The application effectiveness of an early enteral nutrition protocol constructed based on the enhanced recovery after surgery concept in ICU patients

Abstract

Background:

Early enteral nutrition (EEN) is the preferred nutritional strategy for critically ill patients in the intensive care unit (ICU). However, its implementation is often accompanied by various complications that can hinder the achievement of nutritional goals, thereby adversely impacting patient outcomes. To address these challenges, this study proposes an EEN protocol grounded in the principles of Enhanced Recovery After Surgery (ERAS), aiming to optimize nutritional support while minimizing enteral nutrition-related complications.

Methods:

A randomized controlled trial was conducted to develop an ERAS-based EEN protocol for intensive care patients. Using a quasi-experimental design and convenience sampling, 100 patients were randomized to either a control group receiving standard nutritional support or an intervention group receiving the ERAS-based protocol. Within 7 days of the intervention, outcomes – including calorie and protein intake, hemoglobin and albumin levels, gastrointestinal tolerance and ICU length of stay – were assessed and compared between groups.

Results:

After the intervention, the intervention group demonstrated significantly higher calorie intake [(1042.00 ± 232.58) kJ/d] and protein intake [(103.96 ± 13.52) g/d] than the control group [(876.30 ± 190.46) kJ/d and (97.00 ± 11.17) g/d] (P<.05). Initially, hemoglobin and albumin levels did not differ significantly between the 2 groups (P > .05). Post-intervention, the intervention group had higher hemoglobin [(117.16 ± 6.69) g/L] and albumin [(45.58 ± 3.23) g/L] levels compared to the control group [(106.98 ± 6.56) g/L and (41.78 ± 3.70) g/L] (P < .05). The intervention group had lower incidence rates of gastric retention (20.0%), diarrhea (12.0%), abdominal distension (14.0%), and gastrointestinal bleeding (6.0%) than the control group (38.0%, 22.0%, 32.0%, 12.0%). Gastric retention and abdominal distension incidence differences were statistically significant (P < .05). The intervention group’s ICU length of stay [(9.16 ± 3.48) d] was shorter than the control group’s [(11.86 ± 4.09) d] (P < .05).

Conclusion:

The ERAS-based EEN protocol for ICU patients effectively improves nutritional status, improves gastrointestinal tolerance, reduces ICU length of stay, and contributes to better clinical outcomes in critically ill patients. These results provide a valuable reference for the implementation of EEN by ICU nurses.

1. Introduction

Intensive care unit (ICU) patients frequently encounter multiple challenges. Mechanical ventilation, their critical condition, etc, often render them unable to swallow and cause gastric emptying impediments. Additionally, the presence of an acute stress response and hyperactive metabolism place them in a state of high nutritional demand.^[1] The resulting imbalance between supply and demand can lead to severe nutritional disorders and malnutrition. Malnutrition, in turn, may trigger hypoproteinemia and electrolyte disturbances, and escalate the risk of infection, significantly affecting the clinical prognosis of ICU patients.^[2,3] Furthermore, ICU patients commonly suffer from disease-related gastrointestinal edema. This edema inhibits intestinal peristalsis, potentially leading to intestinal paralysis or obstruction. As a consequence, the intestinal mucosal barrier is damaged, followed by bacterial overgrowth,^[4] which may cause symptoms such as increased intra-abdominal pressure and gastrointestinal ischemia in patients.^[5] Accumulating evidence indicates that early enteral nutrition plays a pivotal role in protecting the functional and structural integrity of the intestinal barrier in ICU patients. It reduces the production of inflammatory mediators and mitigates the shift in intestinal flora, thus being the preferred nutritional approach.^[6] Specifically, early enteral nutrition can stimulate intestinal metabolic activity, preserve intestinal function, safeguard the intestinal mucosal barrier, minimize flora translocation and the acute-phase stress response, and down-regulate the cytokine response. These effects are crucial for maintaining the body’s immune function, reducing complications, and facilitating early recovery. However, during early enteral nutrition therapy, some ICU patients often experience food intolerance symptoms, including vomiting, regurgitation, abdominal distension, diarrhea, gastrointestinal bleeding, constipation, and decreased or absent bowel sounds.^[7] Therefore, there is an urgent need to formulate an evidence-based early enteral nutrition program tailored to ICU patients. Such a program should ensure adequate nutritional support while minimizing the incidence of feeding intolerance and bowel dysfunction.

