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. 2023 Mar 23;18(3):e0283593. doi: 10.1371/journal.pone.0283593

Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients

Young Kyun Choi 1, Hyun-Jung Kim 2, Joonghyun Ahn 3, Jeong-Am Ryu 1,4,*
Editor: Raphael Cinotti5
PMCID: PMC10035931  PMID: 36952527

Abstract

Early proper nutritional support is important to critically ill patients. Nutritional support is also associated with clinical outcomes of neurocritically ill patients. We investigate whether early nutrition is associated with clinical outcomes in neurocritically ill patients. This was a retrospective, single-center, observational study including neurosurgical patients who were admitted to the intensive care unit (ICU) from January 2013 to December 2019. Patients who started enteral nutrition or parenteral nutrition within 72 hours after ICU admission were defined as the early nutrition group. The primary endpoint was in-hospital mortality. The secondary endpoint was an infectious complication. Propensity score matching (PSM) and propensity score weighting overlap weights (PSOW) were used to control selection bias and confounding factors. Among 1,353 patients, early nutrition was performed in 384 (28.4%) patients: 152 (11.2%) early enteral nutrition (EEN) and 232 (17.1%) early parenteral nutrition (EPN). In the overall study population, the rate of in-hospital mortality was higher in patients with late nutrition than in those with early nutrition (P<0.001). However, there was no significant difference in in-hospital mortality and infectious complications incidence between the late and the early nutrition groups in the PSM and PSOW adjusted population (all P>0.05). In the overall study population, EEN patients had a low rate of in-hospital mortality and infectious complications compared with those with EPN and late nutrition (P<0.001 and P = 0.001, respectively). In the multivariable analysis of the overall, PSM adjusted, and PSOW adjusted population, there was no significant association between early nutrition and in-hospital mortality and infectious complications (all P>0.05), but EEN was significantly associated with in-hospital mortality and infectious complications (all P<0.05). Eventually, early enteral nutrition may reduce the risk of in-hospital mortality and infectious complications in neurocritically ill patients.

Introduction

Nutrition support plays an important role in the management of critically ill patients [1–3]. Malnutrition is associated with poor clinical outcomes such as higher rates of mortality (32% vs. 14%, P = 0.018) [4], nosocomial infection (23.4% vs. 3.5%, P<0.001) [5], and long stay in intensive care unit (ICU) [4, 6]. Similarly, in critically ill patients with stroke or traumatic brain injury, nutritional support is associated with neurological prognosis and mortality [7–9]. In stroke patients, the mortality rate of malnourished patients was 37%, which was significantly higher than that of patients with normal nutrition which was 21% (P<0.001) [9]. In traumatic brain injury, it was reported that the rate of infection was reduced in early nutrition compared to delayed nutrition (risk ratio: 0.77, P = 0.04) [8]. Patients with brain injury commonly suffer from hypermetabolic reactions that can lead to increased energy and protein expenditure. Therefore, early nutrition may help to improve neurological prognosis [10, 11].

However, it is not easy to focus on nutrition in the early stage of neurocritical illness. Moreover, nutrition support is often underestimated and considered a lower priority than maintaining cerebral perfusion pressure and other medical problems in neurocritical ill patients [8, 12]. In addition, the optimal feeding timing, route, and formula in these patients are still unclear [8, 13]. Therefore, the objective of this study was to investigate whether early nutrition was associated with clinical outcomes in patients who were admitted to the neurosurgical intensive care unit (ICU) and to determine the optimal feeding timing, route, and formula. The early nutrition group was split into early enteral nutrition (EEN) and early parenteral nutrition (EPN) groups and the effects of EEN were investigated. In addition, we evaluated whether early nutrition per se was associated with poor prognosis when severity and factors other than nutritional support were controlled by propensity score matching (PSM) and propensity score weighting overlap weights (PSOW).

Materials and methods

Study population

This was a retrospective, single-center, observational study. Patients who were admitted to the neurosurgical ICU at the Samsung Medical Center, Seoul, Republic of Korea, tertiary referral hospital from January 2013 to December 2019 were eligible. This study was approved by the Institutional Review Board (IRB) of the Samsung Medical Center (IRB approval number: SMC 2020-09-082). Patients’ records were reviewed and published according to the Declaration of Helsinki. The requirement of informed consent was waived by the IRB due to its retrospective nature. We included patients who were hospitalized in the neurosurgical ICU for more than 5 days due to neurocritical illness or neurosurgical postoperative management. We excluded patients who had insufficient medical records, who had a ‘do not resuscitation’ order, who were admitted to departments other than neurosurgery, and who were transferred to other hospitals or with unknown prognoses (Fig 1).

Fig 1. Study flow chart.

Fig 1

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ICU, intensive care unit; EEN, early enteral nutrition; EPN, early parenteral nutrition.

Definitions and endpoints

In this study, baseline characteristics such as comorbidities, behavioral risk factors, ICU management, and laboratory data were collected retrospectively using a Clinical Data Warehouse. Our center constructed a “Clinical Data Warehouse Darwin-C” designed for searching and retrieving de-identified medical records from electronic archives. It contains data for more than four million patients.

Patients who started enteral nutrition or parenteral nutrition within 72 hours after ICU admission were defined as the early nutrition group [8, 10] which was further divided into EEN and EPN groups. Infectious complications were defined as nosocomial infections such as pneumonia, central nervous system infection, bloodstream infection, urinary tract infection, and sepsis [8, 10]. The primary endpoint was in-hospital mortality while the secondary endpoint was an infectious complication.

Statistical analyses

All data are presented as means ± standard deviations for continuous variables or frequencies and proportions for categorical variables. Data were compared using Student’s t-test and one-way analysis of variance for continuous variables and Chi-square test or Fisher’s exact test for categorical variables. In this study, patients with EEN were relatively few compared to those with late nutrition. In addition, the severity scores of patients differed for each nutritional group. Therefore, we used several analysis methods to control various biases arising from these differences. PSM and PSOW were used to control for selection bias and confounding factors [14]. In PSM analysis, each patient with early nutrition or EEN was matched to one control patient with the nearest neighbor matching within calipers determined by the propensity score. A caliper width of 0.2 of the standard deviation of the logit of the propensity score was used for the matching [15]. We compared the balance of baseline covariates between nutrition groups by calculating the standardized mean difference (SMD) [16]. If PSM and PSOW methods were effective for balancing exposure groups, the SMD should be close to zero [17]. Therefore, SMDs of less than 10% were used for proper balancing between the two groups. To evaluate whether there were differences in in-hospital mortality and infectious complications according to nutrition patterns, we performed multiple logistic regression with stepwise variable selection in the overall, PSM, and PSOW population. In the overall population, we tried to obtain results after correcting confounding through regression adjustment. In addition, we performed a doubly robust estimation to additionally correct the bias that might still exist after PSM and PSOW. Variables included in the multiple analyses were age, sex, comorbidities, cause of ICU admission, utilization of organ support modalities (including mechanical ventilators, continuous renal replacement therapy, and vasopressors, intracranial pressure (ICP) monitoring devices, and hyperosmolar therapy), Glasgow Coma Scale (GCS) and Acute Physiology and Chronic Health Evaluation (APACHE) II score on ICU admission, and/or early nutrition, EEN, and EPN. Since there might be biases arising from substantial subject loss after PSM and biased weight due to the misspecified PSOW model in this study, it was necessary to verify the robustness of the results of all the analysis methods. All the tests were two-sided and p values of less than 0.05 were considered statistically significant. All statistical analyses were performed with R Statistical Software version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline characteristics

A total of 12,743 patients were admitted to the neurosurgical ICU during the study period and 1,353 patients were included in the final analysis. In the overall study population, early nutrition was performed in 384 (28.4%) patients (Fig 1); EEN in 152 (11.2%) patients and EPN in 232 (17.1%) patients. The mean age of all the patients was 50.5 ± 23.2 years. There were 707 (52.3%) male patients. Malignancy (55.3%) and hypertension (34.5%) were the most common comorbidities. Brain tumors (37.5%) and intracerebral hemorrhage (17.4%) were the most common reasons for ICU admission (Table 1).

