Reduced exposure to vasopressors through permissive hypotension to reduce mortality in critically ill people aged 65 and over: the 65 RCT

Background Vasopressors are administered to critical care patients to avoid hypotension, which is associated with myocardial injury, kidney injury and death. However, they work by causing vasoconstriction, which may reduce blood flow and cause other adverse effects. A mean arterial pressure target typically guides administration. An individual patient data meta-analysis (Lamontagne F, Day AG, Meade MO, Cook DJ, Guyatt GH, Hylands M, et al. Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. Intensive Care Med 2018;44:12–21) suggested that greater exposure, through higher mean arterial pressure targets, may increase risk of death in older patients. Objective To estimate the clinical effectiveness and cost-effectiveness of reduced vasopressor exposure through permissive hypotension (i.e. a lower mean arterial pressure target of 60–65 mmHg) in older critically ill patients. Design A pragmatic, randomised clinical trial with integrated economic evaluation. Setting Sixty-five NHS adult general critical care units. Participants Critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension. Interventions Intervention – permissive hypotension (i.e. a mean arterial pressure target of 60–65 mmHg). Control (usual care) – a mean arterial pressure target at the treating clinician’s discretion. Main outcome measures The primary clinical outcome was 90-day all-cause mortality. The primary cost-effectiveness outcome was 90-day incremental net monetary benefit. Secondary outcomes included receipt and duration of advanced respiratory and renal support, mortality at critical care and acute hospital discharge, and questionnaire assessment of cognitive decline and health-related quality of life at 90 days and 1 year. Results Of 2600 patients randomised, 2463 (permissive hypotension, n = 1221; usual care, n = 1242) were analysed for the primary clinical outcome. Permissive hypotension resulted in lower exposure to vasopressors than usual care [mean duration 46.0 vs. 55.9 hours, difference –9.9 hours (95% confidence interval –14.3 to –5.5 hours); total noradrenaline-equivalent dose 31.5 mg vs. 44.3 mg, difference –12.8 mg (95% CI –18.0 mg to –17.6 mg)]. By 90 days, 500 (41.0%) patients in the permissive hypotension group and 544 (43.8%) patients in the usual-care group had died (absolute risk difference –2.85%, 95% confidence interval –6.75% to 1.05%; p = 0.154). Adjustment for prespecified baseline variables resulted in an odds ratio for 90-day mortality of 0.82 (95% confidence interval 0.68 to 0.98) favouring permissive hypotension. There were no significant differences in prespecified secondary outcomes or subgroups; however, patients with chronic hypertension showed a mortality difference favourable to permissive hypotension. At 90 days, permissive hypotension showed similar costs to usual care. However, with higher incremental life-years and quality-adjusted life-years in the permissive hypotension group, the incremental net monetary benefit was positive, but with high statistical uncertainty (£378, 95% confidence interval −£1347 to £2103). Limitations The intervention was unblinded, with risk of bias minimised through central allocation concealment and a primary outcome not subject to observer bias. The control group event rate was higher than anticipated. Conclusions In critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension, permissive hypotension did not significantly reduce 90-day mortality compared with usual care. The absolute treatment effect on 90-day mortality, based on 95% confidence intervals, was between a 6.8-percentage reduction and a 1.1-percentage increase in mortality. Future work Future work should (1) update the individual patient data meta-analysis, (2) explore approaches for evaluating heterogeneity of treatment effect and (3) explore 65 trial conduct, including use of deferred consent, to inform future trials. Trial registration Current Controlled Trials ISRCTN10580502. Funding 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. 25, No. 14. See the NIHR Journals Library website for further project information.

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The evolution of mean arterial pressure in critically ill patients on vasopressors before and during a trial comparing a specific mean arterial pressure target to usual care

BMC Anesthesiology ◽

10.1186/s12871-021-01529-w ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Marie-Hélène Masse ◽

Neill K. J. Adhikari ◽

Xavier Théroux ◽

Marie-Claude Battista ◽

Frédérick D’Aragon ◽

...

