The management of sepsis has substantially improved over the past 15 years. In this study, early, goal-directed therapy, which focuses on the initial resuscitation efforts, was compared with usual ...care for the management of severe sepsis in the United Kingdom.
The incidence of severe sepsis and septic shock in adults is estimated to range from 56 to 91 per 100,000 population per year.
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Affected patients have high rates of death, complications, and resource utilization.
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Since 2002, the Surviving Sepsis Campaign (SSC) has promoted best practice, including early recognition, source control, appropriate and timely antibiotic administration, and resuscitation with intravenous fluids and vasoactive drugs.
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Resuscitation guidance is largely based on a 2001 single-center, proof-of-concept study by Rivers et al., which indicated that protocolized delivery of 6 hours of early, goal-directed therapy (EGDT) to patients presenting to the emergency department . . .
IMPORTANCE: Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older ...patients. OBJECTIVE: To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure MAP target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019. INTERVENTIONS: Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307). MAIN OUTCOME AND MEASURES: The primary clinical outcome was all-cause mortality at 90 days. RESULTS: Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean SD age 75 years 7 years; 1387 57% men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, –5.0; 95% CI, –7.8 to –2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, –8.7 mg; 95% CI, –12.8 to −4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, −2.85%; 95% CI, −6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 3.2% vs 33 2.5%) and supraventricular cardiac arrhythmia (12 0.9% vs 13 1.0%). CONCLUSIONS AND RELEVANCE: Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN10580502
This study presents a patient-level meta-analysis of three recent trials of early, goal-directed therapy for septic shock. Results showed that EGDT did not improve outcomes and increased ...hospitalization costs across a broad range of patient and hospital characteristics.
In 2001, Rivers and colleagues reported on a 263-patient, single-center, randomized, controlled trial of early, goal-directed therapy (EGDT) versus usual care in patients presenting with septic shock to an urban emergency department in the United States.
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EGDT is a 6-hour resuscitation protocol for the administration of intravenous fluids, vasopressors, inotropes, and red-cell transfusion to achieve prespecified targets for arterial blood pressure, central venous pressure, central venous oxygen saturation, and hemoglobin level. EGDT reduced hospital mortality from 46.5% to 30.5%,
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prompting many institutions worldwide to adopt EGDT.
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Three subsequent, government-funded, multicenter, randomized, controlled trials from the United States (Protocolized Care for . . .
Increasing evidence suggests the presence of structural changes affecting the right ventricular outflow tract (RVOT) in patients with Brugada Syndrome (BrS). The aim of this study was to characterise ...the RV morphology in BrS and explore associations between morphologic, clinical, electrical, and genetic parameters using non-invasive multimodality testing.
Consecutive BrS patients (recruited 2013-2015) underwent clinical assessment, dedicated RV imaging using cardiac magnetic resonance (CMR) imaging (unless contra-indicated), electrical assessment (electrocardiogram, Holter monitoring, signal-averaged ECGSAECG) and genotyping. Morphologic data were compared to matched control and unmatched ARVC (arrhythmogenic right ventricular cardiomyopathy) cohorts, and potential associations between morphologic parameters and other variables were explored.
BrS patients (n = 42, male 86%, age 46±12 years) exhibited normal global RV volume and function, comparable to control, in contrast to significantly larger, impaired RVs in ARVC cohort (RVESV p = 0.0001; RVEDV p<0.0001, RVEF p = 0.002). Compared with control, BrS patients exhibited larger RVOT volumes (7.4 ± 0.7 vs 5.8 ± 0.7 mL/m2, p<0.0001) and wall motion abnormalities (RWMA) (31% vs 0%, p = 0.005); compared with ARVC cohort, the RVOT volumes were similar (7.4 ± 0.7 vs, 8.1 ± 1.7, p = 0.52) and there were less RWMA (31% vs 76%, p = 0.01). Overall 67% BrS patients had abnormal RVOT morphology. Patients with abnormal RVOT tended to be older (48 ± 12 y vs 41 ± 12y, p = 0.06). Rare genetic variants were only observed in patients with abnormal RVOT morphology (36% vs 0%, p = 0.02).
Patients with BrS frequently exhibit structural abnormalities localised to the RVOT and these changes may be age- and gene-dependent.
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Malnutrition is a common problem in critically ill patients in UK NHS critical care units. Early nutritional support is therefore recommended to address deficiencies in nutritional state and related ...disorders in metabolism. However, evidence is conflicting regarding the optimum route (parenteral or enteral) of delivery.
To estimate the effect of early nutritional support via the parenteral route compared with the enteral route on mortality at 30 days and on incremental cost-effectiveness at 1 year. Secondary objectives were to compare the route of early nutritional support on duration of organ support; infectious and non-infectious complications; critical care unit and acute hospital length of stay; all-cause mortality at critical care unit and acute hospital discharge, at 90 days and 1 year; survival to 90 days and 1 year; nutritional and health-related quality of life, resource use and costs at 90 days and 1 year; and estimated lifetime incremental cost-effectiveness.