Enhanced recovery after surgery (ERAS) represents a cutting-edge concept grounded in evidence-based practices. Its objective is to optimize the perioperative management of patients. Through a multidisciplinary and multimodal care pathway, ERAS aims to decrease the occurrence of complications, expedite the recovery process, and ultimately enable patients to be discharged earlier.^[8] Initially, the ERAS concept was trialed in patients undergoing colorectal surgery. The results have been promising, demonstrating its effectiveness in reducing both the length of hospital stay and the incidence of complications, all while maintaining the safety of patient care.^[9] With the continuous development and widespread adoption of the ERAS concept, it has now been extended to various types of surgical patients. The key interventions of the ERAS concept in the postoperative period for patients include the application of non-opioid analgesia, ensuring adequate sleep, promoting early ambulation, providing early enteral nutrition support, and restricting the volume of intravenous fluids. These measures collectively aim to accelerate the postoperative recovery of patients.^[10] Traditionally, parenteral nutrition has been the mainstay of nutritional support for ICU patients. This approach is thought to reduce the workload on the gastrointestinal tract while providing patients with essential nutrients and minimizing the risk of vomiting and aspiration.^[11] However, in recent years, a growing body of research has indicated that although PN may alleviate the burden on the gastrointestinal tract, it may also lead to a gradual decline in gastrointestinal function and an increased risk of deteriorating malnutrition.^[12,13] Moreover, the absence of peristaltic stimulation of the intestinal tract during PN therapy may result in weakened gastrointestinal motility and the retention of intestinal contents, which can significantly alter the intestinal microbiota.^[14] Recent studies involving intensive care patients have shown that, compared with PN therapy, early EN therapy significantly shortens the hospital stay and reduces the incidence of related complications.^[15] Multiple investigations have now demonstrated the advantages of early EN therapy for ICU patients. Early EN therapy can mitigate the severity of illness in critically ill patients, decrease the occurrence of complications, shorten the duration of mechanical ventilation and ICU stay, improve the prognosis, and lower the morbidity and mortality rates.^[16,17]

Currently, the treatment paradigm for ICU patients centers on addressing the primary disease while incorporating analgesia, and sedation, ensuring proper sleep, promoting early mobilization, providing early enteral nutrition support, and restricting the volume of intravenous infusion. This approach aligns closely with the ERAS concept. Notwithstanding this congruence, the question of whether the ERAS concept can effectively hasten the recovery of ICU patients, lower the incidence of complications, and reduce mortality remains inadequately explored in the domestic and international literature. There is a notable scarcity of reports on this topic. Consequently, this study employed evidence-based methodologies to design an early enteral feeding protocol for ICU patients grounded in the ERAS concept. Clinical trials were then carried out. The overarching aim was to furnish a theoretical foundation for the implementation of early enteral nutrition in ICU patients, thereby filling a significant gap in the existing knowledge regarding the application of ERAS principles in the ICU setting.

2. Objects and methods

2.1. Study subjects

Critically ill patients admitted to the comprehensive ICU of our hospital from January 1, 2023 to December 31, 2023 were selected as study subjects. Inclusion criteria: (1) admitted to the comprehensive ICU and aged > 18 years; (2) the patients were unable to feed orally for 2d and the unified EN pump was used to perform EEN intervention; (3) the circulation was basically normal and the mean arterial pressure (MAP) was above 65 mm Hg without the intervention of vasoactive drugs or dopamine or dobutamine; (4) there were no contraindications to enteral nutrition feeding; and (5) the patients agreed to participate in the study. Those who agreed to participate in the study. Exclusion criteria: ① patients with acute gastrointestinal bleeding; ② patients with various end-stage diseases; ③ patients with contraindications to enteral nutrition (intestinal obstruction, acute gastrointestinal bleeding, acute peritonitis, acute diarrhea, shock); ④ patients with gastrointestinal motility disorders or inflammatory bowel disease. The sample size was calculated according to the formula n1 = n2={(Zɑ/2 + Zβ)×σ/δ}² to compare the means of the 2 samples, taking ɑ=0.05, β = 0.1 and two-sided test, and checking the table, we got Zɑ/2 = 1.96 and Zβ = 1.28. Checking the relevant literature, we took σ=7.52 and δ = 3.49. Substituting the formula, we got n1 = n2 = 47, and the sample size should be 94 cases, but considering the 5% to 10% of lost visits, the sample size was finally determined as 100 cases. Patients were allocated to the control and intervention groups using the random number table method, with 50 cases in each group. The study was approved and authorized by the ethics committee of the first affiliated hospital of Soochow University (2024-670).