Table 1. Baseline characteristics according to the timing of nutrition.

Overall study population
Late nutrition (n = 969) Early nutrition (n = 384) P value SMD
Patient demographics
    Age (year) 50.1 ± 23.7 51.66 ± 22.1 0.267 0.068
    Sex, male 512 (52.8) 195 (50.8) 0.534 0.041
Comorbidities
    Malignancy 528 (54.5) 220 (57.3) 0.382 0.056
    Hypertension 332 (34.3) 135 (35.2) 0.804 0.019
    Diabetes mellitus 131 (13.5) 58 (15.1) 0.502 0.045
    Chronic kidney disease 64 (6.6) 32 (8.3) 0.318 0.066
    Cardiovascular disease 42 (4.3) 10 (2.6) 0.182 0.095
    Chronic liver disease 30 (3.1) 16 (4.2) 0.416 0.057
Behavioral risk factors
    Current alcohol consumption 199 (20.5) 86 (22.4) 0.495 0.045
    Current smoking 98 (10.1) 52 (13.5) 0.086 0.106
Cause of ICU admission 0.002 0.295
    Brain tumor 351 (36.2) 157 (40.9)
    Intracerebral hemorrhage 179 (18.5) 56 (14.6)
    Traumatic brain injury 152 (15.7) 39 (10.2)
    Subarachnoid hemorrhage 122 (12.6) 50 (13.0)
    Elective vascular surgery 72 (7.4) 37 (9.6)
    Cerebral infarction 22 (2.3) 11 (2.9)
    Spinal surgery 17 (1.8) 12 (3.1)
    Central nervous system infection 12 (1.2) 13 (3.4)
    Others 42 (4.3) 9 (2.3)
APACHE II score on ICU admission 8.3 ± 7.7 6.13 ± 5.5 <0.001 0.326
Glasgow coma scale on ICU admission 11.8 ± 4.4 13.7 ± 2.5 <0.001 0.549
ICU management
    Mechanical ventilation 652 (67.3) 207 (53.9) <0.001 0.276
    Continuous renal replacement therapy 39 (4.0) 10 (2.6) 0.272 0.079
    ICP monitoring 407 (42.0) 182 (47.4) 0.081 0.109
    Use of mannitol* 406 (41.9) 167 (43.5) 0.636 0.032
    Use of glycerin* 391 (40.4) 151 (39.3) 0.775 0.021
    Use of vasopressors 160 (16.5) 45 (11.7) 0.033 0.138
Clinical outcomes†
    In-hospital mortality 321 (33.1) 54 (14.1) <0.001
    28-day mortality 295 (30.4) 46 (12.0) <0.001
    ICU mortality 281 (29.0) 38 (9.9) <0.001
    ICU length of stay (hour) 292.1 ± 769.3 329.7 ± 989.9 0.457
    Hospital length of stay (day) 68.9 ± 253.3 78.2 ± 177.9 0.511
    Infectious complications 82 (8.5) 32 (8.3) 0.999
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Data are presented as numbers (%) or means ± standard deviations.

*Some patients received more than one hyperosmolar agent.

†Variables are not retained in the propensity score matching

SMD, standardized mean difference; APACHE II, Acute Physiology and Chronic Health Evaluation; ICP, intracranial pressure, ICU, intensive care unit; ICP, intracranial pressure.

Clinical outcomes

In-hospital mortality

In the overall study population, the rate of in-hospital mortality was higher in patients with late nutrition than in those with early nutrition (33.1% vs. 14.1%, P<0.001) (Table 1). Rates of in-hospital mortality were also different between EEN, EPN, and late nutritional groups (P<0.001) (Table 2). However, such difference might be due to differences in age, causes of ICU admission, and severity scores (all P<0.001) among these three nutritional groups (Table 2).

Table 2. Baseline characteristics of patients with late nutrition, early enteral and early parenteral feeding.
Overall study population
Non-EEN (n = 1201) EEN (n = 152) P value SMD
Late nutrition (n = 969) EPN (n = 232)
Patient demographics
    Age (year) 50.1 ± 23.7 56.7 ± 17.6 44.0 ± 25.7 <0.001 0.379
    Sex, male 512 (52.8) 120 (51.7) 75 (49.3) 0.714 0.047
Comorbidities
    Malignancy 528 (54.5) 122 (52.6) 98 (64.5) 0.047 0.162
    Hypertension 332 (34.3) 90 (38.8) 45 (29.6) 0.171 0.130
    Diabetes mellitus 131 (13.5) 44 (19.0) 14 (9.2) 0.020 0.189
    Chronic kidney disease 64 (6.6) 19 (8.2) 13 (8.6) 0.531 0.049
    Cardiovascular disease 42 (4.3) 6 (2.6) 4 (2.6) 0.328 0.064
    Chronic liver disease 30 (3.1) 8 (3.4) 8 (5.3) 0.390 0.072
Behavioral risk factors
    Current alcohol consumption 199 (20.5) 63 (27.2) 23 (15.1) 0.014 0.198
    Current smoking 98 (10.1) 39 (16.8) 13 (8.6) 0.008 0.167
Cause of ICU admission <0.001 0.490
    Brain tumor 351 (36.2) 85 (36.6) 72 (47.4)
    Intracerebral hemorrhage 179 (18.5) 42 (18.1) 14 (9.2)
    Traumatic brain injury 152 (15.7) 34 (14.7) 5 (3.3)
    Subarachnoid hemorrhage 122 (12.6) 28 (12.1) 22 (14.5)
    Elective vascular surgery 72 (7.4) 14 (6.0) 23 (15.1)
    Cerebral infarction 22 (2.3) 9 (3.9) 2 (1.3)
    Spinal surgery 17 (1.8) 8 (3.4) 4 (2.6)
    Central nervous system infection 12 (1.2) 6 (2.6) 7 (4.6)
    Others 42 (4.3) 6 (2.6) 3 (2.0)
APACHE II score on ICU admission 8.3 ± 7.7 6.4 ± 6.1 5.8 ± 4.4 <0.001 0.264
Glasgow coma scale on ICU admission 11.8 ± 4.4 13.2 ± 2.9 14.5 ± 1.3 <0.001 0.604
ICU management
    Mechanical ventilation 652 (67.3) 155 (66.8) 52 (34.2) <0.001 0.467
    Continuous renal replacement therapy 39 (4.0) 9 (3.9) 1 (0.7) 0.115 0.150
    ICP monitoring 407 (42.0) 105 (45.3) 77 (50.7) 0.114 0.116
    Use of mannitol* 406 (41.9) 93 (40.1) 74 (48.7) 0.216 0.116
    Use of glycerin* 391 (40.4) 119 (51.3) 32 (21.1) <0.001 0.437
    Use of vasopressors 160 (16.5) 29 (12.5) 16 (10.5) 0.075 0.117
Clinical outcomes†
    In-hospital mortality 321 (33.1) 45 (19.4) 9 (5.9) <0.001
    28-day mortality 295 (30.4) 38 (16.4) 8 (5.3) <0.001
    ICU mortality 281 (29.0) 33 (14.2) 5 (3.3) <0.001
    ICU length of stay (hour) 292.1 ± 769.3 298.1 ± 265.6 377.8 ± 1540.6 0.501
    Hospital length of stay (day) 68.9 ± 253.3 67.0 ± 81.9 95.2 ± 263.7 0.415
    Infectious complications 82 (8.5) 29 (12.5) 3 (2.0) 0.001
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Data are presented as numbers (%) or means ± standard deviations.

