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Early in the COVID-19 pandemic, no effective treatment existed to prevent clinical worsening of COVID-19 among recently diagnosed outpatients. At the University of Utah, Salt Lake City, Utah, we conducted a phase 2 prospective parallel group randomized placebo-controlled trial (NCT04342169) to determine whether hydroxychloroquine given early in disease reduces the duration of SARS-CoV-2 shedding. We enrolled nonhospitalized adults (≥18 years of age) with a recent positive diagnostic test for SARS-CoV-2 (within 72 h of enrollment) and adult household contacts. Participants received either 400 mg hydroxychloroquine by mouth twice daily on day 1 followed by 200 mg by mouth twice daily on days 2 to 5 or oral placebo with the same schedule. We performed SARS-CoV-2 nucleic acid amplification testing (NAAT) on oropharyngeal swabs on days 1 to 14 and 28 and monitored clinical symptomatology, rates of hospitalization, and viral acquisition by adult household contacts. We identified no overall differences in the duration of oropharyngeal carriage of SARS-CoV-2 (hazard ratio of viral shedding time comparing hydroxychloroquine to placebo, 1.21; 95% confidence interval [CI], 0.91, 1.62). Overall, 28-day hospitalization incidence was similar between treatments (4.6% hydroxychloroquine versus 2.7% placebo). No differences were seen in symptom duration, severity, or viral acquisition in household contacts between treatment groups. The study did not reach the prespecified enrollment target, which was likely influenced by a steep decline in COVID-19 incidence corresponding to the initial vaccine rollout in the spring of 2021. Oropharyngeal swabs were self-collected, which may introduce variability in these results. Placebo treatments were not identical to hydroxychloroquine treatments (capsules versus tablets) which may have led to inadvertent participant unblinding. In this group of community adults early in the COVID-19 pandemic, hydroxychloroquine did not significantly alter the natural history of early COVID-19 disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT04342169). IMPORTANCE Early in the COVID-19 pandemic, no effective treatment existed to prevent clinical worsening of COVID-19 among recently diagnosed outpatients. Hydroxychloroquine received attention as a possible early treatment; however, quality prospective studies were lacking. We conducted a clinical trial to test the ability of hydroxychloroquine to prevent clinical worsening of COVID-19.
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Research ObjectiveThe risk of serious intracranial injury in pediatric patients with minor head trauma (MHT) is less than 5%;most computerized tomography (CT) scans in MHT are normal or contribute little to management, yet expose children to unnecessary radiation. Despite evidence‐based risk classification criteria from the Pediatric Emergency Care Applied Research Network (PECARN) for assessing appropriate CT use during emergency department (ED) visits, barriers persist to replacing unnecessary scans with structured observation. Field readiness assessments at Intermountain Healthcare suggest that physicians often believe they know the risk factors for traumatic brain injury (TBI) but sometimes misremember elements. Information retrieval when delivering ED care can be cumbersome. Many physicians also perceive ordering CT scans is the safest course of action despite a lack of significant symptoms. We theorized that targeting evidence‐based education at the individual scan decision point, coupled with timely performance feedback, would increase cognitive support for assessing risk of clinically‐important TBI (ciTBI), reducing potentially unnecessary scans.Study DesignWe conducted a prospective pre‐post comparison implementation study. The primary implementation strategies were two‐fold. First, we embedded an alert containing an easy‐to‐understand, information‐rich graphic providing current PECARN risk stratification criteria and supporting evidence for classifying ciTBI, along with a risk assessment prompt linked to a CT order. Second, we provided timely feedback on performance and local prompting to educate physicians. Uptake and effectiveness measures included % adherence change in PECARN guidelines and the CT scan rate. Safety was evaluated by counting 48‐hour readmissions with clinical evidence of ciTBI confirmed via chart review. Acceptability, fidelity and feasibility were assessed using qualitative analysis. Statistical analysis was conducted using tests of proportions.Population StudiedApproximately 14,000 pediatric patients presenting with MHT at 22 EDs from January 2019–December 2020 within a single, integrated delivery system including urban, rural and frontier locations and a children's hospital.Principal FindingsYear 1 adherence to PECARN guidelines was 98.7% with a 14% reduction in the CT scan rate for pediatric MHT patients across geographies with no readmissions for ciTBI (Table). Results were sustained in Year 2 despite increased patient acuity in 2020 due to the novel coronavirus pandemic. Subsequent field discussions found good acceptance by physicians noting the alert was relevant, timely and easy to understand. Implementation fidelity was high given routinization of the alert into clinical workflow.ConclusionsCombining local performance feedback with use of an information‐rich text alert was associated with significant improvements in adherence to PECARN guidelines and a reduction in the CT scan order rate for diagnosis of clinically‐important TBI in MHT patients without impacting safety. The routinized nature of the alert was associated with good practice sustainment over multiple years across geographies.Implications for Policy or PracticeSimple, information‐rich text alerts may prove useful as an implementation strategy for updating physicians on changes in evidence‐based triage and risk classification criteria often associated with de‐implementation of legacy clinical practices.
