Validity and sensitivity to change of the Clinical Frailty Scale-España in patients admitted to intensive care

Abstract

Introduction

Frailty scales, developed to assess elderly patients, are being implemented in critically ill patients. One of the most widely used is Clinical Frailty Scale, wrecently adapted to Spanish(CFS-España).

Objective

To evaluate the validity and sensitivity to change of the CFS-España in a cohort of critically ill patients aged ≥18 years.

Methodology

A prospective, multicenter, observational, metric-based study was conducted between January-2020 and July-2024. Adult patients with ICU stays >48 h were included. Follow-up was performed during the stay and up to one year after discharge. Variables: frailty, sociodemographic characteristics, quality of life, comorbidities, severity(SAPS3), ICU outcome variables, length of stay, and discharge destination. Statistical analysis: exploratory, bivariate regression to assess the relationship between frailty and the recorded variables; multivariate regression of significant variables in bivariate. Spearman correlation of CFS-España with quantitative variables. Comparison of means with Student's t-test for sensitivity to change.

Results

A total of 493 patients were included, 17.4% of whom were frail(CFS-España = 5−9). Age, being female, and being dependent increased the risk of frailty, as did previous hospitalizations, comorbidities, poorer physical quality of life, low academic level, and low annual income. Frailty predicts muscle weakness, hypoglycemia, the need for extrarenal blood pressure, invasive mechanical ventilation, vasoactive drugs, cardiopulmonary resuscitation, or limitation of life-sustaining treatment, and is associated with mortality. Frailty was not associated with mental quality of life, SAPS3, SOFA or ICU/hospital stay. The greatest change observed was between admission and 3 months after discharge. The effect size for changes in CFS-Es between admission, midpoints, and discharge was high (d = 0.832).

Conclusions

The CFS-España shows good convergent validity with age, women, dependency, poorer physical quality of life, days of previous hospitalization, academic level and low annual income. Good predictive validity for the level of vital support in ICU, mortality and destination at hospital discharge.

Resumen

Introducción

Las escalas de fragilidad, desarrolladas para evaluar a pacientes ancianos, se están implementando en pacientes críticos. Una de las más utilizadas es la Clinical Frailty Scale, adaptada recientemente al español (CFS-España).

Objetivo

Evaluar la validez y la sensibilidad al cambio de la CFS-España, en una cohorte de pacientes críticos ≥18 años.

Metodología

Estudio observacional prospectivo, multicéntrico, de carácter métrico entre enero-2020 y julio-2024. Incluidos pacientes adultos con estancias en UCI>48 h. Seguidos durante la estancia y hasta un año del alta. Variables: fragilidad, características sociodemográficas, calidad de vida, comorbilidades, gravedad(SAPS3), variables de evolución en UCI, estancia y destino al alta. Análisis estadístico: exploratorio, regresión bivariante para evaluar la relación entre fragilidad y las variables registradas; regresión multivariante de variables significativas en bivariante. Correlación de Spearman de CFS-España con variables cuantitativas. Comparación de medias con T-Student para sensibilidad al cambio.

Resultados

Incluidos 493 pacientes, 17,4% frágiles (CFS-España = 5−9). La edad, ser mujer y dependiente, aumenta el riesgo de fragilidad; además de los días de ingresos previos, comorbilidades, peor calidad de vida física, bajo nivel académico y rentas anules bajas. La fragilidad es predictiva de debilidad muscular, hipoglucemias, necesidad de depuración extrarrenal, ventilación mecánica invasiva, fármacos vasoactivos, reanimación cardiopulmonar o limitación del tratamiento de soporte vital y se asocia con mortalidad. La fragilidad no muestra relación con calidad de vida mental, SAPS3, SOFA o estancia en UCI/hospital. El mayor cambio observado ha sido entre el ingreso y los 3 meses del alta. El tamaño del efecto de los cambios de la CFS-Es entre ingreso, puntos intermedios y alta fue elevado (d = 0,832).

Conclusiones

La CFS-España muestra buena validez convergente con edad, mujeres, dependencia, peor calidad de vida física, días de hospitalización previa, nivel académico y rentas anuales bajas. Buena validez predictiva para el nivel de soporte vital en UCI, mortalidad y destino al alta hospitalaria.

What is known?

The concept of frailty was developed by geriatricians to evaluate the degree of age-related physiological decline suffered by the human organism. In theory, critically ill patients could have similarities with frail elderly people and, therefore, the frailty scales are being implemented among critically ill patients. The Clinical Frailty Scale has been adapted to over 20 languages, including Castilian Spanish (CFS-España).

What it contributes?

It is important to culturally adapt scales to the population among which they are going to be implemented and it is also vital to determine their metric properties in order to understand their limitations. The present study assess the validity of the Spanish version of the Clinical Frailty Scale (CFS-España) implemented among critically ill patients.

Among the current cohort, it has been noted that frail patients (CFS-España levels 5–9) are older, female, dependent, with worse physical quality of life, low academic level and low annual income. In addition, they require higher levels of vital support at ICUs, have greater mortality and lower probability of a home discharge.

Implications for clinical practice

The validation of scales in different application environments is vital to ensure reliable measurements. The present study examines the validation of the CFS-España scale in the environment of intensive care units (ICUs). Evaluating the frailty of a patient upon admission to the ICU using the CFS-España scale can help to develop specific care plans, according to their frailty. The predictive validity of the scale provides an understanding of the risk of certain negative outcomes and, therefore, helps to develop strategies to avoid them.

Introduction

Frailty can be defined as an increase in vulnerability. Faced with apparently trivial situations, such as new medication, a minor infection or minor surgical procedure, frail individuals may have an unfavourable clinical evolution.¹

A large number of tools have been developed to evaluate frailty.² The most commonly used for the evaluation of frailty among critically ill patients^3–6 are the Clinical Frailty Scale, Fried Frailty phenotype, Frailty Index and the Edmonton frail scale. Of these, the most widespread is the Clinical Frailty Scale (CFS),⁷ which has been adapted to over 20 languages,⁸ including Spanish (CFS-España).⁹

The CFS was developed and validated in the second Canadian Study of Health and Aging (CSHA) to evaluate the frailty of elderly individuals. This scale from 2005, was expanded by the authors with 2 new levels in 2007, going from 7 to 9 levels. Patients in levels 1–3 are defined as not frail, in level 4 they are considered vulnerable and from level 5–8 they are considered as frail patients (slight, moderate, severe or very severe frailty, depending on the level). Patients at level 9 are in terminal condition, with a life expectancy below 6 months, whether they are frail or not. Patients with dementia are stratified as having slight (level 5), moderate (level 6) or severe (level 7) frailty. In 2020, the levels were redefined: individuals in level 4 went from being considered vulnerable to having very slight frailty. Nevertheless, the definition of this level was maintained without changes.¹⁰

Since, in theory, critically ill patients could have similarities with frail elderly patients,¹¹ the frailty scales have been implemented among adult critically ill patients for over a decade. A frailty assessment upon admission to an intensive care unit (ICU) helps to guide the resources and specific care required by such patients, so that care plans and medical treatment may be adjusted in an attempt to minimise the negative consequences of their ICU admission.

