Effect of early parenteral nutrition versus enteral nutrition alone on all-cause mortality in critically ill adults: A systematic review and meta-analysis

Effect of early parenteral nutrition versus enteral nutrition alone on all-cause mortality in critically ill adults: A systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of early parenteral nutrition versus enteral nutrition alone on all-cause mortality in critically ill adults: A systematic review and meta-analysis Yixuan Cai, Airan Liu, Jiaotong Bao, Xinyi Yin, Xi Yang, Wenya Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5646241/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background For nutritional support in critically ill patients, the early initiation of enteral nutrition (EN) in the presence of gastrointestinal function has been agreed upon by most scholars. However, EN support alone cannot fully meet the needs of the body in some cases, so considering supplemental parenteral nutrition (SPN) become the solution to meet patients’ energy target. However, there is no consensus on whom and when parenteral nutrition should be considered in critically ill patients as a total form of nutrition. So, we aimed to compare and evaluate the effect of early PN on the outcome and their safety in critically ill adults. Methods Randomized controlled trials (RCTs) were retrieved from PubMed, Embase, Cochrane Library, and Web of Science (up to March 2024). Adults with critical illness treated with total parenteral nutrition (TPN) or SPN versus EN alone were enrolled. We screened studies and extracted data independently. The primary outcome was all-cause mortality which was evaluated by pooled risk ratio (RR) with the fixed-effects model. The risk of bias was evaluated using Cochrane risk bias of tool and a meta-analysis was conducted using RevMan 5.4 software. This study was prospectively registered in PROSPERO database (CRD42023462386). Results Twenty RCTs enrolling 11303 patients were eligible. No significant disparities were observed in 30-day all-cause mortality (relative risk [RR] 0.96, 95% confidence interval [CI] 0.90–1.03, P = 0.29), hospital mortality (RR 0.96, 95% CI 0.90–1.02, P = 0.17), or 90-day mortality (RR 0.95, 95% CI 0.86–1.04, P = 0.26) between the PN (TPN or SPN) and enteral nutrition (EN) alone groups. However, the use of PN in conjunction with EN was associated with a reduced ICU mortality rate compared to EN alone (RR 0.92, 95% CI 0.86–0.99, P = 0.03). PN therapy was linked to a modest elevation in the risk of infection (RR 1.12, 95% CI 1.05–1.21, P = 0.002), predominantly due to bloodstream infections (RR 1.24, 95% CI 1.08–1.51, P = 0.005). Additionally, PN was associated with a significant reduction in the duration of mechanical ventilation (standardized mean difference [SMD] = -1.47, 95% CI -2.72 to -0.23, P = 0.02) and a decreased incidence of gastrointestinal intolerance events (RR 0.85, 95% CI 0.77–0.94, P = 0.002). Conclusion Administration of PN can reduce ICU mortality, duration of mechanical ventilation and gastrointestinal intolerance events, although it increases total infection especially bloodstream infection rate among critically ill patients. More studies are warranted to confirm these findings. Parenteral nutrition Enteral nutrition Intensive care unit Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 1. Introduction Patients with critical illnesses may suffer from a severe caloric insufficiency and exhaustion of energy reserves. It may lead to reduced lean body mass and increased infectious complications.[ 1 , 2 ] Therefore, as the guideline indicated that every critically ill patient staying for more than 48 h in the ICU should be considered at a risk for malnutrition.[ 3 ] Nutritional therapy is an indispensable part of the treatment of critically ill patients, which can improve the nutritional status and prognosis of patients. In critically ill patients, the early initiation of enteral nutrition (EN) when gastrointestinal function is preserved is widely accepted by scholars[ 3 ]. However, there are situations that EN alone may not sufficiently address energy and protein deficits, or where patients may have contraindications to oral and enteral feeding, thereby necessitating the use of parenteral nutrition (PN) to meet the body's nutritional requirements. Research suggests that the prudent application of supplemental parenteral nutrition (SPN) can fulfill the energy and protein needs of critically ill patients, enhance protein synthesis, improve nitrogen balance, and bolster nutritional status, ultimately reducing complications and improving outcomes[ 4 ]. However, the benefit of PN administration in early stage of critical illness remains controversial[ 5 ]. Current guidelines advocate a conservative approach to PN. The European Society for Clinical Nutrition and Metabolism (ESPEN) recommended that PN should not be initiated until all reasonable strategies to enhance EN tolerance have been explored[ 3 ]. Conversely, delaying PN in patients with gastrointestinal dysfunction who cannot be sufficiently nourished via enteral means may lead to postponed nutrient intake, potentially worsening malnutrition and adversely affecting prognosis.[ 6 , 7 ] The primary objective of this meta-analysis is to investigate the impact of early parenteral nutrition (PN) on outcomes and safety of critical ill patients, and to provide a reference for early nutritional strategies in critically ill patients. 2. Methods We followed the Cochrane Handbook for Systematic Reviews of Intervention in addition to the PRISMA guidelines [ 18 , 19 ]. The protocol for this systematic review and meta-analysis was registered in PROSPERO (CRD42023462386). 2.1 Search strategy and selection criteria We use "supplemental parenteral nutrition", "parenteral nutrition", "enteral nutrition" and "critically ill" as search terms for PubMed, Web of Science, Embase, Cochrane Library. The detailed search strategy is outlined in the Additional file 1. Databases were searched from January 2000 to March 2024. Studies were identified according to the preliminary systematic review process for CONCISE[ 8 ]. Reference lists were manually searched to screen for eligible studies and relevant review articles. After exclusion of duplicates and screening of titles and abstracts according to the eligibility criteria, full-texts of the remaining articles were assessed. 2.2 Inclusion and exclusion criteria The inclusion criteria were as follows: (1) study type: published randomized controlled trials (RCTs); (2) study subjects: adult patients admitted for medical, surgical, or trauma diagnoses, and who stayed in the ICU; (3) intervention: the experimental group was given PN support; (4) controls: control group was given EN support alone; and (5) outcome: the primary outcome was all-cause mortality. The exclusion criteria were as follows: (1) duplicate publications; (2) single-arm studies; (3)pediatric studies; and (4) case reports, animal studies, meeting reports, and reviews. Eligibility for inclusion, if there is still a dispute, all the disagreements were resolved through discussion with a third reviewer (AL). Full texts were assessed by both authors against the predetermined inclusion and exclusion criteria. Data extraction was completed by two authors (YC, BT) independently using standardized extraction forms. Data extraction included publication details, patient characteristics, details of measurement setting. Authors were contacted for missing demographic data. 2.3 Assessment of risk of bias The first author (YC) and the third author (AL) of this article independently apply the risk bias assessment tool of Cochrane Handbook for Systematic Reviews of Interventions[ 9 ], cross-check, and resolve the opinions. If there is still a dispute, the second author will decide. The evaluation criteria include: (1) whether the method of generating random sequences is correct. (2) Whether the allocation concealment is done. (3) Whether to participants and implementers. (4) Whether the blind method is used during the outcome measurement process. (5) Whether the data is complete. (6) Whether all the outcome indicators are fully reported, and whether they are selectively reported. (7) Whether there are other risks of bias. For the paper included in the studies, "low risk", "high risk" and "unknown risk" were judged according to the above 7 criteria. Assessment of risk of bias with RevMan 5.4 software. 