Analysis of physical function, muscle strength, and pulmonary function in surgical cancer patients: a prospective cohort study

The aim of this study was to investigate mobility, physical functioning, peripheral muscle strength, inspiratory muscle strength and pulmonary function in surgical cancer patients admitted to an intensive care unit (ICU). We conducted a prospective cohort study with 85 patients. Mobility, physical functioning, peripheral muscle strength, inspiratory muscle strength, and pulmonary function were assessed using the following tests: ICU Mobility Scale (IMS); Chelsea Critical Care Physical Assessment (CPAx); handgrip strength and Medical Research Council Sum-Score (MRC-SS); maximal inspiratory pressure (MIP) and S-Index; and peak inspiratory flow, respectively. The assessments were undertaken at ICU admission and discharge. The data were analyzed using the Shapiro–Wilk and Wilcoxon tests and Spearman’s correlation coefficient. Significant differences in inspiratory muscle strength, CPAx, grip strength, MRC-SS, MIP, S-Index, and peak inspiratory flow scores were observed between ICU admission and discharge. Grip strength showed a moderate correlation with MIP at admission and discharge. The findings also show a moderate correlation between S-Index scores and both MIP and peak inspiratory flow scores at admission and a strong correlation at discharge. Patients showed a gradual improvement in mobility, physical functioning, peripheral and inspiratory muscle strength, and inspiratory flow during their stay in the ICU.


Introduction
Advances in cancer treatment have led to a considerable increase in survival, with studies reporting long-term survival rates after cancer surgery of almost 60%. [1][2][3] Nevertheless, cancer-related complications are common during the course of the disease. The most common reasons for admitting cancer patients to the intensive care unit (ICU) are risk of developing postoperative complications, disease progression or other non-cancer related factors. [2][3][4] There are many types of cancer treatment, each of which can involve multiple therapies. [1,5] The type of treatment depends on the clinical assessment and type and stage of the cancer, with surgery being the most common method of tumor removal. [5] Surgery combined with chemotherapy, radiotherapy, hormonal therapy, or immunotherapy is therefore common. [6] The effects of these treatments can include an increase in the activity of cytokines, leading to changes in muscle protein metabolism, increased protein degradation, and decreased protein synthesis, ultimately resulting in a reduction in muscle strength. This in turn can lead to sarcopenia, cachexia, and muscle fatigue, as well as a decline in functional capacity and quality of life. [7] Pre-existing health conditions, the stage of the cancer, type of malignancy, presence of neutropenia, and need for mechanical ventilation are also important factors that determine cancer patient outcomes. [8] Functional status has been shown to be an excellent prognostic marker for cancer patients, regardless of age and comorbidities, as functional decline is associated with poorer survival. [8][9][10] Functional status is negatively affected by immobilization after surgery, which can lead to a loss of muscle strength and reduced pulmonary function. [8] .
The early identification of functional status and muscle strength is therefore important for defining individualized preventive and curative measures aimed at improving patient health outcomes. The aim of this study was to investigate mobility, physical functioning, muscle strength and pulmonary function in surgical cancer patients admitted to the ICU.

Type of study
We conducted a prospective cohort study following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [11] guidelines. The study was undertaken in a Surgical ICU in the Federal District Base Hospital between October 2020 and February 2021.
The study protocol was approved by the research ethics committees at the University of Brasilia (CAAE: 31,665,120.0.0000.8093) and Federal District Strategic Management Institute (CAAE: 31,665,120.0.3001.8153). All participants signed an informed consent form.

Participants
The study participants were recruited using convenience sampling, adopting the following inclusion criteria: patients of both sexes aged over 18 who had been in the ICU for more than 24 h and were hemodynamically and neurologically stable and able to understand the proposed tests. The following individuals were excluded: hemodynamically unstable patients; pregnant women; patients with neurological and/ or neuromotor impairments; patients who had undergone head and neck surgeries or thoracic surgeries involving diaphragm plication; patients with unstable bone fractures; patients who had been hospitalized in the last 6 months; and patients receiving palliative care.

