Effect of level of sedation on outcomes in critically ill adult patients: a systematic review of clinical trials with meta-analysis and trial sequential analysis.

Background: Sedation is routinely administered to critically ill patients to alleviate anxiety, discomfort, and patient-ventilator asynchrony. However, it must be balanced against risks such as delirium and prolonged intensive care stays. This study aimed to investigate the effects of different levels of sedation in critically ill adults. Methods: Systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials including critically ill adults admitted to the intensive care unit. CENTRAL, MEDLINE, Embase, LILACS, and Web of Science were searched from their inception to 13 June 2023. Risks of bias were assessed using the Cochrane risk of bias tool. Primary outcome was all-cause mortality. Aggregate data were synthesised with meta-analyses and TSA, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO: CRD42023386960. Findings: Fifteen trials randomising 4352 patients were included, of which 13 were assessed high risk of bias. Meta-analyses comparing lighter to deeper sedation showed no evidence of a difference in all-cause mortality (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.83-1.06; p = 0.28; 15 trials; moderate certainty evidence), serious adverse events (RR 0.99, CI 0.92-1.06; p = 0.80; 15 trials; moderate certainty evidence), or delirium (RR 1.01, 95% CI 0.94-1.09; p = 0.78; 11 trials; moderate certainty evidence). TSA showed that when assessing mortality, a relative risk reduction of 16% or more between the compared interventions could be rejected. Interpretation: The level of sedation has not been shown to affect the risks of death, delirium, and other serious adverse events in critically ill adult patients. While TSA suggests that additional trials are unlikely to significantly change the conclusion of the meta-analyses, the certainty of evidence was moderate. This suggests a need for future high-quality studies with higher methodological rigor. Funding: None.

Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients. SETTING: Outpatient treatment. PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities. INTERVENTIONS: Drug interventions authorised by EMA or FDA. PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events. RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups. CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression. PROSPERO REGISTRATION NUMBER: CRD42020178787.

Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses.

OBJECTIVE: To investigate the effects of fever therapy compared with no fever therapy in a wide population of febrile adults. DESIGN: Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. DATA SOURCES: CENTRAL, BIOSIS, CINAHL, MEDLINE, Embase, LILACS, Scopus, and Web of Science Core Collection, searched from their inception to 2 July 2021. ELIGIBILITY CRITERIA: Randomised clinical trials in adults diagnosed as having fever of any origin. Included experimental interventions were any fever therapy, and the control intervention had to be no fever therapy (with or without placebo/sham). DATA EXTRACTION AND SYNTHESIS: Two authors independently selected studies, extracted data, and assessed the risk of bias. Primary outcomes were all cause mortality and serious adverse events. Secondary outcomes were quality of life and non-serious adverse events. Aggregate data were synthesised with meta-analyses, subgroup analyses, and trial sequential analyses, and the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Forty two trials assessing 5140 participants were included. Twenty three trials assessed 11 different antipyretic drugs, 11 trials assessed physical cooling, and eight trials assessed a combination of antipyretic drugs and physical cooling. Of the participants, 3007 were critically ill, 1892 were non-critically ill, 3277 had infectious fever, and 1139 had non-infectious fever. All trials were assessed as being at high risk of bias. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of death (risk ratio 1.04, 95% confidence interval 0.90 to 1.19; I2=0%; P=0.62; 16 trials; high certainty evidence) and the risk of serious adverse events (risk ratio 1.02, 0.89 to 1.17; I2=0%; P=0.78; 16 trials; high certainty evidence) could be rejected. One trial assessing quality of life was included, showing no difference between fever therapy and control. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of non-serious adverse events could be neither confirmed nor rejected (risk ratio 0.92, 0.67 to 1.25; I2=66.5%; P=0.58; four trials; very low certainty evidence). CONCLUSIONS: Fever therapy does not seem to affect the risk of death and serious adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019134006.

Level of sedation in critically ill adult patients: a protocol for a systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: It is standard of care to provide sedation to critically ill patients to reduce anxiety, discomfort and promote tolerance of mechanical ventilation. Given that sedatives can have differing effects based on a variety of patient and pharmacological characteristics, treatment approaches are largely based on targeting the level of sedation. The benefits of differing levels of sedation must be balanced against potential adverse effects including haemodynamic instability, causing delirium, delaying awakening and prolonging the time of mechanical ventilation and intensive care stay. This systematic review with meta-analysis aims to investigate the current evidence and compare the effects of differing sedation levels in adult critically ill patients. METHODS AND ANALYSES: We will conduct a systematic review based on searches of preidentified major medical databases (eg, MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify trials meeting inclusion criteria. We will include randomised clinical trials comparing any degree of sedation with no sedation and lighter sedation with deeper sedation for critically ill patients admitted to the intensive care unit. We will include aggregate data meta-analyses and trial sequential analyses. Risk of bias will be assessed with domains based on the Cochrane risk of bias tool. An eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed using Grades of Recommendations, Assessment, Development and Evaluation. ETHICS AND DISSEMINATION: No formal approval or review of ethics is required as individual patient data will not be included. This systematic review has the potential to highlight (1) whether one should believe sedation to be beneficial, harmful or neither in critically ill adults; (2) the existing knowledge gaps and (3) whether the recommendations from guidelines and daily clinical practice are supported by current evidence. These results will be disseminated through publication in a peer-reviewed journal.

Hypothermic versus Normothermic Temperature Control after Cardiac Arrest.

BACKGROUND: The evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics. METHODS: An individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence). RESULTS: The primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups. CONCLUSIONS: Hypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

BACKGROUND: COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. METHODS AND FINDINGS: We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. CONCLUSIONS: No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178787.

Comparison of informational vs. energetic masking effects on speechreading performance.

The effects of two types of auditory distracters (steady-state noise vs. four-talker babble) on visual-only speechreading accuracy were tested against a baseline (silence) in 23 participants with above-average speechreading ability. Their task was to speechread high frequency Swedish words. They were asked to rate their own performance and effort, and report how distracting each type of auditory distracter was. Only four-talker babble impeded speechreading accuracy. This suggests competition for phonological processing, since the four-talker babble demands phonological processing, which is also required for the speechreading task. Better accuracy was associated with lower self-rated effort in silence; no other correlations were found.