2.4 Statistical analysis Analysis was performed using the RevMan 5.4 statistical software. Data analysis was completed by three reviewers. The relative risk (RR) for dichotomous outcomes and standardized mean difference (SMD) for continuous outcomes were calculated with 95% CI. Heterogeneity was assessed by the I2 statistic and chi squared test. I 2 values of 25, 50, and 75% were considered as low, moderate, and high levels of heterogeneity, respectively. For outcomes with significant heterogeneity, the random-effects model was reported[ 10 ], for all the others, the fixed-effects model was reported[ 11 ]. The sensitivity analysis was used to evaluate the effect of removing any study on the overall effect size. Further subgroup analysis of the factors that may lead to heterogeneity, D-L random effect model was used to estimate the combined effect size. Funnel plot was applied to analyze publication bias. 3. Results 3.1 Study selection A total of 754 articles were identified by the described search strategy (Fig. 1). After removing duplicates, the titles and abstracts of 610 remaining articles were screened, 512 articles were excluded which left 98 references for assessment of full-text eligibility, twenty studies were included in quantitative analyses ultimately. 3.2 Basic characteristics of the study A total of 11303 patients were included in the 20 studies. The intervention group includes SPN and total parenteral nutrition (TPN), among which 12 studies are SPN, and 8 studies are TPN. The key characteristics of the 20 studies are shown in Table 1. 3.3 Assessment of bias The incorporated studies demonstrate a high general quality with low risk across selection bias, attrition bias, reporting bias, and other biases. However, a high risk of performance bias was found in eight studies. The ‘Risk of Bias’ assessments for each included study in graphs and figures is summarized in Figures 2 and 3. 3.3 Results of the meta-analysis 3.3.1 Primary outcome: all-cause mortality 15 studies reported all-cause mortality, with a total of 10887 patients. To ensure comparability of results, the 15 included studies were based on 30-day or 28-day mortality. Compared with the EN support group, PN support was associated with a comparable risk of all-cause mortality (RR 0.96, 95% CI 0.90-1.03, P=0.29, I 2 =0) (Fig.4). Heterogeneity test showed no significant heterogeneity (I 2 =0, P=0.63) and the funnel plot suggested no publication bias. Sensitivity analysis indicated that the removal of either study enrolled had no significant effect on the result. In order to explore the impact of nutritional therapy in the long term, we compared 90-day mortality. The results show that PN admission has no advantages over reducing the all-cause mortality (RR 0.95, 95% CI 0.86-1.04, P=0.26, I 2 =0) (Fig.5). No significant differences in the hospital mortality were found between the PN and EN alone groups. (RR 0.96, 95%CI 0.90-1.02, P =0.17, I 2 =0) (Fig.6) The ICU mortality events related to PN were lower than those related to EN only (RR 0.92, 95%CI 0.86-0.99, P= 0.03, I 2 =0) (Fig.7), that is, the risk of ICU mortality was reduced by 8% with PN as compared to EN alone. Heterogeneity test showed no significant heterogeneity (I 2 =0, P=0.63) and the funnel plot suggested no publication bias. 3.3.2 Secondary outcomes: mechanical ventilation duration The random-effects model meta-analysis showed that the duration of mechanical ventilation was significantly shorter in the PN group than in the EN group (SMD -1.47, 95%CI -2.72 to -0.23, P=0.02, I2=83%) (Fig. 8). 3.3.3 Length of ICU stay and hospitalization Length of ICU stay was included in 14 studies with significant interstudy heterogeneity (I 2 =86%, P <0.00001), the results of the random-effects model showed that the length of ICU stay was no statistical significance in the PN and EN groups (SMD 0.09, 95%CI -0.05 to 0.23, P=0.08, I 2 =86%) (Fig.9). However, in the subgroup of TPN and EN groups, the random-effects model meta-analysis showed that the EN group had a shorter length of ICU stay (SMD 0.29, 95%CI 0.01 to 0.57, P=0.04) while there was no difference between SPN and EN group (SMD =-0,01, 95%CI= -0.20 to 0.18, P=0.92). There was significant heterogeneity among the 12 studies including total length of hospital stay (I 2 =72%, P <0.00001), the results of the random-effects model meta-analysis showed that the total length of stay in the PN and EN groups was similar (SMD -0.04, 95%CI -0.16 to 0.09, P=0.55, I 2 =72%) (Fig.10). Duration of mechanical ventilation, length of ICU stay and length of hospital stay showed significant heterogeneity, with no significant change in the combined effect size after arbitrarily removing a single study, indicating that the overall stability of the pooled effect size of the included studies. 3.3.4 Infection rate The incidence of new infections was noted in 15 studies, exhibiting considerable heterogeneity. (I 2 =65%, P=0.0002), the results of random-effects model illustrated the new infection rate of PN group was higher than patients in EN group. (RR 1.12, 95% CI 1.05-1.21, P=0.002, I 2 =65%) (Fig.11). Bloodstream infection rate was included in 11 studies with no significant heterogeneity (I2=0%, P=0.48), the results of the fixed-effects model showed that the bloodstream infection rate of PN group was higher than patients in EN group. (RR 1.24,95%CI 1.08-1.51, P=0.005, I 2 =0%) (Fig.12). Respiratory system-related infection rate was included a total of 13 studies, with significant interstudy heterogeneity (I 2 =53%, P=0.01), random-effects model showed no significant difference in infection rate between PN and EN groups. (Fig.13 RR 0.92, 95%CI 0.76 to 1.11, P=0.39, I 2 =53%) (Fig.13). Therefore, we speculate that the source of infection is mainly from the bloodstream. 3.3.5 GI intolerance rate The incidence of GI intolerance events defined as nausea, vomiting, diarrhea, constipation, bowel ischemia and GRV (Gastric Residual Volume)>300ml in this meta-analysis was included in 8 studies. The results of random-effects model showed the GI intolerance events of EN group was higher than patients in PN group with significant heterogeneity (I2=65%, P<0.001). (RR 0.72, 95% CI=0.65-0.80, P<0.001, I2=65%) (Fig.14). 3.3.6 Energy intake To compare the energy intake between EN and PN Admission, we included 12 studies, with significant heterogeneity (I 2 =96%, P<0.00001). We estimate the heterogeneity mainly comes from the different energy unit between different studies. Results of random-effects model demonstrated the energy intake of PN group was much more than that of in EN group (RR 14.89, 95% CI 9.39-20.40, P<0.00001, I2=96%) (Fig.15). 3.3.7. Subgroup analysis We explored several pre-specified subgroups. In subgroup analysis, the pooled RRs for all-cause mortality in studies enrolling patients aged 60 years (OR = 0.95), with the lower APACHE II score (20) (OR = 0.98), or with optimized energy supplementation (OR = 0.94) in the early phase of acute illness were all similar to those in studies enrolling patients aged > 60 years (OR = 0.96), with the higher APACHE II score (>20) (OR = 0.97),or with limited energy supplementation(OR = 0.99) (Table 3.). The best timing to prescribe supplemental PN remains debated[3], so we divided the patients into three groups according to the PN initiating time. PN support was associated with a trend toward decreased rate of all-cause mortality in studies with later initiating time(48h) (OR = 0.61, 95%CI: 0.36–1.02, P = 0.058) though there were no statistically significant differences among all groups. (Table 3). According to ESPEN guideline the best timing and dose of protein administration was unknown, so we divided the patients into two groups according to the protein intake, the higher protein group(>1.2g/kg) patients may benefit more from SPN nutrition support (OR 0.86, 95% CI 0.57-1.31, P = 0.48). Our analysis found that the admission of PN could be used to increase energy delivery closer to the patient’s estimated energy requirement. To eliminate the high heterogeneity caused by different energy units, and explore the impact of energy differences on patients' mortality rate, we conducted subgroup analysis on the ratio of energy intake between the PN group and EN group. There were no statistically significant differences between two groups. 