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Association between early enteral nutrition and 28-Day mortality in mechanically ventilated patients with sepsis: a retrospective analysis of the MIMIC-IV database

BMC Infectious Diseases volume 25, Article number: 628 (2025) Cite this article

Abstract

Background

The optimal timing of enteral nutrition for critically ill septic patients in the intensive care unit (ICU) who require invasive mechanical ventilation has not been determined, and the influence of early enteral nutrition on clinical outcomes is unclear.

Methods

This retrospective observational study utilized data from the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database to investigate patients with sepsis who needed invasive mechanical ventilation post-ICU admission. Patients who had enteral nutrition (EN) initiated within 72 h of ICU were categorized into the early enteral nutrition (EEN) group, while those who began enteral nutrition after 72 h were placed in the delayed enteral nutrition (DEN) group. Propensity score matching analysis was performed to compare outcomes between these two groups, with the primary outcome being 28-day mortality.

Results

The final analysis included 2293 patients, 1546 (67.4%) of whom received enteral nutrition within 72 h of invasive mechanical ventilation. The overall 28-day mortality rate was 31.0%. After propensity score matching employing the proximity matching method, Cox survival analysis revealed that early enteral nutrition was associated with increased 28-day mortality in septic patients on invasive mechanical ventilation (hazard ratio(HR) 1.440, 95% CI 1.179–1.760; p < 0.001). The sensitivity and robustness of the evaluation results under different models, including optimal matching (adjusted odds ratio (aOR) 1.52, 95% CI 1.21–1.92, p < 0.001), inverse probability of treatment weighting (aOR 1.27, 95% CI 1.02–1.58, p = 0.034), and logistic regression analysis (aOR 1.48, 95% CI 1.18–1.84, p = 0.001), confirmed the association between early enteral nutrition and increased 28-day mortality in mechanically ventilated septic patients.

Conclusions

Compared to delayed enteral nutrition, early enteral nutrition is associated with higher 28-day mortality in septic patients on invasive mechanical ventilation. Randomized controlled trials are warranted to validate these findings.

Peer Review reports

Background

Sepsis is a critical condition characterized by life-threatening organ dysfunction resulting from an uncontrolled host response to infection [1, 2]. It poses a significant challenge in modern intensive care and continues to be a leading cause of morbidity and mortality on a global scale [3]. The management of sepsis often requires admission to the intensive care unit (ICU) and, in severe cases, the use of invasive mechanical ventilation to ensure sufficient oxygen delivery and tissue perfusion.

Nutritional support plays a pivotal role in the care of critically ill patients, including those with sepsis. It not only provides the essential macronutrients and micronutrients required for cellular function but also has a profound impact on the immune response, the integrity of the gastrointestinal barrier, and potentially patient outcomes [4,5,6]. Enteral nutrition (EN), which involves delivering nutrients directly to the gastrointestinal tract, is often preferred over parenteral nutrition due to its physiological benefits, including the maintenance of gut barrier function [7, 8]. However, recent large randomized controlled trials have shown comparable overall outcomes between EN and parenteral nutrition, with EN being associated with a higher risk of gastrointestinal complications [9].

Nonetheless, the optimal timing for initiating EN, particularly in septic patients who require invasive mechanical ventilation, remains a subject of debate. Early enteral nutrition (EEN) is suggested to offer advantages such as a reduced risk of infectious complications, modulation of the exaggerated immune response, and improved gut motility [10, 11]. However, concerns related to issues such as aspiration, haemodynamic instability, and the potential exacerbation of gut ischaemia in the context of sepsis have led to hesitancy in its widespread adoption [12, 13].

Given the contrasting views and significance of these issues, our study aimed to elucidate the benefits and potential risks of early enteral nutrition in septic patients receiving invasive mechanical ventilation.

Materials and methods

Study design and participants

We conducted a retrospective analysis of the MIMIC-IV 2.2 database, which contains comprehensive and highly detailed information about well-characterized patients admitted to the intensive care units (ICUs) at Beth Israel Deaconess Medical Center between 2008 and 2019 [14]. Two authors were granted access to the database and were responsible for the data extraction (certification numbers 52712098 and 57,613,237).

