated using a publicly available large language model for a course dealing with common laboratory values. Two independent evaluators with extensive training and experience in writing multiple-choice questions evaluated each question for appropriate formatting, clarity, correctness, relevancy, and difficulty. For each question, a final dichotomous judgment was assigned by each reviewer, usable as written or not usable written. RESULTS: The major finding of this study was that a generative language model (ChatGPT 3.5) could generate multiple-choice questions for assessing common laboratory value information but only about half the questions (50% and 57% for the 2 evaluators) were deemed usable without modification. General agreement between evaluator comments was common (62% of comments) with more than 1 correct answer being the most common reason for commenting on the lack of usability (N = 27). CONCLUSION: The generally positive findings of this study suggest that the use of a generative language model tool for developing examination questions is deserving of further investigation.

Hepatorenal Syndrome With Acute Kidney Injury: Diagnosis and Medical Management.

OBJECTIVES: To review the current definitions and diagnostic criteria for acute kidney injury (AKI) and type 1 hepatorenal syndrome (HRS) now termed HRS-AKI and discuss the challenges in deciding the most appropriate medication regimens to treat patients with HRS-AKI. DATA SOURCES: PubMed (inception to April 2023) with bibliographies of retrieved articles searched for additional articles; organizational websites for clinical practice guidelines (CPGs). STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials (RCTs) evaluating albumin and vasoconstrictors for HRS-AKI. DATA SYNTHESIS: A major change in the most recent revision of definitions and diagnostic criteria for HRS-AKI is the elimination of the set cutoff serum creatinine values for AKI. This change should be considered when comparing studies of HRS-AKI over time. Albumin has been administered to both vasoconstrictor treatment and placebo groups in all recent RCTs; however, there has never been a large RCT evaluating a no-albumin group. Most prospective trials comparing a midodrine/octreotide combination or norepinephrine to placebo or terlipressin have enrolled less than 100 patients limiting any conclusions regarding clinically important outcomes. Terlipressin with albumin has shown mixed results for complete HRS-AKI reversal with no reductions in crude mortality but adverse effect concerns involving ischemic and pulmonary events. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Type 1 hepatorenal syndrome with acute kidney injury is a potentially life-threatening syndrome with diagnostic and treatment challenges. Albumin plus a vasoconstrictor has become the routine HRS-AKI treatment even though there has not been a large RCT evaluating a no-albumin group. Terlipressin is the vasoconstrictor of choice for HRS-AKI in current CPGs, but it has adverse effect concerns and, until recently, was not available in the United States. CONCLUSIONS: In conjunction with changes in the definitions and diagnostic criteria for HRS-AKI, debate continues regarding the optimal therapy for HRS-AKI, particularly considering recent trials demonstrating ischemic and pulmonary adverse events with terlipressin used in combination with albumin.

Management of Critically Ill Patients Receiving Medications for Opioid Use Disorder.

TOPIC IMPORTANCE: Critical care clinicians are likely to see an increasing number of patients admitted to the ICU who are receiving US Food and Drug Administration-approved medications for opioid use disorder (MOUDs) given the well-documented benefits of these agents. Oral methadone, multiple formulations of buprenorphine, and extended-release naltrexone are the three types of MOUD most likely to be encountered by ICU clinicians; however, these drugs vary with respect to formulations, pharmacokinetics, and adverse effects. REVIEW FINDINGS: No published clinical practice guidelines or consensus statements are available to guide decision-making in patients admitted to the ICU setting who are receiving MOUDs before admission. Additionally, no randomized trials and limited observational studies have evaluated issues related to MOUD use in the ICU. Therefore, ICU clinicians caring for patients admitted who are taking MOUDs must base their decision-making on data extrapolation from pharmacokinetic, pharmacologic, and clinical studies performed in non-ICU settings. SUMMARY: Despite the challenges in administering MOUDs in critically ill patients, extrapolation of data from other hospital settings suggests that the benefits of continuing MOUD therapy outweigh the risks in patients able to continue therapy. This article provides guidance for critical care clinicians caring for patients admitted to the ICU already receiving methadone, buprenorphine, or extended-release naltrexone. The guidance includes algorithms to aid clinicians in the clinical decision-making process, recognizing the inherent limitations of the existing evidence on which the algorithms are based and the need to account for patient-specific considerations.