4. Discussion This meta-analysis indicates that the PN support in the early phase of critical illness does not confer an increase in all-cause mortality or hospital mortality when compared to EN alone. But a reduction in ICU mortality risk and mechanical ventilation duration were found to be associated with PN administration. Furthermore, the supplemental of PN enhanced protein and energy intake in critically ill adult patients, highlighting the utility of PN when enteral feeding is insufficient to meet the caloric demands of these patients. These findings illustrate the benefits of PN in situations where enteral feeding alone fails to fulfill the energy requirements of critically ill patients. The European Society for Parenteral and Enteral Nutrition (ESPEN) and the Chinese Expert Consensus on SPN concur that SPN should be employed to supply the additional energy and protein necessary to achieve the nutritional targets and mitigate the risk of malnutrition when EN alone is inadequate [ 3 ]. Additionally, appropriate SPN administration can decrease the initial volume of EN, thereby reducing the risk of gastrointestinal (GI) intolerances such as diarrhea and vomiting. However, the guidelines of the American Association for Parenteral and EN(ASPEN )[ 31 ]recommended not initiating SPN prior to day 7 of ICU admission based on findings of no clinically important benefit in providing SPN early in the ICU admission. Concerning this academic controversy, we have conducted a series of analysis. Previous studies have demonstrated that adverse effects of parenteral nutrition include increased risk of infection, liver dysfunction, metabolic complications (such as hyperglycemia, electrolyte imbalance), thrombosis, and compromised intestinal barrier function. [ 16 , 32 , 33 ]Not similar to previous studies [ 34 , 35 ], our meta-analysis of critically ill patients from 20 RCTs demonstrated that TPN increased the risk of infection, but in the SPN group, there was no statical significance. This interesting phenomenon indicated that EN should be the basic nutritional support to critical ill patients, this is in line with the latest ESPEN guideline. Berger et al. demonstrated that SPN can inhibit the secretion of inflammatory factors IL-6 and TNF-α, significantly improving the immune function of patients from the perspectives of metabolism and immunity[ 36 ]. To identify the primary source of infection, subgroup analyses were conducted on respiratory system-related infection rate and bloodstream-related infection rate. It was found that the rate of bloodstream infections in the PN group was higher than that in the EN group (Fig. 3 – 5 ), suggesting that clinical attention should be paid to the prevention of bloodstream infections like improving catheter care, glycemic control, and avoidance of overfeeding. Early initiation of parenteral nutrition increased caloric intake and mitigating feeding intolerance. The above results show (Fig. 14 ) that PN can greatly increase the energy intake of critical ill patients, to eliminate the high heterogeneity caused by different energy units and explore the impact of energy differences on patients' mortality rate, we conducted subgroup analyses on the ratio of energy intake between the PN group and EN group, there was no statistical difference between the two groups. Our meta-analysis also suggests that admission of PN may reduce the duration of invasive mechanical ventilation in critically ill patients. We hypothesize that the prolonged duration of mechanical ventilation among patients receiving exclusive EN can be attributed to three primary factors. Firstly, the EN alone group experienced a higher incidence of gastrointestinal intolerance. Critically ill patients frequently suffer from gastrointestinal dysfunction due to a multitude of factors, including postoperative ileus, gastric stasis, intestinal hypoperfusion, and the use of certain antibiotics and sedatives [ 37 ]. These multiple dysfunctions increase the risk of reflux and aspiration, consequently leading to an elevated incidence of pneumonia, which may delay weaning from mechanical ventilation [ 38 ]. Secondly, EN alone may be inadequate in providing the necessary caloric intake, thereby increasing the risk of malnutrition and sarcopenia—characterized by a loss of skeletal muscle mass—which is a prevalent issue among undernourished patients admitted to the ICU[ 39 ]. Studies have indicated low skeletal muscle quality at ICU admission is independently associated with higher 6-month mortality in mechanically ventilated patients, muscle quality as well as muscle quantity are prognostic factors in the ICU[ 40 ]. Lastly, SPN has been demonstrated to be more efficacious than EN alone in enhancing diaphragmatic thickness, boosting the success rate of mechanical ventilation weaning, and reducing hospitalization duration in patients with severe neurological conditions. Studies have shown that different timing of SPN initiation also affects prognosis[ 41 ]. There is no debate regarding the need for supplementing PN to EN in the case of prolonged nutritional deficit. However, the best timing to prescribe supplemental PN remains debated. Thus, we compared the impact of varying times of PN initiation on mortality rates. The results revealed no statistically significant differences among groups in the population with early PN initiation, the choice of time point needs to be adjusted according to the individual actual situation of patients to balance the nutritional risks and benefits. The best dose of protein admission in ICU is also a controversial topic. The adequate protein supply provides the body with calories and substrates for recovery. Feeding suppresses autophagy, yet the preservation of autophagy is of great importance. Expert Marik[ 42 ] suggested a brief period of starvation and that be avoidance of “forced mandatory feeding”. Medium doses (not low and not high) are associated with the best outcomes[ 43 ]. The ESPEN guideline recommended that 1.3 g/kg protein equivalents per day can be delivered progressively[ 3 ]. In our subgroup analyses, we define group > 1.2g/kg as the high-dose protein group and group ≤ 1.2g/kg as the low-dose protein group, and there was no significant difference in all-cause mortality between the two groups. There is a need for well-conducted RCTs to answer the question of the optimal dose of protein administration in the ICU. 5. Strengths The important strengths of this meta-analysis are as follows. First, to better thoroughly evaluate the impact of parenteral nutrition on clinical outcomes, this study included a total of 20 studies encompassing the clinical outcomes of TPN and SPN, with a substantial number of subgroup analysis, thus providing a more comprehensive assessment than previous research. Second, we include the most recent relevant literature and exclude studies before 2000, this makes it more closely related to nutrition support strategies in recent years. Third, according to the controversial hotspots of the nutritional guidelines, we explored several pre-specified subgroups to identify the target beneficiary population. 6. Limitations Several limitations warrant consideration in this meta-analysis. Firstly, there was clinical heterogeneity among the trials included. Secondly, the majority of studies employed a single energy requirement prediction formula, such as 25–30 kcal/kg/day, to estimate patient energy needs, which may not specifically or accurately capture the metabolic requirements of individual patients. In several of the studies, patients in the enteral nutrition (EN) group failed to achieve 60% of their target energy intake, while those in the parenteral nutrition (PN) group may have been overfed, introducing confounding factors into our analysis. Thirdly, the studies included may be compromised by methodological quality issues, including inadequate randomization, small sample sizes, and selective reporting of outcomes. 7. Conclusion In conclusion, the results of this study showed that early admission of PN does not reduce long-term overall mortality, but it can decrease the duration of mechanical ventilation and ICU mortality. Concurrently, PN admission increase the incidence of infections, predominantly bloodstream infections, which is more pronounced in the total parenteral nutrition (TPN) group. This meta-analysis suggests that Early PN in critical illness is not as detrimental as previously imagined. Compared with feeding route, the feeding dosage may be a more important determining factor that needs to be taken into consideration. We need to comprehensively use enteral and parenteral nutrition to meet energy requirements while avoiding overfeeding. The initiation of parenteral nutrition should be determined on an individual basis, taking into account the specific clinical characteristics and metabolic needs of each patient. The therapeutic effect of SPN needs to be confirmed by high-quality clinical studies with larger sample size and long-term follow-up. Declarations Acknowledgements We don´t have acknowledgments. Author contributions Protocol development: Yixuan Cai，Airan Liu. Electronic searches: Yixuan Cai. Selection and data extraction: all authors. Data analysis: Yixuan Cai. Drafting manuscript: Yixuan Cai. Substantial edits: All authors. Approval of final version: All authors. Funding This work was supported by the General Program of National Natural Science Foundation of China (No.82072154), Jiangsu Province natural science Foundation project (No. BK20242100). Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate Does not apply. Consent for publication Does not apply. 