Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines

Purpose: To provide evidence-based guidelines for early enteral nutrition (EEN) during critical illness.Methods:We aimed to compare EEN vs. early parenteral nutrition (PN) and vs. delayed EN. We defined "early" EN as EN started within 48 h independent of type or amount. We listed, a priori, conditions in which EN is often delayed, and performed systematic reviews in 24 such subtopics. If sufficient evidence was available, we performed meta-analyses; if not, we qualitatively summarized the evidence and based our recommendations on expert opinion. We used the GRADE approach for guideline development. The final recommendations were compiled via Delphi rounds.Results:We formulated 17 recommendations favouring initiation of EEN and seven recommendations favouring delaying EN. We performed five meta-analyses: in unselected critically ill patients, and specifically in traumatic brain injury, severe acute pancreatitis, gastrointestinal (GI) surgery and abdominal trauma. EEN reduced infectious complications in unselected critically ill patients, in patients with severe acute pancreatitis, and after GI surgery. We did not detect any evidence of superiority for early PN or delayed EN over EEN. All recommendations are weak because of the low quality of evidence, with several based only on expert opinion.Conclusions:We suggest using EEN in the majority of critically ill under certain precautions. In the absence of evidence, we suggest delaying EN in critically ill patients with uncontrolled shock, uncontrolled hypoxaemia and acidosis, uncontrolled upper GI bleeding, gastric aspirate >500 ml/6 h, bowel ischaemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access.

# Introduction
Existing guidelines recommend initiating enteral nutrition (EN) within the first 24-48 h after intensive care unit (ICU) admission if patients are unable to eat, not clearly defining reasons to delay EN [bib_ref] for Parenteral and Enteral Nutrition) (2006) ESPEN guidelines on enteral nutrition: intensive..., Kreymann [/bib_ref] [bib_ref] Metabolism and Nutrition Working Group of the Spanish Society of Intensive Care..., Fernandez-Ortega [/bib_ref] [bib_ref] Guidelines for the provision and assessment of nutrition support therapy in the..., Taylor [/bib_ref]. The present guideline is issued by the Working Group on Gastrointestinal Function within the Metabolism, Endocrinology and Nutrition (MEN) Section of the European Society of Intensive Care Medicine (ESICM) and is endorsed by ESICM. Our objective was to provide evidence-based guidelines for early enteral nutrition (EEN) in critically ill patients, focusing on specific clinical conditions frequently associated with delayed EN. Caloric and protein requirements, time to reach targets, type and route of EN, and timing of supplemental or full parenteral nutrition (PN) were not addressed. A full version of the introduction with references is available in Supplement 1.

# Methods
A full version of methods with references is available in Supplement 1.
We performed a systematic review of "early" EN (EEN) vs. early parenteral nutrition (PN) and EEN vs. delayed EN in adult critically ill patients. After critical appraisal of identified studies and in accordance with current guidelines [bib_ref] for Parenteral and Enteral Nutrition) (2006) ESPEN guidelines on enteral nutrition: intensive..., Kreymann [/bib_ref] [bib_ref] Metabolism and Nutrition Working Group of the Spanish Society of Intensive Care..., Fernandez-Ortega [/bib_ref] [bib_ref] Guidelines for the provision and assessment of nutrition support therapy in the..., Taylor [/bib_ref] , we defined EEN as EN started within 48 h of admission independent of the type or amount.
Thereafter, we predefined conditions in which EN is frequently delayed and performed a systematic review for each of these questions.
If randomised controlled trials (RCT) were available, we gave an evidence-based recommendation; if not, our recommendations were based on expert opinion (very low quality evidence), as all observational studies evaluating EEN are intrinsically biased, because patients who are less severely ill are more likely to receive and tolerate EEN.

## General considerations
We focussed on specific conditions in which EN is frequently delayed and tolerance of EN might be impaired. Therefore, all our recommendations are based on general principles and precaution measures outlined in [bib_ref] Nutrition in the acute phase of critical illness, Casaer [/bib_ref] [bib_ref] Early high protein intake is associated with low mortality and energy overfeeding..., Weijs [/bib_ref] [bib_ref] Permissive underfeeding or standard enteral feeding in critically ill adults, Arabi [/bib_ref] [bib_ref] Editorial on the original article entitled "Permissive underfeeding of standard enteral feeding..., Casaer [/bib_ref] [bib_ref] Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of..., Blaser [/bib_ref]. All study questions and recommendations refer to adult critically ill patients.

# Results
All recommendations with the final agreed results are presented in.
A flow chart with evidence identification process (Supplement 2), number of identified abstracts and assessed full texts for each study question (Supplement 3), Pubmed search formulas (Supplement 4), evidence tables for each question with respective references (Supplement 5), evidence profiles for questions with meta-analyses [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref] , evidence profiles for additional meta-analyses for Question 1 and 11 (Supplement 6), Forest plots for meta-analyses (Figs. 1, 2 and Supplement 7) are provided.