2.2. Methods

The trial was designed as a randomized controlled pilot study. Patients in the control group received standard nutritional care. After ICU admission and stabilization, physicians assessed patients’ nutritional risk and prescribed enteral nutrition accordingly. Nurses administered nutritional support according to physician orders, including placement of an indwelling gastrointestinal tube when indicated to meet energy and nutritional needs. Nutritional support was withdrawn immediately in the event of complications such as diarrhea, vomiting, abdominal distension or hyperglycemia.

The intervention group received an early nutritional support program based on the ERAS concept.^[18,19] First, a multidisciplinary team consisting of the lead physician, lead nurse, dietitian, respiratory therapist, rehabilitation therapist, and Chinese medicine practitioner was established to form an early nutritional support team. After the responsible physician instructed the team members in the ERAS concept, the team members developed an early enteral nutrition support program based on the ERAS concept, taking into account the individual situation of the patient (see Table 1 for details). The content of this early nutrition support program includes (1) early nutritional risk screening; (2) assessment of gastrointestinal function; (3) selection of feeding modes and types of nutritional solutions; (4) nutritional precautions; (5) monitoring and management of food intolerance; (6) implementation of early rehabilitation; and (7) other symptomatic treatments.

Table 1.

Early enteral nutrition support programs based on the ERAS concept.

Project	Specific interventions
1. Early nutritional risk screening	Patients were screened for nutritional risk by the nurse in charge on the day of admission using the NRS 2002 scale[18]; if the screening result was not nutritional risk, they could choose to withhold nutritional support therapy or provide early enteral nutrition according to the patient’s gastrointestinal function and perform daily dynamic screening; if the screening result was nutritional risk, they could choose to withhold nutritional support therapy or provide early enteral nutrition according to the patient’s gastrointestinal function and perform daily dynamic screening. If the screening result is a nutritional risk, the early nutritional support team is activated to discuss the nutritional supportprogramme.
2. Assessment of gastrointestinal function	On the day of admission, patients were assessed by the responsible doctor for gastrointestinal function using the acute gastrointestinal dysfunction (AGI) grading[19], and if there was no injury to gastrointestinal function or if the AGI was graded I–Ⅲ, then early enteral nutrition was initiated; if the AGI was grade Ⅳ, then early enteral nutrition was postponed, and at the same time, the patient complied with the medical advice. Drugs to promote the recovery of gastrointestinal function were given. At the same time, daily dynamic assessment was carried out until the patient was able to start enteral nutrition.
3. Selection of nutritional methods and types of nutritional solution	The type of nutritional infusion was selected according to the patient’s risk of aspiration; those with a low risk of aspiration were infused via nasogastric tube, and those with a high risk of aspiration were infused via nasoenteric tube; At the same time, the type of nutritional solution was selected according to the patients’ AGI grade, ① if the AGI was ≤ grade Ⅰ, enteral nutrition emulsions were used and the initial rate was 25 mL/h; ② those with AGI of Ⅱ to Ⅲ, enteral nutrition preparation was given and the initial rate was 20 to 25 mL/h.
4. Precautions during feeding	Attention should be paid to body position, pumping back and tube flushing during the feeding process. Unless contraindicated, the head of the bed should be kept elevated at an angle of 30 to 45 degrees during feeding, and the semi-recumbent position should be maintained for 30 to 60 minutes after the feeding is finished to avoid choking, vomiting, aspiration, etc. During the feeding, pumping should be done every 4 to 6 hours to check for retention and at the same time, 20 mL of lukewarm boiled water should be used for pulsed flushing of the tubes to avoid clogging of the tubes.
5. Monitoring and management of food intolerance	Evaluate enteral nutrition tolerance according to enteral nutrition tolerance score and dispose accordingly. ① Gastric residual volume: when the gastric residual volume is <200 mL, the infusion rate will be increased by 20 mL every 4 hours; when 200 mL ≤ gastric residual volume < 350 mL, the infusion rate will be reduced to 1/2 of the original rate and monitored again after 4 hours; when 350 mL ≤ gastric residual volume < 500 mL, the infusion rate will be reduced to 1/4 of the original rate and evaluated again after 4 hours; when the gastric residual volume ≥ 500 mL, enteral nutrition will be suspended. When the gastric residual volume is ≥500 mL, suspend enteral nutrition and monitor again after 4 hours. If the gastric residual volume is ≤500 mL, maintain the original speed or increase the speed, and if the gastric residual volume is still >500 mL in the next monitoring, then the implementation of the gastrointestinal decompression combined with the post-pyloric feeding double tube placement strategy should be considered. ② Abdominal distension: mildly maintain the original infusion rate; moderately reduce the infusion rate to 1/2 of the original rate, review every 4 hours, and according to the situation of acupuncture or massage, or the use of gastrointestinal dynamics of the drug; severe stop EEN, and other feeding methods. ③ Diarrhoea: patients with mild or moderate (1–4 times every 12 hours) should keep the original infusion rate and review every 4 hours, together with acupuncture and massage; patients with severe (>4 times every 12 hours) should reduce the infusion rate to 1/2 of the original rate and give antidiarrhoeal medication through the feeding tube, and at the same time conduct fecal cultures to identify the cause of infection and treat the symptoms.
6. Implementation of early rehabilitation	Early rehabilitation is carried out by rehabilitation therapists for patients. Patients with impaired consciousness were given passive physical exercises, such as lower limb pedaling; awake patients were instructed to perform bedside physical exercises, such as hip lifts and aerial pedaling.
7. Other symptomatic treatment	If the patient has other symptoms, give active symptomatic treatment. If the patient is in pain and irritable, give appropriate analgesia and sedation according to the doctor’s prescription; if the patient has high blood sugar and high blood pressure, give appropriate measures to control blood sugar and blood pressure according to the doctor’s prescription.