In this regard, the CFS^3,5,12 has proven to be a useful tool to identify the most vulnerable patients and those at greater risk of increasing their ICU and hospital stay, as well as their mortality. In order to ensure its applicability to different populations, it is essential to have culturally adapted and validated versions. The inter-observer and intra-observer reliability of the CFS-España, among ICU nurses and physicians, has been previously evaluated.¹³ The objective of this study was to evaluate the validity and sensitivity to change of the CFS-España⁹ among a cohort of critically ill patients aged 18 and over.

Methodology

Design and participants

This was an observational, prospective and metric study of a cohort of critically ill patients, conducted in 10 Spanish ICUs between January 2020 and July 2024. The psychometric study was reported following the COSMIN checklist.¹⁴

Patient recruitment took place between January 2020 and July 2023 (interrupted between March 2020 and April 2021 due to the Covid-19 pandemic). Patients were followed for one year (July 2024), via telephone calls at 3, 6, 9 and 12 months of hospital discharge. The study included all patients aged over 18, with stays >48 h in the ICU and who accepted to participate. Patients were not included when they had a diagnosis of present or imminent brain death, limitation of vital support treatment upon admission, readmissions, transfers from other ICUs, with whom communication with them or their relatives was not possible, and when they had been admitted due to Covid-19. The participating centres were selected bearing in mind geographical diversity and availability.

Implementation of the instrument

Frailty assessment using the CFS-España scale was conducted by members of the research team at each participating unit, upon admission to the ICU and at each of the follow-up telephone calls. The assessment was conducted directly with patients or with close relatives, in cases where patients were unable to communicate. The level of frailty was evaluated based on the best condition in the previous month (upon admission) or at the time of the call during follow-up. The researchers did not receive prior training to implement the scale. Fig. 1 shows the classification and definitions of the CFS-España.

Figure 1.

Clinical Frailty Scale-España.

Sample calculation

A sample size of 430 participants was determined, in order to ensure the validity and reliability of the results obtained in the study. This decision was based on the recommendations of various authors, who propose having between 5 and 10 patients per item for confirmatory factor analysis. In addition, having less than 300 participants made it possible to have reliable and robust solutions, and ensured that the results were representative of the study population. This sample size also fulfilled the general rule of having at least 300 participants in order to obtain precise and consistent estimations.¹⁵

Data collection

The following variables were recorded upon admission to the ICU and in follow-up calls: level of frailty (CFS-España), sociodemographic characteristics of the patient (age, gender, body mass index [BMI], marital status, educational level, employment status, annual income), dependency (Barthel¹⁶ and Lawton-Brody¹⁷), quality of life (SF-12¹⁸) and admissions during the previous year to hospital or ICU (upon admission) or during the last 3 months (during follow-up calls).

The following were recorded only upon admission to the ICU: comorbidity index (Charlson¹⁹), osteoporosis, severity (SAPS3²⁰) and daily during ICU stay: glycaemia (maximum and minimum), pain (maximum and minimum; EVN or ESCID²¹), level of agitation/sedation (maximum and minimum; RASS²²), delirium (CAM-ICU^23,24), use of mechanical restraints, maximum mobilisation (IMS-Es²⁵), renal replacement therapy, administration of vasoactive drugs, transfusions, oxygen therapy (invasive and non-invasive mechanical ventilation, high flow nasal cannula), cardiopulmonary resuscitation, limitation of life support measures, adverse events (accidental removal of tracheal tube, reintubation due to failed extubation, central venous catheter-related bacteraemia, ventilator-associated pneumonia, catheter-associated urinary tract infection), organ failure (SOFA²⁶) and physiotherapy. Weekly, from the moment that the patient was able to collaborate, muscular weakness scale (MRC-SS²⁷). The days of ICU and hospital stay were also recorded, as well as the destination upon discharge. The additional material includes the operational definition of the recorded variables.

Statistical analysis

The qualitative variables are presented with absolute (n) and relative (%) frequencies. The quantitative variables are described as median and interquartile range [Q1-Q3], after verifying the absence of normality by applying the Shapiro–Wilk test.

To determine the validity of the CFS-España, a bivariate regression was conducted for each variable with a stratified CFS-España, according to non-frail (CFS-España 1–4) and frail (CFS-España 5–9) patients, as well as a multivariate analysis of the significant variables. The odds ratio (OR) for frailty is presented with a 95% confidence interval (95%CI) and statistical significance (p-value). Furthermore, the assessment of the CFS-España was correlated with the quantitative variables using Spearman correlation, considering correlation as null with values <0.10, weak with 0.10−0.29, moderate with 0.30−0.50 and strong with >0.50.²⁸

Sensitivity to change was measured using the Student’s t test, comparing the difference in means (standard deviation) of the CFS-España at the 5 moments recorded (at baseline situation prior to admission and at 3, 6, 9 and 12 months of hospital discharge). The analysis evaluated the size of effect (d), calculated based on 3 situations: (1) considering only patients who were evaluated up to 12 months from discharge; (2) considering patients who died with the maximum frailty score (CFS-9) and (3) considering patients who died with the score obtained in their last assessment. Cohen d values of <0.49 indicate a small-sized effect; 0.5−0.79 indicate a moderate effect and ≥0.80 indicate a large effect.²⁹

To evaluate the floor and ceiling effect, the proportion of patients with minimum scores (CFS-España = 1) and maximum scores (CFS-España = 9), upon admission and at each follow-up assessment, was determined. Floor and ceiling effects <15% were considered as acceptable.³⁰

The analysis was conducted using SPSS Statistics® for Windows (version 23.0 IBM Corp; USA) and Stata® (version IC14, StataCorp LLC; USA).