Fixed Versus Body-Sized-Based Dosing of Monoclonal Antibodies.

Monoclonal antibody products are an increasing portion of novel drug approvals. The labeling of initial drug approvals frequently involves body-size-based rather than fixed-dose administration regimens for adults without clear rationale for doing so. This presents challenges when prescribing these products for patients with extremes of body habitus who constitute a small portion of enrollment in pre-approval investigations. Fixed-dose regimens allow for standardized preparation with the potential to reduce the risk of calculation errors, drug waste, and make home administration more practical. Fixed-dose rather than body-size-based monoclonal antibody regimens should serve as the initial approach in early phase 1 clinical trials.

Considerations and limitations of buprenorphine prescribing for opioid use disorder in the intensive care unit setting: A narrative review.

PURPOSE: The purpose of this review is to discuss important considerations when prescribing buprenorphine for opioid use disorder (OUD) in the intensive care unit (ICU) setting, recognizing the challenges of providing detailed recommendations in the setting of limited available evidence. SUMMARY: Buprenorphine is a partial mu-opioid receptor agonist that is likely to be increasingly prescribed for OUD in the ICU setting due to the relaxation of prescribing regulations. The pharmacology and pharmacokinetics of buprenorphine are complicated by the availability of several formulations that can be given by different administration routes. There is no single optimal dosing strategy for buprenorphine induction, with regimens ranging from very low-dose to high dose regimens. Faster induction with higher doses of buprenorphine has been studied and is frequently utilized in the emergency department. In patients admitted to the ICU who were receiving opioids either medically or illicitly, analgesia will not occur until their baseline opioid requirements are covered when their preadmission opioid is either reversed or interrupted. For patients in the ICU who are not on buprenorphine at the time of admission but have possible OUD, there are no validated tools to diagnose OUD or the severity of opioid withdrawal in critically ill patients unable to provide the subjective components of instruments validated in outpatient settings. When prescribing buprenorphine in the ICU, important issues to consider include dosing, monitoring, pain management, use of adjunctive medications, and considerations to transition to outpatient therapy. Ideally, addiction and pain management specialists would be available when buprenorphine is prescribed for critically ill patients. CONCLUSION: There are unique challenges when prescribing buprenorphine for OUD in critically ill patients, regardless of whether they were receiving buprenorphine when admitted to the ICU setting for OUD or are under consideration for buprenorphine initiation. There is a critical need for more research in this area.

Recommended Methods of Drug Dosing Adjustment for Patients With Renal Impairment.

Since 2020, there have been changes in Food and Drug Administration guidance and in recommendations by national organizations with a focus on kidney diseases pertaining to the choice of equations used to estimate creatinine clearance and glomerular filtration rate in patients with renal impairment. This includes a recommendation by the National Kidney Foundation to avoid the use of the Cockcroft-Gault equation for drug dosing in patients with renal impairment. This commentary provides an overview of recent recommendations concerning kidney function assessment that have important implications for drug dosing in patients with renal impairment and provides suggestions for implementing these recommendations.

Navigating the Path to Careers in Academic Pharmacy Administration.