## Question 1: should we use een in critically ill adult patients?
The methodology is described in Supplement 1. Do not increase EN in cases of intolerance or new symptoms, such as pain, abdominal distension or increasing intra-abdominal pressure. In these circumstances EN should be either continued at a slow rate or ceased depending on the severity of symptoms and suspected underlying sinister pathology (e.g. mesenteric ischaemia)

## Table 1 general principles and precautions for using een in critically ill patients at risk of intolerance
Energy target during EEN Do not aim to cover full energy target with EEN. The optimal energy and protein target in the early phase of acute critical illness is not known. EEN that exceeds actual energy expenditure appears harmful and should be avoided [bib_ref] Nutrition in the acute phase of critical illness, Casaer [/bib_ref] [bib_ref] Early high protein intake is associated with low mortality and energy overfeeding..., Weijs [/bib_ref] , whereas hypocaloric EEN may be safe [bib_ref] Permissive underfeeding or standard enteral feeding in critically ill adults, Arabi [/bib_ref] [bib_ref] Editorial on the original article entitled "Permissive underfeeding of standard enteral feeding..., Casaer [/bib_ref] Monitoring and protocolised management of GI dysfunction during EEN In case of gastric retention without other new abdominal symptoms use prokinetics and/or postpyloric feeding in a protocolised way [bib_ref] Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of..., Blaser [/bib_ref] During introduction and increasing the rate of EN, measurement of intraabdominal pressure (IAP) provides an additional numeric value to detect negative dynamics of IAP during EN in patients with severe abdominal pathology, hypoperfusion or fluid overload
Individualized approach For patients with diminished consciousness and inadequate swallowing, precautions to prevent aspiration of gastric contents may be useful, including considering postpyloric feeding Premorbid health and course of the acute illness may differ between patients with similar diagnose; therefore an individual approach should always be applied Response rate was 100% in both Delphi rounds (all co-authors responded, methodologist did not participate). Agreement is calculated as percentage of "agree" answers from total Question 1A: Should we use EEN rather than early PN? Eight trials fulfilled the criteria and were included in meta-analyses (Supplement 5, . Results are presented in [fig_ref] Figure 1: Forest plots [/fig_ref].
For mortality, we included seven RCTs (2686 patients). EEN did not reduce mortality compared to early PN (RR 0.95; 95% CI 0.76-1.19; P = 0.64; I 2 = 9%). The certainty of evidence was moderate. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For infection, we included seven RCTs (2729 patients). EEN reduced the risk of infections compared to early PN (RR 0.55; 95% CI 0.35-0.86; P = 0.009; I 2 = 65%). The certainty of evidence was low. We rated down for risk of bias and inconsistency [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
Adding 11 additional studies identified during searches for questions in specified patient groups did not significantly change our results (included studies are presented in Supplement 5, ; evidence profiles in Supplement 6 and Forest plots in Supplement 7, . 1. Although the randomization method was inappropriate or unclear in four RCTs out of ive, we did not downgrade for risk of bias because the overall results did not change after excluding high risk of bias trials from the analysis, it is unlikely that risk of bias affected the mortality estimate. 2. We did not downgrade for inconsistency (I 2 = 9%) 3. We downgraded for imprecision by one level because the CI included signiicant beneit and harms (076, 1.19) 4. We downgraded for risk of bias by one level, most RCTs were non-blinded and had unclear or inappropriate methods of randomization 5. We downgraded for inconsistency by one level due to significant statistical heterogeneity (I 2 = 65%)

## Question 1b
Early EN vs delayed EN in unselected critically ill population (identiied during primary search using key words block on "critical illness") 1. We downgraded by one level for risk of bias, all RCTs had either inappropriate or unclear randomization methods 2. I 2 = 0% 3. We downgraded by one level for imprecision, the CI crosses the line of unity. 4. We did not downgrade for inconsistency, the I 2 = 25% 5. We downgraded the quality of evidence by one level for imprecision, the number of events was small, and the CI included small beneit Question 1B: Should we use EEN rather than delay nutritional intake? Fourteen studies fulfilled the criteria and were included in the meta-analysis (Supplement 5, . Results of the meta-analyses on EEN vs. delayed nutritional intake (including delayed EN, oral diet or PN) are presented in [fig_ref] Figure 2: Forest plots [/fig_ref].
For mortality, we included 12 RCTs (662 patients). EEN did not reduce mortality compared to delayed nutritional intake (RR 0.76; 95% CI 0.52-1.11; P = 0.149; I 2 = 0%).
For infection, we included 11 RCTs (597 patients). EEN reduced risk of infection compared to delayed EN (RR 0.64; 95% CI 0.46-0.90; P = 0.010; I 2 = 25%). We downgraded the quality of evidence by two levels for imprecision, the number of events is very low 2. We downgraded the quality of evidence for risk of bias by one level, studies were non-blinded 3. We downgraded the quality of evidence by two levels for imprecision, the CI is extremely wide contains signiicant substantial beneit and harm
The certainty of evidence was low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
In one study it was not possible to determine whether early PN was also used in some patients in the EEN group [bib_ref] Early nutritional support in severe traumatic patients, Chuntrasakul [/bib_ref]. Adding eight additional studies identified via specific searches did not significantly change the results (included studies are presented in Supplement 5, ; evidence profiles in Supplement 6 and Forest plots in Supplement 7, .

## Recommendation 1. we suggest using een in critically ill adult patients rather than early pn (grade 2c) or delaying en (grade 2c).