2.3. Monitoring indicators

• (1) Caloric intake and protein intake: record the average daily caloric intake and protein intake of the patients from admission to day 7.

• (2) Nutritional indicators: check the values of hemoglobin and albumin in the laboratory results of the 2 groups of patients before and 7 days after the intervention.

• (3) Gastrointestinal tolerance: After 7 days of intervention, record the number of cases of gastric retention (gastric residue > 250 ml in 2 retractions), diarrhea (patients’ bowel movements ≥ 3 times/d, and the water content of feces is more than 80% and unshapely), abdominal distention (weakened bowel sounds, abdominal distention, and drumming sound on percussion), and gastrointestinal bleeding (positive occult blood test in vomitus fluid, gastric contents, or feces; or bleeding visible to the naked eye, such as black stools and vomited blood) in the 2 groups.) Number of cases.

• (4) ICU length of stay: record the ICU length of stay of patients in both groups.

2.4. Statistical analysis

SPSS 22.0 statistical software was used to perform statistical analysis on the data. Measurement data that conformed to normal distribution were expressed as mean ± standard deviation and the t test was used; count data were expressed as number of cases and percentages and the χ² test was used. P < .05 indicated that the difference was statistically significant.

3. Results

3.1. Comparison of general information between the 2 groups of patients

When comparing the 2 groups of patients in terms of age, sex, BMI, type of disease, etc, the differences are not statistically significant (P > .05) and are comparable, see Table 2.

Table 2.

Comparison of general information of patients in 2 groups.

Item	Classification	Control group	Observation group	t/χ2 value	P value
Age (years)		68.72 ± 15.17	66.66 ± 15.49	0.672	.503
Sex	Male	32	27	1.033	.309
	Female	18	23
BMI		21.24 ± 1.25	20.79 ± 1.28	1.748	.077
Type of disease	Respiratory system	15	13
	Circulatory system	8	10
	Nervous system	22	21
	Other	5	7

3.2. Comparison of calorie and protein intake of patients in the 2 groups

The calorie intake and protein intake of patients in the intervention group were higher than those in the control group in 7 days, and the differences were statistically significant (all P < .05), see Table 3.

Table 3.

Comparison of calorie and protein intake between the 2 groups of patients.

Group	Calorie intake in 7 days	Protein intake in 7 days
Control group	876.30 ± 190.46	97.00 ± 11.17
Intervention group	1042.00 ± 232.58	103.96 ± 13.52
t value	‐3.898	‐2.806
P value	<.001	<.001

3.3. Comparison of nutritional indicators between the 2 groups of patients

In a comparison of hemoglobin and albumin levels between the 2 groups of patients before the intervention, the difference is not statistically significant (P > .05), the 2 groups are comparable. After the intervention, the hemoglobin and albumin levels of the 2 groups of patients were higher than before the intervention, and the intervention group was higher than the control group, and the differences were statistically significant (all P < .05), see Table 4.