Ethical considerations

The study was approved by the Research with Medicines Ethics Committee of the reference hospital (CEIm19/42) and by the ethics committees and viability commissions of the collaborating centres. Consent was required from patients, or their closest relatives when they could not give their consent personally.

Results

The study included 493 patients (Fig. 2). The characteristics of participating patients are shown in Table 1 and the characteristics of the units in the additional material (Table S1 of Appendix B). The prevalence of frailty observed upon ICU admission was 17.4%. Out of all the follow-up calls (1,929), 61 were lost (3.2%) due to inability to contact with patients or relatives.

Figure 2.

Patient inclusion algorithm.

Table 1.

Convergent and divergent validity of the Clinical Frailty Scale-España.

	Patients n = 493	CFS-ES 1−4 N = 407	CFS-ES 5−9 N = 86	OR (95%CI)	p
Age, years, median [Q1-Q3]	66.2 [55.6−75.6]	65.1 [53.7−75.0]	72.9 [61.6−79.1]	1.032 [1.013−1.051]	.001
Gender, female, n (%)	190 (38.5)	146 (35.9)	44 (51.2)	1.873 (1.172−2.993)	.009
Lawton and Brody, score, median [Q1-Q3]	8 [7–8]	8 [8–8]	5 [3–8]	0.459 (0.390−0.540)	<.001
Lawton and Brody, patients, n (%)
Independent (8)	341 (69.2)	319 (78.4)	22 (25.6)	Reference
Slight dependence (6−7)	80 (16.2)	63 (15.5)	17 (19.8)	3.913 (1.966−7.787)	<.001
Moderate dependence (4−5)	44 (8.9)	20 (4.9)	24 (27.9)	17.400 (8.352−36.252)	<.001
Severe dependence (2−3)	20 (4.1)	5 (1.2)	15 (17.4)	43.500 (14.473–130.743)	<.001
Total dependence (0−1)	8 (1.6)	0 (0.0)	8 (9.3)	n.a.	n.a.
Barthel, score, median [Q1-Q3]	100 [95−100]	100 [100−100]	85 [75−95]	0.865 (0.836−0.894)	<.001
Barthel, patients, n (%)
Independent (100)	329 (66.7)	311 (76.4)	18 (20.9)	Reference
Slight dependence (95)	54 (11.0)	46 (11.3)	8 (9.3)	3.005 (1.236−7.306)	.015
Moderate dependence (65−90)	93 (18.9)	49 (12.0)	44 (51.2)	15.515 (8.299−29.005)	<.001
Severe dependence (25−60)	15 (3.0)	1 (0.2)	14 (16.2)	241.889 (30.109−1.943.280)	<.001
Total dependence (0−20)	2 (0.4)	0 (0.0)	2 (2.3)	n.a.	n.a.
Prior hospital admission,^apatients, n (%)	131 (26.6)	95 (23.3)	36 (41.9)	2.365 (1.454−3.845)	.001
Days of prior hospital admission, ^adays, median [Q1-Q3]	10 [5–24]	9 [4–18]	16 [8–33]	1.030 (1.008−1.053)	.006
Prior ICU admission,^apatients, n (%)	17 (3.4)	10 (2.5)	7 (8.1)	3.519 (1.300−9.520)	.013
Days of prior ICU admission,^adays, median [Q1-Q3]	6 [3–11]	5 [2–10]	7 [6–31]	1.190 (0.898−1.576)	.226
Charlson, score, median [Q1-Q3]	4 [2–6]	4 [2–5]	4 [4–7]	1.203 (1.100−1.316)	<.001
Charlson, comorbidities, n (%)
0	145 (29.4)	133 (32.7)	12 (14.0)	Reference
1−2	252 (51.1)	204 (50.1)	48 (55.8)	2.608 (1.335−5.092)	.005
>2	96 (19.5)	70 (17.2)	26 (30.2)	4.117 (1.959−8.652)	<.001
SAPS 3, score, median [Q1-Q3]	61 [51–72]	60 [49–71]	63 [56–75]	1.017 (1.003−1.031)	.018
PCS, median [Q1-Q3]^b	47.6 [37.8−55.4]	49.9 [40.5−56.1]	34.6 [29.4−42.6]	0.901 (0.876−0.926)	.001
PCS ≥ 50, n (%)^b	192 (38.9)	188 (49.5)	4 (5.9)	0.064 (0.023−0.179)	<.001
MCS, median [Q1-Q3]b	49.2 [41.4−57.4]	49.8 [41.9−59.5]	46.9 [38.6−56.9]	0.984 (0.962−1.008)	.120
MCS ≥ 50, n (%)^b	215 (43.6)	188 (49.5)	27 (39.7)	0.673 (0.398−1.138)	.139

CFS-Es: Clinical Frailty Scale-España; CFS-Es 1−4: non-frail patients; CFS-Es 5−9: frail patients; CI: confidence interval; MCS: mental component of the SF-12 perceived quality of life questionnaire; n.a.: not applicable; OR: odds ratio; PCS: physical component of the SF-12 perceived quality of life questionnaire; SAPS: Simplified Acute Physiologic Score; SF-12: 12-item Short Form Survey.

a

Previous hospital or ICU admission in the year prior to current admission.

b

Over 448 patients (380 non-frail vs. 68 frail).

Convergent and divergent validity

The bivariate analysis observed that age increased the risk of frailty (odds ratio per year 1.032 [95%CI: 1.013−1.051]) with significant differences by age groups: patients aged over 65 had a 1.765 times higher risk of frailty than those aged under 65 and 2.850 times higher risk than those aged under 50 years; females had higher risk of frailty than males (OR 1.873; 95%CI: 1.172−2.993), as did patients with morbid obesity (BMI > 40) (OR 4.433; 95%CI: 1.337–14.703) and widowed individuals (OR 3.286; 95%CI: 1.291–8.361). On the other hand, the following characteristics were associated to a lower probability of suffering frailty upon admission: having secondary or university studies, living with a partner and having a personal or household annual income above 12,500 ;.

Dependent patients have a higher risk of being frail, both evaluating dependence for instrumental activities (Lawton and Brody scale) and for basic activities of daily life (Barthel scale). Significant differences were observed for each of the activities evaluated in both scales. Having 1 or 2 comorbidities in the Charlson index increased the risk of frailty 2.608 times and having more than 2 comorbidities 4.117 times; the risk was especially increased with the comorbidities of dementia, gastroduodenal ulcer, mild liver disease, diabetes with lesions in target organs and also in patients with osteoporosis.

