Effects of early standardized enteral nutrition on preventing acute muscle loss in the acute exacerbation of chronic obstructive pulmonary disease patients with mechanical ventilation

Yue Li, Yong-peng Xie, Xiao-min Li, Tao Lu

1 School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing 210009, China

2 Department of Emergency and Critical Care Medicine, Lianyungang Clinical College of Nanjing Medical University,Lianyungang 222000, China

KEYWORDS: Acute exacerbation of chronic obstructive pulmonary disease; Enteral nutrition;Cross-sectional area; Erector spine muscle; Growth differentiation factor-15; Intensive care unit-acquired weakness (ICU-AW); Prognosis

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is a chronic disease of the respiratory system characterized by progressive respiratory decline and recurrent lower respiratory tract infections.[1,2]Respiratory failure is a common complication of COPD with high mortality.[3]A study reported that the bodies of patients with acute exacerbation of COPD (AECOPD), who were on mechanical ventilation(MV) and could not eat independently, were in a state of high decomposition, and there was a negative balance of energy and protein metabolism.[4]This greatly aggravates malnutrition and causes acute muscular atrophy.The disease condition was further complicated by muscle weakness, which led to difficulty in weaning, concurrent infection, and increased mortality.Growth differentiation factor-15 (GDF-15) is a divergent member of the transforming growth factor-β (TGF-β) superfamily, which is involved in developing muscle atrophy in various diseases, including COPD, cancer, and pulmonary hypertension.[5]The cross-sectional area of the erector spine muscle (ESMcsa) and plasma GDF-15 levels can be used to assess muscle loss.Therefore, this study aimed to compare the Effects of early standardized enteral nutrition(EN) and conventional EN on preventing acute muscle loss in AECOPD patients with MV by assessing the ESMcsa and plasma GDF-15 levels.

METHODS

Study population

A total of 97 AECOPD patients, who were on invasive MV from April 2020 to May 2022 and had complications of acute respiratory failure, were sequentially screened and recruited in this study.According to the start time (May 2021 as the time node) of the continuous quality improvement project for EN in critically ill patients from the First People’s Hospital of Lianyungang, the study was divided into two stages, including stage I (from April 2020 to April 2021)and stage II (from May 2021 to May 2022).There was a training period from April 2021 to May 2021.The study protocol was approved by the Ethics Committee of the First People’s Hospital of Lianyungang (approval number:LCYJ2020032001).Written informed consent was obtained from the legal representative of each patient before the study.The patients’clinical records/information were anonymized and deidentified before analysis.The study was registered in the China Clinical Trial Center under registration number ChiCTR1900025382.The study was reported according to the STROBE checklist (supplementary Table 1).[6]

Inclusion criteria

All patients were diagnosed based on the Guidelines for the Diagnosis and Management of Chronic Obstructive Pulmonary Disease (Revised in 2021) and had respiratory failure.[7]Other inclusion criteria included indications for invasive MV, ages ranging from 18 to 80 years, consciousness,Glasgow Coma Scale (GCS) score ≥12, estimated MV ≥5 d,and ICU length of stay ≥7 d.

Exclusion criteria

The exclusion criteria were spinal cord injury, acute stroke, lower limb fracture, history of cognitive dysfunction or neuromuscular disease, previously bedridden for a long time and already having muscle atrophy, muscle relaxant treatment,acute and chronic heart failure, pulmonary fibrosis, pulmonary vascular disease, severe edema, intestinal perforation, peritonitis,intestinal fistula, necrosis, other EN contraindications, severe hemodynamic instability, or severe coagulopathy on admission.

EN feeding protocols

In stage I (conventional EN group), the physicians provided EN according to their judgment or experience and did not uniformly set the start time, EN preparation, or energy goals.Before the initiation of stage II (early standardized EN group),all physicians, nurses, and nutritionists involved in the study received a one-month training on the early standardized EN feeding protocol to ensure that they received sufficient training and knowledge on the EN feeding protocol.In addition, a researcher was appointed to monitor and promote compliance with the EN feeding protocol.From May 2021, patients were given early standardized EN according to the feeding protocol.

Based on the clinical practice summary of the American Society for Parenteral and Enteral Nutrition (ASPEN) Guidelines(2020), a process-based nutrition treatment strategy was developed.[8]EN tolerance and complications were evaluated using the EN tolerance scale and EN intolerance algorithm,respectively.The nutritional risk screening (NRS) score 2002 and acute gastrointestinal injury (AGI) score were calculated immediately after admission to the ICU.Before the start of EN treatment, the hemodynamics were stable, the mean arterial pressure (MAP) was >65 mmHg (1 mmHg=0.133 kPa), the lactic acid was <4 mmol/L, and the dose of vasopressor was reduced.Gastrointestinal function was evaluated using the AGI score.For patients with AGI of grades I and II-III, EN and predigestion EN were started at 25 mL/h and 10–15 mL/h, respectively.EN was reserved for those with AGI of grade IV.[9]For patients with a high risk of malnutrition, parenteral nutrition (PN) was recommended, while for other patients, PN was reserved for 7–10 d.EN patients were evaluated every four hours using the tolerance score.When the EN tolerance score was greater than 5, EN was discontinued.

