The current significance of the FOUR score: A systematic review and critical analysis of the literature

Journal Pre-proof The current significance of the FOUR score: A systematic review and critical analysis of the literature

Dimitrios M. Anestis, Parmenion P. Tsitsopoulos, Christos A. Tsonidis, Nikolaos Foroglou PII:

S0022-510X(19)32365-2

DOI:

https://doi.org/10.1016/j.jns.2019.116600

Reference:

JNS 116600

To appear in:

Journal of the Neurological Sciences

Received date:

31 July 2019

Revised date:

4 November 2019

Accepted date:

26 November 2019

Please cite this article as: D.M. Anestis, P.P. Tsitsopoulos, C.A. Tsonidis, et al., The current significance of the FOUR score: A systematic review and critical analysis of the literature, Journal of the Neurological Sciences (2019), https://doi.org/10.1016/j.jns.2019.116600

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© 2019 Published by Elsevier.

The current significance of the FOUR score: A systematic review and critical analysis of the literature Journal Pre-proof Dimitrios M. Anestis1, Parmenion P. Tsitsopoulos1, Christos A. Tsonidis1, Nikolaos Foroglou2

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Department of Neurosurgery, Hippokration General Hospital, Aristotle University School of Health Sciences,

Faculty of Medicine, Thessaloniki, Greece 2

Department of Neurosurgery, AHEPA University Hospital, Aristotle University School of Health Sciences,

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Faculty of Medicine, Thessaloniki, Greece

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Corresponding Author: Dimitrios M. Anestis, MD, MSc. Department of Neurosurgery, Hippokration General

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Hospital, 49 Konstantinoupoleos str., 54642, Thessaloniki, Greece.

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e-mail: [email protected], tel.: +302310892332, fax: +302310992945

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Abstract

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Background: The Full Outline of Un-Responsiveness Score (FOURs) is a scale for clinical assessment of consciousness that was introduced to overcome disadvantages of the widely accepted Glasgow Coma Scale (GCS). Objective: To perform a systematic review and critical analysis of the available literature on the clinical application of FOURs and perform a comparison to GCS, in terms of reliability and predictive value. Methods: Initial search retrieved a total of 148 papers. After applying strict inclusion criteria and further article selection to overcome data heterogeneity, a statistical comparison of inter-rater reliability, in-hospital mortality

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and long-term outcome prediction between the two scales in the adult and pediatric population was done. Results: Even though FOURs is more complicated than GCS, its application remains quite simple. Its

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reliability, validity and predictive value have been supported by an increasing number of studies, especially in

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critical care. A statistically significant difference (p=0.034) in predicting in-hospital mortality in adults, in favor of FOURs when compared to GCS, was found. However, whether it poses a clinically significant advantage in

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detecting patients’ deterioration and outcome prediction, compared to other scaling systems, remains unclear.

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Conclusions: Further studies are needed to discern the FOURs’ clinical usefulness, especially in patients in

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non-critical condition, with milder disorders of consciousness.

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Keywords: Coma Scale; Level of Consciousness; Full Outline of Un-Responsiveness; Glasgow Coma Scale; Predictive Value; Systematic Review

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1. Introduction

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1.1. Rationale Since its introduction by Wijdicks et al in 2005 [1], the Full Outline of Un-Responsiveness Score (FOURs) has gradually gained ground in clinical practice. FOURs was principally designed to overcome shortcomings of the widely used and considered as “gold standard” [1-9] Glasgow Coma Scale (GCS), namely the inability to test the verbal component of comatose patients, the poor differentiation between patients with low scores, the failure to detect subtle changes in the neurologic condition, and the lack of assessment of potentially important clinical indicators (brainstem reflexes, breathing pattern, need of mechanical ventilation) [1, 6, 10-19].

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Moreover, its reliability and correlation with the patients’ outcome have also been questioned [1, 10-17, 19]. The FOURs evaluates additional neurological elements compared to GCS. It involves 4 components: eye

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response, motor response (which includes gesturing in an attempt to replace verbal response), brainstem reflexes and breathing pattern (Table 1). It has already been applied and tested in several centers, which has

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resulted in an increasing number of publications regarding its validation, reliability and predictive value [10-18,

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20-35]. The scale has also been translated from the original English version and validated into several

Chinese [44], Persian [45]).

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1.2. Objectives

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languages (French [36], Spanish [37], Italian [38], Swedish [39], Finnish [40], Polish [41], Turkish [42, 43],

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The present review intends to systematically summarize the existing data and provide a critical analysis on the FOURs, emphasizing on aspects of clinical importance, namely its unique characteristics, potential advantages and drawbacks, reliability, internal consistency, construct validity, face validity and predictive value. The hypothesis whether the FOURs is superior to GCS in terms of inter-rater reliability and predictive value was also tested.

2. Materials & Methods 2.1. Protocol & Eligibility Criteria

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A predefined protocol for literature search and relevance was unanimously agreed by the authors. The

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PRISMA guidelines for reporting of systematic reviews [46, 47] were followed throughout the whole process (Supplementary Table A). All types of studies regarding the FOURs’ statistical documentation were included. Other types of publication (review, commentary etc.) were also included if one of the following criteria was met: a) in-depth commentary on the FOURs’ special characteristics, b) recommendations – guidelines on its application were provided. Publications on both adult and children populations were included. All studies involving pediatric patients were distinguished from the adult population. All available literature in the English language since 2005, the year when the scale was introduced, was included.

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Further criteria were applied for the statistical analysis. Only studies comparing FOURs with GCS were selected for analysis, and, in particular, those comparing inter-rater reliability and predictive value. As per the

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reliability, only studies assessing weighted kappa values were included. As per the predictive value, studies in

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which the protocol predicted patient examination later than the first 24 hours after admission were excluded.