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Studenski, S.A., et al., The FNIH Sarcopenia Project: Rationale, Study Description, Conference Recommendations, and Final Estimates. The Journals of Gerontology: Series A, 2014. 69 (5): p. 547-558. Looijaard, W.G.P.M., et al., Skeletal muscle quality as assessed by CT-derived skeletal muscle density is associated with 6-month mortality in mechanically ventilated critically ill patients. Critical Care, 2016. 20 (1). Sena, M.J., et al., Early Supplemental Parenteral Nutrition Is Associated with Increased Infectious Complications in Critically Ill Trauma Patients. Journal of the American College of Surgeons, 2008. 207 (4): p. 459-467. Marik, P.E., Is early starvation beneficial for the critically ill patient? Curr Opin Clin Nutr Metab Care, 2016. 19 (2): p. 155-60. Lin, J., et al., Trajectories of protein intake and 28-day mortality in critically ill patients: A secondary analysis of a cluster-randomized controlled trial. Clinical Nutrition, 2022. 41 (8): p. 1644-1650. Tables Tables 1 and 3 are available in the Supplementary Files section Table 2 is not available with this version Additional Declarations No competing interests reported. Supplementary Files Tables.docx Searchdetails.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5646241","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":392563181,"identity":"63d95fac-6da8-41b7-bf8c-f795db0bf621","order_by":0,"name":"Yixuan Cai","email":"","orcid":"","institution":"Southeast University","correspondingAuthor":false,"prefix":"","firstName":"Yixuan","middleName":"","lastName":"Cai","suffix":""},{"id":392563182,"identity":"9dc4c078-1606-4732-9636-7233a0ddd17d","order_by":1,"name":"Airan Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuElEQVRIiWNgGAWjYDACZhBRIMHAz8x88AEJWgwkGCTb2ZINSLAKqNbgPI+ZAFGK+dt5H34uMLBI3HyYwYyBocYmmqAWicPsxtIzDCQStx1mSHvAcCwtt4GgnsNsDNI8EC3HDRgbDhPWIn+Yjfk3SMvmZsY2CaK0GBxmYwPbsoGZmY04LYZALdZALcYzgNYZJBDjF7nzx5hv81TUyfb3n//44EONDRHeRwEJpCkfBaNgFIyCUYALAAAD4jTgp60iugAAAABJRU5ErkJggg==","orcid":"","institution":"Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing","correspondingAuthor":true,"prefix":"","firstName":"Airan","middleName":"","lastName":"Liu","suffix":""},{"id":392563183,"identity":"f4568443-bf98-41ec-9174-b932feede66c","order_by":2,"name":"Jiaotong Bao","email":"","orcid":"","institution":"Southeast 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about each risk of bias item presented as\u003c/p\u003e\n\u003cp\u003epercentages across all included studies.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/cd94cd9da3f2bbc79e1e1572.png"},{"id":72283824,"identity":"1064c603-9d41-44db-bbfd-41e742902410","added_by":"auto","created_at":"2024-12-24 16:45:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":107942,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias summary: review authors' judgements about each risk of bias item for each included study.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/58d1bf55c2402904ca0eda3d.png"},{"id":72283826,"identity":"65f7bb71-039d-45fa-b3eb-1b94895835a0","added_by":"auto","created_at":"2024-12-24 16:45:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":90048,"visible":true,"origin":"","legend":"\u003cp\u003e30-day all-cause mortality\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/9721ef819206f2a3f98cb841.png"},{"id":72283830,"identity":"62bbea23-166c-48ed-bd19-615ec8c45d61","added_by":"auto","created_at":"2024-12-24 16:45:01","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":76072,"visible":true,"origin":"","legend":"\u003cp\u003e90-day all-cause mortality\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/f528b96070140e0be2626b01.png"},{"id":72286242,"identity":"b6ca5970-3b51-4c93-a034-1247249f8383","added_by":"auto","created_at":"2024-12-24 17:01:02","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":37335,"visible":true,"origin":"","legend":"\u003cp\u003eHospital mortality\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/aa9abaeec528add0c276c333.png"},{"id":72283838,"identity":"16cb8f2d-1326-4456-a2d2-5d16ad9ba1a0","added_by":"auto","created_at":"2024-12-24 16:45:01","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":43155,"visible":true,"origin":"","legend":"\u003cp\u003eICU mortality\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/38b59573591d7c643aabb963.png"},{"id":72283842,"identity":"a3a64282-f56d-4fc0-a2b9-5bae9e0cbf96","added_by":"auto","created_at":"2024-12-24 16:45:01","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":124497,"visible":true,"origin":"","legend":"\u003cp\u003eMechanical ventilation duration\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/a2f59d3648d8d0c5e6291a80.png"},{"id":72283837,"identity":"698ce37c-730e-4027-b195-4298614465b5","added_by":"auto","created_at":"2024-12-24 16:45:01","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":81043,"visible":true,"origin":"","legend":"\u003cp\u003eLength of ICU stay\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/65b1ef6e735cb203850bdf13.png"},{"id":72285172,"identity":"94f3f89b-91a9-46de-8544-e1732c4b1556","added_by":"auto","created_at":"2024-12-24 16:53:01","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":54783,"visible":true,"origin":"","legend":"\u003cp\u003eTotal length of hospital stay\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/36bc4f31b5de899255e6d1f8.png"},{"id":72283860,"identity":"8e6444de-74fa-4b18-acbe-2fdb0bf0e100","added_by":"auto","created_at":"2024-12-24 16:45:02","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":90134,"visible":true,"origin":"","legend":"\u003cp\u003eNew infection rate\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/b861e193caed75a585b9513e.png"},{"id":72283856,"identity":"da93f8f6-30a9-4ccc-a898-7deae197b2e0","added_by":"auto","created_at":"2024-12-24 16:45:02","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":78701,"visible":true,"origin":"","legend":"\u003cp\u003eBloodstream infection rate\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/9997a91160292dcd562404ad.png"},{"id":72285171,"identity":"9cd544a1-8d3e-4f86-b1f6-3991bf87d479","added_by":"auto","created_at":"2024-12-24 16:53:01","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":85678,"visible":true,"origin":"","legend":"\u003cp\u003eRespiratory system-related infection rate\u003c/p\u003e","description":"","filename":"13.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/d414f1145d345794cc56201c.png"},{"id":72285180,"identity":"b8dfeaa3-14bd-4d63-a000-aebaf2a034a3","added_by":"auto","created_at":"2024-12-24 16:53:02","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":44458,"visible":true,"origin":"","legend":"\u003cp\u003eGI intolerance rate\u003c/p\u003e","description":"","filename":"14.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/cb84f29848c9adfa09a2bd1a.png"},{"id":72283858,"identity":"389f09f1-a711-4b96-8324-753d9f90b94d","added_by":"auto","created_at":"2024-12-24 16:45:02","extension":"png","order_by":15,"title":"Figure 15","display":"","copyAsset":false,"role":"figure","size":127540,"visible":true,"origin":"","legend":"\u003cp\u003eEnergy intake\u003c/p\u003e","description":"","filename":"15.png","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/6b4f28046fe032bb842ac359.png"},{"id":72316251,"identity":"02e1ff7e-62fd-4c5c-bf0c-967997eca35d","added_by":"auto","created_at":"2024-12-25 08:01:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1309612,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/079b1dcb-77da-4cb6-8f88-38be31c5a597.pdf"},{"id":72283840,"identity":"ed8b1708-9ea4-4206-8525-cc870f6d42c2","added_by":"auto","created_at":"2024-12-24 16:45:01","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":62983,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/b21e9d27f6f02916e4c2d544.docx"},{"id":72283827,"identity":"530dc10c-cd62-4c94-b4bf-5e00493711c6","added_by":"auto","created_at":"2024-12-24 16:45:01","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12412,"visible":true,"origin":"","legend":"","description":"","filename":"Searchdetails.docx","url":"https://assets-eu.researchsquare.com/files/rs-5646241/v1/923cc50177ae1d29399156ce.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of early parenteral nutrition versus enteral nutrition alone on all-cause mortality in critically ill adults: A systematic review and meta-analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePatients with critical illnesses may suffer from a severe caloric insufficiency and exhaustion of energy reserves. It may lead to reduced lean body mass and increased infectious complications.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Therefore, as the guideline indicated that every critically ill patient staying for more than 48 h in the ICU should be considered at a risk for malnutrition.