## Question 2: should we delay en in patients with shock receiving vasopressors or inotropes?
No RCTs were retrieved. We identified and analysed four prospective cohort studies, four case series/retrospective cohort studies and two reviews (Supplement 5,. 1. We downgraded the quality of evidence by two levels for imprecision 2. We downgraded the quality of evidence for inconsistency by one level, the I2 = 76% 3. We downgraded the quality of evidence by one level for imprecision, the number of events was small and the CI includes small beneit 4. We downgraded the quality of evidence for risk of bias, trials were not blinded 5. We downgraded the quality of evidence for imprecision, the number of events is small 1. We downgraded by two levels for serious imprecision, the CI is very wide and includes substantial beneit and harm 2. All included trials were at high risk of bias 3. We downgraded by one level for imprecision, the number of events was low
There is concern that EN in shock further jeopardizes the already impaired splanchnic perfusion. Nonocclusive bowel necrosis or non-occlusive mesenteric ischaemia (NOMI) has been reported in fewer than 1% of patients [bib_ref] Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous..., Mancl [/bib_ref] [bib_ref] Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition..., Marvin [/bib_ref] , without evidence for causal relationship between shock, vasopressors, EN and NOMI [bib_ref] Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous..., Mancl [/bib_ref] [bib_ref] Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition..., Marvin [/bib_ref] [bib_ref] Provision of enteral nutrition during vasopressor therapy for hemodynamic instability: an evidence-based..., Wells [/bib_ref] [bib_ref] Early enteral nutrition in patients with hemodynamic failure following cardiac surgery, Lasierra [/bib_ref]. In a large observational study, EEN (<48 h) in patients with 'stable' haemodynamics after fluid resuscitation, whilst receiving at least one vasopressor, was associated with reduced mortality compared to late EN (>48 h) [bib_ref] Early enteral nutrition and outcomes of critically ill patients treated with vasopressors..., Khalid [/bib_ref]. These results suggest that the use of concomitant vasopressors (especially with stable or decreasing doses) should not preclude a trial of EN, despite a high prevalence of feeding intolerance [bib_ref] Upper digestive intolerance during enteral nutrition in critically ill patients: frequency, risk..., Mentec [/bib_ref]. In very unstable patients, EN may not have priority and potential positive effects of EN are unlikely to help improve instability. Persisting lactic acidosis may help identify uncontrolled shock.

## Question 3: should we delay en in patients with:
A. Hypoxaemia; B. Hypercapnia; C. Acidosis?
We found no direct evidence on these subquestions in the literature, and RCTs in this population are unlikely to become available.
The rationale to withhold EN in patients with hypoxaemia, hypercapnia and acidosis is to limit oxygen consumption and CO 2 production. However, the process of starving mobilises endogenous stores and is energy-consuming [bib_ref] Adaptive alterations in metabolism: practical consequences on energy requirements in the severely..., Fontaine [/bib_ref]. Acidosis may represent persistent shock and possibly contribute to gut dysfunction. Identifying and treating the cause of shock has priority over the initiation of EN. Similarly, in uncontrolled life-threatening hypoxaemia and hypercapnia, EN should be delayed until the symptoms are resolving. EN enteral nutrition, PN parenteral nutrition, CI confidence interval, RR risk ratio, GI gastrointestinal
In patients with acute lung injury, an RCT comparing trophic to full EN for up to 6 days was associated with less gastrointestinal intolerance when compared to full EN, without affecting ventilator-free days, infectious complications, physical function, or survival [bib_ref] Permissive underfeeding or standard enteral feeding in critically ill adults, Arabi [/bib_ref] [bib_ref] One year outcomes in patients with acute lung injury randomised to initial..., Needham [/bib_ref]. There are no data suggesting EN in patients with chronic, subacute, compensated or permissive hypercapnia is unsafe or not feasible.

## Recommendation 3. we suggest delaying en in case of uncontrolled life-threatening hypoxaemia, hypercapnia or acidosis, but using een in patients with stable hypoxaemia, and compensated or permissive hypercapnia and acidosis (grade 2d).

## Question 4: should we delay en in patients receiving neuromuscular blocking agents?
One prospective study was identified (Supplement 5, , reporting similar gastric emptying as measured by gastric residual volume (GRV) in sedated patients with or without concomitant use of neuromuscular blocking agents [bib_ref] Gastric emptying in mechanically ventilated critically ill patients: effect of neuromuscular blocking..., Tamion [/bib_ref]. The critical condition necessitating the use of neuromuscular blocking agents always needs to be considered, but these agents per se should not preclude EN. Analgosedation is known to slow gastric emptying [bib_ref] The effects of sedation on gastric emptying and intra-gastric meal distribution in..., Nguyen [/bib_ref]. Increased rate of EN intolerance is expected in deeply sedated patients with/without concomitant use of neuromuscular blocking agents.

## Recommendation 4. we suggest that en should not be delayed solely because of the concomitant use of neuromuscular blocking agents (grade 2d).

## Question 5: should we delay en in patients receiving therapeutic hypothermia?
One case series study addressing EN during therapeutic hypothermia was identified [bib_ref] Is enteral feeding tolerated during therapeutic hypothermia?, Williams [/bib_ref] (Supplement 5, .
During therapeutic hypothermia, energy metabolism might be markedly reduced [bib_ref] Modification of the Harris-Benedict equation to predict the energy requirements of critically..., Saur [/bib_ref] [bib_ref] Fulfilling caloric demands according to indirect calorimetry may be beneficial for post..., Oshima [/bib_ref] when shivering is prevented. The rationale to withhold EN during therapeutic hypothermia is based on the presumed decrease in gut motility due to hypothermia [bib_ref] Experience with prolonged induced hypothermia in severe head injury, Bernard [/bib_ref] [bib_ref] Induced hypothermia in critical care medicine: a review, Bernard [/bib_ref] and required analgosedation [bib_ref] The effects of sedation on gastric emptying and intra-gastric meal distribution in..., Nguyen [/bib_ref]. It has been suggested that EN could be successfully administered to these patients [bib_ref] Is enteral feeding tolerated during therapeutic hypothermia?, Williams [/bib_ref]. Tolerance to enteral feeding was impaired during hypothermia, but improved during rewarming [bib_ref] Is enteral feeding tolerated during therapeutic hypothermia?, Williams [/bib_ref].

## Recommendation 5. we suggest starting low dose een in patients receiving therapeutic hypothermia and increase the dose after rewarming (grade 2d).