Our study focused on adult sepsis patients who met the diagnostic criteria of Sepsis 3.0 and who received enteral nutrition along with invasive mechanical ventilation after admission to the ICU [1]. We excluded patients who had enteral feeding records in multiple ICUs. In order to include a more comprehensive sample of patients receiving invasive mechanical ventilation, we chose to exclude patients with an ICU stay of less than 48 h. Additionally, we excluded patients with invasive mechanical ventilation duration of less than 48 h. Furthermore, we excluded patients who received parenteral nutrition during their ICU stay. Additionally, patients diagnosed with sepsis 24 h after ICU admission were excluded. We also excluded patients who received invasive mechanical ventilation before ICU admission or 24 h after admission, as well as patients whose enteral nutrition was initiated before invasive mechanical ventilation.

This database was established with the approval of the Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA). Informed consent was obtained for the original data collection from the human subject committee review. Importantly, the database encrypts patient information, eliminating the need for an ethical approval statement or informed consent for this study.

Variable extraction and data collection

In this study, baseline characteristics from the MIMIC-IV 2.2 database were collected within the first 24 h after ICU admission and included the following parameters: sex, age, body mass index (BMI), care unit, and race. Additionally, we recorded vital signs, specifically, heart rate, respiratory rate, mean arterial pressure (MAP), temperature, glucose levels, use of vasopressors, and total urine output, within the initial 24 h after ICU admission. The laboratory results included pH, arterial oxygen partial pressure (PO2), arterial carbon dioxide partial pressure (PCO2), Pao2/Fio2 ratio, lactate, white blood cell (WBC) count, haemoglobin levels, platelet count, creatinine, blood urea nitrogen, serum albumin, and blood electrolyte levels (chlorine, calcium, potassium, sodium). In cases where variables were recorded multiple times during the first 24 h, we selected values that corresponded to the most severe disease state. Interventions carried out within the initial 24 h included renal replacement therapy, invasive arterial pressure monitoring, and the insertion of a peripherally inserted central catheter. Severity scores for the first day after ICU admission were assessed using the Acute Physiology Score III (APS III), Oxford Acute Severity of Illness Score (OASIS), Logistic Organ Dysfunction System (LODS), Sequential Organ Failure Assessment (SOFA), and Charlson Comorbidity Index (CCI). Comorbidities, such as congestive heart failure, chronic pulmonary disease, mild liver disease, diabetes, chronic kidney disease, and cancer, were documented. Additionally, we documented the culture results for each patient, considering the specimen type from the first positive culture as the source of infection if the patient's culture yielded positive results.

For the extraction of septic shock data, patients were classified as having septic shock within 24 h of ICU admission if they received vasoactive drugs and had a lactate level exceeding 2 mmol/L. The data extraction code is available on GitHub at https://github.com/MIT-LCP/mimic-iv. PostgreSQL tools (version 15) were used for all the data extraction processes [15].

Primary exposure and outcomes

The primary aim of our study was to compare the association of early versus delayed enteral nutrition (EN) initiation following invasive mechanical ventilation with patient outcomes. We categorized patients into two groups: the"early enteral nutrition"group, which included those who commenced EN within 72 h of ICU admission, and the"delayed enteral nutrition"group, which included those who started EN 72 h or more after ICU admission. It is important to clarify that while our study evaluates the association of early versus delayed EN with patient outcomes, it does not investigate the optimal timing for EN initiation.

Our primary outcome of interest was the 28-day mortality rate. The secondary outcomes included 60-day mortality, 90-day mortality, ICU mortality, in-hospital mortality, and the incidence of ventilator-associated pneumonia (identified through diagnostic codes ICD- 9–99,731 and ICD- 10-J95851).

Statistical analysis

We employed the Kolmogorov‒Smirnov test and the Shapiro‒Wilk test to analyse continuous variables for normal distribution. Continuous variables are represented using either the mean ± standard deviation or the median (interquartile range), depending on their distribution. Categorical variables are presented as proportions. Appropriate statistical tests, such as the t test, analysis of variance, and the Mann‒Whitney U test, were used for comparisons. The χ2 test was used for comparing categorical variables.