Assessment protocol
The assessments were undertaken at ICU admission (24 h after surgery) and discharge. The patients received physical therapy three times a day during their stay in the ICU in accordance with the ICU protocol.
The following data were collected on the patient's first day in the ICU: clinical variables (APACHE II, SOFA score and SAPS II); surgical risk; surgery duration; duration of orotracheal intubation (OTI); type of anesthesia; and length of ICU stay. We also assessed mobility, physical functioning, peripheral muscle strength, respiratory muscle strength, and pulmonary function.
The assessments were carried out by experienced physiotherapists who received prior training in how to use the scales and assessment tools. The physiotherapists explained the assessment beforehand so that the patient was able to perform the task as independently as possible.
Mobility was measured using the single-domain ICU Mobility Scale -IMS. [12,13] The scale is scored from 0 to 10, where 0 indicates no mobility (passively rolled or passively exercised by staff) and 10 indicates a high level of mobility (walking independently without a gait aid). [12] The IMS has been translated into Portuguese and adapted for use in Brazil. [13] Physical functioning in ICU was assessed using the Chelsea Critical Care Physical Assessment (CPAx), [15] developed and validated by Corner et al.. [15,16] The CPAx measures key components of physical functioning (respiratory function, cough, moving within the bed, supine to sitting on the edge of the bed, dynamic sitting, standing balance, sit to stand, transferring from bed to chair, stepping, and grip strength) and is the only physical functioning in ICU assessment tool that includes aspects of respiratory function. The tool consists of 10 physical function items ranging from complete dependence to independence. The score ranges from 0 to 50, where the higher the score the greater the level of independence. [14] The CPAx has been translated into Portuguese and adapted for use in Brazil. [14] Muscle strength was assessed according to grip strength (GS), which was measured using a hydraulic hand-held dynamometer (JAMAR®, Saehan Hydraulic Hand Dynamometer). [17] GS was measured with patients sitting on a standard chair with feet flat on the floor and the elbow flexed at a 90º angle. When this was not possible, the participant was placed in a supine position with elbows supported on the bed at a 45º angle and the bed raised at a 45º angle. The patient was then instructed to squeeze the dynamometer as hard as possible to measure GS. [16][17][18] Three tests were performed on both the dominant and non-dominant hands at one-minute intervals in order to avoid muscle fatigue. The result was taken to be the highest score of the three attempts. [18,19] The test was performed in accordance with the recommendations of the American Society of Hand Therapists (ASHT). [18] Indirect muscle strength was measured using the Medical Research Council Sum-Score (MRC-SS). [20] Participants were considered eligible to participate in the study if they responded at least three of the five commands proposed by De Jonghe [21]: "open/close your eyes"; "look at me"; "open your mouth and put out your tongue"; "nod your head"; and "raise your eyebrows when I have counted up to five." The following six muscle groups were graded on a scale of 0 to 5: abduction of the arm, flexion of the forearm, extension of the wrist, flexion of the hip, extension of the knee, and dorsal flexion of the foot. [22] A maximum score of 60 indicates normal muscle strength, 59 to 48 slight weakness, 47 to 36 significant weakness, and under 36 severe weakness. [22] The MRC-SS is a simple tool for assessing global muscle strength in intensive care patients and has good inter-rater reliability. [22] The tool has been translated into Portuguese and adapted for use in Brazil. [20] Respiratory muscle strength was tested according to maximal inspiratory pressure (MIP) using a respiratory pressure meter (MicroRPM®, Micro Medical, UK). The test was done with the participants seated on a chair with a backrest and armrest and undergoing continuous monitoring. Each participant was encouraged to make maximum voluntary expiratory effort at residual volume (RV) and then instructed to make maximum inspiratory effort to measure MIP. In accordance with American Thoracic Society guidelines, three maneuvers with effort maintained for at least 1 s that varied by less than 20% were performed. [23] The values were recorded and compared with published normal values for the Brazilian population, using Neder et al.'s normalcy prediction equation as a frame of reference. [24] Dynamic inspiratory muscle strength was measured based on the S-Index and peak inspiratory flow (PIF), obtained using the POWERbreathe K5 (POWERbreathe International Ltd., Warwickshire, UK) with disposable filter nozzle and employing the same technique used to measure MIP described above. Ten maneuvers were performed with a 30-s rest between inspiratory maneuvers. The maximum value of the maneuvers was recorded. [25][26][27]

Statistical analysis
The categorical data were presented as absolute (n) and relative (%) frequencies and the continuous variables were described using medians and the interquartile range (IQR). The Kolmogorov-Smirnov test was used to check whether the data followed a normal distribution. All statistical tests were bilateral and adopted a 5% significance level (α = 0.05). The data were divided into two periods: ICU admission (24 h after surgery) and ICU discharge.
The Shapiro-Wilk test was used to show evidence of the non-normality of the clinical variables, followed by the Wilcoxon test for paired samples to provide evidence of eventual differences. Correlations between the test scores at admission and discharge were determined using Spearman's correlation coefficient. We assessed CPAx, IMS and MRC-SS performance at ICU admission and discharge using the floor and ceiling effects, calculated based on the percentage of patients scoring the lowest and highest values, respectively, for each tool. The statistical analyses were performed using R version 4.02.