Data show a comparison between late nutrition, EPN, and EEN.

*Some patients received more than one hyperosmolar agent.

†Variables are not retained in the propensity score matching.

EEN, early enteral nutrition; EPN, early parenteral nutrition; SMD, standardized mean difference; APACHE II, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; ICP, intracranial pressure.

SMDs of covariates were used for propensity score modeling before and after PSM and PSOW adjustments. After adjustment, most covariates showed SMDs within the 10% cutoff (Fig 2). Unlike the overall study population, there were no significant differences in the rates of in-hospital mortality between the late nutrition group and the early nutrition group of the PSM and PSOW adjusted population (P = 0.234 and P = 0.094, respectively) (S1 Table). In multivariable analyses of the overall, PSM adjusted, and PSOW adjusted population, early nutrition was not significantly associated with in-hospital mortality (all P>0.05), but EEN was significantly associated with in-hospital mortality (all P<0.05) (Fig 3A) (S2 Table).

Fig 2.

Fig 2

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Standardized mean differences (SMDs) between nutrition groups (early nutrition vs. late nutrition [A] and early enteral nutrition [EEN] vs. non-EEN [B]) according to propensity score matching (PSM) and propensity score weighting overlap weights (PSOW). The balance of baseline covariates between nutrition groups were compared by calculating the SMD. If PSM and PSOW methods were effective for balancing the exposure groups, the SMD should be less than 10% as proper balancing between the two groups. After adjustment, most covariates showed SMDs within the 10% cutoff. GCS, Glasgow Coma Scale; APACHE II, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; ICP, intracranial pressure; CRRT, continuous renal replacement therapy.

Fig 3.

Fig 3

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In multivariable analyses of the overall population, propensity score matching (PSM) adjusted population, and propensity score weighting overlap weights (PSOW) population, early nutrition was not significantly associated with in-hospital mortality, but EEN was significantly associated with in-hospital mortality (A). In addition, early nutrition was not significantly associated with infectious complications, but EEN was significantly associated with infectious complications (B). Non-EEN means only late nutrition without EPN. nu., nutrition; OR, odds ratio; CI, confidence interval; EEN, early enteral nutrition; EPN, early parenteral nutrition.

Infectious complications

There was no significant difference in infectious complications between the late nutrition group and the early nutrition group in the overall study population and the PSM and PSOW adjusted population (all P>0.05) (Table 1 and S1 Table). However, rates of infectious complications were different between EEN, EPN, and the late nutritional groups (P = 0.001) (Table 2 and S2 Table). In multivariable analyses of the overall, PSM adjusted, and PSOW adjusted population, early nutrition was not significantly associated with infectious complications (all P>0.05), but EEN was significantly associated with infectious complications (all P<0.05) (Fig 3B).

Discussion

In this study, we investigated whether early nutrition was associated with clinical outcomes in patients admitted to neurosurgical ICU. The major findings of this study were as follows. First, early nutrition was performed in approximately one-third of neurocritically ill patients, and two-fifth of early nutrition was administered as EEN. Second, early nutrition, including EEN showed an association with clinical outcomes of neurocritically ill patients in univariable analysis. However, the numbers of patients with EEN and EPN were small and severity levels were different between the nutrition groups. Finally, in the overall, PSM adjusted, and PSOW adjusted population, multivariable analyses revealed that early nutrition was not significantly associated with in-hospital mortality and infectious complications, but EEN was significantly associated with in-hospital mortality and infectious complications.

In the early stages of neurocritically ill patients, appropriate nutritional support is important due to hypermetabolic responses after brain injury [10, 11]. However, sympathetic hyperactivation arising from increased intracranial pressure can affect gastrointestinal function [18–20]. Moreover, early intragastric feeding can increase the risk of gastric residual volume, delayed gastric emptying, and aspiration pneumonia in neurocritically ill patients [12]. Although there has been a lot of debate about the optimal timing and the route of feeding [8, 13], a recent meta-analysis has shown that EPN is superior to EEN in reducing mortality and infectious complications and improving outcomes of patients with traumatic brain injury in the acute gut-intolerant phase [8]. However, in the present study, early nutrition did not affect clinical prognosis. Moreover, EEN, rather than EPN, was associated with decreased mortality and nosocomial infections. EPN may be associated with delayed recovery and more complications, as compared with late parenteral nutrition [21]. Therefore, combining the EEN group with the EPN group, or the late nutrition group with the EPN group might not be useful in evaluating the association between feeding options and clinical outcomes. EPN might affect the outcome as a confounding factor in this study.

EEN has several benefits in the treatment of critically ill patients [22–26]. First, gastrointestinal tract plays an important role in the immune responses [27]. However, the immune function of the gastrointestinal tract is disturbed in the early stage of critically ill patients [28]. In addition, pathogenic bacterial translocation of the gastrointestinal tract can stimulate systemic cytokine release and increase susceptibility to infections [27]. These changes can lead to multiple organ dysfunction and poor clinical outcomes [10, 27]. In the early stages of critically ill patients, enteral nutrition can maintain gastrointestinal integrity and prevent intestinal bacterial translocation [24, 29]. Second, EEN can enhance recovery in the early hypermetabolic stage of patients with multiple traumas including brain injury [26, 30, 31]. Third, enteral feeding is more physiologic, less invasive, and less expensive than total parenteral nutrition [32]. Therefore, EEN is associated with favorable outcomes in critically ill patients [32]. Recent studies have also shown that EEN can reduce rates of mortality and infectious complications in patients with intracranial hemorrhage and traumatic brain injury [26, 29, 30].

Nutritional support could be ignored in the early stages of patients with severely injured brains as the neurocritical or critical issues, including cerebral blood flow, hemodynamic instability, and lung injury, are more focused on than nutrition in these patients [8, 12]. Consequently, it is difficult to provide appropriate nutrition to critical patients in the early stage. Therefore, malnutrition can occur more easily in patients with severe neurological diseases than in those with benign diseases. It is not easy to determine whether late nutrition or inappropriate nutrition is associated with a poor prognosis since severe brain-injured patients generally have poor prognosis. Therefore, PSM and PSOW methods were used to adjust for this confounder in this study. Eventually, EEN was found to be significantly associated with favorable clinical outcomes in neurocritically ill patients.