Given the missing values in the extracted data (Additional Table 1), we addressed this issue by utilizing the Predictive Mean Matching (PMM) method from the MICE package in the R programming language. The PMM method allowed us to perform multiple imputations, generating 20 imputed datasets, each with missing values. Subsequently, we calculated the average of these 20 sets of estimated values to obtain the final imputed dataset. To assess the impact of the imputed data on the results, we also conducted multiple imputations using linear regression methods. Further analyses were carried out to evaluate the robustness of the imputation results.

To compare outcomes between the early and delayed EN groups, we applied a propensity score matching (PSM) method [16]. We utilized a multivariate logistic regression model to estimate the propensity scores of patients in both groups. In our study, 1:1 nearest neighbour matching was employed with a calliper width of 0.05. To assess the effectiveness of PSM, we calculated standardized mean differences (SMDs) and p values. A variable was considered imbalanced between groups when the SMD exceeded 0.1 [17]. To ensure the robustness of our model, we not only used the nearest neighbour matching method but also implemented the best matching method, inverse probability of treatment weighting (IPTW), and conducted logistic regression analyses to confirm the consistency of the outcomes.

In the subgroup analysis, we employed Inverse Probability of Treatment Weighting (IPTW) to adjust the weighted samples derived from the multiple imputation by predictive mean matching (PMM) method, aiming to control for confounding factors. Initially, we constructed a Generalized Linear Model (GLM) to predict the probability of early enteral nutrition and computed the weights for each individual. Subsequently, we determined the cutoff point based on the actual distribution of weights to replace extreme weight values exceeding the 99 th percentile with the cutoff point, thus mitigating the impact of outliers. Lastly, we utilized a weighted design and weighted logistic regression model to assess the effect of early enteral nutrition on 28-day mortality and visualized the results using forest plots.

All the statistical analyses were carried out using R (version 4.3.1), and a p value of < 0.05 (two-sided) was used to indicate statistical significance.

Results

Demographic data and baseline characteristics

A total of 2,293 septic patients requiring invasive mechanical ventilation were enrolled in our study. The patient flow diagram is presented in Fig. 1. Within the study cohort, 1,546 patients received enteral nutrition within 72 h after ICU admission, while 747 patients received enteral nutrition after 72 h of ICU admission. The overall 28-day mortality rate was 31.0%. The characteristics of the patients in the EEN and DEN groups are summarized in Table 1. In general, there were more female patients in the EEN group (681 (44.0) vs. 293 (39.2); p = 0.028). The DEN group had more septic shock patients within 24 h of ICU admission (481 (64.4) vs. 593 (38.4); p < 0.001). The DEN group exhibited a significantly greater Sequential Organ Failure Assessment (SOFA) score (4.00 (3.00–6.00) vs. 3.00 (2.00–5.00); p < 0.001) than did the EEN group. Moreover, the initial lactate levels upon admission were also notably greater in the DEN group (3.80 (2.20–6.50) vs. 2.30 (1.50–3.90); p < 0.001) than in the EEN group. The detailed baseline information of the two groups is shown in Additional Table 2.

Fig. 1
figure 1

The flow diagram of study patients

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Table 1 Demographic data and comparisons between the early EN group and the delayed EN group before and after matching
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Primary outcome

After propensity score matching (PSM) was performed, a total of 747 patients in the DEN group were successfully matched with 1,546 patients in the EEN group using a 1:1 matching algorithm, resulting in 607 patients in each group. The association between early enteral nutrition and 28-day mortality remained statistically significant even after propensity score matching, with an adjusted odds ratio (OR) of 1.51 (95% CI 1.19–1.93; p = 0.001) (Table 2). Subsequently, when the matched data were integrated into the Cox survival analysis model, early enteral nutrition was shown to be associated with an increased risk of 28-day mortality, with a hazard ratio (HR) of 1.440 (95% CI 1.179–1.760; p < 0.001). These findings are further illustrated by the Kaplan–Meier (K–M) survival curve presented in Fig. 2.