Keyword(s):

Mean Arterial Pressure ◽

Arterial Pressure ◽

Usual Care ◽

Critically Ill ◽

Critically Ill Patients ◽

Intervention Group ◽

Control Group ◽

Chronic Hypertension ◽

The Mean ◽

Change In Mean

Abstract Background In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. Methods For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. Results We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). Conclusions The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

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Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Protocol for the 65 randomised clinical trial

Journal of the Intensive Care Society ◽

10.1177/1751143720971433 ◽

2020 ◽

Vol 21 (4) ◽

pp. 281-282

Author(s):

Alvin Richards-Belle ◽

Paul R Mouncey ◽

Richard D Grieve ◽

David A Harrison ◽

M Zia Sadique ◽

...

Keyword(s):

Clinical Trial ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Critically Ill ◽

Critically Ill Patients ◽

Randomised Clinical Trial ◽

Vasopressor Therapy ◽

Permissive Hypotension ◽

Risk Of Death ◽

South Central

Vasodilatory shock is common in critically ill patients and vasopressors are a mainstay of therapy. A meta-analysis suggested that use of a higher, as opposed to a lower, mean arterial pressure target to guide titration of vasopressor therapy, could be associated with a higher risk of death in older critically ill patients. The 65 trial is a pragmatic, multi-centre, parallel-group, open-label, randomised clinical trial of permissive hypotension (a mean arterial pressure target of 60 -65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial is conducted in 2600 patients from 65 United Kingdom adult, general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. The 65 trial received favourable ethical opinion from the South Central - Oxford C Research Ethics Committee and approval from the Health Research Authority. The results will be presented at national and international conferences and published in peer-reviewed medical journals. Trial registration: ISRCTN10580502

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Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Protocol for the 65 randomised clinical trial

Journal of the Intensive Care Society ◽

10.1177/1751143719870088 ◽

2019 ◽

pp. 175114371987008 ◽

Cited By ~ 1

Author(s):

Alvin Richards-Belle ◽

Paul R Mouncey ◽

Richard D Grieve ◽

David A Harrison ◽

M Zia Sadique ◽

...

Keyword(s):

Clinical Trial ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Critically Ill ◽

Critically Ill Patients ◽

Randomised Clinical Trial ◽

Vasopressor Therapy ◽

Permissive Hypotension ◽

Risk Of Death ◽

South Central

Vasodilatory shock is common in critically ill patients and vasopressors are a mainstay of therapy. A meta-analysis suggested that use of a higher, as opposed to a lower, mean arterial pressure target to guide titration of vasopressor therapy, could be associated with a higher risk of death in older critically ill patients. The 65 trial is a pragmatic, multi-centre, parallel-group, open-label, randomised clinical trial of permissive hypotension (a mean arterial pressure target of 60–65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial is conducted in 2600 patients from 65 United Kingdom adult, general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. The 65 trial received favourable ethical opinion from the South Central – Oxford C Research Ethics Committee and approval from the Health Research Authority. The results will be presented at national and international conferences and published in peer-reviewed medical journals. Trial registration: ISRCTN10580502

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Application of Network Meta-Analysis to Assess the Comparative Effectiveness of Oral Care Interventions in Preventing Ventilator Associated Pneumonia in Critically Ill Patients.