Adequate calorie and protein intake is important for recovery in critically ill patients [33, 34]. Adequate nutritional support may also be important in neurocritically ill patients. The patients with severe traumatic brain injury have increased energy expenditure usually increase by 87%–200% above the usual requirement and may be elevated for 30 days due to metabolic changes [26, 35, 36]. In addition, systemic catabolic change could lead to hyperglycemia, protein wasting, and increased calorie demands [26, 35]. Therefore, optimized calorie and protein supply is also important for acute brain injury patients. However, energy expenditure, calorie and protein intake were not considered in this study. Accurate analysis of calorie and protein supply and energy expenditure may be necessary to investigate the relationship between early nutrition and clinical outcomes in neurocritically ill patients.

This study has several limitations. First, this was a retrospective review of medical records using data extracted from a Clinical Data Warehouse. The nonrandomized nature of registry data might have resulted in a selection bias. Second, the amount of EEN or EPN calorie intake for patients in the early stage was not considered in this study due to its retrospective nature. Third, nutritional support was performed occasionally through non-protocol methods for neurocritically ill patients. Finally, the distribution of neurosurgical diseases differed from that of the general neurosurgical ICU and the proportion of patients with brain tumors was particularly high.

Conclusions

In this study, EEN may reduce the risk of in-hospital mortality and infectious complications in neurocritically ill patients. In addition, timely and proper nutritional support may be important to improve clinical outcomes in neurocritically ill patients.

Supporting information

S1 Table. Baseline characteristics according to timing of nutrition in the overall, PSM and PSOW adjusted population.

(DOCX)

Click here for additional data file. (29.5KB, docx)
S2 Table. Baseline characteristics of patients with and without early enteral feeding in the overall, PSM and PSOW adjusted population.

(DOCX)

Click here for additional data file. (32.2KB, docx)

Acknowledgments

We would like to thank the nursing director of the neurosurgical intensive care unit, Suk Kyung Choo, for providing excellent advice and fruitful discussions. We would also like to thank all the nurses of the neurosurgical intensive care unit at the Samsung Medical Center for their support in the completion of this study.

Data Availability

Data Sharing Statement: Our data are available on Harvard Dataverse Network (http://dx.doi.org/10.7910/DVN/3F8WF1).

Funding Statement

Unfunded studies The authors received no specific funding for this work.

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Decision Letter 0

Rishabh Charan Choudhary

10 Jun 2022

PONE-D-21-39517Impact of early nutrition and feeding route on clinical outcomes of neurocrically ill patientsPLOS ONE

Dear Dr. Ryu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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Reviewer #1: Partly

Reviewer #2: Partly

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: Comments:

The authors have provided a very thorough analysis of a retrospective dataset and have added to the body of literature on this important subject. They have also taken into consideration the limitations of this type of study.

Concerns:

In Table 2, it is not clear what the p-values indicate. The legend should indicate what comparison is being evaluated. Is it the comparison between the EEN and the Non-EEN patients or the comparison between the EEN and the EPN patients or between the early nutrition and the late nutrition patients? Based on the title of the table, I would presume that it is the comparison between the EEN and the Non-EEN patients.

In general, the sample size for this study is rather small for the number of variables considered in the analysis. As the authors noted, the number of patients with EEN and with EPN were small and the severity of illness is notably different between these two groups and the late nutrition group of patients.

Other investigators have found that mortality was higher in critically ill children who received parenteral nutrition or that late parenteral nutrition was associated with better outcomes than early parenteral nutrition in critically ill children. Thus, combining the EEN and the EPN groups might not be beneficial. In fact, including the EPN group with the late nutrition group might not be beneficial, particularly for such a small number of patients.

Other factors which should be considered would be the amount of nutrition provided to patients with respect to caloric intake and protein intake. The timing of nutrition may not be as important as the quantity and the composition of the nutrition provided. However, even the timing may impact outcomes. Why did the investigators choose to define early nutrition to be any nutrition before 72 hours? Did they consider 48 hours or even 24 hours?

Finally, I believe the investigators provided the various methods of data analysis to demonstrate a thorough approach, which is impressive, but presenting all analyses is probably unnecessary. Which analytic method is the best for this type of study? Which method retains the most data and most appropriately fits this study design and addresses the concerns of selection bias and confounding by comorbidities, clinical diagnoses, and severity of illness. This should have been determined in advance.

I would recommend revising the analysis to compare the quantity and the composition of the nutrition provided and I would consider excluding those who received EPN from the comparison of EEN to non-EEN. I would also limit the different types of analyses to reflect the most appropriate use of the data.

Reviewer #2: Dear authors,

I congratulate you for this paper. The statistical analysis is robust; however, the manuscript will benefit from major changes before publication.

The authors used retrospective data to evaluate the impact of early nutritional therapy and mortality. Also they analyzed the route of nutritional therapy.

First, I suggest an english review of the manuscript - it is understandable, but difficult to read.

An example in the background:

"Nutritional support is also associated with neurological prognosis and mortality of neurocritically ill patients with stroke or traumatic brain injury [6-8]. Early nutrition is especially important because it can affect neurological prognosis."

Associated with increased risk of mortality or a reduction in mortality? can affect neurological prognosis in what way - good or bad? And this same kind of sentence is repeated throughout the manuscript.

I will comment each part of the manuscript separately.

Abstract:

Background - there is no background information, only the objective of the study. Please include a sentence that explains the current knowledge.

Methods - no study design (retrospective cohort…)

Conclusion - can be clearer - again english editing.

Background:

Better review of literature. Bring the hard data from previous study to support your argument (meaning mortality reduction in % (p=...) or no statistical difference in other study (p =...)). Make it clear what new information this study adds

Methods:

The methods and statistical analysis are clear

Result:

The results are confusing.

I suggest dividing the results into the outcomes: primary (mortality) and secondary (infections complications) and not according statistical analysis.

Also, table 2 - the p is for the comparasion between the 3 groups (late nutrition, EPN and EEN) or between (non-EEN and EEN). It is not clear.

5.Discussion:

The comparison between current literature and the study result has room to be improved, but mostly English editing will help a lot.

There was a lot a of EPN. Any reason why? It is not supported by any guidelines. This should be better addressed in the discussion.

Do you have data regarding calories and protein intake in each group? I imagine that those in the early group would have a lesser caloric and protein deficit

**********

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Reviewer #1: No

Reviewer #2: Yes: Marina Verçoza Viana

**********

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PLoS One. 2023 Mar 23;18(3):e0283593. doi: 10.1371/journal.pone.0283593.r002

Author response to Decision Letter 0

13 Jul 2022

July 11 2022

Dr. Rishabh Charan Choudhary

PLOS ONE

Manuscript ID: PONE-D-21-39517

Title: Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients

Dear Dr. Rishabh Charan Choudhary

Thank you very much for your letter and for the helpful comment from the reviewer. We appreciate the opportunity to resubmit our revised manuscript entitled “Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients”. As always, you and your editorial staff have again provided us with a comprehensive and prompt review. Many of the valuable and constructive points that the reviewers pointed out were well taken by all the authors. After going over the reviewer’s comments, my colleagues and I have performed additional investigation and made some revisions in hopes of improving our paper. The revised and added portions of the manuscript are stated in the “Response to Reviewers” and are underlined and highlighted in the revised manuscript for your convenience.