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In-hospital mortality and poor long-term outcome were selected as the parameters of interest. In order to overcome data heterogeneity, poor long-term outcome was defined as a modified Rankin Scale performance

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2.2. Sources & Literature Search

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of 3 to 6 (a criterion used in most of the available studies), after at least 3 months of observation.

PubMed, Scopus, Web of Science, the Cochrane Library and Google Scholar search engines were used to

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review the existing literature, up to June 1st, 2019. The term used was [[“FOUR score”] OR [(responsiveness OR un-responsiveness OR unresponsiveness) AND “full outline”]], in all available fields. Next, publications dated before 2005, when the scale was introduced, were excluded and the search was limited to publications in English. Full articles were thereafter reviewed for content relevance independently by the first two authors (DMA, PPT). Lastly, duplicates were excluded. Conflicts in article selection between the reviewers were solved by consensus. All articles that were found relevant according to the protocol’s criteria (see above) were selected for the critical analysis section of this review. Studies meeting further criteria (described above) were selected for statistical analysis. 2.3. Data Collection & Analysis

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For quantitative studies, participants’ number, age and characteristics, time of patients’ rating after admission,

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outcome assessment criteria, observation period, kappa values for reliability, Cronbach’s α for internal consistency, Pearson’s or Spearman’s ρ coefficients for construct validity, odds ratios, cut-off scores with sensitivity and specificity and areas under the receiver operating characteristic curve for predictive value, face validity surveys’ results and conclusions were recorded electronically using Microsoft © Office Excel© 2016, Microsoft Corporation, Redmond, Washington, USA. A special focus on the comparison between FOURs and GCS was done. Data extraction was performed by the first author (DMA) and double-checked by the second author (PPT). Normality of data was checked with the Kolmogorov-Smirnov test. Paired sample t-test was applied for

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normally distributed data and the Wilcoxon sign-ranked test for non-normally distributed data between the parameters of interest for the two scales (weighted kappa coefficients for reliability and areas under the

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receiver operating characteristic curve for predictive value). The statistical package SPSS © version 25 (IBM

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Corporation, Armonk, New York, USA) was used for the analysis and calculations.

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The quality of each publication as well as risk of bias were further evaluated by first two authors (DMA, PPT) using the Mixed Methods Appraisal Tool (MMAT), version 2018. This tool, already used in literature [48-50],

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allows the simultaneous evaluation of qualitative, quantitative, and mixed m ethods studies, making it appropriate for this review [51, 52]. Agreement was reached on most of the 5 appraisal items (see

3. Results

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Supplementary Table B), and all discrepancies were resolved through discussion.

After careful screening, a total of 148 publications were eventually included (Figure 1). The characteristics of all quantitative studies and extracted data are summarized in Tables 2 to 4 and Supplementary Tables C to G. Methodological issues such as lack of power analysis, inadequacies such as areas under the curve not tested for statistically significant differences and conclusions not entirely justified were noted and taken into consideration during the publications’ assessment (Supplementary Table B). 3.1. Special Characteristics 3.1.1. Potential Advantages

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The FOURs includes some unique clinical features and characteristics, which its inventors and followers

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present as advantages compared to GCS: 1. The eye tracking test. This is added to the traditional eye opening of the GCS. It incorporates midbrain and pontine functions [19] and has the advantage of detecting vegetative state (the FOURs tests for visual pursuit, which is one of the first signs of recovery of consciousness [53]) and locked-in syndrome (eye movements and blinking on command are characteristic clinical signs, also tested with the FOURs [54]) [1, 8, 9, 53, 54]. 2. Hand gesturing replaces verbal score. It allows assessment of afferent language processing, regardless of endotracheal intubation, aphonia, or trauma to the vocal cords. Furthermore, language disturbances, such as motor, transcortical or global aphasia, might be misclassified as altered consciousness by raters using the

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GCS. With the FOURs, these dysphasic but alert patients can be appropriately evaluated according to their

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actual responsiveness [1, 19, 37].

3. Other motor functions. Overall, these features are similar with the GCS, with the exception that no difference

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is outlined between flexor posturing and normal flexion to pain. The addition of myoclonic status epilepticus is

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another difference, which receives a motor score of zero like the no motor response, reflecting poor outcome after anoxic brain injury [1, 19].

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4. Assessment of brainstem function. The absence of brainstem reflexes testing with the GCS has been

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repeatedly criticized in the literature [1, 10, 12, 13, 15-18, 55]. Pupillary, corneal, and cough reflexes are

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included in the FOURs, facilitating the assessor to localize brainstem lesions and monitor progression of cerebral injury [1, 19, 56, 57]. Along with the assessment of the respiratory pattern, these may likely improve the predictive value of the scale [58].

5. Influence of sedatives and neuromuscular blockers. Critically ill patients may be under sedatives and neuromuscular blocking agents which can interfere in the assessment of the level of consciousness. The FOURs may present with an advantage since it does not include a verbal score, but it does include pupillary assessment which usually remains unaffected by sedative agents. On the other hand, all 3 components of the GCS score are influenced by sedation. Thus, the FOURs may prove to be particularly useful in the neurological assessment of patients under mild or moderate sedation [7, 12, 59, 60]. 6. Recognition of brain death. Another important aspect of the FOURs is its usefulness in recognizing imminent brain death, because a patient with a total score of 0 should be considered a candidate for brain-

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death evaluation [1, 54, 61, 62]. This is an advantage compared to GCS, where even its minimum score of 3

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requires additional assessment of brainstem reflexes before deciding to proceed to brain death tests [61-63]. 3.1.2. Potential Drawbacks The aforementioned possible advantages of the FOURs can be questioned and should be therefore interpreted with caution. Specifically: 1. Application restrictions. The FOURs can be applied in intubated, and generally in patients that are incapable to respond verbally. This is a clear advantage compared to GCS for patients with severe disorders of consciousness and, apparently, low GCS scores. Nevertheless, it has been supported that the FOURs omits

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information which can be crucial when stratifying non-comatose patients, especially those with traumatic brain

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injury. In particular, based on injury severity, most patients present with mild or moderate injury, with the

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distinction between those often depending on the verbal response –a parameter missing from the FOURs [64, 65]. Further, receptive aphasia is a condition that affects the reliability of both coma scales and, therefore,

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influences grading [59]. Moreover, ophthalmic conditions, such as cataract surgery, previous iridectomy and

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corneal opacities, might hinder pupil assessment [25]. Lastly, the natural reduction of cough reflex in the elderly might also result in improper assessment of the level of consciousness [66].

