The sample size calculation was based on data from a review study.⁶ A total estimated sample was 188 individuals, considering a frailty prevalence of 25% and a risk of morbimortality at four times higher for frail individuals, with a power of 90% and an α of 5%. The analyzed data were retrieved from clinical records of 200 consecutive patients who underwent cardiac surgery from January 2015 to June 2017. The inclusion criteria were adults (i.e., ≥ 18 years old), both sexes, who were hospitalized for the following elective cardiac surgeries: 1) coronary artery bypass grafting (CABG), 2) valve replacement, or 3) both. Exclusion criteria included missing clinical record data from pre or postoperative assessment. The Institutional Review Board approved the study on September 29, 2017 (No. 2.306.582).

In the preoperative period at the hospital, characteristics from patients were registered (i.e., age, gender, type of cardiac surgery, and body mass index). The frailty score and MIP were also assessed.

Frailty was assessed using the Fried scale tool, which encompasses slowness, weakness, low physical activity, exhaustion, and unintentional weight loss. Patients who presented three or more of the five items described above were classified as frail, while those who presented none of these features were classified as non-frail. Patients who checked one or two of these items were classified as pre-frail.¹

Slowness was assessed in a five-meter-long corridor, along which the patient walked at their own pace, without running. The ratio between distance and time (meters/second) was calculated.¹⁷ A walking time of six seconds or longer (<0.83 m/s) was selected as the optimal cut-off point for frailty.⁶

Weakness was assessed by handgrip strength,¹⁸ according to the recommendation of the American Society of Hand Therapists.¹⁹ When the participants were ready, they were asked to hold the hydraulic dynamometer (Model HS5001- SAEHAN Corporation, Korea) with their dominant hand and to perform maximum isometric effort, maintaining it for about 5 seconds. The mean of three attempts for their dominant hand was compared to reference values, according to sex and body mass index (kg/m²).¹

Low physical activity was assessed by the Duke Activity Status Index, a 12-item questionnaire used to assess the activities of daily living.²⁰ Each item has a specific weight based on metabolic cost (MET). The participants identified activities which they were able to perform. The final score ranges from zero to 58.2 points. The cut-off point of 4 METs, classified as a poor functional capacity, was considered to characterize frailty.²¹

Exhaustion was assessed by asking patients the questions: (1) Last week, how often did you feel like everything you did was an effort? (2) Last week, how often did you feel like you could not get going? It was considered often when the answer was equal to or more than three days and not often when the answer was fewer than three days. Exhaustion was considered to be present when the answer to both questions was often .⁶ Lastly, the criterion for unintentional weight loss was based on self-reported or measured weight, which was not due to dieting or exercising in the previous year. The cut-off point of 4.5 kg or more was considered for frailty.⁶

Inspiratory muscle strength was assessed by manovacuometry, according to the recommendation of the American Thoracic Society.²² At least three reproducible maneuvers were performed using a digital pressure manometer (MVD300 - Globalmed, Brazil). The highest value was recorded for data analysis as long as it did not exceed the second-highest value by 10%.²² Maximal inspiratory pressure < 40 cmH₂O was selected as the cut-off point for inspiratory muscle weakness.²³

Data on morbidity in the postoperative period was obtained from the patients’ clinical records considering the following items: extracorporeal circulation time (cut-off point of 120 minutes), use of vasopressor (yes or no), mean arterial pressure (MAP) <60 mmHg or >120 mmHg, need for red blood cell (RBC) transfusion (yes or no), the occurrence of cardiac arrhythmia and/or heart arrest (yes or no), presence of intra-aortic balloon pump (yes or no), antibiotic use (yes or no), extubation time (≤8 hours, between 9-12 hours or >12 hours), length of stay in the intensive care unit (ICU) (total days), and length of postoperative stay (total days), which includes the period between surgery and hospital discharge. In-hospital mortality due to clinical complications was also recorded.

The continuous data are presented as mean ± standard deviation (SD) or median and interquartile range (p25-p75), according to the normality of the data. Categorical data are presented in counts and relative frequencies. For continuous variables, normality was tested by the Shapiro-Wilk test. One-way ANOVA with Bonferroni post-hoc test was used to compare normally distributed variables between frailty categories. Asymmetric variables were analyzed using the Kruskal-Wallis test and Dunn's multiple comparisons test with adjustment by Bonferroni. For categorical variables, Pearson's chi-squared or Fisher's exact tests were used. The association between postoperative morbimortality variables and MIP was evaluated by the Spearman test. Afterwards, age, sex, and MIP, which were significantly associated (p<0.05) with frailty, were introduced into multiple regression models to find the independent association between frailty and postoperative variables. The multiple Poisson regression model with robust variances was performed for categorical variables and multiple linear regression through the generalized linear model method with a gamma distribution for continuous variables. All analyses were generated in IBM SPSS Statistics software, Version 20.0 (IBM Corp., Armonk, NY, USA), with a significance level of p<0.05.