All authors contributed to the conception and interpretation of data, drafting of the manuscript, revising it critically for important intellectual content, and final approval of the manuscript. The whole manuscript or part of it, neither has been published and is not being considered for publication elsewhere in any language except as an abstract. None of the authors have any financial relationships with any company or any other bias or conflict of interest.

We believe that these findings have scientific and clinical impact and will be interesting and informative to your readers. We hope that, upon review, our study will be found to be meritorious of publication in the PLOS ONE.

Yours sincerely,

Jeong-Am Ryu, M.D., Ph.D.

Department of Critical Care Medicine and Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea

Tel: 82-2-3410-6399, Fax: 82-2-2148-7088

E-mail: lamyud.ryu@samsung.com

Response to Reviewers

Reviewer #1:

Comments: The authors have provided a very thorough analysis of a retrospective dataset and have added to the body of literature on this important subject. They have also taken into consideration the limitations of this type of study.

Concerns:

In Table 2, it is not clear what the p-values indicate. The legend should indicate what comparison is being evaluated. Is it the comparison between the EEN and the Non-EEN patients or the comparison between the EEN and the EPN patients or between the early nutrition and the late nutrition patients? Based on the title of the table, I would presume that it is the comparison between the EEN and the Non-EEN patients.

R. We apologize for the lack of clear statement. We compared late nutrition, EPN and EEN. We wanted to show which of the late nutrition, EPN, and EEN was the better form of nutrition. As your recommendation, we added the following legend indicated what comparison to revised table 2.

Data show a comparison between late nutrition, EPN and EEN.

In general, the sample size for this study is rather small for the number of variables considered in the analysis. As the authors noted, the number of patients with EEN and with EPN were small and the severity of illness is notably different between these two groups and the late nutrition group of patients.

R. We agree with the reviewer’s comment. There were differences in the number of subjects and the severity of illness among the nutrition groups. In this study, there were small sample size of subjects with EEN or EPN. In addition, it would be difficult to provide appropriate nutrition to neurocritically ill patients in the early stage. Nutritional support may be often ignored in early stages of patients with severely injured brain. Therefore, it is difficult to evaluate association between early proper nutrition and clinical outcomes of neurocritically ill patients. As a result, we performed various statistical methods to correct the bias. We evaluated whether early nutrition per se was associated with poor prognosis when severity and factors other than nutritional support were controlled by propensity score matching and propensity score weighting.

Other investigators have found that mortality was higher in critically ill children who received parenteral nutrition or that late parenteral nutrition was associated with better outcomes than early parenteral nutrition in critically ill children. Thus, combining the EEN and the EPN groups might not be beneficial. In fact, including the EPN group with the late nutrition group might not be beneficial, particularly for such a small number of patients.

R. We agree with the reviewer’s comment. Late parenteral nutrition may be associated with faster recovery and fewer complications, as compared with EPN (Ref. 21). Therefore, combining the EEN and the EPN groups, or the late nutrition and the EPN group might not be beneficial. EPN might affect the outcome as a confounding factor. As your recommendation, we re-analyzed the difference between EEN and non-EEN (only late nutrition, except EPN). We revised Figure 2 & 3 and added the following sentences in the Discussion section of the revised manuscript (line 214-218 in page 15).

EPN may be associated with delayed recovery and more complications, as compared with late parenteral nutrition (Ref. 21). Therefore, combining the EEN group with the EPN group, or the late nutrition group with the EPN group might not be useful in evaluating the association between feeding options and clinical outcomes. EPN might affect the outcome as a confounding factor in this study.

Ref. 21: Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011; 365: 506-17. https://doi.org/10.1056/NEJMoa1102662 PMID: 21714640

Other factors which should be considered would be the amount of nutrition provided to patients with respect to caloric intake and protein intake. The timing of nutrition may not be as important as the quantity and the composition of the nutrition provided. However, even the timing may impact outcomes. Why did the investigators choose to define early nutrition to be any nutrition before 72 hours? Did they consider 48 hours or even 24 hours?

R. We agree with the reviewer’s comment. In Dr. Wang’s study (Ref. 8), which was a well-designed meta-analysis, early nutrition was defined as 72 hours. In our study, early nutrition was also defined as feeding within 72 hours referring to the Dr. Wang’s study. Even the early nutrition, which was defined as feeding within 72 hours, had a smaller sample size in our study. Therefore, it was difficult to perform a statistical analysis with the definition of feeding within 24 or 48 hours because the sample sizes would be so small in these definitions. As a result, in this study, early nutrition was defined as feeding within 72 hours referring to the Dr. Wang’s study.

Ref. 8: Wang X, Dong Y, Han X, Qi XQ, Huang CG, Hou LJ. Nutritional support for patients sustaining traumatic brain injury: a systematic review and meta-analysis of prospective studies. PLoS One. 2013; 8: e58838. https://doi.org/10.1371/journal.pone.0058838 PMID: 23527035

In addition, there was the limitation of this study. Unfortunately, the amount of EEN or EPN calorie intake for patients in the early stage was not considered in this study due to its retrospective nature. We have mentioned these limitations in the limitation section of the revised manuscript.

The amount of EEN or EPN calorie intake for patients in the early stage was not considered in this study due to its retrospective nature.

Finally, I believe the investigators provided the various methods of data analysis to demonstrate a thorough approach, which is impressive, but presenting all analyses is probably unnecessary. Which analytic method is the best for this type of study? Which method retains the most data and most appropriately fits this study design and addresses the concerns of selection bias and confounding by comorbidities, clinical diagnoses, and severity of illness. This should have been determined in advance.

R. We agree with the reviewer’s comment. We performed various statistical methods to correct the bias. However, as your concerns, various statistical methods can confuse the readers. PSTW (a relatively rare method) and IPTW (an inappropriate balance, frequently over 0.1 of SMD) has been removed from the original manuscript. As following graph, severity of the subjects and factors other than nutritional support were well controlled by PSM and PSOW in this study. We revised Figure 2 & 3.

I would recommend revising the analysis to compare the quantity and the composition of the nutrition provided and I would consider excluding those who received EPN from the comparison of EEN to non-EEN. I would also limit the different types of analyses to reflect the most appropriate use of the data.

R. We agree with the reviewer’s comment. As reviewer’s recommendation, those who received EPN have been excluded from the comparison of EEN to non-EEN. We re-analyzed the difference between EEN and non-EEN (only late nutrition, except EPN). We revised Table 2. In addition, PSTW and IPTW has been removed from the original manuscript because of a relatively rare method or an inappropriate balance.

We thank the reviewer for valuable comments. Addressing them fully has significantly strengthened the manuscript.

Reviewer #2:

Dear authors,

I congratulate you for this paper. The statistical analysis is robust; however, the manuscript will benefit from major changes before publication.

The authors used retrospective data to evaluate the impact of early nutritional therapy and mortality. Also they analyzed the route of nutritional therapy.

First, I suggest an english review of the manuscript - it is understandable, but difficult to read.

An example in the background:

"Nutritional support is also associated with neurological prognosis and mortality of neurocritically ill patients with stroke or traumatic brain injury [6-8]. Early nutrition is especially important because it can affect neurological prognosis."