Fig. 2
figure 2

K-M survival curve of 28-day mortality between the EEN group and EDN group after matching using the 1:1 nearest matching method

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Table 2 Primary and secondary outcomes before and after matching
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Sensitivity analysis

To assess whether early enteral nutrition continues to impact the 28-day mortality of septic patients requiring invasive mechanical ventilation, we employed various statistical techniques, including optimal matching, inverse probability of treatment weighting, and logistic regression analysis, to ensure a robust and comprehensive evaluation of the results. The outcomes were rigorously analysed, and the findings were illustrated using forest plots to depict the relationship between early enteral nutrition and 28-day mortality across four different models (refer to Fig. 3 and Additional Table 3). Furthermore, we conducted Cox survival analysis on the dataset that was matched using the optimal matching method and created an adjusted survival analysis graph (see Additional Fig. 1). Notably, the results obtained from this analysis were consistent with those obtained using the neighbour matching method, revealing a hazard ratio (HR) of 1.549(95% CI 1.289–1.860; p < 0.001). Additionally, we investigated whether different missing value imputation models could influence the outcomes. To address this, we employed linear regression for data imputation. We found that the results were in line with those obtained using the PMM method to impute missing values (refer to Additional Table 4 and Additional Fig. 2). The survival curve information of patients after the linear regression method was used to fill in the missing values according to the nearest best matching method and the optimal matching method are presented in Additional Fig. 3 and Additional Fig. 4.

Fig. 3
figure 3

The relationship between EEN and 28-day mortality under different models. (IPTW, Inverse Probability of Treatment Weighting; Logistic Reg, Logistic Regression Analysis; NNM, Nearest Neighbor Matching; OM, Optimal Matching)

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Fig. 4
figure 4

Subgroup analysis results after IPTW removes extreme values

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Secondary outcomes and subgroup analysis

After applying a 1:1 propensity score, we observed that the 60-day mortality rate (adjusted odds ratio (aOR) 1.39, 95% CI 1.10–1.75, p = 0.006) and 90-day mortality rate (aOR 1.36, 95% CI 1.08–1.72, p = 0.008) were significantly greater in the EEN group than in the DEN group. Moreover, ICU mortality (aOR 1.57, 95% CI 1.21–2.04; p = 0.001) and hospital mortality (aOR 1.47, 95% CI 1.15–1.88; p = 0.002) were also elevated in the EEN group. Interestingly, there was no significant difference in the incidence of ventilator-associated pneumonia between the two groups (aOR 0.86, 95% CI 0.65–1.15; p = 0.310), as shown in Table 2.

We conducted a subgroup analysis of the original dataset, categorizing the data based on septic shock status, sex, age, SOFA score, BMI, and lactate levels. Employing inverse probability of treatment weighting (IPTW) and eliminating outliers, we discovered that within the cohort of patients suffering from septic shock and requiring invasive mechanical ventilation, early enteral nutrition significantly increased 28-day mortality (aOR 1.398, 95% CI 1.049–1.872, p = 0.023). Furthermore, in the subgroup of younger female patients with severe disease, early enteral nutrition was associated with higher mortality rates (see Fig. 4 and Additional Table 5 for details).

Furthermore, we conducted a subgroup analysis focusing on septic patients with positive culture results. Within this subset, we observed that the 28-day mortality rate was notably greater in the early enteral nutrition group (aOR 1.491, 95% CI 1.065–2.001; p = 0.023). In the subgroup of patients with positive blood culture results (aOR 2.490, 95% CI 1.248–4.955; p = 0.010) and positive urine culture results (aOR 2.598, 95% CI 1.028–6.695; p = 0.044), the impact of early enteral nutrition on 28-day mortality was particularly pronounced. (Refer to Additional Fig. 5 and Additional Table 6 for further details.)

Discussion

We observed an increased 28-day mortality rate associated with early enteral nutrition in septic patients receiving invasive mechanical ventilation. Subgroup analysis suggested that certain patient groups, such as those with septic shock, young females, and those with severe sepsis, might be more significantly affected.

