Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed

A Target for Increased Mortality Risk in Critically Ill Patients: The Concept of Perpetuity

Background: Emergency medicine is acuity-based and focuses on time-sensitive treatments for life-threatening diseases. Prolonged time in the emergency department, however, is associated with higher mortality in critically ill patients. Thus, we explored management after an acuity-based intervention, which we call perpetuity, as a potential mechanism for increased risk. To explore this concept, we evaluated the impact of each hour above a lung-protective tidal volume on risk of mortality. Methods: This cohort analysis includes all critically ill, non-trauma, adult patients admitted to two academic EDs between 1 November 2013 and 30 April 2017. Cox models with time-varying covariates were developed with time in perpetuity as a time-varying covariate, defined as hours above 8 mL/kg ideal body weight, adjusted for covariates. The primary outcome was the time to in-hospital death. Results: Our analysis included 2025 patients, 321 (16%) of whom had at least 1 h of perpetuity time. A partial likelihood-ratio test comparing models with and without hours in perpetuity was statistically significant (χ2(3) = 13.83, p = 0.0031). There was an interaction between age and perpetuity (Relative risk (RR) 0.9995; 95% Confidence interval (CI95): 0.9991–0.9998). For example, for each hour above 8 mL/kg ideal body weight, a 20-year-old with 90% oxygen saturation has a relative risk of death of 1.02, but a 40-year-old with 90% oxygen saturation has a relative risk of 1.01. Conclusions: Perpetuity, illustrated through the lens of mechanical ventilation, may represent a target for improving outcomes in critically ill patients, starting in the emergency department. Research is needed to evaluate the types of patients and interventions in which perpetuity plays a role

The Physiologically Difficult Airway

Airway management in critically ill patients involves the identification and management of the potentially difficult airway in order to avoid untoward complications. This focus on difficult airway management has traditionally referred to identifying anatomic characteristics of the patient that make either visualizing the glottic opening or placement of the tracheal tube through the vocal cords difficult. This paper will describe the physiologically difficult airway, in which physiologic derangements of the patient increase the risk of cardiovascular collapse from airway management. The four physiologically difficult airways described include hypoxemia, hypotension, severe metabolic acidosis, and right ventricular failure. The emergency physician should account for these physiologic derangements with airway management in critically ill patients regardless of the predicted anatomic difficulty of the intubation

The Physiologically Difficult Airway

Airway management in critically ill patients involves the identification and management of the potentially difficult airway in order to avoid untoward complications. This focus on difficult airway management has traditionally referred to identifying anatomic characteristics of the patient that make either visualizing the glottic opening or placement of the tracheal tube through the vocal cords difficult. This paper will describe the physiologically difficult airway, in which physiologic derangements of the patient increase the risk of cardiovascular collapse from airway management. The four physiologically difficult airways described include hypoxemia, hypotension, severe metabolic acidosis, and right ventricular failure. The emergency physician should account for these physiologic derangements with airway management in critically ill patients regardless of the predicted anatomic difficulty of the intubation

Can Emergency Physicians Perform Common Carotid Doppler Flow Measurements to Assess Volume Responsiveness?

Introduction: Common carotid flow measurements may be clinically useful to determine volume responsiveness. The objective of this study was to assess the ability of emergency physicians (EP) to obtain sonographic images and measurements of the common carotid artery velocity time integral (VTi) for potential use in assessing volume responsiveness in the clinical setting. Methods: In this prospective observational study, we showed a five-minute instructional video demonstrating a technique to obtain common carotid ultrasound images and measure the common carotid VTi to emergency medicine (EM) residents. Participants were then asked to image the common carotid artery and obtain VTi measurements. Expert sonographers observed participants imaging in real time and recorded their performance on nine performance measures. An expert sonographer graded image quality. Participants were timed and answered questions regarding ease of examination and their confidence in obtaining the images. Results: A total of 30 EM residents participated in this study and each performed the examination twice. Average time required to complete one examination was 2.9 minutes (95% CI [2.4-3.4 min]). Participants successfully completed all performance measures greater than 75% of the time, with the exception of obtaining measurements during systole, which was completed in 65% of examinations. Median resident overall confidence in accurately performing carotid VTi measurements was 3 (on a scale of 1 [not confident] to 5 [confident]). Conclusion: EM residents at our institution learned the technique for obtaining common carotid artery Doppler flow measurements after viewing a brief instructional video. When assessed at performing this examination, they completed several performance measures with greater than 75% success. No differences were found between novice and experienced groups. [West J Emerg Med. 2015;16(2):255–259.