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Coronavirus disease (COVID-19) is a potentially fatal illness with no proven therapy beyond excellent supportive care. Treatments are urgently sought. Adaptations to traditional trial logistics and design to allow rapid implementation, evaluation of trials within a global trials context, flexible interim monitoring, and access outside traditional research hospitals (even in settings where formal placebos are unavailable) may be helpful. Thoughtful adaptations to traditional trial designs, especially within the global context of related studies, may also foster collaborative relationships among government, community, and the research enterprise. Here, we describe the protocol for a pragmatic, active comparator trial in as many as 300 patients comparing two current "off-label" treatments for COVID-19-hydroxychloroquine and azithromycin-in academic and nonacademic hospitals in Utah. We developed the trial in response to local pressures for widespread, indiscriminate off-label use of these medications. We used a hybrid Bayesian-frequentist design for interim monitoring to allow rapid, contextual assessment of the available evidence. We also developed an inference grid for interpreting the range of possible results from this trial within the context of parallel trials and prepared for a network meta-analysis of the resulting data. This trial was prospectively registered (ClinicalTrials.gov Identifier: NCT04329832) before enrollment of the first patient.Clinical trial registered with www.clinicaltrials.gov (NCT04329832).
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BACKGROUND: Lung-protective ventilation (LPV) improves outcomes for patients with acute respiratory distress syndrome (ARDS) through the administration of low tidal volumes (≤ 6.5 ml/kg predicted body weight [PBW]) with co-titration of positive end-expiratory pressure and fraction of inspired oxygen. Many patients with ARDS, however, are not managed with LPV. The purpose of this study was to understand the implementation barriers and facilitators to the use of LPV and a computerized LPV clinical decision support (CDS) tool in intensive care units (ICUs) in preparation for a pilot hybrid implementation-effectiveness clinical trial. METHODS: We performed an explanatory sequential mixed methods study from June 2018 to March 2019 to evaluate the variation in LPV adherence across 17 ICUs in an integrated healthcare system with > 4000 mechanically ventilated patients annually. We analyzed 47 key informant interviews of ICU physicians, respiratory therapists (RTs), and nurses in 3 of the ICUs using a qualitative content analysis paradigm to investigate site variation as defined by adherence level (low, medium, high) and to identify barriers and facilitators to LPV and LPV CDS tool use. RESULTS: Forty-two percent of patients had an initial set tidal volume of ≤ 6.5 ml/kg PBW during the measurement period (site range 21-80%). LPV CDS tool use was 28% (site range 6-91%). This study's main findings revealed multi-factorial facilitators and barriers to use that varied by ICU site adherence level. The primary facilitator was that LPV and the LPV CDS tool could be used on all mechanically ventilated patients. Barriers included a persistent gap between clinician attitudes regarding the use of LPV and actual use, the perceived loss of autonomy associated with using a computerized protocol, the nature of physician-RT interaction in ventilation management, and the lack of clear organization measures of success. CONCLUSIONS: Variation in adherence to LPV persists in ICUs within a healthcare delivery system that was an early adopter of LPV. Potentially promising strategies to increase adherence to LPV and the LPV CDS tool for ARDS patients include initiating low tidal ventilation on all mechanically ventilated patients, establishing and measuring adherence measures, and focused education addressing the physician-RT interaction. These strategies represent a blueprint for a future hybrid implementation-effectiveness trial.