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Nutritional therapy is an indispensable part of the treatment of critically ill patients, which can improve the nutritional status and prognosis of patients.\u003c/p\u003e \u003cp\u003eIn critically ill patients, the early initiation of enteral nutrition (EN) when gastrointestinal function is preserved is widely accepted by scholars[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, there are situations that EN alone may not sufficiently address energy and protein deficits, or where patients may have contraindications to oral and enteral feeding, thereby necessitating the use of parenteral nutrition (PN) to meet the body's nutritional requirements. Research suggests that the prudent application of supplemental parenteral nutrition (SPN) can fulfill the energy and protein needs of critically ill patients, enhance protein synthesis, improve nitrogen balance, and bolster nutritional status, ultimately reducing complications and improving outcomes[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, the benefit of PN administration in early stage of critical illness remains controversial[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Current guidelines advocate a conservative approach to PN. The European Society for Clinical Nutrition and Metabolism (ESPEN) recommended that PN should not be initiated until all reasonable strategies to enhance EN tolerance have been explored[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Conversely, delaying PN in patients with gastrointestinal dysfunction who cannot be sufficiently nourished via enteral means may lead to postponed nutrient intake, potentially worsening malnutrition and adversely affecting prognosis.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe primary objective of this meta-analysis is to investigate the impact of early parenteral nutrition (PN) on outcomes and safety of critical ill patients, and to provide a reference for early nutritional strategies in critically ill patients.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eWe followed the Cochrane Handbook for Systematic Reviews of Intervention in addition to the PRISMA guidelines [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The protocol for this systematic review and meta-analysis was registered in PROSPERO (CRD42023462386).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search strategy and selection criteria\u003c/h2\u003e \u003cp\u003eWe use \"supplemental parenteral nutrition\", \"parenteral nutrition\", \"enteral nutrition\" and \"critically ill\" as search terms for PubMed, Web of Science, Embase, Cochrane Library. The detailed search strategy is outlined in the Additional file 1. Databases were searched from January 2000 to March 2024. Studies were identified according to the preliminary systematic review process for CONCISE[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Reference lists were manually searched to screen for eligible studies and relevant review articles. After exclusion of duplicates and screening of titles and abstracts according to the eligibility criteria, full-texts of the remaining articles were assessed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Inclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eThe inclusion criteria were as follows: (1) study type: published randomized controlled trials (RCTs); (2) study subjects: adult patients admitted for medical, surgical, or trauma diagnoses, and who stayed in the ICU; (3) intervention: the experimental group was given PN support; (4) controls: control group was given EN support alone; and (5) outcome: the primary outcome was all-cause mortality. The exclusion criteria were as follows: (1) duplicate publications; (2) single-arm studies; (3)pediatric studies; and (4) case reports, animal studies, meeting reports, and reviews.\u003c/p\u003e \u003cp\u003eEligibility for inclusion, if there is still a dispute, all the disagreements were resolved through discussion with a third reviewer (AL). Full texts were assessed by both authors against the predetermined inclusion and exclusion criteria. Data extraction was completed by two authors (YC, BT) independently using standardized extraction forms. Data extraction included publication details, patient characteristics, details of measurement setting. Authors were contacted for missing demographic data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Assessment of risk of bias\u003c/h2\u003e \u003cp\u003eThe first author (YC) and the third author (AL) of this article independently apply the risk bias assessment tool of Cochrane Handbook for Systematic Reviews of Interventions[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], cross-check, and resolve the opinions. If there is still a dispute, the second author will decide. The evaluation criteria include: (1) whether the method of generating random sequences is correct. (2) Whether the allocation concealment is done. (3) Whether to participants and implementers. (4) Whether the blind method is used during the outcome measurement process. (5) Whether the data is complete. (6) Whether all the outcome indicators are fully reported, and whether they are selectively reported. (7) Whether there are other risks of bias. For the paper included in the studies, \"low risk\", \"high risk\" and \"unknown risk\" were judged according to the above 7 criteria. Assessment of risk of bias with RevMan 5.4 software.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eAnalysis was performed using the RevMan 5.4 statistical software. Data analysis was completed by three reviewers. The relative risk (RR) for dichotomous outcomes and standardized mean difference (SMD) for continuous outcomes were calculated with 95% CI. Heterogeneity was assessed by the I2 statistic and chi squared test. I\u003csup\u003e2\u003c/sup\u003e values of 25, 50, and 75% were considered as low, moderate, and high levels of heterogeneity, respectively. For outcomes with significant heterogeneity, the random-effects model was reported[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], for all the others, the fixed-effects model was reported[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The sensitivity analysis was used to evaluate the effect of removing any study on the overall effect size. Further subgroup analysis of the factors that may lead to heterogeneity, D-L random effect model was used to estimate the combined effect size. Funnel plot was applied to analyze publication bias.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e3.1 Study selection\u003c/p\u003e\n\u003cp\u003eA total of 754 articles were identified by the described search strategy (Fig. 1). After removing duplicates, the titles and abstracts of 610 remaining articles were screened, 512 articles were excluded which left 98 references for assessment of full-text eligibility, twenty studies were included in quantitative analyses ultimately.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.2 Basic characteristics of the study\u003c/p\u003e\n\u003cp\u003eA total of 11303 patients were included in the 20 studies. The intervention group includes SPN and total parenteral nutrition (TPN), among which 12 studies are SPN, and 8 studies are TPN. The key characteristics of the 20 studies are shown in Table 1.\u003c/p\u003e\n\u003cp\u003e3.3 Assessment of bias\u003c/p\u003e\n\u003cp\u003eThe incorporated studies demonstrate a high general quality with low risk across selection bias, attrition bias, reporting bias, and other biases. However, a high risk of performance bias was found in eight studies. The \u0026lsquo;Risk of Bias\u0026rsquo; assessments for each included study in graphs and figures is summarized in Figures 2 and 3.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.3 Results of the meta-analysis\u003c/p\u003e\n\u003cp\u003e3.3.1 Primary outcome: all-cause mortality\u003c/p\u003e\n\u003cp\u003e15 studies\u0026nbsp;reported\u0026nbsp;all-cause mortality, with a total of 10887 patients. To ensure comparability of results, the 15 included studies were based on 30-day or 28-day mortality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompared with the EN support group, PN support was associated with a comparable risk of all-cause mortality (RR 0.96, 95% CI 0.90-1.03, P=0.29, I\u003csup\u003e2\u003c/sup\u003e=0) (Fig.4). Heterogeneity test showed no significant heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=0, P=0.63) and the funnel plot suggested no publication bias. Sensitivity analysis indicated that the removal of either study enrolled had no significant effect on the result. In order to explore the impact of nutritional therapy in the long term, we compared\u0026nbsp;90-day mortality. The results show that PN admission has no advantages over reducing the all-cause mortality (RR 0.95, 95% CI 0.86-1.04, P=0.26, I\u003csup\u003e2\u003c/sup\u003e=0)\u0026nbsp;(Fig.5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo significant differences in the hospital mortality were found between the PN and EN alone groups. (RR 0.96, 95%CI 0.90-1.02, P =0.17, I\u003csup\u003e2\u003c/sup\u003e=0) (Fig.6)\u0026nbsp;The ICU mortality events related to PN were lower than those related to EN only (RR 0.92, 95%CI\u0026nbsp;0.86-0.99, P= 0.03, I\u003csup\u003e2\u003c/sup\u003e=0)\u0026nbsp;(Fig.7),\u0026nbsp;that is, the risk of ICU mortality was reduced by 8% with PN as compared to EN alone. Heterogeneity test showed no significant heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=0, P=0.63) and the funnel plot suggested no publication bias.