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2. Diagnosis of distinct altered states of consciousness. As per detecting vegetative state and minimally

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conscious state, diagnostic criteria utilizing the FOURs have been proposed [67, 68]. However, it must be

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stressed that the discrimination between them might be problematic. The FOURs tests for visual pursuit (the first sign heralding the transition from vegetative to minimally conscious state [69]) but not all the behavioral criteria needed. Thus, it cannot be solely used for the definite distinction between these conditions and should be supplemented by the application of other more specific clinical tools, such as the Revised JFK Coma Recovery Scale (CRS-R) [3, 67, 68, 70-74]. Overall, there is evidence to support that the FOURs can be reliably used only for the assessment of acute disorders of consciousness, since it hasn’t been developed to assess prolonged unconscious patients or severely disabled individuals emerging from coma [75-77]. 3. Detection of the underlying cause of coma. The FOURs includes components with potential localizing value, especially in comatose patients, such as the respiratory pattern [1, 57]; it has to be stressed, however, that coma scales are not designed to diagnose the underlying cause of coma and therefore fail to substitute detailed neurological evaluation [78]. Hence, the combination of GCS with pupil reflex results in a prognostic

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model with similar predictive value with FOURs, eliminating the latter’s potential advantage, since evaluating

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pupils’ reactivity to light is in any case an essential part of the clinical assessment of comatose patients [7981]. Interestingly, brainstem reflexes have been included in a recently proposed score which showed comparable predictive value with the FOURs for 28-day mortality in deeply sedated patients [82]. As a result, the predictive contribution of the additional components included in the FOURs remains questionable [11, 38, 80]. 4. Standardization and scoring. Τhe FOURs has been criticized in the literature as lacking standardized administration and scoring procedures to be consistently applied [73], as well as for potential difficulties in interpreting respiratory patterns in patients on mechanical ventilation [65].

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3.2. Statistical Documentation 3.2.1. Reliability and Validation

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There are 24 available studies (Supplementary Table C) regarding the FOURs’ inter-rater reliability [1, 2, 10,

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12, 13, 22-25, 28, 29, 33, 35, 37-39, 44, 45, 83-88]. The κ values vary between authors and between each one

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of the 4 components of FOURs, but remain higher than 0.6 in almost all reports, which denotes good to excellent inter-observer agreement as stated in literature [1, 2, 12, 13, 22-24, 29, 35, 37, 38, 83, 84]. It is

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comparable to that of GCS [1, 2, 10, 22, 25, 29, 37-39, 83, 84, 87, 89], or even better in some cases [13].

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Nevertheless, some variations between raters of different background have been noted [13]. Fair to good variability between nurses had been initially reported, emphasizing the need for more intense training [1, 90].

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However, it was later supported that even Intensive Care Units’ nurses with minimal experience can reliably use the FOURs [35]. It is also likely that familiarity with the FOURs can result in more reliable results when nurses use this scale [35], while in-depth training, providing standard definitions as guidance, and full demonstrations of the evaluation process are possible ways of limiting inter-rater variations [10]. Other factors, such as the loudness of the rater's voice, the intensity of pain stimulation, the method of measurement of pupil size, the time spent to obtain the response and the fluctuating alertness between ratings may also be associated with variations between raters as well [10]. Among patients with different diagnosis, level of consciousness variability has been reported (lower agreement among drowsy or intoxicated patients), which was comparable for the two scales [13, 37, 91]. Lastly, both GCS and FOURs showed excellent inter-rater agreement between bedside raters and raters utilizing robotic telemedicine. The brainstem component of the latter, however, showed greater variability, resulting in the outperformance of the FOURs by the GCS [92].

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It has been repeatedly noted that intra-rater reliability cannot be evaluated, because there are worries whether

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a rater can assess free of bias a patient after a short time period without being influenced by previous scoring [1, 10, 33, 83]. There is, however, one report, according to which the FOURs yielded an “excellent” test-retest result (Intra-class Correlation Coefficient =0.930) [44]. Nineteen publications comparing inter-rater reliability between FOURs and GCS were found. Weighted κ values had been set as a parameter of interest, which resulted in 12 eligible studies [1, 2, 12, 22, 23, 29, 33, 35, 37, 38, 83, 84], involving a total of 1285 participants, mostly in critical condition. No statistically significant difference was found between the two scales (Table 5).

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3.2.2. Internal Consistency

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Cronbach’s α is used to assess internal consistency in 20 studies [1, 2, 10, 12, 14, 17, 23-25, 29, 31, 35, 37-

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39, 44, 83-85, 93]. An α coefficient above 0.9 is sometimes interpreted as indicating the presence of item redundancy, but in the case of the FOURs the items are already limited and distinctly different, and therefore

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item deletion is not an option [39].

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Most of the reported values are above 0.8 (Supplementary Table C), and consistency is characterized as “good” [2, 10, 84], “good to excellent” [25, 83], “excellent” [85], or found to be of “high” [1, 12, 14, 23, 29, 37-

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3.2.3. Construct Validity

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17, 23, 25, 31, 37, 39].