## Question 6: should we delay en in patients receiving extracorporeal membrane oxygenation (ecmo)?
No RCTs and no prospective cohort studies were identified. Four case series in adult patients with ECMO were assessed (Supplement 5, , suggesting that EN is feasible during ECMO.

## Recommendation 6. we suggest using een in patients receiving ecmo (grade 2d).

## Question 7: should we delay en during prone position?
One prospective cross-over, one cohort and three case series studies were identified (Supplement 5, .
Data on tolerance of EN in prone position are controversial. Observational studies found similar GRVs in prone and supine position [bib_ref] Enteral feeding in the critically ill: comparison between the supine and prone..., Van Der Voort [/bib_ref] , whereas poor feeding tolerance was improved with semi-recumbent position during supine periods and prokinetics [bib_ref] Early enteral nutrition in mechanically ventilated patients in the prone position, Reignier [/bib_ref] [bib_ref] Before-after study of a standardized ICU protocol for early enteral feeding in..., Reignier [/bib_ref]. Although no RCTs on EN tolerance during prone position are available, reported studies do not support withholding EN in

## Remark:
We suggest considering early use of prokinetics followed by post-pyloric feeding in case of persisting gastric retention.

## Question 8: should we delay en in patients with traumatic brain injury?
We identified a Cochrane review with two updates and one recent meta-analysis, comparing early vs. late feeding, independent on the route of nutrition (EN or PN) (Supplement 5, . We identified three RCTs comparing EEN vs. early PN, three RCTs comparing EEN vs. delayed EN (one with restricted randomisation), and one RCT comparing early PN vs. delayed EN (Supplement 5, .

## Question 8a: een vs. early pn
Three RCTs (116 patients) were included. EEN compared to early PN in patients with traumatic brain injury did not affect mortality (RR 1.91; 95% CI 0.59-6.18; P = 0.279; I 2 = 0%) or the risk of pneumonia (RR 1.23; 95% CI 0.79-1.90; P = 0.36; I 2 = 0%). The certainty of evidence for mortality outcome was low, for pneumonia it was very low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, .

## Question 8b: een vs. delayed en
For mortality, two RCTs (86 patients) were included. EEN did not affect mortality compared to delayed EN (RR 0.66; 95% CI 0.18-2.45; P = 0.53; I 2 = 0%). The certainty of evidence was low. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For pneumonia, three RCTs (118 patients) were included. EEN did not affect the risk of pneumonia compared to delayed EN (RR 0.86; 95% CI 0.55-1.35; P = 0.51; I 2 = 0%). The certainty of evidence was very low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, .
In addition to RCTs, five cohort studies addressing this question were identified (Supplement 5, .
Existing evidence did not allow determining or excluding any benefit or harm of EEN, therefore our recommendation is based on expert opinion.

## Recommendation 8. we suggest using een in patients with traumatic brain injury (grade 2d).

## Question 9: should we delay en in patients with stroke (haemorrhagic or ischaemic)?
We identified two RCTs in patients with ischaemic stroke and one retrospective study in patients with hypertensive intracerebral haemorrhage (Supplement 5, Tables 9A, B).
One small RCT compared early vs. delayed EN and reported amelioration of cell-mediated immunity [bib_ref] Impact of early versus late enteral nutrition on cell mediated immunity and..., Bakiner [/bib_ref] ; however, both groups received PN to meet caloric targets from day 1. A large RCT compared EEN ("as soon as possible") to no nutrition within 7 days and reported a trend towards reduction of long-term mortality (6 months) with EN, with an increased risk of poor neurologic outcome in survivors [bib_ref] Effect of timing and method of enteral tube feeding for dysphagic stroke..., Dennis [/bib_ref]. An observational study reported reduction in infectious complications with EEN vs. delayed EN [bib_ref] Impact of early enteral nutrition on in-hospital mortality in patients with hypertensive..., Lee [/bib_ref].

## Recommendation 9. we suggest using een in patients with stroke (ischaemic or haemorrhagic) (grade 2d).

## Question 10: should we delay en in patients with spinal cord injury?
One RCT addressed EEN (<72 h) vs. delayed EN in cervical spinal injury [bib_ref] Early vs late enteral feeding in patients with acute cervical spinal cord..., Dvorak [/bib_ref]. No differences in outcome variables were identified. One retrospective cohort study addressed safety of EN early after spinal cord injury and reported no major complications [bib_ref] Is early enteral feeding safe in patients who have suffered spinal cord..., Rowan [/bib_ref] (Supplement 5, Tables 10A, B).

## Recommendation 10. we suggest using een in patients with spinal cord injury (grade 2d).

## Question 11: should we delay en in patients with severe acute pancreatitis (sap)?
We identified five systematic reviews with meta-analyses comparing EN to PN while not considering timing (Supplement 5, . All meta-analyses concluded that EN was beneficial in reducing infections and three reported reduced mortality [bib_ref] Guidelines for the provision and assessment of nutrition support therapy in the..., Taylor [/bib_ref] [bib_ref] Enteral nutrition and the risk of mortality and infectious complications in patients..., Petrov [/bib_ref] [bib_ref] Meta-analysis of enteral nutrition versus total parenteral nutrition in patients with severe..., Cao [/bib_ref].
We identified five RCTs addressing EEN ("early" as defined by the authors) vs. early PN in SAP whereas only two studies defined "early" as <48 h. Three further RCTs addressed EEN vs. early PN and one RCT EEN vs. delayed EN in "predicted SAP". Two RCTs addressing acute pancreatitis independent of severity and one RCT studying mixed patients undergoing abdominal surgery were not included. Supplement 5, .
We performed three separate meta-analyses all comparing EEN vs. early PN: (A) SAP and "early" as defined by the authors of the original study; (B) predicted SAP and "early" as defined by the authors of the original study; (C) predicted SAP and early defined as <48 h.

