The Penn Medicine COVID-19 Therapeutics Committee-Reflections on a Model for Rapid Evidence Review and Dynamic Practice Recommendations During a Public Health Emergency.

The Penn Medicine COVID-19 Therapeutics Committee-an interspecialty, clinician-pharmacist, and specialist-front line primary care collaboration-has served as a forum for rapid evidence review and the production of dynamic practice recommendations during the 3-year coronavirus disease 2019 public health emergency. We describe the process by which the committee went about its work and how it navigated specific challenging scenarios. Our target audiences are clinicians, hospital leaders, public health officials, and researchers invested in preparedness for inevitable future threats. Our objectives are to discuss the logistics and challenges of forming an effective committee, undertaking a rapid evidence review process, aligning evidence-based guidelines with operational realities, and iteratively revising recommendations in response to changing pandemic data. We specifically discuss the arc of evidence for corticosteroids; the noble beginnings and dangerous misinformation end of hydroxychloroquine and ivermectin; monoclonal antibodies and emerging viral variants; and patient screening and safety processes for tocilizumab, baricitinib, and nirmatrelvir-ritonavir.

Characteristics, Outcomes, and Trends of Patients With COVID-19-Related Critical Illness at a Learning Health System in the United States.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally. OBJECTIVE: To describe the epidemiology of COVID-19-related critical illness, including trends in outcomes and care delivery. DESIGN: Single-health system, multihospital retrospective cohort study. SETTING: 5 hospitals within the University of Pennsylvania Health System. PATIENTS: Adults with COVID-19-related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic. MEASUREMENTS: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions. RESULTS: Among 468 patients with COVID-19-related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change. LIMITATIONS: Single-health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications. CONCLUSION: Among patients with COVID-19-related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Predictors of Cisatracurium Continuous Infusion Dose in Acute Respiratory Distress Syndrome.

Neuromuscular blockade (NMB) with cisatracurium may improve outcomes in the acute respiratory distress syndrome (ARDS) population; however, optimal dosing strategy remains unknown. Factors affecting pharmacokinetics and pharmacodynamics of cisatracurium may impact the dose required to achieve adequate train-of-four (TOF) response. The aims of this study were to determine cisatracurium dose requirements in a critically ill ARDS population and to identify clinical factors that affect dosing. This was a single-center, retrospective cohort study of medical intensive care patients who received cisatracurium infusion for treatment of ARDS. "Stable dose" was defined as the infusion rate producing 2 consecutive TOFs of 1/4 to 2/4. Factors examined for association with dose were temperature, pH, age, and the presence of acute kidney injury (AKI). The analysis included 39 patients. The median stable dose of cisatracurium was 2.8 (2.0, 3.1) µg/kg/min. Multivariable linear regression model for weight-normalized dose identified AKI as a factor independently associated with steady-state dose requirements (% change -31.4, 95% confidence interval [CI]: -51.9, -2.3). Our study provides information on cisatracurium doses required in patients with ARDS to reduce time required to reach goal TOF. Further studies are needed to determine effect of AKI on cisatracurium dose requirements and clinical outcomes.

Recombinant activated factor VII use in critically ill patients: clinical outcomes and thromboembolic events.