According to our inclusion criteria, a total of 432 patients were eligible for the study; 232 patients were excluded due to missing data in their clinical records. The study flow diagram is shown in Figure 1 . The majority of patients were male (68.5%), with a mean age of 65.7±7.2 years (from 48 to 87 years old), classified as overweight (45%) and non-frail (63.5%). Forty-three (21.5%) patients undergoing cardiac surgery were younger than 60 years old.

Figure 1 BMI: body mass index; CABG: coronary artery bypass grafting; ICU: intensive care unit; MAP: mean arterial pressure; MIP: maximal inspiratory pressure; RBC: red blood cell.

The median postoperative follow-up time was 8 (7-11) days. The pre and postoperative clinical characteristics of the sample were summarized in Table 1 . Coronary artery bypass grafting was the most prevalent surgery (68.5%), followed by valve replacement surgery (19%) and by the association of CABG and valve replacement (12%). MIP was below 40 cmH₂O in 22 (11%) individuals.

Table 1

Variables	Overall (n=200)	Frail (n=28)	Pre-frail (n=45)	Non-frail (n=127)	p-value
Age, years	65.7 ± 7.2	68.6 ± 8.1a	67.6 ± 7.3a	64.4 ± 6.6	0.002
Sex- n (%)					<0.001
Men	137 (68.5)	13 (9.5)a	24 (17.5)a	100 (73.0)*
Women		15.0 (23.8)a*	21.0 (33.3)a*	27.0 (42.9)
BMI, kg/m2- n (%)					0.656
Underweight/Normal	65 (32.5)	8 (12.3)	17 (26.2)	40 (61.5)
Overweight	90 (45.0)	11 (12.2)	20 (22.2)	59 (65.6)
Obese	45 (22.5)	9 (20.0)	8 (17.8)	28 (62.2)
MIP, cmH2O- n (%)					<0.001
≥40	178 (89.0)	18 (10.1)	40 (22.5)b	120 (67.4)b
<40	22 (11.0)	10 (45.5)*	5 (22.7)b	7 (31.8)b
Postoperative morbidity- n (%)
Extracorporeal circulation time, min					0.126
<120	183 (91.5)	27 (96.4)	38 (84.4)	118 (92.9)
>120	17 (8.5)	17 (3.6)	1 (15.6)	9 (7.1)
Vasopressor use	175 (87.5)	24 (85.7)	37 (82.2)	114 (89.8)	0.442
MAP <60 or >120 mmHg	76 (38.0)	13 (46.4)	20 (44.4)	43 (33.9)	0.278
RBC transfusion	64 (32.0)	14 (50.0)a	20 (44.4)a	30 (23.6)	0.003
Occurrence of arrhythmia	51 (25.5)	11 (39.3)a	15 (33.3)a	25 (19.7)	0.038
Cardiac arrest	13 (6.5)	2 (7.1)	5 (11.1)	6 (4.7)	0.358
Intra-aortic balloon pumping	9 (4.5)	0 (0)	4 (8.9)	5 (3.9)	0.154
Death	8 (4.0)	2 (7.1)	3 (6.7)	3 (2.4)	0.303
Antibiotic use	32 (16.0)	9 (32.1)	6 (13.6)	17 (13.4)	0.052
Length of postoperative stay, days	8 (7-11)	9 (7-13)	9 (7-14)b	7 (7-9)b	0.019
Length of stay in the ICU, days	2.0 (2-4)	2.5 (2-4)	3.0 (2-4)	2.0 (2-3)	0.207
Extubation time, hours					0.034
≤8	59 (29.5)	5 (17.9)	8 (17.8)	46 (36.2)c
9-12	90 (45.0)	12 (42.9)	22 (48.9)	56 (44.1)
>12	51 (25.5)	11 (39.3)	15 (33.3)	25 (19.7)b

Continuous variables expressed as mean ± SD or median [interquartile range (p25-p75)]. Categorical variables expressed as numbers (%). BMI: body mass index; ICU: intensive care unit; MAP: mean arterial pressure; MIP: maximal inspiratory pressure; RBC: red blood cell. ^a Difference from non-frail (p<0.05). ^b Difference from frail (p<0.05). ^c Difference from pre-frail (p<0.05). ^*Difference for the variable in the same frailty category (p<0.05).

The mean age of patients in pre-frail and frail categories was greater (p=0.002) when compared to non-frails. Considering sex, the prevalence of frail and pre-frail patients was greater for women than men (p<0.001). However, there was no difference between frailty categories according to body mass index (BMI). Red blood cell transfusion (p=0.003) and occurrence of arrhythmia (p=0.038) were more prevalent in pre-frail and frail patients. The extubation time over 12 hours was also more prevalent in frail than non-frail patients (p=0.034). Maximal inspiratory pressure below 40 cmH₂O (p<0.001) and length of postoperative stay (p=0.019) were more prevalent in frail patients than non-frail ones. Finally, there was no difference between frailty categories and the following outcomes: extracorporeal circulation time, vasopressor use, MAP alterations, cardiac arrest, death, antibiotic use, and length of stay in the ICU ( Table 1 ).

