Major Publications in the Critical Care Pharmacotherapy Literature: 2023.

OBJECTIVES: We aimed to summarize the most significant and impactful publications describing the pharmacotherapeutic care of critically ill patients in 2023. DATA SOURCES: PubMed/MEDLINE and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. STUDY SELECTION: Randomized controlled trials and prospective studies of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2023, and December 31, 2023, were eligible for inclusion in this article. DATA EXTRACTION: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included. An a priori defined three-round modified Delphi process was employed to achieve consensus on the most impactful publications based on the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. DATA SYNTHESIS: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update returned a total of 1202 articles, of which 1164 were excluded. The remaining 38 articles underwent a three-round modified Delphi process. In each round, articles were independently scored based on overall contribution to scientific knowledge and novelty to the literature. Included articles are summarized and their impact discussed. Article topics included hydrocortisone for severe community-acquired pneumonia, inhaled amikacin for prevention of ventilator-associated pneumonia, methylene blue for septic shock, restrictive vs. liberal fluid management for sepsis-induced hypotension, andexanet alfa for major bleeding associated with factor Xa inhibitors, and early administration of four-factor prothrombin complex concentrate in patients with trauma at risk for massive transfusion. CONCLUSIONS: This review provides a summary and perspective on the potential impact of the most relevant articles in 2023 describing advances in the pharmacotherapeutic care of critically ill patients.

Multicenter study evaluating target attainment of anti-Factor Xa levels using various enoxaparin prophylactic dosing practices in adult trauma patients.

STUDY OBJECTIVE: Enoxaparin is standard of care for venous thromboembolism (VTE) prophylaxis in adult trauma patients, but fixed-dose protocols are suboptimal. Dosing based on body mass index (BMI) or total body weight (TBW) improves target prophylactic anti-Xa level attainment and reduces VTE rates. A novel strategy using estimated blood volume (EBV) may be more effective based on results of a single-center study. This study compared BMI-, TBW-, EBV-based, and hybrid enoxaparin dosing strategies at achieving target prophylactic anti-Factor Xa (anti-Xa) levels in trauma patients. DESIGN: Multicenter, retrospective review. DATA SOURCE: Electronic health records from participating institutions. PATIENTS: Adult trauma patients who received enoxaparin twice daily for VTE prophylaxis and had at least one appropriately timed anti-Xa level (collected 3 to 6 hours after the previous dose after three consecutive doses) from January 2017 through December 2020. Patients were excluded if the hospital-specific dosing protocol was not followed or if they had thermal burns with > 20% body surface area involvement. INTERVENTION: Dosing strategy used to determine initial prophylactic dose of enoxaparin. MEASUREMENTS: The primary end point was percentage of patients with peak anti-Xa levels within the target prophylactic range (0.2-0.4 units/mL). MAIN RESULTS: Nine hospitals enrolled 742 unique patients. The most common dosing strategy was based on BMI (43.0%), followed by EBV (29.0%). Patients dosed using EBV had the highest percentage of target anti-Xa levels (72.1%). Multiple logistic regression demonstrated EBV-based dosing was significantly more likely to yield anti-Xa levels at or above target compared to BMI-based dosing (adjusted odds ratio (aOR) 3.59, 95% confidence interval (CI) 2.29-5.62, p < 0.001). EBV-based dosing was also more likely than hybrid dosing to yield an anti-Xa level at or above target (aOR 2.30, 95% CI 1.33-3.98, p = 0.003). Other pairwise comparisons between dosing strategy groups were nonsignificant. CONCLUSIONS: An EBV-based dosing strategy was associated with higher odds of achieving anti-Xa level within target range for enoxaparin VTE prophylaxis compared to BMI-based dosing and may be a preferred method for VTE prophylaxis in adult trauma patients.

Multimodal Pain Management Protocol to Decrease Opioid Use and to Improve Pain Control After Thoracic Surgery.

BACKGROUND: Opioid addiction continues to be a devastating problem in our communities, and up to 40% of patients begin their addiction with legally prescribed opioids after injury or surgical procedure. An opioid-free multimodal pain regimen was developed with the goal of decreasing opioid exposure while maintaining adequate pain control. METHODS: A retrospective single-institution study was conducted of 313 consecutive patients undergoing minimally invasive lobectomy before (n = 211) and after (n = 102) implementation of an opioid-free protocol from 2016 to 2020. Data analysis was conducted on preoperative characteristics, postoperative opioid use at set time points (postoperative day 0, postoperative days 1 to 7, and total stay), pain scores, discharge with opioid prescription, and postoperative outcomes. RESULTS: Patients on the opioid-free protocol had significantly lower average total morphine milligram equivalents at all time points. In addition, 56% of patients in the opioid-free group received no oral opioids at all, and 91% did not receive a patient-controlled analgesia pump. Average pain scores were significantly lower in the opioid-free protocol patients along with percentage of time spent with pain scores <3 and <6. With implementation of the protocol, 62% of patients are discharged without an opioid prescription compared with only 7% previously. CONCLUSIONS: Implementation of an opioid-free protocol led to a significant decrease in the use of postoperative opioids at all time points while improving overall management of pain. In addition, most patients are discharged with no home opioid prescription, decreasing a potential source of community opioid spread.

Clinical and Procedural Evaluation of a Pharmacy Pharmacokinetic Consult Service.