Associated with increased risk of mortality or a reduction in mortality? can affect neurological prognosis in what way - good or bad? And this same kind of sentence is repeated throughout the manuscript.

I will comment each part of the manuscript separately.

R. We appreciate valuable comments. We have revised the redundant phrase. In our study, neurological outcomes were not investigated. Primary endpoint was in-hospital mortality. A more accurate expression is “EEN may reduce the risk of mortality in neurocritically ill patients”. We changed conclusion as “EEN may reduce the risk of in-hospital mortality and infectious complications in neurocritically ill patients.” In addition, as your recommendation, we revised each part of the manuscript separately.

Abstract:

Background - there is no background information, only the objective of the study. Please include a sentence that explains the current knowledge.

Methods - no study design (retrospective cohort…)

Conclusion - can be clearer - again english editing.

R. As your comments, we revised the manuscript. Revised sentences have been underlined and highlighted in the revised manuscript for your convenience.

Background:

Better review of literature. Bring the hard data from previous study to support your argument (meaning mortality reduction in % (p=...) or no statistical difference in other study (p =...)). Make it clear what new information this study adds

R. As your comment, we revised the section of Background. We provided accurate data and p-value in the text as the following sentences (line 35-42 in page 5).

Malnutrition is associated with poor clinical outcomes such as higher rates of mortality (32% vs. 14%, P=0.018) [Ref. 4], nosocomial infection (23.4% vs. 3.5%, P<0.001) [Ref. 5], and long stay in intensive care unit (ICU) [Ref. 4,6]. Similarly, in critically ill patients with stroke or traumatic brain injury, nutritional support is associated with neurological prognosis and mortality [Ref. 7-9]. In stroke patients, the mortality rate of malnourished patients was 37%, which was significantly higher than that of patients with normal nutrition which was 21% (P<0.001) [Ref. 9]. In traumatic brain injury, it was reported that the rate of infection was reduced in early nutrition compared to delayed nutrition (risk ratio: 0.77, P=0.04) [Ref. 8].

Methods:

The methods and statistical analysis are clear

R. We appreciated your kind comment. We performed various statistical methods to correct the bias. However, as other reviewer’s opinion, various statistical methods can confuse the readers. Therefore, PSTW (a relatively rare method) and IPTW (an inappropriate balance, frequently over 0.1 of SMD) has been removed from the original manuscript.

Result:

The results are confusing.

I suggest dividing the results into the outcomes: primary (mortality) and secondary (infections complications) and not according statistical analysis.

R. As your comment, we revised the section of Results (line 138-171).

Also, table 2 - the p is for the comparasion between the 3 groups (late nutrition, EPN and EEN) or between (non-EEN and EEN). It is not clear.

R. We apologize for the lack of clear statement. We compared late nutrition, EPN, and EEN. We added the following legend indicated what comparison to revised table 2.

Data show a comparison between late nutrition, EPN and EEN. (the legend of revised Table 2)

As other reviewer’s recommendation, we re-analyzed the difference between EEN and non-EEN (only late nutrition, except EPN). Late parenteral nutrition may be associated with faster recovery and fewer complications, as compared with EPN (Ref. 21). Therefore, combining the EEN and the EPN groups, or the late nutrition and the EPN group might not be useful to evaluate the association between nutrition types and clinical outcomes. EPN might affect the outcome as a confounding factor. We revised Figure 2 & 3.

Ref. 21: Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011; 365: 506-17. https://doi.org/10.1056/NEJMoa1102662 PMID: 21714640

5.Discussion:

The comparison between current literature and the study result has room to be improved, but mostly English editing will help a lot.

There was a lot a of EPN. Any reason why? It is not supported by any guidelines. This should be better addressed in the discussion.

Do you have data regarding calories and protein intake in each group? I imagine that those in the early group would have a lesser caloric and protein deficit

R. We agree with the reviewer's comments. In the early stages, the sympathetic tone may be elevated in patients with elevated intracranial pressure (Ref. 8). Therefore, paralytic ileus, abdominal distension, and vomiting may not be uncommon in these patients. Hence, PN would be preferred occasionally compared with EN in our center.

There was the limitation of this study. Unfortunately, the amount of EEN or EPN calorie intake for patients in the early stage was not considered in this study due to its retrospective nature. We have mentioned these limitations in the limitation section of the revised manuscript.

The amount of EEN or EPN calorie intake for patients in the early stage was not considered in this study due to its retrospective nature.

Ref. 8: Wang X, Dong Y, Han X, Qi XQ, Huang CG, Hou LJ. Nutritional support for patients sustaining traumatic brain injury: a systematic review and meta-analysis of prospective studies. PLoS One. 2013; 8: e58838. https://doi.org/10.1371/journal.pone.0058838 PMID: 23527035

As your recommendation, our manuscript has been proofread by a professional English editing service. We thank the reviewer for valuable comments. Addressing them fully has significantly strengthened the manuscript.

Attachment

Submitted filename: Response to reviewers PLoS ONE_final.docx

Click here for additional data file. (437.3KB, docx)

Decision Letter 1

Rishabh Charan Choudhary

1 Sep 2022

PONE-D-21-39517R1Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patientsPLOS ONE

Dear Dr. Ryu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Please insert comments here and delete this placeholder text when finished. Be sure to:

  • Indicate which changes you require for acceptance versus which changes you recommend

  • Address any conflicts between the reviews so that it's clear which advice the authors should follow

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Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact.

For Lab, Study and Registered Report Protocols: These article types are not expected to include results but may include pilot data. 

==============================

Please submit your revised manuscript by Oct 16 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Rishabh Charan Choudhary

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Second Review

Thank you for the revised manuscript. It is much improved.

Concerns:

The legend for Table 2 clarifies the comparison. However, since there are three groups being compared it would seem that comparison of continuous variables would have required ANOVA rather than Student’s t-test. If this was done, please add this to the description of the data analysis. If this was not done, please explain what method of analysis was used to compare data for continuous variables in three groups.

In Figure 2, there are lines for the IPTW analysis, but you reported removing this analysis from the manuscript. It should be removed from the Figure as well.

Finally, I previously recommended that you compare the quantity and the composition of the nutrition provided but you indicated that these data are not available. You also indicated that you mentioned this as a limitation in your discussion section. I would encourage you to expand upon this in the discussion. Because the data for the quantity and the composition of the nutrition provided were not available, you are only comparing the timing of initiating nutrition by either the enteral or the parenteral route. However, the quantity of nutrition may have an impact on the findings of your study. Some previous studies have shown a difference in outcomes based on calories delivered, based on protein delivered, and some on both calories and protein delivered. This is an unfortunate deficit in your study.

Reviewer #2: Dear authors,

Thank you for your answers.

I do believe the manuscript is improved and all questions have been adequately answered.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Marina V Viana

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Mar 23;18(3):e0283593. doi: 10.1371/journal.pone.0283593.r004

Author response to Decision Letter 1

2 Sep 2022

September 2 2022

Dr. Rishabh Charan Choudhary

PLOS ONE

Manuscript ID: PONE-D-21-39517

Title: Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients

Dear Dr. Rishabh Charan Choudhary

Thank you very much for your letter and for the helpful comment from the reviewer. We appreciate the opportunity to resubmit our revised manuscript entitled “Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients”. As always, you and your editorial staff have again provided us with a comprehensive and prompt review. Many of the valuable and constructive points that the reviewers pointed out were well taken by all the authors. After going over the reviewer’s comments, my colleagues and I have performed additional investigation and made some revisions in hopes of improving our paper. The revised and added portions of the manuscript are stated in the “Response to Reviewers” and are underlined and highlighted in the revised manuscript for your convenience.