The purpose of this commentary is to discuss the qualifications, responsibilities, and keys to success for pharmacy faculty considering a department (or division) chair (head) or dean (including assistant or associate dean) position. The perspectives are those of a department chair, vice dean, and past dean of colleges of pharmacy with extensive experience in pharmacy administration. The qualifications for these administrative positions vary by institution, particularly with respect to the institution's focus on research. Because the dean is the chief executive officer of a college of pharmacy, previous administrative experience is almost always a basic requirement for the position. For associate/assistant deans and department chairs, previous experience as a faculty member is a typical minimum requirement and may include experience as a department vice chair or director of a unit within the department or division. The dean has a fiduciary duty to university administration, as well as to other external and internal stakeholders, to educate and graduate competent pharmacists and to operate within budget. Associate/assistant deans often have responsibility for specific functions of the college, such as student or professional affairs, and it is common for deans to delegate authority, responsibility, and accountability to associate/assistant deans. Department chairs have a unique perspective with respect to college activities because they must not only think about the "big picture" when considering issues with other college administrators but must oversee the implementation and monitoring of strategic initiatives through the faculty and staff who report to them.

Recommendations for Assessing the Quality of Clinical Faculty Members' Journal Publications.

Evaluation of clinical faculty involves an assessment of the quality of their publications in addition to quantity (number) of publications. In contrast to assessing quantity, assessing quality is difficult. The purpose of this paper is to discuss practical considerations and provide recommendations related to quality of publications that clinical faculty members should bear in mind as part of their overall scholarship activity. College and schools of pharmacy may not provide written criteria for assessing quality of publications, so it is important that clinical faculty members seek guidance from their department chair or direct supervisor, experienced colleagues, and formal or informal mentors or advisers. One criterion for assessing quality is whether a publication was evaluated through a peer-review process although there are other considerations including dissemination of the paper via search engines such as PubMed. Clinical faculty also need to consider authorship order on their papers and potential journals for submission.

Best Practice Strategies for Retaining Faculty During Times of Rapid Change.

Faculty retention is an issue of concern to schools and colleges of pharmacy. The reasons why faculty leave are multifactorial but often involve a breach of unwritten contract obligations between the faculty member and the organization. This article provides strategies for retaining faculty based on published literature that include perceived breaches of unwritten contracts and our own perspectives as departmental and university administrators and senior faculty members who have been involved in devising and implementing institutional change. Retention begins with recruitment but then needs to be nurtured during onboarding and as part of the overall enculturation process for new faculty members. Particular attention to the factors that influence the retention of underrepresented minorities must be incorporated to help ensure that pharmacy educators reflect the diversity of the US population.

International Analgesia and Sedation Weaning and Withdrawal Practices in Critically Ill Adults: The Adult Iatrogenic Withdrawal Study in the ICU.

OBJECTIVES: Iatrogenic withdrawal syndrome (IWS) associated with opioid and sedative use for medical purposes has a reported high prevalence and associated morbidity. This study aimed to determine the prevalence, utilization, and characteristics of opioid and sedative weaning and IWS policies/protocols in the adult ICU population. DESIGN: International, multicenter, observational, point prevalence study. SETTING: Adult ICUs. PATIENTS: All patients aged 18 years and older in the ICU on the date of data collection who received parenteral opioids or sedatives in the previous 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ICUs selected 1 day for data collection between June 1 and September 30, 2021. Patient demographic data, opioid and sedative medication use, and weaning and IWS assessment data were collected for the previous 24 hours. The primary outcome was the proportion of patients weaned from opioids and sedatives using an institutional policy/protocol on the data collection day. There were 2,402 patients in 229 ICUs from 11 countries screened for opioid and sedative use; 1,506 (63%) patients received parenteral opioids, and/or sedatives in the previous 24 hours. There were 90 (39%) ICUs with a weaning policy/protocol which was used in 176 (12%) patients, and 23 (10%) ICUs with an IWS policy/protocol which was used in 9 (0.6%) patients. The weaning policy/protocol for 47 (52%) ICUs did not define when to initiate weaning, and the policy/protocol for 24 (27%) ICUs did not specify the degree of weaning. A weaning policy/protocol was used in 34% (176/521) and IWS policy/protocol in 9% (9/97) of patients admitted to an ICU with such a policy/protocol. Among 485 patients eligible for weaning policy/protocol utilization based on duration of opioid/sedative use initiation criterion within individual ICU policies/protocols 176 (36%) had it used, and among 54 patients on opioids and/or sedatives ≥ 72 hours, 9 (17%) had an IWS policy/protocol used by the data collection day. CONCLUSIONS: This international observational study found that a small proportion of ICUs use policies/protocols for opioid and sedative weaning or IWS, and even when these policies/protocols are in place, they are implemented in a small percentage of patients.