Sample size
The appropriate sample size the CPAx (tested using the Wilcoxon test for paired samples) was calculated based on the means and respective standard deviations reported by Whelan in a pilot study with 85 patients conducted in 2018 [28]: 32 and 44.35, respectively, and 11.34 and 9.66, respectively, considering a correlation of 0.48. Based on these measures it was possible to determine effect size using the Cohen method, resulting in 1.1711. Minimal sample size for a bilateral test was calculated using G Power version 3.1.9.7 based on a type I error of 0.05, type II error of 0.8, and effect of 1.1711, resulting in nine patients.

Results
Ninety-one of the 491 patients admitted to the ICU during the data collection period were eligible. Six of these patients were excluded (two patient deaths, one patient who refused to perform the second assessment, and three patients without laboratory tests), resulting in a final sample of 85 patients (Fig. 1).
Median surgery duration and duration of VM was less than seven hours and general or regional anesthesia was used in 93% of patients. Mechanical ventilation (MV) was not required in the majority of patients (92.9%) ( Table 1).
MIP, S-Index, and peak inspiratory flow scores also showed a significant change between ICU admission and discharge (p = 0.000; p = 0.000; and p = 0.000, respectively). Length of ICU stay had a positive influence, leading to a significant increase in scores (Fig. 2F-H).
The association analysis showed a weak correlation between IMS and CPAx scores at admission (r = 0.418; p = 0.00) and moderate correlation at discharge (r = 0.51; p = 0.00). There was a moderate correlation between RGS and LGS scores and MIP scores at both admission and discharge (r = 0.55; p = 0.00 and r = 0.52; p = 0.00 and r = 0.52; p = 0.00 and r = 0.51; p = 0.00, respectively). The findings also show a moderate correlation between S-Index scores and both MIP and peak inspiratory flow scores at admission (r = 0.58; p = 0.00 and r = 0.59; p = 0.00, respectively) and a strong correlation at discharge (r = 0.75; p = 0.00 and r = 0.74; p = 0.00, respectively) ( Fig. 4) ( Table 3).