We hope that, upon review, our study will be found to be meritorious of publication in the PLOS ONE.

Yours sincerely,

Jeong-Am Ryu, M.D., Ph.D.

Department of Critical Care Medicine and Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea

Tel: 82-2-3410-6399, Fax: 82-2-2148-7088

E-mail: lamyud.ryu@samsung.com

Response to Reviewers

Reviewer #1:

Reviewer #1: Second Review

Thank you for the revised manuscript. It is much improved.

Concerns:

The legend for Table 2 clarifies the comparison. However, since there are three groups being compared it would seem that comparison of continuous variables would have required ANOVA rather than Student’s t-test. If this was done, please add this to the description of the data analysis. If this was not done, please explain what method of analysis was used to compare data for continuous variables in three groups.

In Figure 2, there are lines for the IPTW analysis, but you reported removing this analysis from the manuscript. It should be removed from the Figure as well.

Finally, I previously recommended that you compare the quantity and the composition of the nutrition provided but you indicated that these data are not available. You also indicated that you mentioned this as a limitation in your discussion section. I would encourage you to expand upon this in the discussion. Because the data for the quantity and the composition of the nutrition provided were not available, you are only comparing the timing of initiating nutrition by either the enteral or the parenteral route. However, the quantity of nutrition may have an impact on the findings of your study. Some previous studies have shown a difference in outcomes based on calories delivered, based on protein delivered, and some on both calories and protein delivered. This is an unfortunate deficit in your study.

R1. We apologize for the lack of clear statement. We compared late nutrition, EPN and EEN in original manuscript. In table 2, we used one-way analysis of variance (ANOVA) for continuous variables. We performed ANOVA analysis using the tableone package and the moonBook package of R program.

We added the following sentences in the Methods section of the revised manuscript

Line 90-92: Data were compared using Student’s t-test and one-way analysis of variance for continuous variables and Chi-square test or Fisher’s exact test for categorical variables.

R2. In revised figure 2, there was no line for IPTW. We showed the line for IPTW only in the first rebuttal letter for your comprehension.

R3. We agree with the reviewer’s comment. Unfortunately, the amount of EEN or EPN calorie intake for patients in the early stage was not considered in this study due to its retrospective nature. As your recommendation, we added these limitations in the discussion section of the revised manuscript.

Line 244-253: Adequate calorie and protein intake is important for recovery in critically ill patients [33,34]. Adequate nutritional support may also be important in neurocritically ill patients. The patients with severe traumatic brain injury have increased energy expenditure usually increase by 87%–200% above the usual requirement and may be elevated for 30 days due to metabolic changes [26,35,36]. In addition, systemic catabolic change could lead to hyperglycemia, protein wasting, and increased calorie demands [26,35]. Therefore, optimized calorie and protein supply is also important for acute brain injury patients. However, energy expenditure, calorie and protein intake were not considered in this study. Accurate analysis of calorie and protein supply and energy expenditure may be necessary to investigate the relationship between early nutrition and clinical outcomes in neurocritically ill patients.

Ref 26. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H. Early enteral nutrition in patients with severe traumatic brain injury: a propensity score-matched analysis using a nationwide inpatient database in Japan. Am J Clin Nutr. 2020; 111: 378-84. https://doi.org/10.1093/ajcn/nqz290 PMID: 31751450

Ref 33. Yamamoto S, Allen K, Jones KR, Cohen SS, Reyes K, Huhmann MB. Meeting Calorie and Protein Needs in the Critical Care Unit: A Prospective Observational Pilot Study. Nutr Metab Insights. 2020; 13: 1178638820905992. https://doi.org/10.1177/1178638820905992 PMID: 32153344

Ref 34. Hartl WH, Kopper P, Bender A, Scheipl F, Day AG, Elke G, et al. Protein intake and outcome of critically ill patients: analysis of a large international database using piece-wise exponential additive mixed models. Crit Care. 2022; 26: 7. https://doi.org/10.1186/s13054-021-03870-5 PMID: 35012618

Ref 35. Abdullah MI, Ahmad A, Syed Saadun Tarek Wafa SWW, Abdul Latif AZ, Mohd Yusoff NA, Jasmiad MK, et al. Determination of calorie and protein intake among acute and sub-acute traumatic brain injury patients. Chin J Traumatol. 2020; 23: 290-4. https://doi.org/10.1016/j.cjtee.2020.04.004 PMID: 32423779

Ref 36. Kurtz P, Rocha EEM. Nutrition Therapy, Glucose Control, and Brain Metabolism in Traumatic Brain Injury: A Multimodal Monitoring Approach. Front Neurosci. 2020; 14: 190. https://doi.org/10.3389/fnins.2020.00190 PMID: 32265626

We thank the reviewer for valuable comments. Addressing them fully has significantly strengthened the manuscript.

Reviewer #2:

Reviewer #2: Dear authors,

Thank you for your answers.

I do believe the manuscript is improved and all questions have been adequately answered.

R. We thank the reviewer for valuable comments. Addressing them fully has significantly strengthened the manuscript.

Attachment

Submitted filename: Response to reviewers PLoS ONE_minor_20220902.docx

Click here for additional data file. (28.6KB, docx)

Decision Letter 2

Rishabh Charan Choudhary

29 Sep 2022

PONE-D-21-39517R2Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patientsPLOS ONE

Dear Dr. Ryu,

Thank you for submitting your revised version to PLOS ONE. I am pleased to let you know that your paper has been accepted for the publication however it still needs minor corrections before final acceptance. Please check the response belowReviewer's comment:

The legend for Table 2 clarifies the comparison. However, since there are three groups being compared it would seem that comparison of continuous variables would have required ANOVA rather than Student’s t-test. If this was done, please add this to the description of the data analysis. If this was not done, please explain what method of analysis was used to compare data for continuous variables in three groups.

In Figure 2, there are lines for the IPTW analysis, but you reported removing this analysis from the manuscript. It should be removed from the Figure as well.

Finally, I previously recommended that you compare the quantity and the composition of the nutrition provided but you indicated that these data are not available. You also indicated that you mentioned this as a limitation in your discussion section. I would encourage you to expand upon this in the discussion. Because the data for the quantity and the composition of the nutrition provided were not available, you are only comparing the timing of initiating nutrition by either the enteral or the parenteral route. However, the quantity of nutrition may have an impact on the findings of your study. Some previous studies have shown a difference in outcomes based on calories delivered, based on protein delivered, and some on both calories and protein delivered. This is an unfortunate deficit in your study.