## Question 11a: sap (as stated by the authors). early ("early" as defined by the authors) en vs. pn
For mortality we included five RCTs (283 patients). EEN did not reduce the risk of death compared to PN (RR 0.57; 95% CI 0.23-1.38; P = 0.21; I 2 = 35.1%). The certainty of evidence was low. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For any infections we included five RCTs (283 patients). EEN reduced the risk of infections compared to PN (RR 0.48; 95% CI 0.23-0.98; P = 0.045; I 2 = 76%). The certainty of evidence was low. We rated down for inconsistency and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For pancreatic infections we included four RCTs (233 patients). EEN reduced the risk of pancreatic infections compared to PN (RR 0.33; 95% CI 0.21-0.52; P < 0.0001; I 2 = 0%) The certainty of evidence was low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, .

## Question 11b: predicted sap. early ("early" as defined by the authors) en vs. pn
For mortality we included eight RCTs (417 patients). EEN did not reduce the risk of death compared to PN (RR 0.50; 95% CI 0.22-1.13; P = 0.09; I 2 = 38%). The certainty of evidence was low. We rated down for imprecision (Supplement 6).
For any infections we included eight RCTs (417 patients). EEN reduced the risk of infections compared to PN (RR 0.53; 95% CI 0.30-0.91; P = 0.023; I 2 = 63.5%). The certainty of evidence was low. We rated down for risk of bias and inconsistency (Supplement 6).
For pancreatic infections we included five RCTs (202 patients). The use of EEN reduced the risk of pancreatic infections compared to PN (RR 0.35; 95% CI 0.24-0.52; P < 0.0001; I 2 = 0%). The certainty of evidence was low. We rated down for risk of bias and imprecision (Supplement 6). Supplement 7, .

## Question 11c: predicted sap. early (<48 h) en vs. pn
For mortality we included five RCTs (232 patients). EEN (<48 h) did not reduce the risk of death compared to PN (RR 0.61; 95% CI 0.15-2.55; P = 0.50; I 2 = 41%). The certainty of evidence was low. We rated down for imprecision (Supplement 6).
For any infections we included five RCT (232 patients), EEN (<48 h) reduced the risk of infections compared to PN (RR 0.49; 95% CI 0.28-0.83; P = 0.008, I 2 = 9%). The certainty of evidence was low. We rated down for risk of bias, inconsistency and imprecision (Supplement 6).
For pancreatic infections we included three RCTs (167 patients). EEN (<48 h) reduced the risk of pancreatic infections compared to PN (RR 0.40; 95% CI 0.22-0.73; P = 0.003; I 2 = 0%). The certainty of evidence was low. We rated down for risk of bias and imprecision (Supplement 6). Supplement 7, .
Taken together, the studies in different subpopulations have demonstrated a reduction of infections but no convincing effect of EEN on mortality.
Recommendation 11. We suggest using EEN in patients with severe acute pancreatitis (Grade 2C).

## Question 12: should we delay en in patients after gi surgery?
Out of three published meta-analyses [bib_ref] Early versus traditional postoperative feeding in patients undergoing resectional gastrointestinal surgery: a..., Osland [/bib_ref] [bib_ref] Early enteral nutrition within 24 h of intestinal surgery versus later commencement..., Lewis [/bib_ref] [bib_ref] Early enteral feeding versus "nil by mouth" after gastrointestinal surgery: systematic review..., Lewis [/bib_ref] addressing early postoperative feeding including early oral diet, the two more recent papers [bib_ref] Early versus traditional postoperative feeding in patients undergoing resectional gastrointestinal surgery: a..., Osland [/bib_ref] [bib_ref] Early enteral nutrition within 24 h of intestinal surgery versus later commencement..., Lewis [/bib_ref] reached different conclusions: reduced mortality and length of stay (LOS) but increased risk of vomiting analysing 15 RCTs [bib_ref] Early enteral nutrition within 24 h of intestinal surgery versus later commencement..., Lewis [/bib_ref] vs. no difference in mortality and LOS, but reduced complications in early group from 13 RCTs [bib_ref] Early versus traditional postoperative feeding in patients undergoing resectional gastrointestinal surgery: a..., Osland [/bib_ref].
We identified three RCTs comparing early vs. delayed EN after emergency GI surgery and six RCTs in elective GI surgery. Two RCTs compared EEN vs. early PN in patients after elective GI surgery (Supplement 5,.

## Question 12a: emergency gi surgery. een vs delayed en
Three RCTs (343 patients) were included. EEN did not affect mortality compared to delayed EN (RR 0.80; 95% CI 0.46-1.40; P = 0.44; I 2 = 0%). EEN reduced the risk of infections compared to delayed EN (RR 0.61; 95% CI 0.40-0.93; P = 0.02; I 2 = 0%). The certainty of evidence was low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].

## Question 12b: elective gi surgery. een vs. delayed en
For mortality three RCTs (346 patients) were included. EEN did not affect mortality compared to delayed EN in patients after elective GI surgery (RR 0.83; 95% CI 0.25-2.81; P = 0.77; I 2 = 17%). The certainty of evidence was low. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For any infections six RCTs (432 patients) were included. EEN reduced the risk of infections compared to delayed EN (RR 0.43; 95% CI 0.23-0.82; P = 0.01; I 2 = 46%). The certainty of evidence was low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
Five RCTs (404 patients) reported anastomotic leak. EEN reduced the risk of surgical leak compared to delayed EN (RR 0.43; 95% CI 0.20-0.93; P = 0.03; I 2 = 0%). The certainty of evidence was low. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].

