Background
New onset atrial fibrillation (NOAF), usually defined as atrial fibrillation (AF) occurring in patients with no known history of AF [
1], is a common arrhythmia in critically ill patients [
2]. NOAF occurs in 5–11% of patients admitted to an intensive care unit (ICU) [
3‐
6], and up to 46% of patients with septic shock [
7,
8]. NOAF in critically ill patients can cause cardiovascular instability [
5] and is associated with increased risk of thromboembolism [
9], increased mortality [
10] and length of ICU stay [
11], and higher healthcare costs [
11].
Guidelines for management of AF [
12,
13] do not directly apply to critically ill patients. NOAF in patients treated on an ICU differs from AF in patients in the community in terms of causes of rhythm disturbance [
14,
15], risks and effectiveness of treatments [
16]. The lack of evidence for managing NOAF in patients treated on an ICU means treatment practice differs widely [
17].
We conducted a scoping review to provide an overview of current evidence for the effectiveness and safety of pharmacological, electrical, and other non-pharmacological NOAF treatments, prophylactic strategies, and acute anticoagulation for stroke prophylaxis in critically ill patients. We also aimed to describe commonly used definitions of NOAF in patients treated on an ICU and suggest recommendations and barriers for future research.
A recent scoping review described the incidence, risk factors, outcomes and management strategies related to NOAF during critical illness [
10]. It included patients with pre-existing AF and studies conducted outside ICUs. Our review focusses on the comparative evidence for treatment of NOAF in patients treated on an ICU.
Materials and methods
Search and identification of studies
We developed our search strategy with an information specialist (TP) in MEDLINE with no date or language restrictions. We included terms used for NOAF combined with terms used for intensive care (see Additional file
1).
We adapted the MEDLINE search strategy to identify papers in the following databases in March 2019: MEDLINE, EMBASE, CINAHL, Web of Science (including Conference Proceedings Citation Index: Science), OpenGrey, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Database of Abstracts of Reviews of Effects (DARE) to 2015. The following clinical trial databases were searched for studies in progress, or completed but not reported: ISRCTN, ClinicalTrials.gov, the EU Clinical Trials register, additional WHO ICTRP trial databases, and the NIHR Clinical Trials Gateway.
Eligibility criteria
We included studies of adults (age ≥ 16 years) in general medical, surgical or mixed ICUs. We excluded studies of cohorts defined by a single disease or narrow disease group not normally admitted to a general ICU, and studies based on service-specific ICUs. We included studies of pharmacological, electrical and other non-pharmacological treatment strategies for treatment or prophylaxis of NOAF and the use of acute anticoagulation. The outcomes of interest were rhythm and rate control, length of ICU and hospital stay, mortality (ICU, hospital, 30-day, long term), arterial thromboembolism and adverse treatment effects. Quantitative studies, reviews, practitioner surveys, and opinion pieces were eligible for this review.
Study selection and data charting
We used EPPI-Reviewer 4 software (Evidence for Policy and Practice Information and Co-ordinating Centre, University of London, London, UK) to identify duplicate records and for title and abstract screening. Two reviewers (LD and LOB) independently screened titles, abstracts and full-text articles, with discrepancies resolved through discussion or by a third reviewer (MC).
We also reviewed reference lists of included studies for further relevant citations. Full-text articles not published in English were screened by native speakers.
We developed data charting forms (see Additional file
1: Tables S1–S10) for the following study designs: randomised controlled trials (RCTs), prospective comparative studies, retrospective comparative studies, and non-comparative studies. The extracted data included: details of the study, population characteristics, description of intervention and comparator(s), methods to address confounding, results, and recommendations for future research.
Decisions about which population characteristics to extract were informed by a systematic review on risk factors for NOAF on the ICU [
18] and a retrospective observational study on predictors for sustained NOAF in the critically ill [
19]. Data were extracted by one reviewer (LD) and checked by another (JB); disagreements were referred to a third reviewer (MC).
Critical appraisal
We evaluated RCTs using version 2 of the Cochrane risk of bias tool [
20]. We evaluated non-randomised comparative studies for risk of bias using the ROBINS-I tool [
21] if they were reported as full papers, included at least 100 patients per treatment arm and reported on methods to adjust for confounding.
Studies which did not meet these criteria were deemed to be at a critical risk of bias. The ROBINS-I tool was adapted by including a stopping rule: the assessment stopped if a serious, or critical, risk of bias judgement was made for the ‘bias due to confounding’ domain. For the confounding domain, decisions regarding which covariates should be reported as being controlled for in analyses were made by the clinical experts in the CAFE study team and are reported in Additional file
1 along with the risk of bias judgements (see Additional file
1: Tables S11).
Collating and summarising results
We presented details of the primary studies in structured tables categorised by pairwise drug comparison and by study design. For each type of study design, we described the extent, range and nature of the identified research. Study parameters and results were then described and summarised narratively.