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39, 44, 93] or “very high” [24] degree by authors. Τhe reported results are similar for the GCS [1, 10, 12, 14,

Correlation coefficients between the FOURs and the GCS score have been measured above 0.8 (Supplementary Table C) in most of the 25 available studies [1, 10, 12-14, 17, 18, 22, 25, 27, 29, 37, 38, 44, 45, 56, 83-85, 87, 94-98]. The correlation between the “standard” GCS score and the FOURs is used in order to assess construct validity of the latter which, according to the reported values, was found to be “strong” [13], “significant” [83, 84], “high” [12, 14, 29, 44, 85, 98], “good” [1, 10, 25, 27, 37], “good to very good” [18] or “excellent” [95]. Other reported correlations are between the FOURs and the National Institutes of Health Stroke Scale (NIHSS, Spearman’s ρ=-0.61), and in particular with the latter’s level of consciousness item (Spearman’s ρ=0.78), in Stroke Unit patients [37], as well as with the Hunt-Hess (ρ=-0.71) and Fisher (ρ=-0.66) scores in patients with aneurysmal subarachnoid hemorrhage [93].

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with a FOURs of 2 or more (84% vs. 44%, respectively) [112].

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Τhe predictive value of FOURs in patients with traumatic brain injury has been well documented. Kasprowicz

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et al tested multivariate predictive models, concluding that the FOURs performs equally well as the combination of GCS and pupil reactivity. The GCS, however, has been proven useful in further classifying

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patients with high FOUR scores (>14), when predicting 3-month outcome. On the contrary, in terms of in-ICU

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mortality, the FOURs was useful in sub-categorizing patients with the lowest GCS value [94]. In another study, FOURs on ICU discharge correlated with 12-month outcome. However, only GCS was predictive for outcome

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in multivariate analysis [111]. Finally, a strong correlation between the FOURs and the jugular bulb oxygen

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saturation 72 hours after traumatic brain injury was recently found [110], while both FOURs and GCS were

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found to be negatively correlated with the pulsatility index in patients examined with transcranial doppler [113]. The FOURs has been investigated as a predictive factor in patients with anoxic -ischemic encephalopathy following cardiopulmonary resuscitation [114-119]. Total FOURs on day 3 as well as its visual and motor components have been recognized as good predictors of outcome [120]. Another study of patients after cardiac arrest (CA) supports the FOURs’ predictive value of mortality, when assessed on the 3 rd to 5th postictal day. Its predictive performance was found at least equal to that of the GCS, the minimum score of which was not invariably linked to death [121]. The difference between the FOURs on days 1 and 3 was tested as a prognostic factor of 6-month outcome in patients suffering out-of-hospital CA; worsening or absence of improvement showed accurate predictive performance [122]. Further, in a limited series of patients treated with hypothermia after CA, low FOURs on admission was not associated with their good outcome [123], but in a recent study, the FOURs had better prognostic value than the GCS [124].

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The FOURs has been tested as a predictor for in-hospital mortality in patients with acute ischemic stroke, with

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findings comparable to GCS and NHISS [101]. Τhe latter, however, seemed to be superior in predicting unfavorable outcome [101]. Furthermore, the brainstem and motor components have been included in a proposed prognostic model for conscious awareness recovery of comatose patients after ischemic stroke [125]. Assessment of cirrhotic patients with potential overt hepatic encephalopathy with the FOURs demonstrated good performance in diagnosing this condition since a score lower than 16 was linked with increased risk of death (hazard ratio of 2.77). In the same study, it was also hypothesized that brainstem and respiratory components might also constitute a prognostic advantage to the GCS for this group of patients [126]. As per

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predicting sepsis-associated encephalopathy in patients under critical care, the GCS was found to perform better than the FOURs [127].

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In a retrospective analysis of patients with spontaneous intracerebral hemorrhage (ICH), a FOURs of 10 or

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less has been associated with a 4-fold higher risk of mortality and a 1.6-fold higher risk of poor functional

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outcome at discharge [128]. In another retrospective review of patients with primary intraventricular hemorrhage, again a FOURs of 10 or less was identified as an independent predictor of in-hospital mortality

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[129]. Kuznietsov tested the FOURs’ correlation of midline shift in patients with spontaneous supratentorial ICH, concluding that the FOURs shows higher diagnostic informative value compared to GCS [130]. On the

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contrary, Klaas et al did not include the FOURs in their predictive model for ICU need following supratentorial

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ICH, despite the fact that low FOURs values were identified as a predictive factor. Instead, the GCS score was preferred, due to its wider acceptance [131]. In another study, the FOUR score was not found to be independently associated with outcome [132]. Finally, in a retrospective analysis of patients with spontaneous ICH, the GCS item of the ICH Score [133] was replaced with the FOURs in 3 sub-groups (2 points for 0-6, 1 point for 7-13 and 0 points for 14-16). This proposed prognostic model showed comparable but not superior predictive value compared to the ICH score [108]. The FOURs has been successfully tested for predicting mortality and outcome in patients with subarachnoid hemorrhage [93, 105, 109]. Specifically, the FOURs on admission and post-ictal day 7 was especially associated with mortality, and 1- & 6-month outcomes (defined as modified Rankin Scale ≥4 or Glasgow Outcome Scale ≤3), while that at day 14, only with 6-month outcome [105]. In the same report, the post-ictal day 7 total FOURs was linked with clinical vasospasm, with this finding requiring further confirmation, as stated

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by the authors [105]. In another study, a one-point increase in FOURs at admission was linked with a 1.64-fold

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increase in the likelihood of a good recovery (GOS>3 in one month) [93]. The FOURs was found to be associated with unfavorable outcome in patients with bacterial meningitis, but it was equally predictive with the GCS [98]. Since the FOURs is applicable in intubated patients, its potential correlation with weaning from the respirator and extubation failure is of importance. In 2 retrospective studies, there was no significant difference in the FOUR scores between patients successfully and unsuccessfully extubated [134, 135]. Furthermore, in a recent study, the FOURs was also not independently associated with extubation failure. In the same study, the proposed predictive score included the visual item of the CRS-R as an index of the neurologic status instead

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[136]. In another report, the FOURs showed greater accuracy than the GCS in predicting extubation failure

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[103].