The EN used in this study consisted of the whole protein Nengquanli (enteral nutritional suspension, Nutricia Pharmaceuticals,the Netherlands) and short peptide Baipuli (enteral nutritional suspension, Nutricia Pharmaceuticals, the Netherlands).

Observation indicators

Baseline data

The patient’s gender, age, weight, body mass index(BMI), Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, underlying medical history, smoking history, mechanical ventilation parameters,and arterial blood gas analysis were recorded in detail.

ESMcsa

All patients in this study received a chest and abdominal computed tomography (CT) scan before or on the first day of admission.CT re-examination was performed at 7 d after treatment.The mediastinal window of the chest and abdominal CT was used for the ESMcsa analysis.The inferior margin of the T-12 vertebra was the target of the ESM analysis.The detailed results of ESMcsa were recorded.The right and left ESMs were identified in the CT images, and the pseudocolor images of the ESMs were delineated manually.

As shown in supplementary Figure 1, the ESMcsa on each side and the total ESMcsa on both sides of the spine were calculated.All measurements were performed by two trained physicians.Each physician obtained three measurements each time from each patient.First, to determine the coefficient of variation (CV), two additional measurements were taken (3×3 measurements for the first 15 patients).The CV of the first 15 patients was controlled within 8.1% and that of other patients was 8.3%, showing good inter-observer reliability.

Plasma GDF-15

Blood samples were collected into ethylene diamine tetraacetic acid (EDTA) tubes on days 1 and 7.Plasma was separated from the blood samples by centrifugation at 3,500 r/min for 10 min within 2 h of collection.The plasma samples were stored at –80 ℃ until they were processed.The plasma GDF-15 concentration was determined using an enzyme-linked immunosorbent assay (ELISA) kit (Life-tech, USA) according to the manufacturer’s instructions.

Muscle strength

All sedatives and analgesics were discontinued on days 1 and 7 of ICU admission.All patients were awake and responsive during the examination.Muscle strength was evaluated with the Medical Research Council (MRC)sum score.This score appoints a value between 0 (no contraction at all) and 5 (normal muscle strength) for six muscle groups, including shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and dorsiflexion of the ankle, all scored bilaterally.The sum score ranges between 0 and 60, and intensive care unitacquired weakness (ICU-AW) is diagnosed with a total score of <48.In this study, the MRC scores were given simultaneously by the two trained physicians.

ICU management indicators

The incidence of ICU-AW, sepsis, and ventilator-associated pneumonia (VAP), the time of invasive mechanical ventilation,ICU and hospital length of stay, and 28-day mortality in the two groups were statistically analyzed in detail.

Statistical analyses

The statistical data were analyzed using SPSS 22.0 statistical software and GraphPad Prism version 6.0.All the continuous variables were expressed as the mean±standard deviation (SD) and compared using two independent samplet-tests.The comparisons of the data counts were performed using the Chi-square test.AP-value <0.05 was considered statistically significant.

RESULTS

Comparison of the general data

Among the 143 enrolled patients, 32 patients were excluded based on the exclusion criteria.For the remaining 111 patients, 10 patients were excluded due to <7 d of their stay time, against-advice discharge, or death, and four patients were excluded for not completing the chest CT re-examination and ESMcsa measurements on day 7.Ultimately, a total of 97 patients, including 61 males and 36 females, were enrolled in this study.Among these 97 patients, 46 patients were in stage I (conventional EN group), and 51 patients were in stage II (early standardized EN group) (supplementary Figure 2).There were no significant differences in sex, age, weight,body mass index (BMI), basic medical history, smoking history, MV parameters, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, or other baseline levels (allP>0.05) between the two groups, as listed in Table 1.

Comparison of ESMcsa, GDF-15, and MRC scores

There were no significant differences in the ESMcsa,plasma GDF-15, or MRC scores between the two groups on day 1 (allP>0.05).On day 7, the plasma GDF-15 levels in the early standardized EN group were significantly lower than those in the conventional EN group, while the ESMcsaand MRC scores were significantly higher than those in the conventional EN group (allP<0.05) (Figure 1).The ESMcsa on day 7 in the two groups decreased compared to that on day 1, suggesting that both groups showed acute muscular atrophy with a significant decrease in the skeletal muscle content.This decline was more obvious in the conventional EN group(supplementary Figure 3).