Table 4.

Comparison of nutritional indicators between the 2 groups of patients.

Group	Number of cases	Haemoglobin level (g/L)		Albumin level (g/L)
		Pre-intervention	post-intervention	Pre-intervention	Post-intervention
Control group	50	84.64 ± 7.71	106.98 ± 6.56	34.14 ± 3.12	41.78 ± 3.70
Intervention group	50	84.72 ± 5.05	117.16 ± 6.69	34.12 ± 2.34	45.58 ± 3.23
t value		‐0.061	‐7.684	0.036	‐5.465
P value		.951	<.001	0.971	<.001

3.4. Comparison of gastrointestinal tolerability and feed interruption between the 2 groups of patients

After the intervention, the difference in the incidence of diarrhea and gastrointestinal bleeding between the 2 groups was not statistically significant (P > .05); the incidence of gastric retention and abdominal distension was lower in the intervention group than in the control group, and the difference was statistically significant, see Table 5.

Table 5.

Comparison of gastrointestinal tolerance between the 2 groups of patients.

Group	Number of cases	Gastric retention	Diarrhoea	Bloating	Gastrointestinal bleeding
Control group	50	19 (38.0%)	11 (22.0%)	16 (32.0%)	6 (12.0%)
Intervention group	50	10 (20.0%)	6 (12.0%)	7 (14.0%)	3 (6.0%)
χ2 value		3.934	1.772	4.574	1.099
P value		.047	.183	.032	.295

3.5. Comparison of ICU length of stay between the 2 groups of patients

After the intervention, the ICU stay of patients in the intervention group (9.16 ± 3.48) was shorter than that of the control group (11.86 ± 4.09) days, and the difference was statistically significant (t = 3.237, P = .018).

4. Discussion

The findings of this study revealed that, within 7 days of admission, the caloric and protein intake of patients in the intervention group surpassed that of the control group. This indicates that the early enteral nutrition program developed based on the ERAS concept effectively increased patients’ caloric and protein uptake. These results are consistent with those reported by Chen et al^[20] As we know, the ERAS concept emphasizes the importance of early enteral nutrition during the perioperative period, replacing the traditional practice of postoperative fasting and fluid restriction. This clearly provides a theoretical underpinning for early supportive enteral nutrition therapy in ICU patients. In the ERAS-based early enteral nutrition program of this study, nutritional risk screening and gastrointestinal function assessment were initiated on the day of admission. For patients without gastrointestinal dysfunction, enteral nutrition was commenced promptly, ensuring an early start to calorie and protein intake, and thus enabling an increase in caloric and protein uptake within 7 days. In this early nutrition program, patients were categorized according to their nutrition risk screening levels and gastrointestinal function assessment results. The timing and method of initiating early enteral nutrition were then determined accordingly. Meanwhile, daily dynamic assessment of enteral nutrition tolerance allowed nursing staff to evaluate patients’ tolerance risk levels, dynamically adjust feeding rates and routes, and decide whether to continue feeding. This effectively ensured the successful implementation of early enteral nutrition for patients, thereby facilitating an increase in calorie and protein intake.

Building on these nutritional intake improvements, the study further demonstrated that the hemoglobin and albumin levels of the intervention group were higher than those of the control group after the intervention, and hemoglobin and albumin are key indicators reflecting the nutritional status of ICU patients. Evidently, this suggests that the early enteral nutrition program constructed based on the ERAS concept can improve the nutritional status of ICU patients, which is consistent with the results of the study conducted by Zheng and others.^[21] The early enteral nutrition program based on the ERAS concept points out the precautions in the process of nutrition implementation, assesses and monitors the possible complications and intolerances in advance, and provides anticipatory treatment in advance. As a result, it can reduce the incidence of feeding interruptions in patients, and is conducive to achieving the feeding goal of patients and then improving their nutritional status. In addition, in this study, there was still a decreasing trend in serum albumin in both groups after the nutritional intervention. The reason may be that, on the one hand, stress catabolism is much greater than anabolism in the critical state of ICU patients, and protein consumption increases^[22]; on the other hand, the first 3 days of the early enteral nutrition program mainly follows the principle of low calorie and low protein, and the protein supply is low, resulting in inadequate supply and decreased albumin synthesis, so there will still be a decrease in the level of serum albumin, which is consistent with the research results of Chen et al^[23] Nevertheless, the degree of albumin decline was lower in the intervention group than in the control group, which again suggests that the ERAS-based early enteral nutrition program can reduce the degree of albumin decline. One possible explanation for this may be that the early enteral nutrition program based on the ERAS concept includes nutritional risk, gastrointestinal function and tube placement, and other components of assessing the appropriate early feeding, which reduces the occurrence of diarrhea and other symptoms of feeding intolerance, thereby reducing the amount of intestinal protein loss.