A FOURs lower than 4 was tested but finally not included in a prognostic model predicting time of death after

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withdrawal of life support in neurocritical patients, which is of interest in cases of organ donation after cardiac

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death [137].

In conclusion, the FOURs has been successfully evaluated for its predictive value for various conditions. Its

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close relationship to mortality and poor neurological outcome has been well documented [138]. However, its

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potential superiority to GCS remains unclear since some reports have concluded that the two scales are

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comparable in predicting mortality and outcome [11, 14, 17, 18, 21, 22, 24, 26, 28, 30, 38, 44, 84, 85, 96, 99, 101-103, 106], but others recognize a potential advantage of the FOURs [1, 12, 15, 16, 23, 25, 27, 29, 31, 32, 34, 88, 95, 100, 104, 105, 107, 139]. It must be noted though that studies reporting a superiority of FOURs compared to GCS were carried out in intensive care units, implying that the additional neurological elements included in the FOURs are of value especially in critically ill patients. Moreover, mortality was higher in patients with the lowest FOUR score compared to the lowest GCS score, posing another potential advantage of the former in patients with severe disorders of consciousness [1, 12, 23]. According to our selection criteria, 18 studies, involving a total of 4532 participants, were found eligible for comparison of the predictive value for in-hospital mortality between FOURs and GCS when applied within the first 24 hours after admission [1, 11, 12, 14, 17, 21, 24, 27, 28, 31, 34, 44, 84, 96, 98, 101, 104, 106]. A

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statistically significant difference was found, with the FOURs performing better than the GCS (Table 5). It has

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to be mentioned, however, that the vast majority of participants were ICU patients (3904, exceeding 86%). As per comparing the performance of the two scales in predicting long-term outcome, this was not found to be significantly different between the two scales (Table 5), based on, however, only 7 studies with 789 participants in total [1, 11, 12, 14, 44, 101, 103]. 3.2.5. Face Validity Data regarding the face validity of the FOURs are derived from 5 surveys am ong raters, who were asked to evaluate the scale’s clinical usefulness. Most agreed (or strongly agreed) that it is easy to use [1, 2, 10, 85], it

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can be obtained in appropriate time [1, 2, 10, 13, 85], it is a good alternative to GCS [1, 2, 10, 85] or even

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better when looking for the depth of coma or patient deterioration [1], or when applied in intubated patients or

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non-native speakers [13], and that they would use the scale if it becomes generally accepted [1, 2, 10]. However, there were concerns about patient disturbance and its feasibility compared to GCS, even if the

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FOURs in general fulfills the requirements of a practical and psychometrically sound clinical instrument [10].

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On the other hand, pre-hospital care providers that received training on the FOURs without having applied the scale in clinical practice yielded similar responses, but indicated that its application is more time-consuming

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than the GCS [4].

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3.3. Application in the Pediatric Population

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When applied in children, statistical parameters of the FOURs have been studied in the literature (Supplementary Table F) [140-148]. Inter-rater reliability was found to be good to excellent [141-145, 148]; internal consistency was also good [142, 143]; and correlation with the GCS has been reported as high [142] or very high [143].

In agreement with the application in adults, it seems that the adaptation of FOURs in pediatric patients with neurological compromise is a valid predictor of mortality and outcome (Supplementary Table G) [141, 143, 144, 147], and particularly useful in patients with the lowest GCS values [145], but it remains unclear whether it provides a significant benefit when compared to the most commonly used GCS [140-142, 144-148]. It should be mentioned that there are no widely accepted cut-off points for the FOURs when applied in children (Table 4).

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Τhe face validity of the FOURs and its application in children has been evaluated in two reports, where most

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participants agreed that it is clinically relevant, fast and easy to use, a good alternative to the GCS, they were eager to use it in case it becomes widely accepted [141, 143], and that it allows for a more comprehensive assessment of the depth of coma, as well as the identification of c linical worsening when compared to the GCS [143]. The FOURs has been recently included in pediatric neurologic emergency life support courses [149], however, its acceptance is limited to 3% among Pediatric Intensive Care Units in the United States [150]. Therefore, there is evidence to support that the FOURs is a reliable and easy to use tool for the assessment of children as well. Its prognostic value should be further evaluated, but, based on the available data, it seems to

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be at least comparable to GCS.

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Studies including patients in childhood are limited in number, 8 in total, and only 5 of them [140, 141, 144, 146, 147] were found eligible for statistical analysis, with a total of 383 participants. No significant difference

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between the predictive performance of the two scales for in-hospital mortality was found (Table 5).

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4. Discussion

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The ideal coma scale should be reliable, valid, linear (providing equal weight to all components), simple and easy to use, reproducible, applicable to most patients, sensitive enough to identify those who deteriorate or

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are at risk for deterioration, and predictive of their outcome. Under these circumstances, a coma scale turns into a useful tool in formulating an appropriate diagnosis, prognosis and treatment plan in cases with impaired level of consciousness [12, 19, 71, 151].