Improvement in the Safety of Rapid Sequence Intubation in the Emergency Department with the Use of an Airway Continuous Quality Improvement Program

Introduction: Airway management in the critically ill is associated with a high prevalence of failed first attempts and adverse events which negatively impacts patient care. The purpose of this investigation is to describe an airway continuous quality improvement (CQI) program and its effect on the safety of rapid sequence intubation (RSI) in the emergency department (ED) over a 10-year period. Methods: An airway CQI program with an ongoing airway registry was initiated in our ED on July 1, 2007 (Academic Year 1) and continued through June 30, 2017 (Academic Year 10). Data were prospectively collected on all patients intubated in the ED during this period using a structured airway data collection form. Key data points included method of intubation, drugs and devices used for intubation, operator specialty and level of training, number of intubation attempts, and adverse events. Adult patients who underwent RSI in the ED with an initial intubation attempt by emergency medicine (EM) resident were included in the analysis. The primary outcome was first pass success which was defined as successful tracheal intubation with a single laryngoscope insertion. The secondary outcome was the prevalence of adverse events associated with intubation. Educational and clinical interventions were introduced throughout the study period with the goal of optimizing these outcomes. Data were analyzed by academic year and are reported descriptively with 95% confidence intervals (CI) of the difference of means. Results: EM residents performed RSI on 342 adult patients during Academic Year 1 and on 445 adult patients during Academic Year 10. Over the 10-year study period, first pass success increased from 73.1% to 92.4% (difference = 19.3%, 95% CI 14.0% to 24.6%). The percentage of patients who experienced an adverse event associated with intubation decreased from 22.5% to 14.4% (difference = -7.9%, 95% CI -13.4% to -2.4%). The percentage of patients with first pass success without an adverse event increased from 64.0% to 80.9% (difference = 16.9%, 95% CI 10.6% to 23.1%). Conclusion: The use of an airway CQI program with an ongoing airway registry resulted in a substantial improvement in the overall safety of RSI in the ED as evidenced by an increase in first pass success and a decrease in adverse events.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Can Emergency Physicians Perform Common Carotid Doppler Flow Measurements to Assess Volume Responsiveness?

Introduction: Common carotid flow measurements may be clinically useful to determine volumeresponsiveness. The objective of this study was to assess the ability of emergency physicians (EP)to obtain sonographic images and measurements of the common carotid artery velocity time integral(VTi) for potential use in assessing volume responsiveness in the clinical setting.Methods: In this prospective observational study, we showed a five-minute instructional videodemonstrating a technique to obtain common carotid ultrasound images and measure the commoncarotid VTi to emergency medicine (EM) residents. Participants were then asked to image thecommon carotid artery and obtain VTi measurements. Expert sonographers observed participantsimaging in real time and recorded their performance on nine performance measures. An expertsonographer graded image quality. Participants were timed and answered questions regarding easeof examination and their confidence in obtaining the images.Results: A total of 30 EM residents participated in this study and each performed the examinationtwice. Average time required to complete one examination was 2.9 minutes (95% CI [2.4-3.4 min]). Participants successfully completed all performance measures greater than 75% of the time, with theexception of obtaining measurements during systole, which was completed in 65% of examinations.Median resident overall confidence in accurately performing carotid VTi measurements was 3 (on ascale of 1 [not confident] to 5 [confident]).Conclusion: EM residents at our institution learned the technique for obtaining common carotidartery Doppler flow measurements after viewing a brief instructional video. When assessed atperforming this examination, they completed several performance measures with greater than 75%success. No differences were found between novice and experienced groups. [West J Emerg Med.2015;16(2):255–259.