In the multivariate analysis, adjusted by variables described in Table 2, frailty upon ICU admission was associated to being female, having moderate dependence for instrumental and basic activities of daily life and the number of days of hospital admission in the year prior to the current admission.

Table 2.

Multivariate analysis of variables related to frailty upon ICU admission.

	OR (95%CI)	p
Age	0.994 (0.945−1.046)	.823
Female gender	3.809 (1.160−12.506)	.027
Dependence, Lawton and Brody
Independent (8)	Reference
Slight dependence (6−7)	1.347 (0.318−5.790)	.680
Moderate dependence (4−5)	5.446 (1.026−28.918)	.047
Severe dependence (2−3)	2.322 (0.119−45.257)	.578
Total dependence (0−1)	n.a.	n.a
Dependence, Barthel
Independent (100)	Reference
Slight dependence (95)	1.736 (0.295−10.235)	.542
Moderate dependence (65−90)	7.462 (1.699−32.762)	.008
Severe dependence (25−60)	n.a.	n.a.
Total dependence (0−20)	n.a.	n.a.
Comorbidities, Charlson
0	Reference
1−2	1.653 (0.220−12.399)	.625
>2	1.328 (0.146−12.100)	.802
Days of hospital admission in previous year	1.043 (1.008−1.079)	.043

CI: confidence interval; n.a.: not applicable; OR: odds ratio.

A negative and strong correlation was observed between the CFS-España and the Barthel scale (the higher the frailty, the lower the independence) and with the quality-of-life scales, the physical (PCS) upon admission and at 3, 6, 9 and 12 months and the mental (MCS) at 9 months (the higher the frailty, the worse the quality of life). There was a moderate negative correlation with the Lawton and Brody scale and a correlation, also moderate but positive, with age and with the Charlson index. A weak correlation was observed with previous days of hospitalisation and with the severity upon admission estimated by the SAPS3 (Table 3; and Table S2, S3 and S4 of Appendix B).

Table 3.

Validity of the CFS-España. Correlations.

Convergent and divergent validity of the CFS-España. Spearman’s correlations
Correlated variables	r	Correlation	p
CFS-Es vs. age	0.306	Moderate	<.001
CFS-Es vs. Lawton and Brody	−0.499	Moderate	<.001
CFS-Es vs. Barthel	−0.569	Strong	<.001
CFS-Es vs. days of prior admission*	0.288	Weak	.001
CFS-Es vs. days of prior ICU*	0.300	No correlation	.242
CFS-Es vs. Charlson	0.418	Moderate	<.001
CFS-Es vs. SAPS 3	0.209	Weak	.014
CFS-Es admission vs. PCS admission	−0.604	Strong	<.001
CFS-Es admission vs. MCS admission	−0.194	Weak	<.001
CFS-Es 3 months vs. PCS 3 months	−0.644	Strong	<.001
CFS-Es 3 months vs. MCS 3 months	−0.408	Moderate	<.001
CFS-Es 6 months vs. PCS 6 months	−0.741	Strong	<.001
CFS-Es 6 months vs. MCS 6 months	−0.472	Moderate	<.001
CFS-Es 9 months vs. PCS 9 months	−0.735	Strong	<.001
CFS-Es 9 months vs. MCS 9 months	−0.510	Strong	<.001
CFS-Es 12 months vs. PCS 12 months	−0.750	Strong	<.001
CFS-Es 12 months vs. MCS 12 months	−0.422	Moderate	<.001
CFS-Es vs. IMC	0.048	No correlation	.289

Predictive validity of CFS-España. Spearman correlations
Correlated variables	r	Correlation	p
CFS-Es vs. SOFA day 1	0.113	Weak	.015
CFS-Es vs. SOFA stay at ICU	0.133	Weak	.003
CFS-Es vs. days of passive mobilisation	0.090	Nula	.046
CFS-Es vs. days of active mobilisation	−0.009	No correlation	.841
CFS-Es vs. days of renal replacement therapy	0.169	Weak	<.001
CFS-Es vs. ICU stay	0.108	Weak	.017
CFS-Es vs. hospital stay	0.036	No correlation	.430
CFS-Es admission vs. PCS 3 months	−0.369	Moderate	<.001
CFS-Es admission vs. MCS 3 months	−0.104	No correlation	.051
CFS-Es admission vs. PCS 6 months	−0.386	Moderate	<.001
CFS-Es admission vs. MCS 6 months	−0.125	Weak	.020
CFS-Es admission vs. PCS 9 months	−0.379	Moderate	<.001
CFS-Es admission vs. MCS 9 months	−0.138	Weak	.011
CFS-Es admission vs. PCS 12 months	−0.367	Moderate	<.001
CFS-Es admission vs. MCS 12 months	−0.081	No correlation	.140
CFE-Es vs. days from ICU admission until ICU-AW	−0.105	No correlation	.132
CFS-Es vs. days with delirium	0.050	No correlation	.268
CFS-Es vs. days with mechanical restraint	0.079	No correlation	.081

CFS-Es: Clinical Frailty Scale-España; ICU: intensive care unit; ICU-AW: ICU acquired weakness; MCS: mental component of the SF-12 perceived quality of life questionnaire; PCS: physical component of the SF-12 perceived quality of life questionnaire; SAPS: Simplified Acute Physiologic Score; SF-12: 12-item Short Form Survey; SOFA: Sequential Organ Failure Assessment.

*

Previous hospital or ICU admission in the year prior to current admission.

Predictive validity

With regard to the predictive validity of the CFS-España scale, that is, the ability to predict future episodes, it was observed that frailty (CFS-España: 5−9) is a risk factor for relevant negative outcomes (Tables 3 and 4).

Table 4.

Predictive validity of the Clinical Frailty Scale-España.