Inspiratory muscle weakness was associated with RBC transfusion since 59.1% of the individuals with MIP < 40 cmH₂O needed blood transfusion compared to 28.7% of individuals with MIP > 40 cmH₂O (p=0.004). MIP was also associated with a longer postoperative stay. The median was 21.5 (16.5-33.8) days for patients with MIP < 40 cmH₂O vs. 18 (14.0-22.0) days for those patients with MIP > 40 cmH₂O (p=0.020). There was no association between MIP and the other morbimortality variables.

Frailty was not associated with postoperative variables in multiple regression models when adjusted by age, sex, and MIP. Instead, the regression analysis revealed that age was an independently determinant for MAP (p=0.025), RBC transfusion (p=0.014), extubation time (p<0.001), length of stay in the ICU (p=0.005), and length of postoperative stay (p=0.015). Female sex was also an independently determinant for RBC transfusion (p=0.002) ( Table 2 ).

Table 2

Postoperative variables	PR	ß	95% CI	P
Vasopressor use Age Female sex MIP<40 cmH2O Pre-frailty Frailty	1.006 1.064 1.039 0.882 0.902		0.999 – 1.013 0.967 – 1.171 0.889 – 1.214 0.761 – 1.022 0.759 – 1.071	0.102 0.204 0.630 0.096 0.239
MAP <60 or >120 mmHg Age Female sex MIP<40 cmH2O Pre-frailty Frailty	1.028 1.320 1.254 1.099 1.038		1.003 - 1.053 0.910 - 1.914 0.803 – 1.960 0.726 – 1.665 0.640 – 1.682	0.025* 0.144 0.320 0.654 0.881
RBC transfusion Age Female sex MIP<40 cmH2O Pre-frailty Frailty	1.034 1.969 1.345 1.378 1.345		1.007 – 1.062 1.272 – 3.047 0.833 – 2.171 0.849 – 2.239 0.799 – 2.264	0.014* 0.002* 0.225 0.195 0.264
Occurrence of arrhythmia Age Female sex MIP<40 cmH2O Pre-frailty Frailty	1.027 1.099 1.345 1.486 1.568		0.994 – 1.061 0.676 – 1.786 0.726 – 2.492 0.827 – 2.672 0.823 – 2.987	0.106 0.705 0.347 0.186 0.171
Cardiac arrest Age Female sex MIP< 40cmH2O Pre-frailty Frailty	1.031 0.631 2.597 2.181 1.063		0.958 – 1.111 0.199 – 2.001 0.685 – 9.847 0.635 – 7.487 0.202 – 5.594	0.412 0.435 0.160 0.215 0.942
Intra-aortic balloon pumping Age Female sex MIP< 40cmH2O Pre-frailty Frailty	1.003 0.440 4.238 2.262 1.318		0.933 – 1.079 0.094 – 2.062 0.992 – 18.101 0.545 – 9.390 0.258 – 6.733	0.929 0.298 0.051 0.261 0.740
Death Age Female sex MIP< 40cmH2O Pre-frailty Frailty	1.074 0.502 0.956 2.548 2.486		0.985 – 1.170 0.122 – 2.067 0.168 – 5.422 0.416 – 15.600 0.390 – 15.850	0.107 0.340 0.959 0.312 0.335
Antibiotic use Age Female sex MIP< 40cmH2O Pre-frailty Frailty	1.041 0.949 1.098 0.899 1.968		0.992 – 1.093 0.460 – 1.958 0.442 – 2.732 0.336 – 2.409 0.863 – 4.491	0.101 0.887 0.840 0.833 0.108
Extubation time, hours Age Female sex MIP<40 cmH2O Pre-frailty Frailty	1.052 1.225 1.095 1.342 1.451		1.023 – 1.083 0.763 – 1.966 0.594 – 2.018 0.760 – 2.369 0.783 – 2.691	0.000* 0.401 0.772 0.310 0.237
Length of postoperative stay, days Age Female sex MIP<40 cmH2O Pre-frailty Frailty		0.017 0.013 0.247 0.133 -0.092	0.003 – 0.031 -0.169 – 0.195 -0.130 – 0.635 -0.124 – 0.391 -0.337 – 0.153	0.015* 0.889 0.199 0.310 0.461
Length of stay in the ICU, days Age Female Sex MIP<40 cmH2O Pre-frailty Frailty		0.031 -0.035 0.228 0.124 -0.289	0.010 – 0.053 -0.322 – 0.253 -0.282 – 0.737 -0.294 – 0.541 -0.635 – 0.057	0.005* 0.813 0.381 0.562 0.101

Multiple regression models adjusted by age, sex, and MIP. Male sex, MIP ≥40 cmH₂O and Non-frail: reference categories. PR: prevalence ratio for categorical variables; ß- Regression coeficient for continuous variables. CI: confidence interval. ICU: intensive care unit; MAP: mean arterial pressure; MIP: maximal inspiratory pressure; RBC: red blood cell. * Significant association between adjustment criteria and postoperative variables (p<0.05).