BACKGROUND: Hemorrhage and coagulopathy are associated with morbidity and mortality in critically ill patients. Recombinant activated factor VII (rFVIIa) is frequently used in these situations to control bleeding; however, few controlled clinical trials have demonstrated clinical benefit and prolonged survival. OBJECTIVE: To compare clinical outcomes and thromboembolic events in intensive care unit (ICU) patients who received rFVIIa versus ICU patients who did not between 2000 and 2005. METHODS: A total of 2918 nonhemophiliac adult ICU patients, which included 1459 who received at least 1 dose of rFVIIa and 1459 matched controls who did not, were included in a retrospective database study. Data were extracted from the Solucient ACTracker database, which included 550 hospitals across the US. Measures included patient demographics, rFVIIa prescribing, death, thromboembolic events, discharge disposition, length of stay, and transfusion data. RESULTS: The most common primary diagnoses for patients receiving rFVIIa included traumatic brain injury, cirrhosis, and nontraumatic intracranial hemorrhage. Patients receiving rFVIIa were more likely to have comorbidities, including mechanical ventilation, acute kidney injury, sepsis, hemodialysis, and gastrointestinal bleeding (p < 0.0001). The average rFVIIa dose was 4.8 mg and 82% of patients received 1 dose. Compared to controls, patients receiving rFVIIa had greater odds of death (OR 2.1, 95% CI 1.8-2.6, p < 0.0001), transfusion (OR 2.1, 95% CI 1.8-2.5, p < 0.0001), and longer length of stay (p < 0.001). There was no significant difference in thromboembolic events between groups. CONCLUSIONS: While we cannot show direct causality between rFVIIa and the poor clinical outcomes documented in ICU patients, they provide important insight for critical care clinicians.

Antimicrobial use in a critical care unit: a prospective observational study.

OBJECTIVE: The purpose of this study was to describe antimicrobial utilization, consumption, indications and microbial resistance in a medical-surgical-trauma intensive care unit (ICU) of a teaching hospital to identify potential targets for antimicrobial stewardship. METHODS: This was a 30-day prospective observational study enrolling adults admitted to the ICU for at least 24 h and having received antimicrobial therapy. Primary endpoints included utilization as percentage use of antimicrobials by class and agent, consumption measured as days of therapy per 1000 patient days (DOT/1000PD), indications for use and prescriber. Secondary endpoints included reasons for modifications to therapy and microbial resistance. KEY FINDINGS: Eighty-three patients were screened and 61 enrolled, receiving 133 courses of antimicrobial therapy, mainly intravenously and prescribed by ICU staff. The most frequently prescribed agents were piperacillin/tazobactam (20%), cefazolin (17%) and vancomycin (13%). The indications for therapy were empirical (50%), directed (27%) and prophylactic (23%). Overall consumption was 1368.54 DOT/1000PD and was mainly attributed to empirical therapy (734.25). Prolonged durations were noted for carbapenems and for surgical prophylaxis. There were 86 therapy modifications involving indication (36), efficacy (25), safety (18) and route (7). Suboptimal or excessive dosing were common contributors to efficacy and safety modifications, respectively. Infections due to microorganisms with notable resistance included methicillin-resistant Staphylococcus aureus (5), Pseudomonas aeruginosa (1) and Streptococcus pneumoniae (1). CONCLUSIONS: Antimicrobial utilization and consumption based on DOT/1000PD were prospectively determined providing a comparator for other ICUs. Potential targets identified for antimicrobial stewardship initiatives include empirical therapy, treatment duration, dosing and route.

Drug interaction between carbapenems and extended-release divalproex sodium in a patient with schizoaffective disorder.

BACKGROUND: Clinicians prescribing divalproex sodium (DVX) are well aware of its potential to cause a drug-drug interaction. One specific interaction occurs between the carbapenem antibiotics and DVX resulting in decreased valproic acid (VPA) levels immediately following the initiation of this antibiotic class. OBJECTIVE/METHOD: We describe a case of a 46 year-old Caucasian male who had an undetectable VPA level following treatment with carbapenems. RESULTS: On admission the patient's VPA level was 115 µg/ml; however, a routine VPA level on day 19 of his hospitalization returned a value of 16 µg/ml. At this point, he had received a total of 15 days of carbapenem antibiotics for treatment of lower leg cellulitis. His DVX dose was increased to a maximum of 6g daily, twice his home dose, but it did not produce a therapeutic VPA concentration. The patient was lost to follow-up before an outpatient VPA level was drawn. CONCLUSION: Our case report is the first to document this drug-drug interaction in a patient diagnosed with schizoaffective disorder, bipolar type.