	Patients n = 493	CFS-ES 1−4 N = 407	CFS-ES 5−9 N = 86	OR (95%CI)	p
ICU-AW (MRC < 48), Patients, n (%)	207 (42.0)	163 (40.0)	44 (51.2)	2.622 (1.499−4.587)	.001
Only passive mobilisation (IMS-Es 0−3), ^a patients, n (%)	343 (69.6)	275 (67.6)	68 (79.1)	1.749 (1.046−2.925)	.033
Physiotherapy in ICU, patients, n (%)	189 (38.3)	156 (38.3)	33 (38.4)	1.002 (0.621−1.616)	.994
Patients with glycaemia^b
<80 mg/dL, n (%)	151 (30.6)	116 (28.5)	35 (40.7)	1.722 (1.064−2.785)	.027
From 80–180 mg/dL, n (%)	492 (99.8)	406 (99.8)	86 (100)	n.a.	n.a
From 181–215 mg/dL, n (%)	282 (57.2)	223 (54.8)	59 (68.6)	1.803 (1.099−2.959)	.022
>215 mg/dL, n (%)	203 (41.2)	161 (39.6)	42 (48.8)	1.458 (0.914−2.327)	.118
Patients with NRS / ESCID,^bn (%)
From 0 to 3	490 (99.4)	405 (99.5)	86 (98.8)	0.420 (0.038−4.682)	.481
From 4 to 10	294 (59.6)	236 (58.0)	58 (67.4)	1.501 (0.918−2.455)	.106
Patients with RASS,^bn (%)
From +4 to +1	234 (47.5)	186 (45.7)	48 (55.8)	1.501 (0.940−2.397)	.089
0	437 (88.6)	365 (89.7)	72 (83.7)	0.592 (0.307−1.140)	.117
From −1 to −2	292 (59.2)	238 (58.5)	54 (62.8)	1.198 (0.742−1.936)	.460
−3	205 (41.6)	161 (39.6)	44 (51.2)	1.601 (1.003−2.554)	.048
From −4 to −5	245 (49.7)	190 (46.7)	55 (64.0)	2.026 (1.252−3.279)	.004
Patients with diagnosis of delirium, n (%)	71 (14.4)	58 (14.3)	13 (15.1)	1.072 (0.558−2.057)	.853
Patients with mechanical restraint, n (%)	270 (54.8)	222 (54.5)	48 (55.8)	1.053 (0.659−1.681)	.830
Transfusions, patients, n (%)
Full blood	59 (12.0)	47 (11.5)	12 (14.0)	1.242 (0.628−2.455)	.533
Red blood cells	102 (20.7)	73 (17.9)	29 (33.7)	2.328 (1.393−3.891)	.001
Plasma	37 (7.5)	29 (7.1)	8 (9.3)	1.337 (0.589−3.035)	.488
Platelets	41 (8.3)	35 (8.6)	6 (7.0)	0.797 (0.324−1.959)	.621
Renal replacement therapy, patients, n (%)	57 (11.6)	38 (9.3)	19 (22.1)	2.754 (1.498−5.064)	.001
Patients with,^b n (%)
Invasive MV	332 (67.3)	264 (64.9)	68 (79.1)	2.046 (1.171−3.575)	.012
Non-invasive MV	48 (9.7)	42 (10.3)	6 (7.0)	0.652 (0.268−1.586)	.345
High flow	147 (29.8)	117 (28.7)	30 (34.9)	1.328 (0.811−2.173)	.259
Vasoactive drugs, patients, n (%)	284 (57.6)	215 (52.8)	69 (80.2)	3.625 (2.060−6.379)	<.001
Adverse events in ICU,^bpatients, n (%)	102 (20.7)	84 (20.6)	18 (20.9)	1.018 (0.574−1.804)	.952
Adverse events,^bn (%)
Non-programmed extubation	8 (1.6)	6 (1.5)	2 (2.3)	1.591 (0.316−8.021)	.574
Re-intubation due to failed extubation	29 (5.9)	21 (5.2)	8 (9.3)	1.885 (0.806−4.410)	.144
CVC-related bacteraemia	28 (5.7)	23 (5.7)	5 (5.8)	1.031 (0.381−2.791)	.953
Ventilator-associated pneumonia	47 (9.5)	42 (10.3)	5 (5.8)	0.536 (0.206−1.398)	.203
Catheter-associated urinary tract infection	28 (5.7)	25 (6.1)	3 (3.5)	0.552 (0.163−1.872)	.341
CPR manoeuvres,^bpatients, n (%)	19 (3.9)	8 (2.0)	11 (12.8)	7.315 (2.847−18.793)	<.001
LST limitation,^bpatients, n (%)	45 (9.1)	28 (6.9)	17 (19.8)	3.335 (1.732−6.420)	<.001
Destination upon hospital discharge, n (%)
Home	331 (67.1)	291 (71.5)	40 (46.5)	0.405 (0.195−0.844)	.016
Long stay centre	49 (10.0)	37 (9.1)	12 (14.0)	2.467 (1.184−5.137)	.016
Mortality, patients, n (%)
At ICU	53 (10.8)	33 (8.1)	20 (23.3)	3.434 (1.859−6.346)	<.001
At hospital	87 (17.6)	54 (13.3)	33 (38.4)	4.070 (2.419−6.850)	<.001
Before 3 months	104 (21.1)	63 (15.5)	41 (47.7)	4.975 (3.014−8.212)	<.001
Before 6 months	114 (23.1)	71 (17.4)	43 (50.0)	4.732 (2.887−7.757)	<.001
Before 9 months	124 (25.2)	79 (19.4)	45 (52.3)	4.557 (2.794−7.433)	<.001
Before 12 months	133 (27.0)	87 (21.4)	46 (53.5)	4.230 (2.603−6.873)	<.001
PCS ≥ 50 at 3 months, n (%)^c	79 (22.2)	79 (24.8)	0 (0.0)	n.a.	n.a
MCS ≥ 50 at 3 months, n (%)^c	134 (37.6)	125 (39.3)	9 (23.7)	0.479 (0.219−1.046)	.065
PCS ≥ 50 at 6 months, n (%)^c	102 (29.3)	99 (31.8)	3 (8.1)	0.189 (0.057−0.630)	.007
MCS ≥ 50 at 6 months, n (%)^c	143 (41.1)	129 (41.5)	14 (37.8)	0.859 (0.426−1.732)	.671
PCS ≥ 50 at 9 months, n (%)^c	109 (32.2)	106 (34.8)	3 (8.8)	0.182 (0.054−0.608)	.006
MCS ≥ 50 at 9 months, n (%)^c	141 (41.6)	128 (42.0)	13 (38.2)	0.856 (0.413−1.773)	.676
PCS ≥ 50 at 12 months, n (%)^c	115 (34.4)	112 (37.5)	3 (8.6)	0.157 (0.047−0.523)	.003
MCS ≥ 50 at 12 months, n (%)^c	144 (43.1)	133 (44.5)	11 (31.4)	0.572 (0.270−1.210)	.144