## Question 12c: elective gi surgery. een vs early pn
Two RCTs (440 patients) were included. EEN did not reduce the risk of pneumonia compared to early PN (RR 0.59; 95% CI 0.31-1.14; P = 0.12, I 2 = 0%), but reduced the risk of anastomotic leak compared to early PN (RR 0.42; 95% CI 0.19-0.95; P = 0.04; I 2 = 63%). The certainty of evidence was low. We rated down for risk of bias, inconsistency and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].

## Recommendation 12. we suggest using een in patients after gi surgery (grade 2c).

## Question 13: should we delay en in patients after abdominal aortic surgery?
No RCTs but two cohort studies were identified (Supplement 5, [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Cohort studies both in elective [bib_ref] A cohort study of nutrition practices in the intensive care unit following..., Ksienski [/bib_ref] and emergency repair [bib_ref] Nutrition therapy for the critically ill surgical patient with aortic aneurysmal rupture:..., Rahman [/bib_ref] did not compare EEN with any of our comparators, but showed that EEN was successful in a minority of patients. A multimodal approach has been proposed [bib_ref] Nutrition barriers in abdominal aortic surgery: a multimodal approach for gastrointestinal dysfunction, Van Zanten [/bib_ref] , including early removal of nasogastric tubes, immediate postoperative mobilisation early oral or enteral feeding, accepting GRV up to 500 ml and use of prokinetics. Although these patients are at risk of bowel ischaemia with prevalence reported between 7 and 17% [bib_ref] Circulating intestinal fatty acid-binding protein as an early marker of intestinal necrosis..., Vermeulen Windsant [/bib_ref] [bib_ref] Editor's choice-hybrid treatment of thoracic, thoracoabdominal, and abdominal aortic aneurysms: a multicenter..., Rosset [/bib_ref] , the risk itself should not lead to withholding EN, unless bowel ischaemia is suspected (see also .

## Recommendation 13. we suggest using een in patients after abdominal aortic surgery (grade 2d).

## Question 14: should we delay en in patients with abdominal trauma?
Ten RCTs and ten cohort studies addressing EEN in trauma patients (RCTs: within 6-48 h; cohort studies: within 12-96 h) were identified, but abdominal trauma specifically was addressed in six RCTs, four of them compared EEN to early PN and two EEN to delayed EN (Supplement 5, .

## Question 14a: een vs early pn
For mortality two RCTs (142 patients) were included. EEN did not affect mortality compared to early PN (RR 0.49; 95% CI 0.09-2.69; P = 0.41; I 2 = 0%). The certainty of evidence was very low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For any infection four RCTs (219 patients) were included. EEN did not affect the risk of infections compared to early PN (RR 0.59; 95% CI 0.24-1.42; P = 0.24; I 2 = 59%). The certainty of evidence was very low. We rated down for risk of bias, inconsistency and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].

## Question 14b: een vs delayed en
Two RCTs (101 patients) were included. EEN did not affect mortality compared to delayed EN (RR 0.74; 95% CI 0.18-3.11; P = 0.708). The certainty of evidence was very low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
EEN did not affect the risk of infections compared to delayed EN (RR 0.83; 95% CI 0.41-1.70; P = 0.837). The certainty of evidence was very low. We rated down for risk of bias, inconsistency and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. See Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].
Of note, earlier studies in this patient group almost exclusively used surgical jejunostomy for EN.
Existing evidence did not allow verifying or excluding any benefit or harm of EEN; therefore our recommendation is based on expert opinion. In addition to RCTs, nine observational studies were identified (Supplement 5, .
An earlier meta-analysis in adult trauma patients in ICU (not specifically abdominal trauma) showed survival benefit in EEN commenced within 24 h after trauma [bib_ref] Early enteral nutrition reduces mortality in trauma patients requiring intensive care: a..., Doig [/bib_ref].

## Recommendation 14. we suggest using een in patients with abdominal trauma when the continuity of the gi tract is confirmed/restored (grade 2d).

## Question 15: should we delay en in patients with bowel ischaemia?
We identified no clinical studies, but physiological knowledge and common sense support withholding EN in patients with overt bowel ischaemia. However, patients with endoscopic evidence of mild to moderate large bowel mucosal ischaemia, without signs of transmural ischaemia or bowel distension, might profit from low dose EN. In this case we support considering EN. In a recent retrospective study, survivors were more often fed enterally before the diagnosis of acute mesenteric ischaemia, but no independent association between EN and mortality was demonstrated [bib_ref] Outcome of acute mesenteric ischemia in the intensive care unit: a retrospective,..., Leone [/bib_ref].

## Recommendation 15. we suggest delaying en in patients with overt bowel ischaemia (grade 2d).

## Question 16: should we delay en in critically ill adult patients with intestinal fistula?
We identified one retrospective cohort study and two case series, all showing outcome benefit of "early" EN (Supplement 5, . However, "early" was defined as EN started within 7 days or 14 days of admission. Retrospective design further diminishes the importance of these studies.
Intolerance of EN or increasing fistula output causing skin breakdown or fluid/electrolyte imbalance are evident reasons to decrease or discontinue EN [bib_ref] Metabolic and nutritional support of the enterocutaneous fistula patient: a three-phase approach, Polk [/bib_ref].

## Recommendation 16. we suggest delaying en in patients with high-output intestinal fistula if reliable feeding access distal to the fistula is not achievable (grade 2d).