Despite being a much newer scale, which is less accepted and applied in clinical practice and with less experienced evaluators [1, 13], the FOURs seems to be equally reliable with the GCS. It should be noted, however, that, so far, it has failed to prove a clinically significant advantage in terms of inter-rater reliability [23]. The FOURs provides more neurological details mainly useful for the assessment of comatose patients, especially for those unable to respond verbally or those who exhibit abnormal respiratory pattern. However, its predicting significance remains to some extent unclear. In particular, the brainstem and respiratory pattern components seemingly do not provide the expected benefit, and the combination of eye and motor responses

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may be the most useful predictor for mortality and long-term outcome [11, 23, 38, 138]. However, this is not

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generally accepted [34]. Assessment of consciousness in children should follow the developmental stage of each individual. Infants are unable to follow commands and communicate verbally. They also present with a higher normal respiratory rate than toddlers and adults. Those parameters, movement, communication and respiratory rate, change gradually, from infancy to childhood, until they reach normal adulthood levels. Thus, coma scales suitable for application in infants and children should be adjusted accordingly, in order to take into account ageappropriate responses [142, 148]. As a result, a modified version of the GCS is available and recommended for use in infants and children [152]. A modified FOURs (Pediatric FOUR Score Scale, PFSS) which takes into

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consideration age-appropriate spontaneous movements, breathing pattern and rate, and the varying methods of respiration support, has also been proposed [142], which may be useful especially in children younger than

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2 years old [148].

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When FOURs and GCS are compared in terms of their predictive value, it is concluded that the FOURs’

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alleged superiority to the GCS has yet to be proven [138], but, based on the available data, a potential advantage of the FOURs for predicting in-hospital mortality in adults is emerging. This, however, should be

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interpreted with caution. The heterogeneity and limited number of studies are two factors that might affect the

importance of its findings.

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reliability of any comparison between the predictive value of the scales, and, as a res ult, the clinical

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This questioned superiority compared to the GCS score in terms of predictive value raises concerns about the FOURs’ applicability and usefulness. This is, however, premature to support, since prognosis cannot be solely based on the level of consciousness. Sophisticated predictive models utilizing the specific characteristics of every condition should be proposed, studied and applied. The fact that even more simplified alternatives to the GCS have been suggested [153] puts in question another alleged advantage of the FOURs, its greater neurological detail. Apparently, the usefulness and reliability of those simpler scales must be thoroughly investigated, not only in terms of prognosis, but regarding their sensitivity and reliability to detect patients’ deterioration as well. Another advantage of the FOURs that has been suggested is its usefulness in further sub-categorizing patients with the lowest GCS score of 3, mostly based on the evaluation of respiratory pattern and brainstem reflexes [1, 15, 59]. Furthermore, a possible difference in the predictive value, since mortality in patients with

15

the lowest FOURs values is possibly higher than mortality in patients with the lowest GCS scores, has been

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reported [18, 22, 23]. It is hard to accept that a 20-item scale (FOURs) is easier to learn and remember than a 15-item one (GCS, 3 items of which are in fact “no response”), especially when more complicated neurological details and extra training are needed for the evaluation of brainstem reflexes and respiratory pattern. Therefore, it is expected that the application of FOURs may typically require longer time than GCS and is more complicated to implement in acute situations, in particular, by inexperienced assessors [23]. However, this is the reasonable price someone has to pay in order to extract in-depth information missing from GCS, regarding the patient’s neurological function. Moreover, its complexity does not seem to discourage professionals to use it in clinical

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practice, since the information acquired through a typical neurologic evaluation is sufficient to score a patient according to FOURs [25].

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In critically ill patients such as those intubated or presenting with low GCS, the FOURs is probably more

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appropriate compared to the GCS. Other reported potential benefits of the FOURs include better decision

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making, better outcome prediction, and significantly more information for clinical trials [28]. The additional aspects of the FOURs are also useful in diagnosing vegetative state, locked-in syndrome, minimally conscious

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state and brain death. However, available evidence show that the FOURs cannot definitely diagnose those conditions and additional assessments are required for confirmation. Furthermore, its value in identifying

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potential organ donors after circulatory death, although postulated, has not been confirmed yet. The time

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between withdrawal of life-sustaining measures and death highly affects the organs’ quality, and, if it exceeds 1 hour, can result in donor ineligibility [137]; thus, it is of interest to successfully identify those patients who will die within this time limit. Lastly, the FOURs’ usefulness in predicting extubation failure has not been confirmed by available studies yet. However, its applicability in intubated patients and the resulting advantage in accuracy compared to the GCS [103] are intriguing enough to justify further studies. Sensitivity of the FOURs is another issue. As previously stated, “the GCS may not be able to detect subtle changes during examination” [1]. It is, however, interesting to point out that the FOURs ignores important information when assessing patients with mild, or even medium, disorders of consciousness: These patients would likely present with no brainstem and breathing pattern pathological findings, leaving their level of consciousness grading only on motor and eye responses. Therefore, a reasonable question is raised whether the FOURs is the preferable clinical tool for monitoring non-ICU patients, who would possibly show

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disproportionally influenced GCS than FOUR, with the latter being close to normal. This has not been

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researched yet, even though it is likely that the GCS is probably more suitable for mild disorders of consciousness [5]. Further studies are needed to clarify this issue. The FOURs has already been suggested as a useful tool for clinical assessment and a valid alternative to GCS in conditions such as traumatic brain injury [154], post-operative evaluation of neurosurgical patients [155] and clinical monitoring of patients with acute ischemic stroke [156, 157]. It has also been included in the guidelines for unified reporting of outcome data in studies of resuscitation from drowning, but only as supplementary data, since the application of GCS and AVPU (alert / voice / pain / unresponsive) is typically recommended in the initial neurologic examination [158].