CFS-Es: Clinical Frailty Scale-España; CFS-Es 1−4: non-frail patients; CFS-Es 5−9: frail patients; CI: confidence interval; CPR: cardiopulmonary resuscitation; CVC: central venous catheter; ESCID: escala de conductas indicadoras de dolor (Spanish behavioural pain scale); ICU: intensive care unit; LST: life-supporting treatment; MCS: mental component of the SF-12 perceived quality of life questionnaire; MRC: Medical Research Council; MV: mechanical ventilation; n.a: not applicable; NRS: numerical rating scale; OR: odds ratio; PCS: physical component of the SF-12 perceived quality of life questionnaire; RASS: Richmond Agitation-Sedation Scale; SF-12: 12-item Short Form Survey; UCI-AW: ICU acquired weakness.

a

Patients with only passive mobilisation were never mobilised actively during ICU admission.

b

Patients who, at some point of ICU admission, have suffered glycaemia in any of the ranges considered; who at some point during ICU admission have had pain or agitation/sedation assessments within the contemplated strata; who at some point during ICU admission have undergone treatment with invasive mechanical ventilation, non-invasive mechanical ventilation or high flow, or have suffered a contemplated adverse episode.

c

The results of the PCS and MCS at 3 months of hospital discharge are with 356 patients (318 non-frail and 38 frail), at 6 months of hospital discharge with 348 patients (311 non-frail and 37 frail), at 9 months of hospital discharge with 339 patients (305 non-frail and 34 frail) and at 12 months of hospital discharge with 334 patients (299 non-frail and 35 frail).

Having CFS-España frailty levels upon admission was a risk factor for, during ICU stay, patients to be mobilised only passively (IMS-Es <4) (OR 1.749; 95%CI: 1.046−2.925), developing muscular weakness (ICU-AW) (OR 2.622; 95%CI: 1.499−4.587), suffering episodes of hypoglycaemia (<80 mg/dL) (OR 1.722; 95%CI: 1.064−2.785) or moderate hyperglycaemia (181−215 mg/dL) (OR 1.803; 95%CI: 1.099−2.959), requiring renal replacement therapy (OR 2.754; 95%CI: 1.498−5.064), invasive mechanical ventilation (OR 2.406; 95%CI: 1.171−3.575), vasoactive medication (OR 3.625; 95%CI: 2.060−6.379), cardiopulmonary resuscitation techniques (OR 7.315; 95%CI: 2.847−18.793) and limitation of life support measures (OR 3.335; 95%CI: 1.732−6.420). Differences were observed between the levels of sedation of frail patients. Those with CFS-España >4 had deeper sedations, but no differences were observed with regards to pain or a diagnosis of delirium.

The correlation between the assessment of CFS-Es and SOFA was weak, both when correlating with the SOFA on day 1 of admission (r = 0.113) and with the median of SOFA values throughout the entire ICU stay (r = 0.133). No differences were observed in ICU or hospital stay; the CFS-España upon admission had a weak correlation with ICU stay (r = 0.108) and there was no correlation (p = .430) with hospital stay. Frail patients had a 2.467 higher risk of being discharged to a long-term stay centre than non-frail ones (OR 2.467; 95%CI: 1.184−5.137).

Frailty upon admission (CFS-España: 5−9) was associated to greater mortality in the ICU (OR 3.434; 95%CI: 1.859−6.346]), in the hospital (OR 4.070; 95%CI: 2.419−6.850) and even up to one year after hospital discharge (OR 4.230; 95%CI: 2.603−6.873).

Among hospital survivors, the percentage of patients with good mental quality of life (MCS ≥ 50) was higher among the non-frail than among the frail at 3, 6, 9 and 12 months, although the differences were not significant. Good physical quality of life (PCS ≥ 50) was significantly higher among non-frail patients. The correlation between CFS-España before admission and perceived physical quality of life (PCS) at each moment of evaluation was moderate, whereas there was no correlation or it was weak between CFS-España upon admission and mental quality of life (MCS) at each moment of evaluation.

Sensitivity to change and floor and ceiling effect

The size of the effect of changes in the CFS-España between the moment of inclusion, intermediate points and discharge was high, both considering only survivors at 12 months from discharge (d = 0.832), and considering the deceased with CFS-España of 9 (d = 0.894) or considering the deceased with the last assessment conducted (d = 0.874). The greatest change observed was between admission and 3 months of discharge (the CFS-España increased in 55.7% of patients and decreased in 9.3%) or between admission and 12 months of discharge (frailty increased in 50.3% and decreased in 14.5%). At the moment of inclusion, the percentage of patients with the lowest frailty score (CFS-España = 0) was of 6.7% and with the highest score (CFS-España = 9) it was 0.0%. In all other assessment moments, the percentages were similar, always presenting acceptable values (<15%) (Tables S5 and S6 of Appendix B).

Discussion

Convergent and divergent validity

This study observed that the CFS-España had a good convergent validity with age, gender, dependence, both for instrumental activities and for those of daily life, comorbidity and socioeconomic factors prior to admission.

The relationship between the CFS and age (the greater the age, the higher the likelihood of frailty) has been reported previously by studies which applied the CFS in patients older than 1631,32 or 18 years.^33–44 Nevertheless, other authors have not found differences in the age of frail and non-frail patients after employing the CFS in patients aged over 16 years,⁴⁵ between 50 and 65 years⁴⁶ and over 70⁴⁷ or 80 years.⁴⁸ This discrepancy could be explained by the fact that the correlation of CFS-España with age is moderate. Moreover, the controversy suggests that not all frailty is explained by the advanced age of patients. In fact, frailty can also be observed among young patients upon admission to the ICU. In addition, it is important to differentiate between chronological and physiological age⁴⁹: it is possible for younger individuals to suffer an accumulation of deficits or illnesses which entail a considerably older physiological age than their chronological age.

Furthermore, a greater incidence of frailty has previously been reported among females,^{32,35,38,41,42,45,47,50} although the risk of frailty among females reported by Remelli et al.⁴² (OR 3,31; 95%CI: 1.04–10.50) was higher than that obtained in the present study.

The relationship observed between frailty and dependence for instrumental activities and those of daily life and frailty, also reported by other authors,46,50,51 has a slightly lower correlation to that described by Vrettos et al.⁵¹ (r = −0.725) between the CFS and the Barthel index.