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.3.2 Secondary outcomes: mechanical ventilation duration\u003c/p\u003e\n\u003cp\u003eThe random-effects model meta-analysis showed that the duration of mechanical ventilation was significantly shorter in the PN group than in the EN group (SMD -1.47, 95%CI -2.72 to -0.23, P=0.02, I2=83%) (Fig. 8).\u003c/p\u003e\n\u003cp\u003e3.3.3 Length of ICU stay and hospitalization\u003c/p\u003e\n\u003cp\u003eLength of ICU stay was included in 14 studies with significant interstudy heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=86%, P \u0026lt;0.00001), the results of the random-effects model showed that the length of ICU stay was no statistical significance in the PN and EN groups (SMD 0.09, 95%CI -0.05 to 0.23, P=0.08, I\u003csup\u003e2\u003c/sup\u003e=86%) (Fig.9). However, in the subgroup of TPN and EN groups, the random-effects model meta-analysis showed that the EN group had a shorter length of ICU stay (SMD 0.29, 95%CI 0.01 to 0.57, P=0.04) while there was no difference between SPN and EN group (SMD =-0,01, 95%CI= -0.20 to 0.18, P=0.92).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere was significant heterogeneity among the 12 studies including total length of hospital stay (I\u003csup\u003e2\u003c/sup\u003e=72%, P \u0026lt;0.00001), the results of the random-effects model meta-analysis showed that the total length of stay in the PN and EN groups was similar (SMD -0.04, 95%CI -0.16 to 0.09, P=0.55, I\u003csup\u003e2\u003c/sup\u003e=72%) (Fig.10).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Duration of mechanical ventilation, length of ICU stay and length of hospital stay showed significant heterogeneity, with no significant change in the combined effect size after arbitrarily removing a single study, indicating that the overall stability of the pooled effect size of the included studies. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.3.4 Infection rate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe incidence of new infections was noted in 15 studies, exhibiting considerable heterogeneity. (I\u003csup\u003e2\u003c/sup\u003e=65%, P=0.0002), the results of random-effects model illustrated the new infection rate of PN group was higher than patients in EN group. (RR 1.12, 95% CI 1.05-1.21, P=0.002, I\u003csup\u003e2\u003c/sup\u003e=65%) (Fig.11). Bloodstream infection rate was included in 11 studies with no significant heterogeneity (I2=0%, P=0.48), the results of the fixed-effects model showed that the bloodstream infection rate of PN group was higher than patients in EN group.\u0026nbsp;(RR 1.24,95%CI 1.08-1.51, P=0.005,\u0026nbsp;I\u003csup\u003e2\u003c/sup\u003e=0%) (Fig.12). Respiratory system-related infection rate was included a total of 13 studies, with significant interstudy heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=53%, P=0.01), random-effects model showed no significant difference in infection rate between PN and EN groups. (Fig.13 RR 0.92, 95%CI 0.76 to 1.11, P=0.39, I\u003csup\u003e2\u003c/sup\u003e=53%) (Fig.13). Therefore, we speculate that the source of infection is mainly from the bloodstream.\u003c/p\u003e\n\u003cp\u003e3.3.5 GI intolerance rate\u003c/p\u003e\n\u003cp\u003eThe incidence of GI intolerance events defined as nausea, vomiting, diarrhea, constipation, bowel ischemia and GRV (Gastric Residual Volume)\u0026gt;300ml in this meta-analysis was included in 8 studies. The results of random-effects model showed the GI intolerance events of EN group was higher than patients in PN group with significant heterogeneity (I2=65%, P\u0026lt;0.001). (RR 0.72, 95% CI=0.65-0.80, P\u0026lt;0.001, I2=65%) (Fig.14).\u003c/p\u003e\n\u003cp\u003e3.3.6 Energy intake\u003c/p\u003e\n\u003cp\u003eTo compare the energy intake between EN and PN Admission, we included 12 studies, with significant heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=96%, P\u0026lt;0.00001). We estimate the heterogeneity mainly comes from the different energy unit between different studies. Results of random-effects model demonstrated the energy intake of PN group was much more than that of in EN group (RR 14.89, 95% CI 9.39-20.40, P\u0026lt;0.00001, I2=96%) (Fig.15).\u003c/p\u003e\n\u003cp\u003e3.3.7. Subgroup analysis\u003c/p\u003e\n\u003cp\u003eWe explored several pre-specified subgroups. In subgroup analysis, the pooled RRs for all-cause mortality in studies enrolling patients aged 60 years (OR = 0.95), with the lower APACHE II score (20) (OR = 0.98), or with optimized energy supplementation (OR = 0.94) in the early phase of acute illness were all similar to those in studies enrolling patients aged \u0026gt; 60 years (OR = 0.96), with the higher APACHE II score (\u0026gt;20) (OR = 0.97),or with limited energy supplementation(OR = 0.99) (Table 3.). The best timing to prescribe supplemental PN remains debated[3], so we divided the patients into three groups according to the PN initiating time. PN support was associated with a trend toward decreased rate of all-cause mortality in studies with later initiating time(48h) (OR = 0.61, 95%CI: 0.36\u0026ndash;1.02, P = 0.058) though there were no statistically significant differences among all groups. (Table 3). According to ESPEN guideline the best timing and dose of protein administration was unknown, so we divided the patients into two groups according to the protein intake, the higher protein group(\u0026gt;1.2g/kg) patients may benefit more from SPN nutrition support (OR 0.86, 95% CI 0.57-1.31, P = 0.48). Our analysis found that the admission of PN could be used to increase energy delivery closer to the patient\u0026rsquo;s estimated energy requirement. To eliminate the high heterogeneity caused by different energy units, and explore the impact of energy differences on patients\u0026apos; mortality rate, we conducted subgroup analysis on the ratio of energy intake between the PN group and EN group. There were no statistically significant differences between two groups.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis meta-analysis indicates that the PN support in the early phase of critical illness does not confer an increase in all-cause mortality or hospital mortality when compared to EN alone. But a reduction in ICU mortality risk and mechanical ventilation duration were found to be associated with PN administration. Furthermore, the supplemental of PN enhanced protein and energy intake in critically ill adult patients, highlighting the utility of PN when enteral feeding is insufficient to meet the caloric demands of these patients.\u003c/p\u003e \u003cp\u003eThese findings illustrate the benefits of PN in situations where enteral feeding alone fails to fulfill the energy requirements of critically ill patients. The European Society for Parenteral and Enteral Nutrition (ESPEN) and the Chinese Expert Consensus on SPN concur that SPN should be employed to supply the additional energy and protein necessary to achieve the nutritional targets and mitigate the risk of malnutrition when EN alone is inadequate [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Additionally, appropriate SPN administration can decrease the initial volume of EN, thereby reducing the risk of gastrointestinal (GI) intolerances such as diarrhea and vomiting. However, the guidelines of the American Association for Parenteral and EN(ASPEN )[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]recommended not initiating SPN prior to day 7 of ICU admission based on findings of no clinically important benefit in providing SPN early in the ICU admission. Concerning this academic controversy, we have conducted a series of analysis.\u003c/p\u003e \u003cp\u003ePrevious studies have demonstrated that adverse effects of parenteral nutrition include increased risk of infection, liver dysfunction, metabolic complications (such as hyperglycemia, electrolyte imbalance), thrombosis, and compromised intestinal barrier function. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]Not similar to previous studies [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], our meta-analysis of critically ill patients from 20 RCTs demonstrated that TPN increased the risk of infection, but in the SPN group, there was no statical significance. This interesting phenomenon indicated that EN should be the basic nutritional support to critical ill patients, this is in line with the latest ESPEN guideline. Berger et al. demonstrated that SPN can inhibit the secretion of inflammatory factors IL-6 and TNF-α, significantly improving the immune function of patients from the perspectives of metabolism and immunity[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. To identify the primary source of infection, subgroup analyses were conducted on respiratory system-related infection rate and bloodstream-related infection rate. It was found that the rate of bloodstream infections in the PN group was higher than that in the EN group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), suggesting that clinical attention should be paid to the prevention of bloodstream infections like improving catheter care, glycemic control, and avoidance of overfeeding.\u003c/p\u003e \u003cp\u003eEarly initiation of parenteral nutrition increased caloric intake and mitigating feeding intolerance. The above results show (Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e14\u003c/span\u003e) that PN can greatly increase the energy intake of critical ill patients, to eliminate the high heterogeneity caused by different energy units and explore the impact of energy differences on patients' mortality rate, we conducted subgroup analyses on the ratio of energy intake between the PN group and EN group, there was no statistical difference between the two groups. Our meta-analysis also suggests that admission of PN may reduce the duration of invasive mechanical ventilation in critically ill patients. We hypothesize that the prolonged duration of mechanical ventilation among patients receiving exclusive EN can be attributed to three primary factors. Firstly, the EN alone group experienced a higher incidence of gastrointestinal intolerance. Critically ill patients frequently suffer from gastrointestinal dysfunction due to a multitude of factors, including postoperative ileus, gastric stasis, intestinal hypoperfusion, and the use of certain antibiotics and sedatives [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. These multiple dysfunctions increase the risk of reflux and aspiration, consequently leading to an elevated incidence of pneumonia, which may delay weaning from mechanical ventilation [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Secondly, EN alone may be inadequate in providing the necessary caloric intake, thereby increasing the risk of malnutrition and sarcopenia\u0026mdash;characterized by a loss of skeletal muscle mass\u0026mdash;which is a prevalent issue among undernourished patients admitted to the ICU[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Studies have indicated low skeletal muscle quality at ICU admission is independently associated with higher 6-month mortality in mechanically ventilated patients, muscle quality as well as muscle quantity are prognostic factors in the ICU[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Lastly, SPN has been demonstrated to be more efficacious than EN alone in enhancing diaphragmatic thickness, boosting the success rate of mechanical ventilation weaning, and reducing hospitalization duration in patients with severe neurological conditions.\u003c/p\u003e \u003cp\u003eStudies have shown that different timing of SPN initiation also affects prognosis[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. There is no debate regarding the need for supplementing PN to EN in the case of prolonged nutritional deficit. However, the best timing to prescribe supplemental PN remains debated. Thus, we compared the impact of varying times of PN initiation on mortality rates. The results revealed no statistically significant differences among groups in the population with early PN initiation, the choice of time point needs to be adjusted according to the individual actual situation of patients to balance the nutritional risks and benefits. The best dose of protein admission in ICU is also a controversial topic. The adequate protein supply provides the body with calories and substrates for recovery. Feeding suppresses autophagy, yet the preservation of autophagy is of great importance. Expert Marik[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] suggested a brief period of starvation and that be avoidance of \u0026ldquo;forced mandatory feeding\u0026rdquo;. Medium doses (not low and not high) are associated with the best outcomes[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. The ESPEN guideline recommended that 1.3 g/kg protein equivalents per day can be delivered progressively[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In our subgroup analyses, we define group\u0026thinsp;\u0026gt;\u0026thinsp;1.2g/kg as the high-dose protein group and group\u0026thinsp;\u0026le;\u0026thinsp;1.2g/kg as the low-dose protein group, and there was no significant difference in all-cause mortality between the two groups. There is a need for well-conducted RCTs to answer the question of the optimal dose of protein administration in the ICU.\u003c/p\u003e"},{"header":"5. Strengths","content":"\u003cp\u003eThe important strengths of this meta-analysis are as follows. First, to better thoroughly evaluate the impact of parenteral nutrition on clinical outcomes, this study included a total of 20 studies encompassing the clinical outcomes of TPN and SPN, with a substantial number of subgroup analysis, thus providing a more comprehensive assessment than previous research. Second, we include the most recent relevant literature and exclude studies before 2000, this makes it more closely related to nutrition support strategies in recent years. Third, according to the controversial hotspots of the nutritional guidelines, we explored several pre-specified subgroups to identify the target beneficiary population.\u003c/p\u003e"},{"header":"6. Limitations","content":"\u003cp\u003eSeveral limitations warrant consideration in this meta-analysis. Firstly, there was clinical heterogeneity among the trials included. Secondly, the majority of studies employed a single energy requirement prediction formula, such as 25\u0026ndash;30 kcal/kg/day, to estimate patient energy needs, which may not specifically or accurately capture the metabolic requirements of individual patients. In several of the studies, patients in the enteral nutrition (EN) group failed to achieve 60% of their target energy intake, while those in the parenteral nutrition (PN) group may have been overfed, introducing confounding factors into our analysis. Thirdly, the studies included may be compromised by methodological quality issues, including inadequate randomization, small sample sizes, and selective reporting of outcomes.\u003c/p\u003e"},{"header":"7. Conclusion","content":"\u003cp\u003eIn conclusion, the results of this study showed that early admission of PN does not reduce long-term overall mortality, but it can decrease the duration of mechanical ventilation and ICU mortality. Concurrently, PN admission increase the incidence of infections, predominantly bloodstream infections, which is more pronounced in the total parenteral nutrition (TPN) group.\u003c/p\u003e\n\u003cp\u003eThis meta-analysis suggests that Early PN in critical illness is not as detrimental as previously imagined. Compared with feeding route, the feeding dosage may be a more important determining factor that needs to be taken into consideration. We need to comprehensively use enteral and parenteral nutrition to meet energy requirements while avoiding overfeeding. The initiation of parenteral nutrition should be determined on an individual basis, taking into account the specific clinical characteristics and metabolic needs of each patient. The therapeutic effect of SPN needs to be confirmed by high-quality clinical studies with larger sample size and long-term follow-up.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe don\u0026acute;t have acknowledgments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProtocol development: Yixuan Cai，Airan Liu. Electronic searches:\u0026nbsp;Yixuan Cai. Selection and data extraction: all authors. Data analysis:\u0026nbsp;Yixuan Cai. Drafting manuscript:\u0026nbsp;Yixuan Cai. Substantial edits: All authors. Approval of final version: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the General Program of National Natural Science Foundation of China (No.82072154), Jiangsu Province natural science Foundation project (No. BK20242100).