The optimal timing of enteral nutrition in septic patients has been explored in several studies with varying findings. One study indicated that septic shock patients receiving less than 600 kcal/day of enteral nutrition within the initial 48 h experienced a reduced duration of mechanical ventilation and shorter stays in the intensive care unit [18]. Another study found that in patients with sepsis and septic shock, a higher daily average protein intake may lead to lower in-hospital mortality, while a higher energy intake may be associated with reduced 30-day mortality, particularly among those with high modified nutritional risk scores. Furthermore, the benefits of enteral nutrition with supplemental parenteral nutrition appear to be more pronounced in well-nourished patients than in underfed patients [19]. Importantly, the current research does not provide conclusive evidence that early enteral nutrition can significantly reduce mortality in critically ill patients [20, 21,22,23,24]. Additionally, a study revealed that critically ill patients receiving caloric intake of 70% or more within the first 72 h of hospitalization did not show improved short-term or one-year outcomes [25]. Moreover, in critically ill adults with shock, early isocaloric enteral nutrition did not result in reduced mortality or a decreased risk of secondary infections but was associated with a greater risk of digestive complications than early isocaloric parenteral nutrition [26]. Furthermore, oropharyngeal microaspiration was more prevalent in patients with shock who received invasive mechanical ventilation and enteral nutrition [27].

Interestingly, the separation of survival curves in our study occurred as early as days 2–3, suggesting a potential early impact of EEN on mortality. Several factors may contribute to this phenomenon. First, early enteral nutrition in critically ill septic patients may exacerbate hemodynamic instability and gastrointestinal intolerance, leading to increased complications such as feeding intolerance and aspiration [26]. Second, excessive caloric intake during the acute phase of critical illness has been associated with metabolic stress and impaired autophagy, potentially worsening outcomes. Additionally, unmeasured confounders, including variations in clinical management and patient selection biases, may have influenced early mortality risk. These findings align with prior studies that suggest the potential harm of early aggressive enteral feeding in critically ill patients [7]. A recent study highlighted a significant association between early nutritional support and increased mortality in critically ill ICU patients, particularly among younger individuals with less severe conditions [28]. Our findings align with this trend, indicating that early enteral nutrition is linked to increased 28-day mortality in septic shock patients receiving invasive mechanical ventilation, particularly among young female patients with severe sepsis. However, these results are hypothesis-generating, given the observational nature of this study, and require further validation through randomized controlled trials to confirm their significance.

In a physiological context, the early provision of enteral nutrition (EN) to critically ill patients upon admission to the intensive care unit has been shown to exert beneficial effects by downregulating systemic immune responses, reducing oxidative stress, and improving patient outcomes [10]. After 3 days of enteral nutrition, the plasma citrulline concentration was found to be greater than that after 3 days of parenteral nutrition, suggesting that enteral nutrition may promote a more rapid restoration of the number of enterocytes [29]. The administration of EEN to critically ill patients has been associated with increased plasma acetylcholine (Ach) levels and decreased inflammatory marker levels, and part of these effects are attributed to elevated cholecystokinin (CCK) levels. Higher levels of plasma Ach are indicative of a better prognosis [30]. Furthermore, EEN has shown the potential to regulate the imbalance of Th17/Treg cell ratios and suppress the IL- 23/IL- 17 axis during sepsis. It has also been observed that EEN can reduce the clinical severity of sepsis; however, it does not significantly reduce the 28-day mortality rate among septic patients [31].

Current research on nutritional support for septic patients receiving invasive mechanical ventilation is limited, necessitating extreme caution when considering nutritional interventions. A recent study revealed that sepsis patients who require invasive mechanical ventilation within 24 h of ICU admission may be at a higher risk of developing enteral feeding intolerance. This intolerance is linked to reduced enteral nutrition delivery and unfavourable clinical outcomes [32]. Importantly, feeding intolerance is a common issue during the early stages of ICU admission, particularly among patients receiving mechanical ventilation (MV) and continuous renal replacement therapy (CRRT) [33]. Studies have demonstrated that enteral nutrition is independently associated with acute mesenteric ischaemia in critically ventilated patients in shock. In critically ill ventilated patients requiring vasopressors, enteral nutrition should be delayed or administered cautiously if cardiac output is low, necessitating the need for dobutamine and/or in the setting of multiorgan failure with a high SAPS II score [34]. Our study findings align with these observations and suggest that while early enteral nutrition offers several benefits, the potential risks may outweigh the advantages of mechanical ventilation in septic patients. The most severe patients could have greater endogen production of energy related to catabolism and therefore be at risk of overfeeding in the case of early EN. Early EN is associated with a greater risk of feeding intolerance, which is associated with a poor prognosis. Early EN could increase the risk of acute mesenteric ischaemia in the most severe patients with shock, as demonstrated by the NUTRIREA2 study [26].