Infection risk and management strategies for patients with cirrhosis taking proton pump inhibitors.

PURPOSE: The purpose of this review is to discuss infectious disease-related adverse effects associated with long-term proton pump inhibitor (PPI) therapy in patients with cirrhosis and to provide recommendations for appropriate use and choice of PPI when such therapy is indicated. SUMMARY: Long-term PPI therapy in patients with cirrhosis increases the risk of infections, with infections in turn increasing the risk of mortality in this patient population. Expert recommendations include restricting long-term PPI use in cirrhosis to patients with appropriate gastrointestinal indications, using a PPI for the shortest possible duration and at the lowest possible dose, and avoiding PPIs with unfavorable pharmacogenetic properties. CONCLUSION: Long-term PPI use in patients with cirrhosis has been associated with increased infections. The risk of adverse effects in observational studies, including decompensation, severe infection (especially spontaneous bacterial peritonitis), and increased mortality, appears to increase as the dose and duration of PPI increase.

Critical Care Pharmacist Attitudes and Perceptions of Neuromuscular Blocker Infusions in ARDS.

BACKGROUND: Current critical care pharmacist (CCP) practices and perceptions related to neuromuscular infusion (NMBI) use for acute respiratory distress syndrome (ARDS) maybe different with the COVID-19 pandemic and the publication of 2020 NMBI practice guidelines. OBJECTIVE: To evaluate CCP practices and perceptions regarding NMBI use for patients with moderate-severe ARDS. METHODS: We developed, tested, and electronically administered a questionnaire (7 parent-, 42 sub-questions) to 409 American College of Clinical Pharmacy (ACCP) Critical Care Practice and Research Network members in 12 geographically diverse states. The questionnaire focused on adults with moderate-severe ARDS (PaO2:FiO2<150) whose causes of dyssynchrony were addressed. Two reminders were sent at 10-day intervals. RESULTS: Respondents [131/409 (32%)] primarily worked in a medical intensive care unit (ICU) 102 (78%). Compared to COVID-negative(-) ARDS patients, COVID positive(+) ARDS patients were twice as likely to receive a NMBI (34 ± 18 vs.16 ± 17%; P < 0.01). Respondents somewhat/strongly agreed a NMBI should be reserved until after trials of deep sedation (112, 86%) or proning (92, 81%) and that NMBI reduced barotrauma (88, 67%), dyssynchrony (87, 66%), and plateau pressure (79, 60%). Few respondents somewhat/strongly agreed that a NMBI should be initiated at ARDS onset (23, 18%) or that NMBI reduced 90-day mortality (12, 10%). Only 2/14 potential NMBI risks [paralysis awareness (101, 82%) and prolonged muscle weakness (84, 68%)] were frequently reported to be of high/very high concern. Multiple NMBI titration targets were assessed as very/extremely important including arterial pH (109, 88%), dyssynchrony (107, 86%), and PaO2: FiO2 ratio (82, 66%). Train-of-four (55, 44%) and BIS monitoring (36, 29%) were deemed less important. Preferred NMBI discontinuation criteria included absence of dysschrony (84, 69%) and use ≥48 hour (72, 59%). CONCLUSIONS AND RELEVANCE: Current critical care pharmacists believe NMBI for ARDS patients are best reserved until after trials of deep sedation or proning; unique considerations exist in COVID+ patients. Our results should be considered when ICU NMBI protocols are being developed and bedside decisions regarding NMBI use in ARDS are being formulated.

Medication dosing in adult patients with reduced lean body mass and kidney injury: A focus on cystatin C.