Improvement in the Safety of Rapid Sequence Intubation in the Emergency Department with the Use of an Airway Continuous Quality Improvement Program

Introduction: Airway management in the critically ill is associated with a high prevalence of failed first attempts and adverse events which negatively impacts patient care. The purpose of this investigation is to describe an airway continuous quality improvement (CQI) program and its effect on the safety of rapid sequence intubation (RSI) in the emergency department (ED) over a 10-year period.Methods: An airway CQI program with an ongoing airway registry was initiated in our ED on July 1, 2007 (Academic Year 1) and continued through June 30, 2017 (Academic Year 10). Data were prospectively collected on all patients intubated in the ED during this period using a structured airway data collection form. Key data points included method of intubation, drugs and devices used for intubation, operator specialty and level of training, number of intubation attempts, and adverse events. Adult patients who underwent RSI in the ED with an initial intubation attempt by emergency medicine (EM) resident were included in the analysis. The primary outcome was first pass success which was defined as successful tracheal intubation with a single laryngoscope insertion. The secondary outcome was the prevalence of adverse events associated with intubation. Educational and clinical interventions were introduced throughout the study period with the goal of optimizing these outcomes. Data were analyzed by academic year and are reported descriptively with 95% confidence intervals (CI) of the difference of means.Results: EM residents performed RSI on 342 adult patients during Academic Year 1 and on 445 adult patients during Academic Year 10. Over the 10-year study period, first pass success increased from 73.1% to 92.4% (difference = 19.3%, 95% CI 14.0% to 24.6%). The percentage of patients who experienced an adverse event associated with intubation decreased from 22.5% to 14.4% (difference = -7.9%, 95% CI -13.4% to -2.4%). The percentage of patients with first pass success without an adverse event increased from 64.0% to 80.9% (difference = 16.9%, 95% CI 10.6% to 23.1%).Conclusion: The use of an airway CQI program with an ongoing airway registry resulted in a substantial improvement in the overall safety of RSI in the ED as evidenced by an increase in first pass success and a decrease in adverse events

First Pass Success Without Adverse Events Is Reduced Equally with Anatomically Difficult Airways and Physiologically Difficult Airways

Introduction: The goal of emergency airway management is first pass success without adverse events (FPS-AE). Anatomically difficult airways are well appreciated to be an obstacle to this goal. However, little is known about the effect of the physiologically difficult airway with regard to FPS-AE. This study evaluates the effects of both anatomically and physiologically difficult airways on FPS-AE in patients undergoing rapid sequence intubation (RSI) in the emergency department (ED).Methods: We analyzed prospectively recorded intubations in a continuous quality improvement database between July 1, 2014–June 30, 2018. Emergency medicine (EM) or emergency medicine/pediatric (EM-PEDS) residents recorded patient, operator, and procedural characteristics on all consecutive adult RSIs performed using a direct or video laryngoscope. The presence of specific anatomically and physiologically difficult airway characteristics were also documented by the operator. Patients were analyzed in four cohorts: 1) no anatomically or physiologically difficult airway  characteristics; 2) one or more anatomically difficult airway characteristics; 3) one or more physiologically difficult airway characteristics; and 4) both anatomically and physiologically difficult airway characteristics. The primary outcome was FPS-AE. We performed a multivariable logistic regression analysis to determine the association between anatomically difficult airways or physiologically difficult airways and FPS-AE.Results: A total of 1513 intubations met inclusion criteria and were analyzed. FPS-AE for patients without any difficult airway characteristics was 92.4%, but reduced to 82.1% (difference = - 10.3%, 95% confidence interval (CI), - 14.8% to - 5.6%) with the presence of one or more anatomically difficult airway characteristics, and 81.7% (difference = - 10.7%, 95% CI, - 17.3% to - 4.0%) with the presence of one or more physiologically difficult airway characteristics. FPS-AE was further reduced to 70.9% (difference = - 21.4%, 95% CI, - 27.0% to - 16.0%) with the presence of both anatomically and physiologically difficult airway characteristics. The adjusted odds ratio (aOR) of FPS-AE was 0.37 [95% CI, 0.21 - 0.66] in patients with anatomically difficult airway characteristics and 0.36 [95% CI, 0.19 - 0.67] for patients with physiologically difficult airway characteristics, compared to patients with no difficult airway characteristics. Patients who had both anatomically and physiologically difficult airway characteristics had a further decreased aOR of FPS-AE of 0.19 [95% CI, 0.11 - 0.33].Conclusion: FPS-AE is reduced to a similar degree in patients with anatomically and physiologically difficult airways. Operators should assess and plan for potential physiologic difficulty as is routinely done for anatomically difficulty airways. Optimization strategies to improve FPS-AE for patients with physiologically difficult airways should be studied in randomized controlled trials