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There is ample evidence to suggest the FOURs as a reliable alternative to the GCS in critical care [159]. Most importantly, the International Multidisciplinary Consensus Conference on Multimodality Monitoring in

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Neurocritical Care concluded that “assessments with either the GCS (combined with pupil assessment) or the

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FOURs [should] be routinely performed in comatose adult patients with acute brain injury” [160]. Similarly, the

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recommendations of the European Society of Intensive Care Medicine also accept the new scale’s usefulness in critical patients’ care [161]. However, in a 2016 survey among neuroscience nurses in 11 European

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countries, less than 10% of the participants were aware of the FOURs and none of them were using it in clinical practice. Specifically, the GCS was found to remain by far (84.9%) the most popular tool for

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assessment of consciousness [162].

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Some limitations pertaining to the current review must be noted. Our search was limited to publications in English, and thus some studies in other languages might have been missed. Findings were based on published evidence. All publications were thoroughly checked for bias and methodological is sues have been noted, as already mentioned above. Considerable heterogeneity existed [59, 148], and thus, a complete metaanalysis could not be reliably performed. As such, the presented statistical analysis was based on a limited number of studies, with important differences in size and participants’ characteristics (diagnosis, department of admission), in the time of patients’ clinical rating, the observation period and the raters’ level of experience, to name some. Our selection criteria could not fully address these issues, especially when comparing the predictive value of the two scales. Moreover, ratings during the first 24 hours of admission might not be comparable, since time of ictus was not taken into consideration and patient deterioration could not be reliably assessed. Further, the suitability and usability of the FOURs and the GCS when monitoring patients in danger

17

of deterioration could not be fully addressed. Lastly, in some occasions, the observation limit of >3 months

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might have included populations with significant inherent differences.

5. Conclusions The FOURs is already accepted in clinical practice as a reliable and valid tool for the assessment of level of consciousness. Its potential advantages become clear when it is used for patients in critical condition or when the GCS score cannot be applied reliably. Hence, its role in critical care patents is essential. Nevertheless, it is probably unrealistic to anticipate that one coma scale could fulfill all requirements. Further studies are needed

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especially on the evaluation of its usefulness in monitoring less severe neurological conditions of disturbed level of consciousness. Its predictive value should also be further investigated, preferably in an attempt to

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develop prognostic models separately for each neurological pathology.

Funding

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-

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Author contribution

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profit sectors.

DMA contributed to the conception and design of the work, the acquisition and evaluation of data and the

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drafting of the manuscript. PPT contributed to the conception and design of the work, the evaluation of data, and the critical revision of the content. CAT contributed to the conception of the work and the critical revision of the content. NF contributed to the critical revision of the content. All authors were involved in the final approval of the manuscript.

Declarations of Interest None.

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Full Outline of Un-Responsiveness Score

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Eye Response 4: Eyelids 3: Eyelids 2: Eyelids 1: Eyelids 0: Eyelids

open or opened, tracking, or blinking to command open but not tracking closed but open to loud voice closed but open to pain remain closed w ith pain

Motor Response 4: Thumbs-up, fist, or peace sign 3: Localizing to pain 2: Flexion response to pain 1: Extension response to pain 0: No response to pain or generalized myoclonus status Brainstem Reflexes 4: Pupil and corneal reflexes present 3: One pupil w ide and fixed 2: Pupil or corneal reflexes absent 1: Pupil and corneal reflexes absent 0: Absent pupil, corneal, and cough reflex

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Respiration

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4: Not intubated, regular breathing pattern 3: Not intubated, Cheyne–Stokes breathing pattern 2: Not intubated, irregular breathing 1: Breathes above ventilator rate 0: Breathes at ventilator rate or apnea Table 1. The Full Outline of Un-Responsiveness Score (FOURs).

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Reference

Journal Pre-proof

Study Sam ple

Rating Tim e

End Point

Value

Sensitivity

Specificity

Discharge

9

0.750

0.760

Wijdicks et al [1]

120 Neuro ICU patients

2

Eken et al [11]

185 ED patients

Admission

Discharge 3 months

4 9

N/A N/A

N/A N/A

3

Akavipat et al [20]

304 patients

Admission or deterioration

Discharge

10

0.710

0.930

4

Marcati et al [38]

87 Neurology, Neurosurgery, Stroke Unit & ICU patients

Within 7 days

Discharge

10

0.910

0.860

5

Chen et al [15]

101 Neuro ICU patients

Day 1

30 days

4

0.500

0.957

6

Gorji et al [24]

53 TBI ICU patients

Within 24 hours

Discharge

4

0.900

0.900

7

Okasha et al [31]

60 TBI ICU patients

Admission

Discharge

9

0.730

0.800

8

Gorji et al [100]

80 TBI ICU patients

Within 24 hours

0 - 14 days 15 days - Discharge

9

Mansour et al [101]

127 Acute Ischemic Stroke patients

Day 1 Day 3

Discharge

4 6 11 8

0.920 0.900 0.840 1.000

0.870 0.820 0.570 0.860

10

Peng et al [44]

120 Neurosurgical ICU patients

Day 1

Discharge

9

0.750

0.850

11

Saika et al [18]

138 TBI ED patients

Admission

2 w eeks

7

0.975

0.882

12

Ayasi et al [102]

80 TBI ICU patients

Day 1

≤14 days >14 days

4 6

0.900 0.730

0.900 0.900

13

Khanal et al [27]

97 ICU patients

Within 24 hours

Discharge

6.5

0.793

0.794

14

Said et al [103]

86 ICU patients

Within 24 hours

28 days

9

0.844

0.796

15

Babu et al [104]

98 TBI ICU patients

Within 24 hours

Discharge

8

0.799

0.816

16

Baratloo et al [66]

52 TBI ED patients

Admission 6 hours

1 month

17

Hosseini et al [26]

80 TBI ICU patients

Within 24 hours

≤14 days >14 days

8&9 5 4 6

0.615 0.846 0.900 0.730

0.872 0.974 0.900 0.900

18

Momenyan et al [29]