## Question 17: should we delay en in patients with an open abdomen?
Seven observational studies (one prospective cohort study, three retrospective cohort studies and four case series) were identified; two studies compared EEN (different definitions) vs delayed EN and reported higher rate of early abdominal closure, less fistula formation and lower incidence of ventilator-associated pneumonia in the "early" EN group (Supplement 5, . The largest study comparing EN to no EN in patients with open abdomen after abdominal trauma reported independent associations between EN and ultimate fascial closure and decreased mortality rate in patients without bowel injury, but no difference in a subgroup of patients with bowel injury [bib_ref] Who should we feed? Western Trauma Association multi-institutional study of enteral nutrition..., Burlew [/bib_ref].

## Recommendation 17. we suggest using een in patients with open abdomen (grade 2d).

## Question 18: should we delay en in patients with intra-abdominal hypertension?
Four observational studies were identified (Supplement 5, , only one addressed early vs. delayed EN [bib_ref] Early enteral nutrition prevents intra-abdominal hypertension and reduces the severity of severe..., Sun [/bib_ref]. All studies reported high incidence of feeding intolerance associated with intra-abdominal hypertension, but data are not conclusive regarding causality. A recently published study demonstrated that EEN did not increase intra-abdominal pressure, but values exceeding 15 mmHg were associated with higher rates of feeding intolerance in patients with severe acute pancreatitis [bib_ref] Early enteral nutrition prevents intra-abdominal hypertension and reduces the severity of severe..., Sun [/bib_ref].
No prospective study addressing EN in patients with abdominal compartment syndrome [bib_ref] Pediatric Guidelines Sub-Committee for the World Society of the Abdominal Compartment Syndrome..., Kirkpatrick [/bib_ref] was identified. As abdominal compartment syndrome is an immediately life-threatening condition with jeopardized splanchnic perfusion, we suggest to withhold or stop EN and try to lower intra-abdominal pressure.
Recommendation 18a. We suggest using EEN in patients with intra-abdominal hypertension without abdominal compartment syndrome, but consider temporary reduction or discontinuation of EN when intra-abdominal pressure values further increase under EN (Grade 2D).
Recommendation 18b. We suggest delaying EN in patients with abdominal compartment syndrome (Grade 2D).

## Question 19: should we delay en in patients with upper gi bleeding?
No studies addressing EEN were identified. One RCT in bleeding due to gastric or duodenal ulcer reported shorter hospital stay (4.2  1.2 vs. 5.9  1.4 days, P < 0.001) in the early oral feeding group [bib_ref] Effects of early oral feeding on relapse and symptoms of upper gastrointestinal..., Khoshbaten [/bib_ref].
EN as protection against stress ulceration and GI bleeding is suggested in one meta-analysis [bib_ref] Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis, Marik [/bib_ref] , one retrospective study in burns [bib_ref] The value of early enteral nutrition in the prophylaxis of stress ulceration..., Raff [/bib_ref] and several reviews [bib_ref] Stress prophylaxis in intensive care unit patients and the role of enteral..., Hurt [/bib_ref] [bib_ref] Use of enteral nutrition for stress ulcer prophylaxis, Maclaren [/bib_ref] [bib_ref] Prevention of gastrointestinal bleeding due to stress ulceration: a review of current..., Pilkington [/bib_ref]. An RCT comparing ranitidine and sucralfate reported EN as an independently protective factor against GI bleeding [bib_ref] Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical..., Cook [/bib_ref]. The main rationale to prohibit eating/EN is based on fear for disturbed visibility in a further endoscopy/intervention due to rebleeding. Therefore, delaying EN for 48-72 h in patients with a high risk of rebleeding has been suggested [bib_ref] Feeding the patients with upper gastrointestinal bleeding, Hebuterne [/bib_ref]. Considering the absence of evidence to support this time frame, we suggest starting EN during the first 24-48 h after bleeding has been stopped; prolonged postponement of EN is unnecessary or even harmful because of increased risk of stress ulceration. Importantly, there is no evidence that fine-bore nasogastric tubes cause variceal bleeding [bib_ref] Feeding the patients with upper gastrointestinal bleeding, Hebuterne [/bib_ref].
Recommendation 19. We suggest delaying EN in patients with active upper GI bleeding, and starting EN when the bleeding has stopped and no signs of rebleeding are observed (Grade 2D).

## Question 20: should we delay en in patients with acute liver failure?
We could not identify any study in acute or acute-onchronic liver failure patients. Some benefits of EN have been shown in patients with alcoholic hepatitis, malnourished patients with cirrhosis and patients with liver transplantation [bib_ref] Short and long term outcome of severe alcohol-induced hepatitis treated with steroids..., Cabre [/bib_ref] [bib_ref] Effect of total enteral nutrition on the short-term outcome of severely malnourished..., Cabre [/bib_ref] [bib_ref] Early enteral nutrition support in patients undergoing liver transplantation, Hasse [/bib_ref] , where glycogen stores may be depleted after an overnight fast and metabolic conditions resemble prolonged starvation in healthy individuals [bib_ref] Energy expenditure and substrate metabolism in patients with cirrhosis of the liver:..., Verboeket-Van De Venne [/bib_ref]. EN in fulminant acute liver failure has never been studied. These patients often present with hypoglycaemia, which should be corrected with intravenous glucose, sometimes together with insulin. Fulminant liver failure is associated with increased serum amino acid concentrations, especially glutamine [bib_ref] Plasma glutamine concentrations in liver failure, Helling [/bib_ref] [bib_ref] Aromatic amino acid metabolism during liver failure, Dejong [/bib_ref]. It seems likely that a failing liver is unable to provide effective metabolic support required for nutrition. The pathophysiological rationale to delay EN in fulminant hepatic failure would be to "spare" the severely injured liver from the duties of metabolising and storing nutrition during a period of stress and also to avoid additional increases in ammonia. Intravenous provision of nutrients except correction of hypoglycemia and appropriate provision of vitamins and trace elements may be futile or harmful early in the clinical course [bib_ref] Pathogenesis and treatment of parenteral nutritionassociated liver disease, Xu [/bib_ref].
Recommendation 20. We suggest starting low dose EN when acute, immediately life-threatening metabolic derangements are controlled with or without liver support strategies, independent on grade of encephalopathy (Grade 2D).
Remark: Arterial ammonia levels should be monitored.