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDoes not apply. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDoes not apply.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they do not have competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eSoutheast University, Nanjing, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eJiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, People\u0026apos;s Republic of China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDvir, D., J. 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1120-1124.\u003c/li\u003e\n\u003cli\u003eHeidegger, C.P., et al., \u003cem\u003eOptimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial.\u003c/em\u003e Lancet, 2013. \u003cstrong\u003e381\u003c/strong\u003e(9864): p. 385-93.\u003c/li\u003e\n\u003cli\u003eDoig, G.S., et al., \u003cem\u003eEarly Parenteral Nutrition in Critically Ill Patients With Short-term Relative Contraindications to Early Enteral Nutrition A Randomized Controlled Trial.\u003c/em\u003e JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2013. \u003cstrong\u003e309\u003c/strong\u003e(20): p. 2130-2138.\u003c/li\u003e\n\u003cli\u003eHarvey, S.E., et al., \u003cem\u003eTrial of the Route of Early Nutritional Support in Critically Ill Adults.\u003c/em\u003e NEW ENGLAND JOURNAL OF MEDICINE, 2014. \u003cstrong\u003e371\u003c/strong\u003e(18): p. 1673-1684.\u003c/li\u003e\n\u003cli\u003eFan, M., et al., \u003cem\u003eEarly Enteral Combined with 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Helmy, \u003cem\u003eA comparative Study between Tube Feeding versus Parenteral Nutrition in GIT Cancer Patients in ICU.\u003c/em\u003e QJM, 2021. \u003cstrong\u003e114\u003c/strong\u003e(SUPPL 1).\u003c/li\u003e\n\u003cli\u003eCompher, C., et al., \u003cem\u003eGuidelines for the provision of nutrition support therapy in the adult critically ill patient: The American Society for Parenteral and Enteral Nutrition.\u003c/em\u003e Journal of Parenteral and Enteral Nutrition, 2022. \u003cstrong\u003e46\u003c/strong\u003e(1): p. 12-41.\u003c/li\u003e\n\u003cli\u003eReignier, J., et al., \u003cem\u003eLow versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).\u003c/em\u003e Lancet Respir Med, 2023. \u003cstrong\u003e11\u003c/strong\u003e(7): p. 602-612.\u003c/li\u003e\n\u003cli\u003eCao, L., et al., \u003cem\u003eEfficacy and safety of different insulin infusion methods in the 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patients: The SPN2 randomized tracer study.\u003c/em\u003e Clinical Nutrition, 2019. \u003cstrong\u003e38\u003c/strong\u003e(5): p. 2408-2416.\u003c/li\u003e\n\u003cli\u003eTatsumi, H., \u003cem\u003eEnteral tolerance in critically ill patients.\u003c/em\u003e J Intensive Care, 2019. \u003cstrong\u003e7\u003c/strong\u003e: p. 30.\u003c/li\u003e\n\u003cli\u003eLi, J., et al., \u003cem\u003eDifferent definitions of feeding intolerance and their associations with outcomes of critically ill adults receiving enteral nutrition: a systematic review and meta-analysis.\u003c/em\u003e Journal of Intensive Care, 2023. \u003cstrong\u003e11\u003c/strong\u003e(1): p. 29.\u003c/li\u003e\n\u003cli\u003eStudenski, S.A., et al., \u003cem\u003eThe FNIH Sarcopenia Project: Rationale, Study Description, Conference Recommendations, and Final Estimates.\u003c/em\u003e The Journals of Gerontology: Series A, 2014. \u003cstrong\u003e69\u003c/strong\u003e(5): p. 547-558.\u003c/li\u003e\n\u003cli\u003eLooijaard, W.G.P.M., et al., \u003cem\u003eSkeletal muscle quality as assessed by CT-derived skeletal muscle density is associated with 6-month mortality in mechanically ventilated critically ill patients.\u003c/em\u003e Critical Care, 2016. \u003cstrong\u003e20\u003c/strong\u003e(1).\u003c/li\u003e\n\u003cli\u003eSena, M.J., et al., \u003cem\u003eEarly Supplemental Parenteral Nutrition Is Associated with Increased Infectious Complications in Critically Ill Trauma Patients.\u003c/em\u003e Journal of the American College of Surgeons, 2008. \u003cstrong\u003e207\u003c/strong\u003e(4): p. 459-467.\u003c/li\u003e\n\u003cli\u003eMarik, P.E., \u003cem\u003eIs early starvation beneficial for the critically ill patient?\u003c/em\u003e Curr Opin Clin Nutr Metab Care, 2016. \u003cstrong\u003e19\u003c/strong\u003e(2): p. 155-60.\u003c/li\u003e\n\u003cli\u003eLin, J., et al., \u003cem\u003eTrajectories of protein intake and 28-day mortality in critically ill patients: A secondary analysis of a cluster-randomized controlled trial.\u003c/em\u003e Clinical Nutrition, 2022. \u003cstrong\u003e41\u003c/strong\u003e(8): p. 1644-1650.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 3 are available in the Supplementary Files section\u003c/p\u003e\n\u003cp\u003eTable 2 is not available with this version\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parenteral nutrition, Enteral nutrition, Intensive care unit, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-5646241/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5646241/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFor nutritional support in critically ill patients, the early initiation of enteral nutrition (EN) in the presence of gastrointestinal function has been agreed upon by most scholars. However, EN support alone cannot fully meet the needs of the body in some cases, so considering supplemental parenteral nutrition (SPN) become the solution to meet patients\u0026rsquo; energy target. However, there is no consensus on whom and when parenteral nutrition should be considered in critically ill patients as a total form of nutrition. So, we aimed to compare and evaluate the effect of early PN on the outcome and their safety in critically ill adults.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eRandomized controlled trials (RCTs) were retrieved from PubMed, Embase, Cochrane Library, and Web of Science (up to March 2024). Adults with critical illness treated with total parenteral nutrition (TPN) or SPN versus EN alone were enrolled. We screened studies and extracted data independently. The primary outcome was all-cause mortality which was evaluated by pooled risk ratio (RR) with the fixed-effects model. The risk of bias was evaluated using Cochrane risk bias of tool and a meta-analysis was conducted using RevMan 5.4 software. This study was prospectively registered in PROSPERO database (CRD42023462386).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTwenty RCTs enrolling 11303 patients were eligible. No significant disparities were observed in 30-day all-cause mortality (relative risk [RR] 0.96, 95% confidence interval [CI] 0.90\u0026ndash;1.03, P\u0026thinsp;=\u0026thinsp;0.29), hospital mortality (RR 0.96, 95% CI 0.90\u0026ndash;1.02, P\u0026thinsp;=\u0026thinsp;0.17), or 90-day mortality (RR 0.95, 95% CI 0.86\u0026ndash;1.04, P\u0026thinsp;=\u0026thinsp;0.26) between the PN (TPN or SPN) and enteral nutrition (EN) alone groups. However, the use of PN in conjunction with EN was associated with a reduced ICU mortality rate compared to EN alone (RR 0.92, 95% CI 0.86\u0026ndash;0.99, P\u0026thinsp;=\u0026thinsp;0.03). PN therapy was linked to a modest elevation in the risk of infection (RR 1.12, 95% CI 1.05\u0026ndash;1.21, P\u0026thinsp;=\u0026thinsp;0.002), predominantly due to bloodstream infections (RR 1.24, 95% CI 1.08\u0026ndash;1.51, P\u0026thinsp;=\u0026thinsp;0.005). Additionally, PN was associated with a significant reduction in the duration of mechanical ventilation (standardized mean difference [SMD] = -1.47, 95% CI -2.72 to -0.23, P\u0026thinsp;=\u0026thinsp;0.02) and a decreased incidence of gastrointestinal intolerance events (RR 0.85, 95% CI 0.77\u0026ndash;0.94, P\u0026thinsp;=\u0026thinsp;0.002).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAdministration of PN can reduce ICU mortality, duration of mechanical ventilation and gastrointestinal intolerance events, although it increases total infection especially bloodstream infection rate among critically ill patients. More studies are warranted to confirm these findings.\u003c/p\u003e","manuscriptTitle":"Effect of early parenteral nutrition versus enteral nutrition alone on all-cause mortality in critically ill adults: A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-24 16:44:56","doi":"10.21203/rs.3.rs-5646241/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9071be9a-2ace-4f85-868c-198901ccac42","owner":[],"postedDate":"December 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-25T07:53:42+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-24 16:44:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5646241","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5646241","identity":"rs-5646241","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}