Studies evaluating the CFS and the Charlson comorbidity index among patients of different age groups (older than 80⁴⁸ years, aged 65⁵¹ years, aged 50 years^52,53 and aged 16 years³¹) have found significant differences between the Charlson comorbidity index among frail and non-frail patients. In our study, in addition to finding correlation with that scale, we observed significant differences between non-frail and frail patients in other comorbidities which had not been described previously.

With regard to socioeconomic factors, like Hewitt and Booth⁴⁵ and Bagshaw et al.,⁴⁶ a greater percentage of frail patients was observed in the group with a basic education level. In addition, a lower probability of frailty was observed among patients with family and economic stability. These findings had not been described previously.

The strong correlation with the physical component (PCS) of the SF-12 perceived quality of life questionnaire leads to the conclusion that the higher the frailty, the lower the physical quality of life. The correlation with the mental component was lower, so the association with frailty was not as strong. No studies were found which evaluated the convergent validity of the CFS scale with quality of life, although the predictive validity was evaluated.

Predictive validity

The significant differences in severity upon ICU admission (SAPS3) observed between non frail and frail patients, have also been reported by De Geer et al.,³⁷ in a cohort of patients aged over 18 (median [Q1-Q3]: 49^39–62 vs. 62^54–72; p < .001), although the severity of non-frail patients in the cohort of De Geer et al.³⁷ was lower than that of the present cohort, with differences that were clinically irrelevant and a weak correlation between CFS-España and SAPS3.

Frailty (CFS > 4) has been related with the level of vital support in terms of need for renal replacement therapy during admission in intensive care,^35,43,53,54 need for mechanical ventilation,^35,36,42,55 vasoactive medication35,43 and a higher likelihood of having treatment limitation orders.^12,36,37,56 In our cohort it was also observed that the CFS-España predicted the need for those therapies.

Although frailty has been related to delirium,⁵⁷ that association was not found in this cohort. Sahle et al.,⁵⁸ in a study analysing the relationship between frailty (measured with CFS) and delirium (evaluated through the CAM-ICU scale), reported that frail patients had a higher probability of delirium episodes (OR 1.86; 95%CI: 1.77–1.95). Both in that study and in reviews^59,60 analysing the relationship between those 2 ailments, patients were aged over 65, or were in postoperative care for several surgeries. In addition, there was considerable heterogeneity in the instruments used to measure both frailty and delirium. Since the different frailty scales do not discriminate equally between frail and non-frail patients, the conclusions of those reviews should be taken with caution. Thus, frailty measured by the FRAIL scale, less implemented so far among critically ill patients, seems to be a good predictor of delirium among elderly patients admitted to an ICU.⁵⁷ Our findings, which disagree with previous studies, could be affected by the fact that it was only possible to evaluate delirium 49.1% of the recorded time. Therefore, further studies are necessary to clarify the relationship between these 2 variables in adult critically ill patients.

The relationship between levels of frailty and duration of ICU and hospital stay is controversial. While some studies have found significant differences, with prolonged ICU stay^{34,35,37,38,52,54,55,61,62} and hospital stay^{35,43,52,54,61,62} for frail patients, other reviews have not detected any relationship.^3,5,12 In our case, that difference was not observed either. One possible explanation could be the difference in vital support and limitation needs, as well as differences in mortality. It is likely that frail patients with high demands died sooner.

There was a coincidence in the predictive value of frailty, as evaluated with the CFS, with regards to short-term and long-term mortality. Higher ICU mortality was reported among frail patients, both when implementing the CFS in young patients^{3,32,36–38,40,41,63} and in patients aged over 50 years,^52,53,64 over 60 years,⁵⁵ 65 years,²⁶ and aged 80 years.^65–67 Higher hospital mortality has also been reported,^{3,32,34–36,38,40,43,47,52–54,56,61,63,64,68,69} at 3 months of hospital discharge,^37,40,47,70 at 6 months,^{3,5,32,37,40,42,44,47,53,71–74} and at 12 months.^{32,38,40,45,47,48,69,70,74} In our analysis, we also found a relationship between frailty and mortality.

In the case of patients who did not die in hospital, a relationship was observed between frailty and the fact that the destination upon discharge was not their home. This finding had also been reported by studies including non-elderly populations.^{31,32,35,45,53}

Furthermore, there was a significant relationship between frailty at the time of admission and perceived physical quality of life after hospital discharge.^{3,61,70,71,75} Brummel et al.⁷⁰ reported a significant relationship of the CFS with worse physical quality of life at 3 and 12 months of discharge. Bagshaw et al.⁶¹ reported lower PCS scores among frail patients at 6 and 12 months, while the correlation reported by McNelly et al.⁷⁵ was moderate (r = 0.56). In the validation of the CFS-España, a negative and moderate correlation was observed between frailty at the time of admission and each of PCS assessments during follow-up. Moreover, Brummel et al.⁷⁰ reported non-significant associations between the CFS upon admission and the mental component of the SF-36 in assessments (3 and 12 months after discharge), and although Bagshaw et al.⁶¹ also reported lower levels of MCS among frail patients at 6 and 12 months, McNelly et al.⁷⁵ informed of a weak correlation between frailty and the MCS (r = 0.21). These results were similar to those obtained in the validation of the CFS-España, with lower MCS scores among the patients, but without reaching statistical significance. The correlations between the CFS-España upon admission and the MCS at each moment of assessment were weak or non-existent.

Sensitivity to change and floor and ceiling effect

No authors were found who had evaluated the sensitivity to change of the CFS, although the floor and ceiling effect have been evaluated. The CFS-España scale presents a better floor effect (6.7%) than that reported by Tipping et al.⁶⁴ (36%), with the same ceiling effect (0%).

Practical relevance

The results obtained highlight that the CFS-España scale has good validity to evaluate the frailty of critically ill adult patients, both by nurses and intensive care specialists,¹³ and serves to adjust the care and medical treatment plans so as to mitigate the negative consequences of ICU admission. Applying the scale requires little time⁹ and should be part of the comprehensive patient assessment conducted upon admission. Although frailty is still not extensively known in the field of intensive care and, therefore, its assessment is not widespread, the dissemination of the findings in this study could contribute to greater use of the scale.

Strengths and limitations

One of the limitations of this study was the impossibility to assess all the daily variables for all the patients. This was due to several causes, mainly the level of consciousness of patients, either due to disease (35.7% were admitted for neurological or neurosurgical conditions), or else due to the level of sedation (patients had values below −2 in 28% of the RASS scale daily assessments). One of these variables which could not be evaluated daily, for the reasons mentioned, was delirium. This could contribute to the fact that no relationship was found between frailty and delirium, even though it has been reported by other authors.