84 TBI ICU patients

Within 7 days

Discharge

6

1.000

0.620

19

Nyam et al [30]

55 TBI ICU patients

Admission

ICU Discharge

5

0.625

0.894

20

Silvitasari et al [86]

74 ICU patients

Undefined

7 days

6

0.861

0.816

21

Surabenjaw ong et al [95]

60 Stroke ED patients

Undefined

3 months

10

N/A

N/A

22

Kafle et al [96]

122 TBI patients

Admission

Discharge

8

1.000

0.918

23

Oktarina & Simajuntak [88]

33 ICU patients

Undefined

7 days

9

0.867

0.833

24

Ramazani & Hosseini [107]

300 ICU patients

Admission

ICU Discharge

6.5

0.783

0.782

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Admission or deterioration

Pr

Nr

Table 2. FOURs cut-off scores for mortality, according to available studies in adult population. ICU: Intensive Care Unit, ED: Emergency Department, TBI: Traumatic Brain Injury, N/A: Not Available

26

Nr

Reference

Study Sam ple

Rating Tim e

Criterion

End Point

Values

Sensitivity

Specificity

1

Akavipat et al [20]

304 patients

Admission or deterioration

GOS≥3

Discharge

14

0.770

0.950

2

Gorji et al [24]

53 TBI ICU patients

Within 24 hours

GOS≤3

Discharge

6

0.860

0.870

3

Okasha et al [31]

60 TBI ICU patients

Admission

GOSE≤4

1 month

11

0.800

0.640

4

Mansour et al [101]

127 Acute Ischemic Stroke patients

Day 1 Day 3

mRS≥3

3 months

11 11

0.790 0.840

0.850 0.940

5

Peng et al [44]

120 Neurosurgical ICU patients

Day 1

mRS≥3

3 months

13

0.790

0.740

6

Said et al [103]

86 ICU patients

Within 24 hours

mRS≥3

3 months

9

1.000

0.727

7

Momenyan et al [29]

84 TBI ICU patients

Within 7 days

mRS≥3

Discharge

6

1.000

0.911

8

Surabenjaw ong et al [95]

60 Stroke ED patients

Undefined

mRS≥4

3 months

10

N/A

N/A

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Table 3. FOURs cut-off scores for outcome, according to available studies in adult population. TBI: Traumatic Brain Injury, ICU: Intensive Care Unit, ED: Emergency Department, GOS: Glasgow Outcome Scale, GOSE: Glasgow Outcome Scale Extended, mRS: Modified Rankin Scale, N/A: Not Available

27

Journal Pre-proof

Reference

Study Sam ple

Rating Tim e

1

Cohen [141]

60 ICU patients

Within 30 minutes or w hen ordered

Criterion Mortality mRS≥3

End Point Discharge Discharge

Value 13 15

Sensitivity 0.75 0.61

Specificity 0.86 0.95

2

Buyukcam et al [140]

100 TBI ED patients

Admission

Mortality

Discharge

9

N/A

N/A

3

*Czaikow ski et al [142]

78 ICU patients

ICU Admission & Discharge (Average used)

Mortality PCPC≥4

Discharge ICU Discharge

7 12

0.8574 0.9333

0.9437 0.7903

4

Khajeh et al [145]

200 ICU patients

Admission

Mortality

Discharge

8

N/A

N/A

5

Kochar et al [146]

70 patients

Within 2 hours

Mortality

Discharge

10

0.81

0.81

6

Ramazani & Hosseini [147]

90 ICU patients

Within 24 hours

Mortality

Discharge

5.5

0.676

0.875

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Table 4. FOURs cut-off scores for mortality and outcome, according to available published studies in pediatric population. ICU: Intensive Care Unit, TBI: Traumatic Brain Injury, ED: Emergency Department, mRS: Modified Rankin Scale, PCPC: Pediatric Cerebral Performance Category, N/A: Not Available. *Slightly modified as Pediatric FOUR Score Scale (PFSS)

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Param eter

N

Scale

K-S

Mean SD p 0.845 0.094 12 0.382 GCS 0.197 0.833 0.107 FOURs 0.200 0.834 0.078 In-hospital mortality in adults 18 0.034* (areas under the curve) GCS 0.200 0.819 0.084 FOURs 0.200 0.800 0.065 Poor outcome in adults 7 0.439 (areas under the curve) GCS 0.200 0.795 0.072 FOURs 0.093 0,862 0,088 In-hospital mortality in children 5 0.244 (areas under the curve) GCS 0.200 0,842 0,098 Table 5. Comparison betw een FOURs and GCS. Paired samples T-tests w ere performed between weighted kappa coefficients [1, 2, 12, 22, 23, 29, 33, 35, 37, 38, 83, 84] for reliability and betw een the areas under the receiver operating characteristic curve for predicting in-hospital mortality [1, 11, 12, 14, 17, 21, 24, 27, 28, 31, 34, 44, 84, 96, 98, 101, 104, 106] and poor long-term outcome (modified Rankin Scale 3-6 after at least 3 months of observation) in adults [1, 11, 12, 14, 44, 101, 103] and in-hospital mortality in children [140, 141, 144, 146, 147]. Studies w ith evaluations later than the first 24 hours after admission w ere excluded for consistency. K-S: Kolmogorov-Smirnov test for normality values, SD: Standard Deviation, Confidence Interval: 95%, Significance Level: p<0.050, (*): indicates statistically significant difference.

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Reliability (w eighted kappa coefficients)

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Figure 1. Flow chart show ing literature search and data selection.

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Highlights

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 The FOUR score is a reliable and more detailed alternative to GCS score  Its validity and predictive value are well documented in neurocritical patients

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 More investigation is needed for milder disorders of consciousness

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