Table 1.Comparison of the baseline data and mechanical ventilation variables between the two groups

Evaluation of the ICU-associated indicators

The incidence of ICU-AW, MV time, and ICU and hospital length of stay in the early standardized EN group were significantly lower than those in the conventional EN group (allP<0.05).The first-time success rate of the spontaneous breathing test (SBT) was significantly higher in the early standardized EN group (P<0.05).However, there were no significant differences in the incidence of sepsis or VAP, or re-intubation rate between the groups (P>0.05, supplementary Table 2).

Correlation analysis of the decrease in the ESMcsa with the GDF-15 level and MRC score on day 7

The correlation analysis showed that on day 7, the ESMcsa loss was significantly positively and negatively correlated with the plasma GDF-15 level and MRC score, respectively (r=0.452 and –0.328, allP<0.001)(supplementary Figure 4).

Evaluation of the 28-day prognosis

The 28-day survival rate of the enrolled patients was assessed.The Kaplan-Meier survival curve analysis showed that the 28-day survival rates were 80.40% and 73.90% in the early standardized EN group and conventional EN group,respectively (P=0.406, Figure 2).

DISCUSSION

COPD patients may have a long course of the disease,and the repeated inflammatory consumption may lead to malnutrition.[10]The study has not focused on EN standardization in patients with AECOPD during MV,[11]which might lead to insufficient nutrition, immune function injury, infection, or an increase in death.Therefore, it is important to implement early standardized EN for AECOPD patients with MV.

Figure1.Comparison of the ESMcsa,GDF-15levels,and MRC scores between the two groups.EN: enteral nutrition;ESMcsa:cross-sectional area of erector spine muscle; GDF-15: growth differentiation factor-15; MRC score:Medical Research Council score; ns:not signifciant.*P<0.05.

The results showed that the ESMcsa loss and plasma levels of GDF-15 were significantly lower in the early standardized EN group than in the conventional EN group.This indicated that early standardized EN could significantly reduce ICU-AW.The acute reduction in the mass of skeletal muscles is a main reason for the loss of muscle strength in critically ill patients.[12]Since the ESM is an important antigravity skeletal muscle in the human body, clinical studies have reported that ESMcsa could objectively reflect the contents and function of skeletal muscle in patients and was related to the prognosis of lung diseases, such as COPD and pulmonary fibrosis.[13]Gosker et al[14]reported that AECOPD patients were prone to acute muscular atrophy due to acute energy consumption, nutritional deficiencies, and passive bed rest, resulting in skeletal muscle atrophy and acute loss of muscle function and strength.

Figure 2.The 28-day survival rate of the two groups.EN: enteral nutrition.

Early standardized EN in critically ill patients could effectively alleviate the acute consumption of muscle tissues.In addition, COPD patients on MV often have a high risk of ICU-AW.[15]In COPD patients with acute respiratory failure,early respiratory muscle weakness might prolong the MV time and increase the risk of complications, such as VAP and ICU-AW,[16]which was consistent with our study results.Our previous study also showed that a decrease in the ES Mcsa had a certain clinical diagnostic potential for ICU-AW.[17]In addition, this study also showed that the ESMcsa loss was significantly positively correlated with plasma GDF-15 levels on day 7.This indicated that GDF-15 might reflect the muscle loss.Therefore, GDF-15 levels might synergistically evaluate the degree of sarcopenia in patients.GDF-15 is an important regulator of the protein synthesis/catabolism balance and might be involved in the activation process of these proteolytic pathways.[18]The abnormal activation of GDF-15 in the human body might reduce muscle protein synthesis, thereby causing muscle atrophy.The involvement of GDF-15 in muscle atrophy has also been confirmed in anin vitrostudy.[19]

Limitations

There were some limitations to this study.First, the lack of information on the EN-related complications and dosage of PN might affect the results.Second, this was a beforeand-after study.Therefore, confounding factors could not be fully controlled, especially unmeasured confounding factors.We tried to control confounding factors using multivariable analysis, and the results were consistent with those obtained from the unadjusted analysis.Last, this study was a singlecenter clinical trial.Therefore, there might be a certain bias.These results need to be further verified in a multicenter study.

CONCLUSIONS

The ESMcsa loss in AECOPD patients with MV was correlated with GDF-15 levels, both of which indicated acute muscular atrophy and skeletal muscle dysfunction.Early standardized EN may prevent acute muscle loss and ICU-AW in AECOPD patients.

Funding:This study was funded by the Social Development Project of Jiangsu Provincial Department of Science and Technology(BE2020670) and the Social Development Project of Lianyungang Science and Technology (SF2117).

Ethical approval:The study protocol was approved by the Ethics Committee of the First People’s Hospital of Lianyungang (approval number: LCYJ2020032001).

Conflicts of interest:The authors do not have a financial interest or relationship to disclose regarding this research.

Contributors:YL and YPX contributed equally to this work.All authors approved the final version.

All the supplementary files are available at http://wjem.com.cn.