A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation.
Adult general critical care units in 33 NHS hospitals in England.
2400 eligible patients.
Five days of early nutritional support delivered via the parenteral (n = 1200) and enteral (n = 1200) route.
All-cause mortality at 30 days after randomisation and incremental net benefit (INB) (at £20,000 per quality-adjusted life-year) at 1 year.
By 30 days, 393 of 1188 (33.1%) patients assigned to receive early nutritional support via the parenteral route and 409 of 1195 (34.2%) assigned to the enteral route had died p = 0.57; absolute risk reduction 1.15%, 95% confidence interval (CI) -2.65 to 4.94; relative risk 0.97 (0.86 to 1.08). At 1 year, INB for the parenteral route compared with the enteral route was negative at -£1320 (95% CI -£3709 to £1069). The probability that early nutritional support via the parenteral route is more cost-effective - given the data - is < 20%. The proportion of patients in the parenteral group who experienced episodes of hypoglycaemia (p = 0.006) and of vomiting (p < 0.001) was significantly lower than in the enteral group. There were no significant differences in the 15 other secondary outcomes and no significant interactions with pre-specified subgroups.
Blinding of nutritional support was deemed to be impractical and, although the primary outcome was objective, some secondary outcomes, although defined and objectively assessed, may have been more vulnerable to observer bias.
There was no significant difference in all-cause mortality at 30 days for early nutritional support via the parenteral route compared with the enteral route among adults admitted to critical care units in England. On average, costs were higher for the parenteral route, which, combined with similar survival and quality of life, resulted in negative INBs at 1 year.
Nutritional support is a complex combination of timing, dose, duration, delivery and type, all of which may affect outcomes and costs. Conflicting evidence remains regarding optimum provision to critically ill patients. There is a need to utilise rigorous consensus methods to establish future priorities for basic and clinical research in this area.
Current Controlled Trials ISRCTN17386141.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 28. See the NIHR Journals Library website for further project information.
Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty ...remains over its clinical effectiveness and cost-effectiveness.
The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness.
A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation.
Fifty-six NHS hospitals in England.
A total of 1260 patients who presented at EDs with septic shock.
EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1.
All-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year.
Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at -£725 (95% CI -£3000 to £1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events.
Recruitment was lower at weekends and out of hours. The intervention could not be blinded.
There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%.
The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability.
Current Controlled Trials ISRCTN36307479.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information.
Missing data are an inevitable challenge in Randomised Controlled Trials (RCTs), particularly those with Patient Reported Outcome Measures. Methodological guidance suggests that to avoid incorrect ...conclusions, studies should undertake sensitivity analyses which recognise that data may be 'missing not at random' (MNAR). A recommended approach is to elicit expert opinion about the likely outcome differences for those with missing versus observed data. However, few published trials plan and undertake these elicitation exercises, and so lack the external information required for these sensitivity analyses. The aim of this paper is to provide a framework that anticipates and allows for MNAR data in the design and analysis of clinical trials.
We developed a framework for performing and using expert elicitation to frame sensitivity analysis in RCTs with missing outcome data. The framework includes the following steps: first defining the scope of the elicitation exercise, second developing the elicitation tool, third eliciting expert opinion about the missing outcomes, fourth evaluating the elicitation results, and fifth analysing the trial data. We provide guidance on key practical challenges that arise when adopting this approach in trials: the criteria for identifying relevant experts, the outcome scale for presenting data to experts, the appropriate representation of expert opinion, and the evaluation of the elicitation results.The framework was developed within the POPPI trial, which investigated whether a preventive, complex psychological intervention, commenced early in ICU, would reduce the development of patient-reported post-traumatic stress disorder symptom severity, and improve health-related quality of life. We illustrate the key aspects of the proposed framework using the POPPI trial.
For the POPPI trial, 113 experts were identified with potentially suitable knowledge and asked to participate in the elicitation exercise. The 113 experts provided 59 usable elicitation questionnaires. The sensitivity analysis found that the results from the primary analysis were robust to alternative MNAR mechanisms.
Future studies can adopt this framework to embed expert elicitation within the design of clinical trials. This will provide the information required for MNAR sensitivity analyses that examine the robustness of the trial conclusions to alternative, but realistic assumptions about the missing data.
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The Cretaceous-Paleogene boundary approximately 65.5 million years ago marks one of the three largest mass extinctions in the past 500 million years. The extinction event coincided with a large ...asteroid impact at Chicxulub, Mexico, and occurred within the time of Deccan flood basalt volcanism in India. Here, we synthesize records of the global stratigraphy across this boundary to assess the proposed causes of the mass extinction. Notably, a single ejecta-rich deposit compositionally linked to the Chicxulub impact is globally distributed at the Cretaceous-Paleogene boundary. The temporal match between the ejecta layer and the onset of the extinctions and the agreement of ecological patterns in the fossil record with modeled environmental perturbations (for example, darkness and cooling) lead us to conclude that the Chicxulub impact triggered the mass extinction.
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