Infections from different sources may also affect the timing of initiating enteral nutrition in septic patients. For instance, patients with gastrointestinal infections or intestinal perforation may experience gastrointestinal dysfunction and impaired absorption capacity, thereby affecting the commencement of enteral feeding [35, 36]. In contrast, other types of infections such as pulmonary or tissue infections may have less impact on the initiation of enteral nutrition [37]. As our research analysis found in the subsets of blood culture-positive and urine culture-positive groups, early enteral nutrition was associated with increased 28-day mortality(Additional Fig. 5). Patients with bloodstream or urinary tract infections in sepsis may be more prone to eliciting stronger immune responses and systemic inflammatory reactions early on, thereby impairing gastrointestinal function and increasing their mortality rates [38]. Hence, when determining the initiation of enteral nutrition in septic patients, consideration needs to be given to the type of infection and its impact on gastrointestinal function.

This study has several limitations. First, it relied on electronic medical records, which inherently contain missing data and outliers, addressed through multiple imputation methods. The limited number of culture-positive patients in the subgroup analysis may have introduced selection bias. A major limitation is the lack of information on caloric doses during the first few days of ICU admission, which may affect the interpretation of the association between early enteral nutrition and mortality, as early caloric intake is crucial to outcomes. Studies by Prof. Daren Heyland’s group and the FRANS study emphasize this point, highlighting that the absence of caloric dose data in our study limits our conclusions about EEN and mortality. Additionally, propensity score matching was used to balance baseline characteristics, but this may have impacted the sample size. Despite various statistical methods, residual confounding factors, such as total caloric intake, interruptions in enteral nutrition, and baseline nutritional assessments, were not accounted for and may have influenced outcomes. Finally, as a single-centre, retrospective study, the findings may not be generalizable, necessitating further validation in other settings.

Conclusion

By conducting a retrospective analysis of the MIMIC-IV 2.2 database, our study revealed that early enteral nutrition (EEN) appears to be associated with a statistically significant increase in 28-day mortality among septic patients requiring invasive mechanical ventilation. This association was particularly notable in the subgroup of septic shock patients and critically ill young female patients receiving invasive mechanical ventilation; however, these findings should be interpreted as hypothesis-generating. In light of these observations, randomized controlled trials are needed to comprehensively assess and compare the efficacy of early enteral nutrition and delayed enteral nutrition in patients diagnosed with sepsis who are also receiving invasive mechanical ventilation.

Data availability

https://physionet.org/content/mimiciv/2.2/

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Acknowledgements

We sincerely thank all study group members for their collaboration and motivation during the period. We acknowledge the MIMIC IV 2.2 database for providing a valuable platform and data.

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Authors and Affiliations

  1. Department of Emergency Medicine, Drum Tower Hospital, Nanjing Medical University, Nanjing, 210008, China

    Fuchao Xu, Geng Lu, Hao Sun & Jun Wang

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  1. Fuchao Xu
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  2. Geng Lu
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  3. Hao Sun
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  4. Jun Wang
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Contributions

F.X. and G.L. contributed equally to this work. F.X. conceived the study and drafted the manuscript. G.L. carried out data verification, cleaning, and management. F.X. and G.L. conducted the acquisition and statistical analysis of data. J.W. and H.S. delivered a critical manuscript revision with improvements to the important intellectual content. J.W. and H.S. contributed equally to this work. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hao Sun or Jun Wang.

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Ethics approval and consent to participate

The Massachusetts Institute of Technology Institutional Review Board approves the MIMIC IV database. All the database patients are de-identified for privacy protection and the Nanjing Drum Tower Hospital Ethics Committee waives informed consent. The study followed the principles of the Declaration of Helsinki.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Xu, F., Lu, G., Sun, H. et al. Association between early enteral nutrition and 28-Day mortality in mechanically ventilated patients with sepsis: a retrospective analysis of the MIMIC-IV database. BMC Infect Dis 25, 628 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12879-025-10912-8

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12879-025-10912-8

Keywords

BMC Infectious Diseases

ISSN: 1471-2334

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