Randomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges ...and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or ...placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence. Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab 0·82 0·71-0·95, p = 0·008 and sarilumab 0·80 0·61-1·04, p = 0·09 compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 95%CI 0·81-1·32, p = 0·80. The p-value for the global test of inconsistency was 0·28. Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Intensive care units (ICUs) are high-risk areas for transmission of antimicrobial-resistant bacteria, but no controlled study has tested the effect of rapid screening and isolation ...of carriers on transmission in settings with best-standard precautions. We assessed interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in European ICUs. Methods We did this study in three phases at 13 ICUs. After a 6 month baseline period (phase 1), we did an interrupted time series study of universal chlorhexidine body-washing combined with hand hygiene improvement for 6 months (phase 2), followed by a 12–15 month cluster randomised trial (phase 3). ICUs were randomly assigned by computer generated randomisation schedule to either conventional screening (chromogenic screening for meticillin-resistant Staphylococcus aureus MRSA and vancomycin-resistant enterococci VRE) or rapid screening (PCR testing for MRSA and VRE and chromogenic screening for highly resistant Enterobacteriaceae HRE); with contact precautions for identified carriers. The primary outcome was acquisition of resistant bacteria per 100 patient-days at risk, for which we calculated step changes and changes in trends after the introduction of each intervention. We assessed acquisition by microbiological surveillance and analysed it with a multilevel Poisson segmented regression model. We compared screening groups with a likelihood ratio test that combined step changes and changes to trend. This study is registered with ClinicalTrials.gov , number NCT00976638. Findings Seven ICUs were assigned to rapid screening and six to conventional screening. Mean hand hygiene compliance improved from 52% in phase 1 to 69% in phase 2, and 77% in phase 3. Median proportions of patients receiving chlorhexidine body-washing increased from 0% to 100% at the start of phase 2. For trends in acquisition of antimicrobial-resistant bacteria, weekly incidence rate ratio (IRR) was 0·976 (0·954–0·999) for phase 2 and 1·015 (0·998–1·032) for phase 3. For step changes, weekly IRR was 0·955 (0·676–1·348) for phase 2 and 0·634 (0·349–1·153) for phase 3. The decrease in trend in phase 2 was largely caused by changes in acquisition of MRSA (weekly IRR 0·925, 95% CI 0·890–0·962). Acquisition was lower in the conventional screening group than in the rapid screening group, but did not differ significantly (p=0·06). Interpretation Improved hand hygiene plus unit-wide chlorhexidine body-washing reduced acquisition of antimicrobial-resistant bacteria, particularly MRSA. In the context of a sustained high level of compliance to hand hygiene and chlorhexidine bathings, screening and isolation of carriers do not reduce acquisition rates of multidrug-resistant bacteria, whether or not screening is done with rapid testing or conventional testing. Funding European Commission.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose
Infections caused by antimicrobial-resistant bacteria (AMRB) are increasing worldwide, especially in intensive care units (ICUs). Chlorhexidine body washing (CHG-BW) has been proposed as a ...measure to limit the spread of AMRB. We have systematically assessed the evidence on the effectiveness of CHG-BW in reducing colonization and infection with AMRB in adult ICU patients.
Methods
PubMed, Embase, CINAHL, and OpenSigle databases were searched using synonyms for “intensive care unit,” “hospital,” and “chlorhexidine.” All potentially relevant articles were examined by two independent reviewers. Inclusion was limited to studies with ICU patients as domain, providing outcomes related to colonization or infection with AMRB. Data from 16 studies were extracted; 9 were excluded because of assessed high risk of bias or inadequate analyses. The remaining studies differed markedly in (co-)interventions and case mix, which precluded pooling of data in a formal meta-analysis.
Results
Incidences of MRSA acquisition were reduced significantly in three studies in which this was the primary endpoint. Significant reduction in MRSA infection rates was observed in only one of five studies. Carriage and bacteremia rates of VRE were assessed in one study, and both significantly declined. There were hardly any data on the effects of CHG-BW on antibiotic-resistant gram-negative bacteria (ARGNB).
Conclusions
CHG-BW may be effective in preventing carriage, and possibly bloodstream infections, with MRSA and VRE in different ICU settings. As CHG-BW protocols, co-interventions and case mix varied widely, attribution of these effects to CHG-BW alone should be done with care. Evidence that CHG-BW reduces carriage of or infections with ARGNB is lacking.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
The changed epidemiology of extended spectrum beta-lactamases (ESBL), the spread to the community and the need for prudent use of carbapenems require updated knowledge of risk factors for ...colonization with ESBL-producing enterobacteriaceae (ESBL-PE).
Methods
An 8-month prospective study in the medical ICU of an 850-bed general and university-affiliated hospital.