Discussion
This study identified a gradual increase in mobility, physical functioning, peripheral and respiratory muscle strength, and inspiratory flow during ICU stay.
The incidence of neoplasms in Brazil has risen sharply in recent years. This rise is partially attributable to population aging, which directly influences the incidence of cancer as somatic mutations arising from exposure to endogenous and exogenous agents are determining factors in the process of carcinogenesis. In addition, lifestyle factors such sedentarism, drinking and smoking increase the risk of developing cancer, especially among the younger population. [29,30] Cancer surgery is an important factor in the prognosis of cancer patients. However, prior assessment of surgical risk is an effective way of analyzing patient health status in order to estimate the probability of death and potential complications and define intervention and recovery strategies. [31] Our findings show that patients had a generally low surgical risk, which is consistent with the findings of previous studies reporting a reduction in prognostic indicators of disease severity and organ dysfunction at admission and risk of mortality. [10,[31][32][33] In this regard, prior health status is a key factor influencing disease prognosis in cancer patients. [31][32][33] The most common types of cancer in Brazil after nonmelanoma skin cancer are prostate cancer among men and breast cancer in women, followed by colon and rectum cancer. [34] Our findings show that the most common types of cancers were those of the gastrointestinal tract, as the public hospital where the study was undertaken is a leading cancer treatment center.
Moreover, some factors potentially influence the development of the disease. The malignancy, the stage of cancer, has been associated with higher mortality, due to the possibility of infiltrative/ metastatic organ dysfunction and the increasing the risk the acute respiratory failure and sepsis. [35] In addition, growing older, can cumulative risk for all cancers increases, up to age 70 years then decreases slightly. [36] Furthermore, the types of anesthesia are a potential complication that tumor progression is facilitated by surgical stress, volatile anesthetics, opioids, and blood transfusions. [37] Different tools are currently used to measure ICU mobility and physical functioning and which tool is used depends on the patient's situation. [38] Our findings show a decline in mobility in comparison to performance prior to admission. This decline is influenced by the type of surgery, surgical incision, sedation, mechanical ventilation, and level of residual pain, which can restrict bed mobility and lead to immobility. [39,40] In the present study functional status was measured using the CPAx, with scores showing a gradual increase during ICU stay. In a study with intensive care burn patients, Corner et al. (2014) [16] observed that a 6-point or more change in the CPAx score could be considered a clinically significant change in the physical function of ICU patients. Functional status is currently an important prognostic marker in    [41,42] The patients in our study showed a gradual loss of peripheral muscle strength during ICU stay. Cancer accelerates loss of muscle strength, giving rise to muscle fatigue, cachexia and sarcopenia, and leading to functional decline. [41] In a study assessing patients with solid cancer, Norman et al. [43] reported that malnutrition, age and gender were factors contributing to reduced peripheral muscle strength, and muscle strength measured using a manual dynamometer was associated with functional status and quality of life.
Our findings also show a reduction in respiratory muscle strength. Loss of skeletal muscle mass is present in between 20 and 70% of cancer patients [41] and can affect respiratory muscles. Oxidative stress caused by cancer or chemotherapy can also cause muscle weakness, affecting respiratory muscles and increasing fatigue. [44] In addition, surgery and surgical incisions can also lead to a reduction in the contractile force of the diaphragm. [31] .
Our findings show a correlation between peripheral and respiratory muscle strength during ICU stay. O'Donnell et al. [45] also observed a correlation between peripheral and respiratory muscle strength, showing that breast cancer patients have general skeletal muscle weakness. Our findings also showed an association between MIP and dynamic muscle strength. Da Silva et al. [26] presented similar results in a study assessing patients with chronic diseases, suggesting the use of the S-Index as a way of assessing inspiratory muscle strength.
The presence of f loor and ceiling effects is an important consideration in the assessment of the effectiveness of therapeutic procedures adopted during admission to the ICU. A high floor effect suggests that test items are very difficult, while a high ceiling effect indicates that they are very easy, limiting the capacity to detect changes in physical function. Recent studies using quantitative measurement scales and tools reported functional decline in surgical patients during ICU stays, [46] highlighting that the impairment of musculoskeletal and cardiovascular systems is a significant risk factor. The early identification of potential causes of system imbalance can therefore help define timely actions to interrupt these processes and improve treatment outcomes. [46,47] The f loor and ceiling effects found in the present study show that the CPAx was the best-performing tool, suggesting that it is an effective tool for assessing surgical cancer patients.
Advances in cancer and supportive care have led to improved prognosis and extended survival time for cancer patients, [48] so the detection of factors that influence functional capacity is important for an individualized rehabilitation, with clinical strategies that impact the modifiable characteristics of diseases. [49] This study has some limitations. First, the heterogeneity of the type and stage of the cancer meant that the patient sample was not homogeneous. Caution should therefore be taken when extrapolating these results to other populations. Second, the assessment of mobility prior to admission was self-reported, meaning that it may have been overestimated by the patient. Third, comprehensive assessments of body composition can result in a reduction in skeletal muscle strength. Four, it was not possible to monitor the patients after hospital discharge to investigate possible factors influencing muscle strength and physical functioning among the sample.

Conclusion
Our findings show a gradual improvement in mobility, physical functioning, peripheral and respiratory muscle strength, and inspiratory flow among surgical cancer patients admitted to the ICU.
Further research into mobility, physical functioning, and peripheral and respiratory muscle strength is needed to identify the mechanisms that influence changes in physical function and muscle strength after admission of surgical cancer patients to the ICU.
Author contribution LPBR, FRM, and HNO had full access to all of the data in the study and takes responsibility for the integrity of the data, including any adverse effects. GCJr and GFBC contributed with data analysis and interpretation. LPBR, RV, and GFBC contributed with analysis and interpretation of data, and the writing of manuscript. GCJr revised it critically for important intellectual content; GFB has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data, and the writing of manuscript.

Declarations
Ethical approval The study protocol was approved by the research ethics committees at the University of Brasilia (CAAE: 31665120.0.0000.8093) and Federal District Strategic Management Institute (CAAE: 31665120.0.3001.8153). All participants signed an informed consent form.

Conflict of interests
The authors declare no competing interests.