PURPOSE: Though previous studies have shown benefit with pharmacist-managed dosing of antibiotics, many institutions still do not offer such services. Our objective was to determine and report novel outcomes associated with the implementation of a pharmacist-managed pharmacokinetic/pharmacodynamic consult service and to assess the impact of direct pharmacist involvement in therapeutic drug monitoring. METHODS: Retrospective cohort study of patients who received vancomycin or an aminoglycoside in the medical intensive care unit from January 5, 2013, to January 6, 2015, divided into 2 groups: before/after implementation of the consult service on January 6, 2014. RESULTS: Nine-hundred sixty-two patients were included. Groups were similar at baseline. There were fewer critical values after implementation of the consult service (40.8% vs 27.3%, P < .001). The intervention group had significantly more vancomycin troughs within therapeutic range (15.4% vs 32.8%, P = .019). Time from order entry to medication administration was shorter when pharmacists entered the medication order, although this difference was nonsignificant (103 minutes vs 77 minutes, P = .054). CONCLUSION: Implementation of a pharmacist-managed dosing and monitoring program led to significantly decreased rates of critical value drug concentrations and increased rates of therapeutic concentrations, with a 25% (NS) decreased time-to-antibiotic administration, therefore demonstrating the additive value of the pharmacist-managed over pharmacist-monitored approach.

Analysis of a new best-practice advisory on time to initiation of antibiotics in surgical intensive care unit patients with septic shock.

BACKGROUND: Early administration of antibiotics in septic shock is associated with decreased mortality. Promptly identifying sepsis and eliciting a response are necessary to reduce time to antibiotic administration. METHODS: A best-practice advisory was introduced in the surgical intensive care unit to identify patients with septic shock and promote timely action. The best-practice advisory is triggered by blood culture orders and vasopressor administration within 24 h. The nurse or provider who triggers the alert may send an automatic notification to the intensive care unit resident, clinical pharmacist, and charge nurse, prompting bedside response and closer evaluation. Patients who met best-practice advisory criteria in the surgical intensive care unit from May 2016 through March 2017 were included. Outcomes included changes in antibiotics within 24 h, response to best-practice advisory, and time-to-antibiotics. Time-to-antibiotics was compared between a retrospective pre-intervention period and a six-month prospective post-intervention period defined by launch of the new best-practice advisory in September 2016. Data were analyzed by chi square, Mann-Whitney U, and Kruskal-Wallis. RESULTS: During the first six months of best-practice advisory implementation, 191 alerts were triggered by 97 unique patients. Alert notification was transmitted in 79 best-practice advisories (41%), with pharmacist bedside response in 53 (67%). New antibiotics were started within 24 h following 83 best-practice advisories (43%). There was a trend toward decreased time-to-antibiotics following implementation of the best-practice advisory (7.4 vs. 4.2 h, p = 0.057). Compared to the entire cohort, time-to-antibiotics was shorter when the team was notified and when a pharmacist responded to the bedside (4.2 vs. 1.6 vs. 1.2 hours). CONCLUSIONS: A new best-practice advisory has been effective at eliciting a rapid response and reducing the time-to-antibiotics in surgical intensive care unit patients with septic shock. Team notification and pharmacist response are associated with decreased time-to-antibiotics.

Comparative Effectiveness and Safety Analysis of Dual Antiplatelet Therapies Within an Integrated Delivery System.

BACKGROUND: Dual antiplatelet therapy is a mainstay of care for percutaneous coronary intervention (PCI) patients; however, uncertainty exists in real-world practice about comparative effectiveness and safety outcomes. OBJECTIVE: To evaluate outcomes of different oral P2Y12 inhibitors in PCI patients. METHODS: We retrospectively studied patients treated between July 1, 2010, and December 31, 2013. Patients received clopidogrel, prasugrel, ticagrelor, or more than 1 antiplatelet (switch) during PCI. Outcomes were evaluated for major adverse cardiovascular events (MACE) and bleeding at 1 year. Propensity score matching with Cox proportional hazards analysis was used to determine predictors of MACE and bleeding. RESULTS: A total of 8127 patients were included: clopidogrel (n = 6872), prasugrel (n = 605), ticagrelor (n = 181), and switch (n = 469). Treatment with prasugrel was associated with the lowest risk of MACE using multivariate regression (odds ratio [OR] = 0.57; 95% CI = 0.36-0.92; P = 0.02). In the propensity score-matched analysis, only the prasugrel group was associated with a lower risk of MACE compared with the clopidogrel group. Clopidogrel was associated with the lowest risk of major bleeding using multivariate regression (OR = 0.64; 95% CI = 0.42-0.98; P = 0.042). Both ticagrelor (hazard ratio [HR] = 2.00; 95% CI = 1.11-3.59) and the switch groups (HR = 1.65; 95% CI = 1.09-2.50) were associated with a greater risk of major bleeding compared with clopidogrel. However, no differences were found in the propensity score-matched analysis. CONCLUSIONS: Dual antiplatelet therapies differed in both MACE and bleeds in a real-world setting of PCI. Prasugrel was associated with fewer MACE, whereas clopidogrel had fewer major bleeding events.

Multicomponent synthesis of diverse 1,4-benzodiazepine scaffolds.

The 1,4-benzodiazepine (BDZ) scaffold is of particular interest in drug design due to a balanced ensemble of beneficial physicochemical properties including a semirigid and compact diazepine ring with spatial placements of several substituents, combined with low number of rotatable bonds, hydrogen bond donors and acceptors, and intermediate lipophilicity. As an alternative to traditional multistep sequential syntheses, we designed routes employing one-pot MCRs to accelerate access diverse BDZ scaffolds in two or three steps.