## Question 21: should we delay en in patients with large gastric aspirate volumes (gav)?
We identified no study addressing this question. Based on existing evidence from two RCTs comparing the threshold volumes to stop already started EN [bib_ref] Gastric residual volume during enteral nutrition in ICU patients: the REGANE study, Montejo [/bib_ref] [bib_ref] Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia..., Reignier [/bib_ref] , a clear threshold volume (in ranges up to 500 ml) that increased the risk of ventilator-associated pneumonia was not identified. Measurements of GAV/GRV are not a gold standard and alternative methods (like ultrasound) can be applied to diagnose overfilling of the stomach. Gross distension of the stomach is likely to be undesirable and therefore we suggest that EN should be delayed when GAV/GRV is >500 ml/6 h [bib_ref] Gastric residual volume during enteral nutrition in ICU patients: the REGANE study, Montejo [/bib_ref] , either for a limited time period or until administration of prokinetics. For patients with persistently large GAV/GRVs the use of postpyloric feeding should be considered rather than withholding EN, unless bowel ischaemia or obstruction is suspected (see also .

## Recommendation 21.
We suggest delaying EN if gastric aspirate volume is above 500 ml/6 h (Grade 2D).

## Question 22: should we delay en in patients with absent bowel sounds?
One cohort study was identified [bib_ref] Early enteral feeding in intestinal anastomosis, Thapa [/bib_ref] (Supplement 5,. Bowel sounds are frequently absent in mechanically ventilated patients and this is associated with impaired outcome [bib_ref] Gastrointestinal symptoms in intensive care patients, Reintam [/bib_ref]. The concept that bowel sounds must be present before initiation of enteral feeding is not based on evidence and should be abandoned [bib_ref] Enteral nutrition in the critically ill patient: a prospective survey, Heyland [/bib_ref]. After laparotomy small intestinal motility is frequently preserved despite gastric and colonic paresis. The small intestine may contract silently (absence of gas), while feeding is well tolerated [bib_ref] Enteral nutrition in the critically ill patient: a prospective survey, Heyland [/bib_ref]. Gastric and colonic paresis may effectively be treated with prokinetics [bib_ref] Gastric emptying in the critically illthe way forward?, Frost [/bib_ref]. Initiation of EN in absence of bowel sounds might be associated with earlier return of bowel sounds, fewer episodes of vomiting, and shorter ICU and hospital stay [bib_ref] Early enteral feeding in intestinal anastomosis, Thapa [/bib_ref].
Recommendation 22. We suggest using EEN regardless of the presence of bowel sounds unless bowel ischaemia or obstruction is suspected (Grade 2D).

## Question 23: should we delay en in patients with diarrhoea?
There were no studies testing delay of EN in case of diarrhoea, but diarrhoea is often considered as a reason to delay EN [bib_ref] Enteral feeding in the critically ill: are nursing practices contributing to hypocaloric..., Marshall [/bib_ref]. Prevalence of diarrhoea in unselected ICU population is between 14 and 21% [bib_ref] Diarrhoea in the ICU: respective contribution of feeding and antibiotics, Thibault [/bib_ref] [bib_ref] Diarrhoea in the critically ill, Blaser [/bib_ref]. Causes include impaired digestion/absorption, bacterial overgrowth or infection such as Clostridium difficile. Observational studies [bib_ref] Managing diarrhoea in intensive care, Ferrie [/bib_ref] [bib_ref] Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The..., Montejo [/bib_ref] suggest that diarrhoea can be effectively managed with protocolised measures other than immediate cessation in EN. We recommend analysing the causes of diarrhoea and treat appropriately (e.g. C. difficile colitis). We also suggest considering treating bacterial overgrowth by selective decontamination, fibreenriched or semi-elementary diet or digestive enzymes to reduce diarrhoea.

## Recommendation 23. we suggest using een in patients with diarrhoea (grade 2d).

# Conclusions
We suggest using EEN, initiated at a low rate, in the majority of critically ill patients; however, the evidence is weak. Beneficial effects in terms of infection prevention have been demonstrated in unselected critically ill patients, as well as in patients with severe acute pancreatitis and after GI surgery. However, we suggest delaying EN in patients with uncontrolled shock (haemodynamic and tissue perfusion goals are not met despite of fluids and vasopressors), uncontrolled hypoxaemia and acidosis, uncontrolled GI bleeding, overt bowel ischaemia (occlusive or non-occlusive), bowel obstruction (mechanical ileus), abdominal compartment syndrome, gastric aspirate volume >500 ml/6 h or high-output fistula if reliable distal feeding access is not achievable.
[fig] Figure 1: Forest plots (a mortality; b infections) Question 1A: early EN (EEN) vs. early PN (EPN) in unselected critically ill patients [/fig]
[fig] Figure 2: Forest plots (a mortality; b infections) Question 1B: early EN (EEN) vs. delayed EN (DEN) in unselected critically ill patients prone position. Gastric emptying seems not to be significantly influenced by prone position and adverse events in most studies not increased. Recommendation 7. We suggest that EN should not be delayed solely because of prone positioning (Grade 2D). [/fig]
[table] Table 3: Evidence profiles for the questions where meta-analyses were performed [/table]
[table] Question 12: AEmergency GI surgery. Early EN vs delayed EN. [/table]