In addition, the results of this study show that after starting enteral nutrition support therapy, the incidence of gastric retention and abdominal distension is lower in the intervention group than in the control group (P < .05), indicating that the early enteral nutrition program based on the ERAS concept is able to reduce gastrointestinal intolerance in ICU patients. In the early enteral nutrition program based on the ERAS concept, patients’ gastrointestinal tolerance is assessed early and dynamically, and in case of intolerance such as abdominal distension, diarrhea, constipation, gastric retention, and gastrointestinal bleeding, multidisciplinary consultations are held, Multidisciplinary consultations are held to provide patients with causal or symptomatic treatments, to slow down the volume of the drug and dilute its concentration, and to change the feeding route if necessary, while at the same time providing traditional Chinese medicine treatments such as acupuncture, massage, and other medicines to promote gastrointestinal dynamics. Patients in the control group were more likely to have abdominal pain. Compared with the control group, in which nutritional support therapy was stopped immediately when adverse reactions such as flatulence, diarrhea, vomiting, and hyperglycemia occurred, the early enteral nutrition program in the intervention group included monitoring and treatment of food intolerance, which effectively allowed early detection of symptoms of food intolerance and early intervention, and reduced the incidence of food intolerance. Moreover, early functional exercise and traditional Chinese medicine interventions such as acupuncture and abdominal massage were added to the program of the intervention group, which could improve patients’ bowel paralysis, reduce intra-abdominal pressure, accelerate metabolism, improve symptoms of food intolerance such as gastric retention and abdominal distension, and promote effective absorption of enteral nutrition so that the target feeding volume could be reached as soon as possible.^[24]

Finally, The results of this study show that the ICU stay of the patients in the intervention group is shorter than that of the control group (P < .05), indicating that the early enteral nutrition program constructed based on the ERAS concept can shorten the ICU stay of the patients, which is consistent with the results of the study by Xie et al^[25] ICU patients have high energy consumption, early enteral nutrition intervention can meet the energy required for diaphragmatic contraction, balance the body’s supply and demand, promote protein synthesis, and improve patients’ nutritional status; At the same time, the early enteral nutrition program based on the concept of ERAS has increased the content of early rehabilitation, which can improve the respiratory muscle strength of mechanically ventilated patients and the organismic function of non-mechanically ventilated patients, avoid the occurrence of ICU-acquired debilitation,^[26] and thus shorten the length of ICU stay. Additionally, the early enteral nutrition program based on the ERAS concept in the intervention group included other symptomatic therapeutic measures, such as the analgesic sedation advocated in the ERAS concept, which improves patient comfort and compliance by giving patients analgesic sedation, thus improving the prognosis of patients and reducing the length of stay in the ICU.

5. Conclusion

In summary, the early enteral nutrition program developed in line with the ERAS concept offers multiple benefits for ICU patients. It effectively increases their energy and protein intake, thereby improving their nutritional status. Additionally, it mitigates gastrointestinal intolerance among ICU patients, ultimately shortening their length of stay in the ICU. Given these advantages, this program warrants promotion for clinical application. However, this study has certain limitations. The sample size was relatively small, and the comparison of nutritional indicators was confined to 7 days post-intervention. As a result, the study findings may be subject to some constraints. For future research, the next steps should include further increasing the sample size, conducting multi-center studies, and extending the observation period. These measures will help to more comprehensively verify the effectiveness of the proposed protocol.

Author contributions

Conceptualization: Weili Xu, Xiuxiu Ding.

Data curation: Weili Xu.

Formal analysis: Weili Xu.

Methodology: Weili Xu, Xiuxiu Ding.

Project administration: Xiuxiu Ding.

Writing – original draft: Weili Xu.

Writing – review & editing: Weili Xu, Xiuxiu Ding.