Discussion
The evidence base for NOAF management for patients in ICU was limited. Many studies identified in this scoping review were non-comparative studies (i.e. lacking a comparator group,
n = 12). Of the 25 primary studies included in the review only two were RCTs [
22,
23] and only three of the non-randomised comparative studies [
25,
33,
34] attempted to control for confounding factors. In the studies which used more robust approaches, there were nevertheless still concerns about how bias (arising from their designs and/or analyses) might affect their results. Moreover, considerable heterogeneity defining NOAF, treatment doses (e.g. total dose ranging from less than a gram to eight grams for amiodarone) [
5,
23,
24,
26,
30,
44,
45], administration (e.g. bolus or continuous infusion), and timepoints to assess conversion to sinus rhythm (e.g. within two [
22], four [
23], 12 [
23], and 24 h [
5,
24,
26,
32] was observed across studies. Similarly, a systematic review was not able to make evidence-based recommendations for pharmacologic rhythm conversion strategies for patients who develop NOAF in a general ICU due to considerable methodological heterogeneity of the included studies [
48]. There is therefore a need to establish optimal treatment dosing and administration regimens, as well as standardised and validated outcome measures of treatment success.
The limited evidence from this review [
26,
30,
32] suggests that beta-blockers may be equivalent to amiodarone for rhythm control. Where reduced mortality in those who received beta-blockers compared to those who received amiodarone was reported [
26,
33], there were significant concerns about bias. Despite this, some review articles [
46,
50,
51] argued that beta blockers may be a reasonable first-choice treatment due to the current evidence of decreased mortality [
46], and improved heart rate control [
46,
50]. Two opinion pieces [
14,
57] also favoured the use of beta-blockers as the initial pharmacotherapy, given the limited and indirect evidence. In contrast, five reviews discussed amiodarone as a potentially effective treatment [
47,
49,
52‐
54], though it was also recognised that amiodarone has potentially significant side effects [
47,
52,
54].
Calcium channel blockers appeared to be less effective for conversion to sinus rhythm when compared with beta blockers, and result in more hypotension than amiodarone [
22,
23]. Two studies [
25,
29] reported that hydrocortisone may be effective as a prophylactic treatment. However, these results are subject to much uncertainty due to methodological limitations.
International guidelines [
12,
13] provide advice regarding the management of patients presenting acutely with AF, and/or patients with AF with haemodynamic instability. However, the evidence base and expert consensus on which these guidelines are based does not appear to include patients in the intensive care unit setting. Therefore, whilst they may be used to guide some general aspects of AF management in any patient, such as the recommendation to use cardioversion if the patient is acutely haemodynamically unstable, recommendations regarding pharmacological therapy and whether or not the patient should be anticoagulated, either short or long-term, may not apply to this specific patient population.
Comparative evidence for or against electrical cardioversion for patients in ICU with NOAF was not identified in our review. Electrical cardioversion should be considered in patients where AF is contributing to marked haemodynamic instability. NOAF often occurs alongside haemodynamic instability but is more likely to be a significant contributor where ventricular rates are very high or where there is underlying structural heart disease. As with other treatments, electrical cardioversion should be used alongside aggressive management of underlying AF drivers. Further procedural considerations are detailed elsewhere [
58].
It is unclear whether to administer therapeutic anticoagulation in critically ill patients with NOAF for stroke prevention. Limited evidence suggests bleeding risk outweighs the increased risk of thromboembolism whilst in ICU [
5,
39], but optimal timing of anticoagulation is unknown [
34,
52]. Two review articles [
51,
56] proposed a patient-centred approach to only administer anticoagulants in patients with high risk of arterial thromboembolic events. Notably, 64% of respondents of a UK wide survey [
17] reported that they would not use anticoagulant therapy in critically ill patients with NOAF.
Included studies were consistent in recommending further research as optimal management strategies have yet to be determined. Findings from previous studies of NOAF in patients in ICU may have been affected by the heterogeneity of patients in a general ICU. Future studies of narrower populations may therefore be helpful to determine best practice in specific clinical scenarios.
Conclusions
Our systematic scoping review focusses on the comparative evidence for treatment of NOAF in patients in ICU. Interpretation of the evidence is limited due to study design flaws and important differences in definitions of NOAF, outcomes and treatment dose. Calcium channel blockers may result in more cardiovascular instability and slower rhythm control than amiodarone or beta blockers. More evidence is required about risk of bleeding and thromboembolism in the short and long term after NOAF onset. However, the little evidence available does not support therapeutic anticoagulation for NOAF whilst patients are critically ill. International guidelines regarding management of AF are largely based on studies and expert consensus that may not be applicable to this specific patient population. Given the significant morbidity and mortality associated with NOAF, adequately powered RCTs are needed to inform management of this common phenomenon. Consensus definitions of NOAF, and of treatment success will improve future studies.
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