Results
Of 610 patients admitted, 531 (87 %) had a rectal swab obtained at admission, showing a 15 % (82 patients) ESBL-PE carriage rate, mostly of
E. coli
(
n
= 51, 62 %); ESBL-PE caused 9 (3 %) infections on admission. By multivariable analysis, transfer from another ICU (OR = 2.56
1
,
22
), hospital admission in another country OR = 5.28 (1.56–17.8), surgery within the past year OR = 2.28 (1.34–3.86), prior neurologic disease OR = 2.09 (1.1–4.0), and prior administration of third generation cephalosporin (within 3–12 months before ICU admission) OR = 3.05 (1.21–7.68) were independent predictive factors of colonization by ESBL-PE upon ICU admission. Twenty-eight patients (13 % of those staying for more than 5 days) acquired ESBL carriage in ICU, mostly with
E. cloacae
(
n
= 13, 46 %) and
K. pneumoniae
(
n
= 10, 36 %). In carriers, ESBL-PE caused 10 and 27 % of first and second episodes of ICU-acquired infections, respectively.
Conclusion
We found a high prevalence of ESBLE-PE colonization on admission to our ICU, even in the subgroup admitted from the community, but few first infections. Identifying risk factors for ESBL-PE colonization may help identifying which patients may warrant empiric ESBL-targeted antimicrobial drug therapy as a means to limit carbapenem use.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
7.
Focus on clinical trial interpretation Møller, Morten Hylander; Derde, Lennie P. G.; Sweeney, Rob Mac
Intensive care medicine,
04/2020, Volume:
46, Issue:
4
Journal Article
Peer reviewed
Open access
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The global emergence of infections caused by Enterobacteriaceae resistant to expanded-spectrum cephalosporins (ESCs) in intensive care units (ICUs) is, at least partly, driven by cross-transmission. ...Yet, individual transmission capacities of bacterial species have not been quantified.
In this post hoc analysis of a multicenter study in 13 European ICUs, prospective surveillance data and a mathematical model were used to estimate transmission capacities and single-admission reproduction numbers (RA) of Escherichia coli and non-E. coli Enterobacteriaceae (non-EcE), all being ESC resistant. Surveillance was based on a chromogenic selective medium for ESC-resistant Enterobacteriaceae, allowing identification of E. coli and of Klebsiella, Enterobacter, Serratia, and Citrobacter species, grouped as non-EcE.
Among 11420 patients included, the admission prevalence was 3.8% for non-EcE (74% being Klebsiella pneumoniae) and 3.3% for E. coli. Acquisition rates were 7.4 and 2.6 per 100 admissions at risk for non-EcE and E. coli, respectively. The estimated transmission capacity of non-EcE was 3.7 (95% credibility interval CrI, 1.4-11.3) times higher than that of E. coli, yielding single-admission reproduction numbers (RA) of 0.17 (95% CrI, .094-.29) for non-EcE and 0.047 (95% CrI, .018-.098) for E. coli.
In ICUs, non-EcE, mainly K. pneumoniae, are 3.7 times more transmissible than E. coli. Estimated RA values of these bacteria were below the critical threshold of 1, suggesting that in these ICUs outbreaks typically remain small with current infection control policies.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Purpose
Readmission of patients colonized with antimicrobial-resistant bacteria (AMRB) is important in the nosocomial dynamics of AMRB. We assessed the duration of colonization after discharge from ...the intensive care unit (ICU) with highly resistant Enterobacteriaceae (HRE), methicillin-resistant
Staphylococcus aureus
(MRSA), and vancomycin-resistant enterococci (VRE).
Methods
Data were obtained from a cluster-randomized trial in 13 ICUs in 8 European countries (MOSAR-ICU trial, 2008–2011). All patients were screened on admission and twice weekly for AMRB. All patients colonized with HRE, MRSA, or VRE and readmitted to the same ICU during the study period were included in the current analysis. Time between discharge and readmission was calculated, and the colonization status at readmission was assessed. Because of interval-censored data, a maximum likelihood analysis was used to calculate the survival function, taking censoring into account. A nonparametric two-sample test was used to test for differences in the survival curves.
Results
The MOSAR-ICU trial included 14,390 patients, and a total of 64,997 cultures were taken from 8,974 patients admitted for at least 3 days. One hundred twenty-five unique patients had 141 episodes with AMRB colonization and at least 1 readmission. Thirty-two patients were colonized with two or more AMRBs. Median times until clearance were 4.8 months for all AMRB together, 1.4 months for HRE, <1 month for MRSA, and 1.5 months for VRE. There were no significant differences between the survival curves.
Conclusion
Fifty percent of the patients had lost colonization when readmitted 2 or more months after previous ICU discharge.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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