Please submit your revised manuscript by Nov 13 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Rishabh Charan Choudhary

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Mar 23;18(3):e0283593. doi: 10.1371/journal.pone.0283593.r006

Author response to Decision Letter 2

25 Oct 2022

September 2 2022

Dr. Rishabh Charan Choudhary

PLOS ONE

Manuscript ID: PONE-D-21-39517

Title: Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients

Dear Dr. Rishabh Charan Choudhary

Thank you very much for your letter and for the helpful comment from the reviewer. We appreciate the opportunity to resubmit our revised manuscript entitled “Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients”. As always, you and your editorial staff have again provided us with a comprehensive and prompt review. Many of the valuable and constructive points that the reviewers pointed out were well taken by all the authors. After going over the reviewer’s comments, my colleagues and I have performed additional investigation and made some revisions in hopes of improving our paper. The revised and added portions of the manuscript are stated in the “Response to Reviewers” and are underlined and highlighted in the revised manuscript for your convenience.

We hope that, upon review, our study will be found to be meritorious of publication in the PLOS ONE.

Yours sincerely,

Jeong-Am Ryu, M.D., Ph.D.

Department of Critical Care Medicine and Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea

Tel: 82-2-3410-6399, Fax: 82-2-2148-7088

E-mail: lamyud.ryu@samsung.com

Response to Reviewers

Reviewer #1:

Reviewer #1: Second Review

Thank you for the revised manuscript. It is much improved.

Concerns:

The legend for Table 2 clarifies the comparison. However, since there are three groups being compared it would seem that comparison of continuous variables would have required ANOVA rather than Student’s t-test. If this was done, please add this to the description of the data analysis. If this was not done, please explain what method of analysis was used to compare data for continuous variables in three groups.

In Figure 2, there are lines for the IPTW analysis, but you reported removing this analysis from the manuscript. It should be removed from the Figure as well.

Finally, I previously recommended that you compare the quantity and the composition of the nutrition provided but you indicated that these data are not available. You also indicated that you mentioned this as a limitation in your discussion section. I would encourage you to expand upon this in the discussion. Because the data for the quantity and the composition of the nutrition provided were not available, you are only comparing the timing of initiating nutrition by either the enteral or the parenteral route. However, the quantity of nutrition may have an impact on the findings of your study. Some previous studies have shown a difference in outcomes based on calories delivered, based on protein delivered, and some on both calories and protein delivered. This is an unfortunate deficit in your study.

R1. We apologize for the lack of clear statement. We compared late nutrition, EPN and EEN in original manuscript. In table 2, we used one-way analysis of variance (ANOVA) for continuous variables. We performed ANOVA analysis using the tableone package and the moonBook package of R program.

We added the following sentences in the Methods section of the revised manuscript

Line 90-92: Data were compared using Student’s t-test and one-way analysis of variance for continuous variables and Chi-square test or Fisher’s exact test for categorical variables.

R2. In revised figure 2, there was no line for IPTW. We showed the line for IPTW only in the first rebuttal letter for your comprehension.

R3. We agree with the reviewer’s comment. Unfortunately, the amount of EEN or EPN calorie intake for patients in the early stage was not considered in this study due to its retrospective nature. As your recommendation, we added these limitations in the discussion section of the revised manuscript.

Line 244-253: Adequate calorie and protein intake is important for recovery in critically ill patients [33,34]. Adequate nutritional support may also be important in neurocritically ill patients. The patients with severe traumatic brain injury have increased energy expenditure usually increase by 87%–200% above the usual requirement and may be elevated for 30 days due to metabolic changes [26,35,36]. In addition, systemic catabolic change could lead to hyperglycemia, protein wasting, and increased calorie demands [26,35]. Therefore, optimized calorie and protein supply is also important for acute brain injury patients. However, energy expenditure, calorie and protein intake were not considered in this study. Accurate analysis of calorie and protein supply and energy expenditure may be necessary to investigate the relationship between early nutrition and clinical outcomes in neurocritically ill patients.

Ref 26. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H. Early enteral nutrition in patients with severe traumatic brain injury: a propensity score-matched analysis using a nationwide inpatient database in Japan. Am J Clin Nutr. 2020; 111: 378-84. https://doi.org/10.1093/ajcn/nqz290 PMID: 31751450

Ref 33. Yamamoto S, Allen K, Jones KR, Cohen SS, Reyes K, Huhmann MB. Meeting Calorie and Protein Needs in the Critical Care Unit: A Prospective Observational Pilot Study. Nutr Metab Insights. 2020; 13: 1178638820905992. https://doi.org/10.1177/1178638820905992 PMID: 32153344

Ref 34. Hartl WH, Kopper P, Bender A, Scheipl F, Day AG, Elke G, et al. Protein intake and outcome of critically ill patients: analysis of a large international database using piece-wise exponential additive mixed models. Crit Care. 2022; 26: 7. https://doi.org/10.1186/s13054-021-03870-5 PMID: 35012618

Ref 35. Abdullah MI, Ahmad A, Syed Saadun Tarek Wafa SWW, Abdul Latif AZ, Mohd Yusoff NA, Jasmiad MK, et al. Determination of calorie and protein intake among acute and sub-acute traumatic brain injury patients. Chin J Traumatol. 2020; 23: 290-4. https://doi.org/10.1016/j.cjtee.2020.04.004 PMID: 32423779

Ref 36. Kurtz P, Rocha EEM. Nutrition Therapy, Glucose Control, and Brain Metabolism in Traumatic Brain Injury: A Multimodal Monitoring Approach. Front Neurosci. 2020; 14: 190. https://doi.org/10.3389/fnins.2020.00190 PMID: 32265626

We thank the reviewer for valuable comments. Addressing them fully has significantly strengthened the manuscript.

Reviewer #2:

Reviewer #2: Dear authors,

Thank you for your answers.

I do believe the manuscript is improved and all questions have been adequately answered.

R. We thank the reviewer for valuable comments. Addressing them fully has significantly strengthened the manuscript.

Attachment

Submitted filename: Response to reviewers PLoS ONE_minor_20220902.docx

Click here for additional data file. (28.6KB, docx)

Decision Letter 3

Raphael Cinotti

14 Mar 2023

Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients

PONE-D-21-39517R3

Dear Dr. Ryu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Raphael Cinotti, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the revised manuscript. It is much improved, and all my questions have been answered satisfactorily.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

Acceptance letter

Raphael Cinotti

16 Mar 2023

PONE-D-21-39517R3

Impact of early nutrition and feeding route on clinical outcomes of neurocritically ill patients

Dear Dr. Ryu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Pr. Raphael Cinotti

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Baseline characteristics according to timing of nutrition in the overall, PSM and PSOW adjusted population.

    (DOCX)

    Click here for additional data file. (29.5KB, docx)
    S2 Table. Baseline characteristics of patients with and without early enteral feeding in the overall, PSM and PSOW adjusted population.

    (DOCX)

    Click here for additional data file. (32.2KB, docx)
    Attachment

    Submitted filename: Response to reviewers PLoS ONE_final.docx

    Click here for additional data file. (437.3KB, docx)
    Attachment

    Submitted filename: Response to reviewers PLoS ONE_minor_20220902.docx

    Click here for additional data file. (28.6KB, docx)
    Attachment

    Submitted filename: Response to reviewers PLoS ONE_minor_20220902.docx

    Click here for additional data file. (28.6KB, docx)

    Data Availability Statement

    Data Sharing Statement: Our data are available on Harvard Dataverse Network (http://dx.doi.org/10.7910/DVN/3F8WF1).

    Articles from PLOS ONE are provided here courtesy of PLOS

    RESOURCES