PURPOSE: Creatinine-based estimates of glomerular filtration rate (GFR) have been the standard for classifying kidney function and guiding drug dosing for over 5 decades. There have been many efforts to compare and improve different methods to estimate GFR. The National Kidney Foundation recently updated the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations without race for creatinine (CKD-EPIcr_R) and creatinine and cystatin C (CKD-EPIcr-cys_R), and the 2012 CKD-EPI equation based on cystatin C (CKD-EPIcys) remains. The focus of this review is to highlight the importance of muscle atrophy as a cause for overestimation of GFR when using creatinine-based methods. SUMMARY: Patients with liver disease, protein malnutrition, inactivity, denervation, or extensive weight loss may exhibit markedly lower creatinine excretion and serum creatinine concentration, leading to overestimation of GFR or creatinine clearance when using the Cockcroft-Gault equation or CKD-EPIcr (deindexed). In some cases, estimated GFR appears to exceed the physiological normal range (eg, >150 mL/min/1.73 m2). Use of cystatin C is recommended when low muscle mass is suspected. One would expect discordance between the estimates such that CKD-EPIcys < CKD-EPIcr-cys < CKD-EPIcr ≈ Cockcroft-Gault creatinine clearance. Clinical evaluation can then occur to determine which estimate is likely accurate and should be used for drug dosing. CONCLUSION: In the setting of significant muscle atrophy and stable serum creatinine levels, use of cystatin C is recommended, and the resulting estimate can be used to calibrate interpretation of future serum creatinine measurements.

Precision fluid and vasoactive drug therapy for critically ill patients.

There are several clinical practice guidelines concerning the use of fluid and vasoactive drug therapies in critically ill adult patients, but the recommendations in these guidelines are often based on low-quality evidence. Further, some were compiled prior to the publication of landmark clinical trials, particularly in the comparison of balanced crystalloid and normal saline. An important consideration in the treatment of critically ill patients is the application of precision medicine to provide the most effective care to groups of patients most likely to benefit from the therapy. Although not currently widely integrated into these practice guidelines, the utility of precision medicine in critical illness is a recognized research priority for fluid and vasoactive therapy management. The purpose of this narrative review was to illustrate the evaluation and challenges of providing precision fluid and vasoactive therapies to adult critically ill patients. The review includes a discussion of important investigations published after the release of currently available clinical practice guidelines to provide insight into how recommendations and research priorities may change future guidelines and bedside care for critically ill patients.

Echinocandin exposures in obese patients: A scoping review and clinical perspectives.

PURPOSE: Echinocandins are favored drugs for the treatment of fungal infections. There is growing evidence that obese patients treated with echinocandins have lower exposures due to pharmacokinetic (PK) alterations. We conducted a scoping review to characterize, evaluate, and summarize the available evidence on echinocandins exposures in obese patients. SUMMARY: A comprehensive search of PubMed, Embase, and Cochrane Library for studies on echinocandins published from database inception to October 28, 2022, was conducted using PRISMA-ScR methodology. A total of 25 studies comprising more than 3,174 subjects (8 micafungin studies, 7 caspofungin studies, 9 anidulafungin studies, and 1 rezafungin study) were included in this review. Seventeen studies reported lower echinocandins exposures in overweight and obese individuals compared with normal-weight individuals; the authors of these studies recommended dose adjustments. Conversely, 8 studies did not find significant differences in echinocandin exposure among subjects in varying body weight categories. Clinicians may consider dose adjustments of echinocandins in obese patients; however, there is limited evidence on the ideal dose adjustment strategy to overcome the low echinocandins exposures in obese patients. CONCLUSION: This scoping review shed light on a growing body of evidence indicating that obese patients have lower echinocandin exposures relative to targeted PK indices, which may lead to negative therapeutic implications. Currently, a lack of high-quality evidence impedes reaching consensus on recommendations for echinocandin dosing adjustment in obese patients. Future research evaluating the optimal echinocandin dosing strategy for obese patients is needed.