10.21203/rs.3.rs-23653/v1 ◽

2020 ◽

Author(s):

Satheeshkumar PS ◽

Stephen Sonis

Keyword(s):

Usual Care ◽

Critically Ill ◽

Critically Ill Patients ◽

Povidone Iodine ◽

Meta Analysis ◽

Oral Care ◽

Forest Plot ◽

Care Groups ◽

Ranking Order ◽

Hierarchical Assessment

Abstract Background In this research, we assessed the efficacy of a novel analytic, network metanalysis (NMA), in creating a hierarchy to define the most effective oral care intervention (OCI) for the prevention and management of ventilation-associated pneumonia (VAP). Methods We applied NMA to a previously published robust pairwise meta-analysis (PMA). Statistical analyses were based on comparing rates of total VAP events between intervention groups and placebo-usual care groups. We synthesized a netgraph, reported ranking order of the treatment and summarized our output by a forest plot with a reference treatment placebo/usual care. Results With our inclusion and exclusion critiera for the NMA we extracted 25 studies (4473 subjects). The NMA included 16 treatments, 29 pairwise comparisons and 15 designs. Based on the results of multiple comparisons with frequentist ranking probability P scores, tooth brushing (P score fixed of 0.9353, P score random of 0.8892), toothbrushing with povidone iodine (P score fixed of 0.9091, P score random 0.8801), and furacillin (P score fixed of 0.8798, P score random 0.8358) were the best three interventions for preventing VAP. Conclusion NMA appeared to be an effective platform from which multiple interventions reported in disparate clinical trials could be compared to derive a hierarchical assessment of efficacy in the intervention of VAP. According to the NMA outcome, toothbrushing alone or toothbrushing along with a potent antiseptic mouthwash povidone iodine was related to the highest response rate in preventing VAP in critically ill patients followed by furacillin and chlorhexidine 0.2%, respectively.

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Role of Automatic Tube Compensation as Spontaneous Breathing Trial in Critically Ill Patients: A Systematic Review and Meta-Analysis

10.22514/sv.2020.16.0053 ◽

2020 ◽

Keyword(s):

Confidence Interval ◽

Hospital Mortality ◽

Critically Ill ◽

Critically Ill Patients ◽

Spontaneous Breathing ◽

Meta Analysis ◽

Stay Hospital ◽

Successful Extubation ◽

Tube Compensation

Objectives: The role of automatic tube compensation (ATC) compared to other spontaneous breathing trials (SBTs) in critically ill receiving mechanical ventilation remains uncertain. The aim of this meta-analysis was to determine the role of ATC in critically ill patients compared to alternative SBT techniques. Methods: We searched PubMed, Cochrane Library, and Embase to capture all potential randomized controlled trials (RCTs) investigating the comparative efficacy of ATC related to other SBT techniques including pressure support (PS), T-piece, continuous positive airway pressure (CPAP) from their inception to February 2020. Primary outcomes were successful extubation rate. Duration of weaning, intensive care unit (ICU) stay, hospital stay, and hospital mortality was regarded as secondary outcomes. We used a risk ratio with accompanying 95% confidence interval (CI) to express estimates. Reviewer Manager (RevMan) 5.1.0 was used to complete all statistical analyses. Results: We included 13 studies enrolling 1117 patients in the final analysis. Pooled results indicated no significant difference when ATC plus CPAP (ATC/CAPA) compared to PS (6 RCTs; 572 patients; risk ratio [RR], 1.15; 95% confidence interval [CI], 1.00 to 1.31), ATC versus T-piece (2 RCTs; 157 patients; RR, 1.14; 95% CI, 0.93 to 1.40), ATC plus PS (ATC/PS) versus PS alone (1 RCTs; 100 patients; RR, 1.15; 95% CI, 0.98 to 1.35), ATC/CPAP versus CPAP alone (3 RCTs; 247 patients; RR, 1.12; 95% CI, 0.97 to 1.29) in terms of successful extubation. Additionally, ATC was also not superior to PS, T-piece, or CPAP in improving the rate of reintubation, the duration of weaning, ICU stay, hospital stay, and hospital mortality. Conclusions: Compared to alternative SBT techniques including PSV and T-piece, ATC may have comparable predictive power of successful extubation in critically ill patients. However, a definite conclusion on this topic can not be drawn due to limited data. Therefore, further studies were required to establish our findings due to limited number of eligible studies and small accumulated sample size.

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