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• W4327905003 abstract "Editor’s Note: The Annals of Emergency Medicine Journal Club monthly provides a succinct review of high-impact articles from this and other premier medical journals relevant to emergency medicine. The reviews are followed by questions demonstrating principles by which readers—be they clinicians, academics, residents, or medical students—may critically appraise the literature. We are interested in receiving feedback about this feature. Please email with your comments. The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Early restrictive or liberal fluid management for sepsis-induced hypotension. N Engl J Med. Published online January 21, 2023. In adult patients with sepsis and hypotension, did a restrictive fluid strategy prioritizing vasopressors, compared with a liberal fluid strategy prioritizing fluid administration, result in superior all-cause mortality? Design: Unblinded, randomized superiority trial Setting: 60 hospitals in the United States Population: A planned population of 2,250 adult patients with sepsis and hypotension following initial fluid resuscitation Intervention: A restrictive fluid therapy in which vasopressor use preceded additional fluid resuscitation or a liberal fluid therapy in which further fluid boluses preceded initiation of vasopressors. Primary and Secondary Outcomes: The primary outcome was all-cause mortality before discharge home within 90 days. Secondary outcomes included ventilator-free days, vasopressor-free days, days out of the ICU, and days out of the hospital. Sponsors: National Heart, Lung, and Blood Institute ClinicalTrials.gov: NCT03434028. The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis Trial (CLOVERS) trial was halted for futility after enrollment of the first 1,563 patients. All-cause mortality before discharge home at day 90 occurred in 14.0% of the restrictive group compared with 14.9% of the liberal fluid group (difference, –0.9%; 95% confidence interval [CI], –4.4 to 2.6). Statistically significant treatment effects were not observed in any of the prespecified subgroups. However, in 73 patients with end-stage renal disease, mortality was 27.3% in the restrictive group compared with 47.5% in the liberal group (difference, –20.2%; 95% CI, –41.9 to 1.5). Serious adverse events were rare in each group. The authors conclude, in patients with sepsis and hypotension following initial fluid resuscitation, that a restrictive fluid strategy did not result in significantly lower (or higher) mortality before discharge to home than a liberal fluid strategy. In this trial, the authors attempted to demonstrate the superiority of a restrictive fluid strategy versus a liberal one. However, it is challenging to translate the observations from this trial into practice. Patients in the restrictive fluids group still received, in the first 24 hours of treatment, a median of 3,300 mL of crystalloid. This practice, although restrictive compared with the median 5,400 mL received by the liberal fluids group, does not substantially deviate in a truly restrictive fashion from the present approach to sepsis with hypotension. The most reasonable and generalizable conclusion to draw from these observations is that after the initial bolus, a range of reasonable individualized treatment decisions may be made, and no single protocol is clearly a universal strategy. It unfortunately remains an open question regarding whether mandated weight-based boluses are harmful or the best treatment strategy for patients whose shock persists despite adequate and appropriate fluid resuscitation and vasopressor use. 1.The CLOVERS trial was criticized as “deeply flawed and exposes subjects to unacceptable dangers” in a prominent letter to the Office for Human Research Protections (OHRP).1Carome M.A. Wolfe S.M. Letter to the OHRP regarding CLOVERS. Public Digital Correspondence.https://www.citizen.org/wp-content/uploads/2446.pdfDate accessed: January 23, 2023Google Scholar How were these criticisms framed and how were they addressed? A 2018 letter from the Public Citizen raised issues relating primarily to the trial procedures and their lack of representativeness of the standard of care for patients with sepsis and hypotension. The authors of the critique suggested that neither arm of the trial reflected a management strategy used clinically in usual care. Specifically, the liberal fluid arm protocolized care requiring up to 5 L of crystalloid resuscitation before intervention with vasopressors, a practice dissimilar to the volumes administered in other sepsis trials. Contrariwise, the restrictive fluid arm required clinicians to eschew intravenous fluids through the initial phase of care in a manner inconsistent with any established practice, rendering it truly experimental. The concerns regarding trial procedures we considered to also affect the adequacy of the informed consent document. These issues were addressed by the trial investigators by implementing a raft of minor changes to the trial protocol.2Buchanan L.R. September 28, 2020—Crystalloid liberal or vasopressors early resuscitation in sepsis trial. Public Digital Correspondence.https://www.hhs.gov/ohrp/compliance-and-reporting/determination-letters/2020/september-28-2020-crystalloid-liberal-or-vasopressors-early-resuscitation-in-sepsis-trial/index.htmlDate accessed: January 23, 2023Google Scholar The most material change to the trial protocol involved modification of the liberal fluid administration arm. Although the protocol already allowed treatment decisions to be made in the best interests of the patient at any time, the protocol was amended to explicitly require an assessment of the appropriateness of ongoing fluid resuscitation following the first protocolized liter of crystalloid. Subsequent to the amendment, 13.5% of patients were affected by cessation of fluid administration following the first liter after being assessed as fluid replete. Other changes improved clarity regarding clinically appropriate treatments in each arm that would not result in protocol violations. The informed consent document was also modified to expand on the balance of risks and benefits in each arm. The important principle demonstrated here, and ultimately further emphasized by the OHRP, is the necessity of careful consideration of equipoise during design of a clinical trial. Specific supporting evidence is necessary to justify each arm of a trial as reflecting competing reasonable standards of care.2.How might modifications to the trial protocol have affected the outcomes reported? Revisions to the protocol allowed for a more personalized approach to fluid administration in patients randomized to the liberal fluid group. Effectively, by mandating a fluid assessment after the first liter, this allowed the clinicians to evaluate whether a patient’s clinical status was worsened by excessive volume expansion. The net result of the changes included a reduction in the fluid provided, as described above, further narrowing the differences in treatment between arms. Considering the trial was stopped early for futility because of a failure to observe a difference between groups, this protocol change more likely than not accelerated its early termination.3.Clinicians were allowed to refuse entry into the trial if they felt one of the trial arms was inappropriate for their patient. What effect does the equipoise of treating clinicians have on the ultimate trial population? The clinical trial protocol for CLOVERS explicitly states patients could be excluded if the treating physician was either: (1) unwilling to give additional fluids as directed by the liberal protocol or (2) unwilling to use vasopressors as directed by the restrictive protocol. These exclusion criteria, effectively, allows the treatment equipoise of individual clinicians to exert a selection bias on the trial population. There were 12,276 patients assessed for eligibility having met the inclusion criteria as adults with sepsis-induced hypotension. Of these, there were 4,868 who otherwise met clinical eligibility criteria. From these, only 1,563 underwent randomization. Most of those who did not undergo randomization were excluded because of the inability to obtain informed consent, but 873 were not randomized because of “MD refusal.” The effect this would have on the trial population requires consideration of the most likely reasons behind refusal. Factors influencing whether a clinician might consider study procedures inappropriate for a patient include relevant guidelines, such as those from the Surviving Sepsis Campaign, primarily supporting an aggressive fluids-first protocol.3Evans L. Rhodes A. Alhazzani W. et al.Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.Crit Care Med. 2021; 49: e1063-e1143Crossref PubMed Scopus (476) Google Scholar Patients may also have been excluded by refusal or by inability to obtain consent in a timely fashion, if severe illness reduced the likelihood of inclusion. It is reasonable to suggest that the trial population is, therefore, skewed in some fashion, reducing generalizability to the larger ED sepsis population." @default.
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• W4327905003 title "Usual Care, Unusual Care, and the Lessons From CLOVERS" @default.
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• W4327905003 doi "https://doi.org/10.1016/j.annemergmed.2023.02.005" @default.
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