Other limitations were derived from the Covid-19 pandemic. Strict limitations were imposed on visits to ICUs for over a year, preventing communication with relatives and, therefore, delaying patient recruitment. For this reason, patients with Covid-19 were not included in the study. Since they could not be included from the beginning, they were excluded when recruitment was restarted.

The scarce sampling of some variables, such as morbid obesity, the need for cardiopulmonary resuscitation manoeuvres and postgraduate educational level, forced us to be cautious about their interpretation. In addition, the relationship between frailty and morbid obesity has an additional limitation, since body weight, used for the calculation of BMI, does not distinguish between lean and fatty body mass, thus confusing the relationship observed.

The researchers had no prior training enabling them to adequately implement the scale. Although it is true that each level of the scale contains a description of the characteristics of the patients and the evaluator could guide patient assessment according to this description, the lack of experience and the learning curve for evaluators may have biased the results. Nevertheless, we consider that these are the same conditions that clinicians find themselves in when applying the scale during their usual clinical practice and, moreover, all the evaluators had experience in the assessment of critically ill patients.

Generalisability

Although participating units were limited, we believe that their geographical dispersion and characteristics make the population very representative of the population of patients admitted to an ICU.

Changes in the instrument

The CFS-España has proven to be a good tool to evaluate frailty among adult critically ill patients and we do not consider it necessary to make adjustments or changes in the instrument. Nevertheless, level 9 does not seem operational in intensive care,⁹ since admission of these patients to an ICU is unlikely. In fact, this cohort did not contain any patient in this level upon ICU admission.

Future research

Although there are numerous tools to evaluate patient frailty, none of them have been developed for non-elderly adult patients or critically ill patients. It is worth considering if it would be adequate to develop a specific tool for this critical adult population, instead of adapting existing ones. Perhaps this could be an interesting line of research.

Moreover, the Clinical Frailty Scale was not available in Spain in a version adapted to the language. This is the first study with an adult Spanish population in intensive care conducted with the Spanish version (CFS-España). Further studies in Spanish critical care units would be necessary in order to consolidate the findings.

As previously stated, there is certain controversy related to the relationship between frailty and age. An interesting future line of research would be to analyse the relationship between frailty and biological age, and not with chronological age.

Conclusions

The CFS-España shows a good convergent validity with age, with female gender, with dependence for instrumental and basic activities of daily life, with worse physical quality of life, with days of hospitalisation in the previous year, with academic level and with low annual income. Frailty has not shown a relationship with mental quality of life, with severity upon ICU admission, with SOFA or with ICU or hospital stay. In addition, it has predictive validity for the level of vital support during ICU stay, for mortality at all the moments evaluated and for destination upon hospital discharge.

Ethical considerations and informed consent

The study was evaluated and considered acceptable by the Ethics Committee of Research with Medicines of Getafe University Hospital, on 4 October 2019, with file number CEIm19/42.

Patients were informed about the study and accepted to participate voluntarily, signing an informed consent form. If the level of consciousness did not allow patient authorisation, the information was provided to the closest relatives, who signed the consent form. In this case, ratification was sought from the patients as soon as their level of consciousness allowed it.

Financing

This study was financed by a grant of the Strategic Action for Health of the Carlos III Health Institute, PI20/01231.

Declaration of competing interest

Since Susana Arias-Rivera and Marta Raurell-Torredà are editors of Journal Enfermería Intensiva, the present work was evaluated according to the procedure described in the publication guidelines for such cases. The remaining authors declare no conflict of interest.

Appendix A

CFS-Es-ICU Group

Hospital Universitario de Getafe (Madrid): M. del Mar Sánchez-Sánchez, Raquel Jareño-Collado, Raquel Sánchez-Izquierdo, Eva I. Sánchez-Muñoz, Virginia López-López, Pedro Vadillo-Obesso, Sonia López-Cuenca, Lorena Oteiza-López, María Nogueira-López, Marta Suero-Domínguez, M. Carmen Martín-Guzmán, Olga Rodríguez-Estevez, Juan Enrique Mahía-Cures. Hospital Universitario Central de Asturias (Oviedo): Emilia Romero-de San Pío, Julieta Alonso-Soto, Esther González-Alonso, Lara María Rodríguez-Villanueva, Montserrat Fernández-Menéndez, Roberto Riaño-Suárez, María González-Pisano, Adrián González-Fernández, Helena Fernández-Alonso, José Antonio Gonzalo-Guerra. Complejo Hospitalario Universitario Insular Materno-Infantil (Las Palmas de Gran Canaria): Yeray Gabriel Santana-Padilla, Zaida Alamo-Rodríguez, Famara Díaz-Marrero, Benjamín Guedes-Santana, Aridane Méndez-Santana, José Rodríguez-Alemán, Lorea Ugalde-Jauregui. Hospital General Universitario Gregorio Marañón (Madrid): Mónica Juncos Gozalo, Ángeles Ponce-Figuereo, Ana Muñoz-Martínez, Iñaki Erquicia-Peralt. Hospital Universitario de Bellvitge (Hospitalet de Llobregat, Barcelona): Gemma Via-Clavero, Laia Martínez-Bosch, Jordi Torreblanca-Parra, Vicente Corral-Vélez. Hospital Clínico Universitario de Santiago, (Santiago de Compostela, La Coruña): M. del Rosario Villar-Redondo, Leticia Esmoris López, Natalia Vázquez Rodríguez, Gloria Güeto Rial, Isabel Lara Granja Gómez. Hospital Universitario Vall d'Hebron (Barcelona): Elisabet Gallart Vivé, Montserrat Aran Esteve, Bernat Planas Pascual. Hospital Universitario del Sureste, Arganda del Rey (Madrid): Mónica Juncos Gozalo. Hospital Universitario 12 de Octubre (Madrid): M. Jesus Frade-Mera, María Teresa Pulido Martos, Candelas López López, Laura Martín Velázquez, Isabel Martínez Yegles, Amanda Lesmes González de Aledo, Francisco Javier Zarza Bejarano, Marta Sánchez Cortés, M. del Ara Murillo Pérez, Clara Cornejo Bauer, Laura Hernández López, Francisco de Paula Delgado Moya, Miguel Angel Bejerano Casillas.