Enteral versus parenteral nutrition and enteral versus a combination of enteral and parenteral nutrition for adults in the intensive care unit

Sharon R Lewis; Oliver J Schofield‐Robinson; Phil Alderson; Andrew F Smith

doi:10.1002/14651858.CD012276.pub2

. 2018 Jun 8;2018(6):CD012276. doi: 10.1002/14651858.CD012276.pub2

Enteral versus parenteral nutrition and enteral versus a combination of enteral and parenteral nutrition for adults in the intensive care unit

Sharon R Lewis ^1,^✉, Oliver J Schofield‐Robinson ¹, Phil Alderson ², Andrew F Smith ³

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC6353207 PMID: 29883514

Abstract

Background

Critically ill people are at increased risk of malnutrition. Acute and chronic illness, trauma and inflammation induce stress‐related catabolism, and drug‐induced adverse effects may reduce appetite or increase nausea and vomiting. In addition, patient management in the intensive care unit (ICU) may also interrupt feeding routines. Methods to deliver nutritional requirements include provision of enteral nutrition (EN), or parenteral nutrition (PN), or a combination of both (EN and PN). However, each method is problematic. This review aimed to determine the route of delivery that optimizes uptake of nutrition.

Objectives

To compare the effects of enteral versus parenteral methods of nutrition, and the effects of enteral versus a combination of enteral and parenteral methods of nutrition, among critically ill adults, in terms of mortality, number of ICU‐free days up to day 28, and adverse events.

Search methods

We searched CENTRAL, MEDLINE, and Embase on 3 October 2017. We searched clinical trials registries and grey literature, and handsearched reference lists of included studies and related reviews.

Selection criteria

We included randomized controlled studies (RCTs) and quasi‐randomized studies comparing EN given to adults in the ICU versus PN or versus EN and PN. We included participants that were trauma, emergency, and postsurgical patients in the ICU.

Data collection and analysis

Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We assessed the certainty of evidence with GRADE.

Main results

We included 25 studies with 8816 participants; 23 studies were RCTs and two were quasi‐randomized studies. All included participants were critically ill in the ICU with a wide range of diagnoses; mechanical ventilation status between study participants varied. We identified 11 studies awaiting classification for which we were unable to assess eligibility, and two ongoing studies.

Seventeen studies compared EN versus PN, six compared EN versus EN and PN, two were multi‐arm studies comparing EN versus PN versus EN and PN. Most studies reported randomization and allocation concealment inadequately. Most studies reported no methods to blind personnel or outcome assessors to nutrition groups; one study used adequate methods to reduce risk of performance bias.

Enteral nutrition versus parenteral nutrition

We found that one feeding route rather than the other (EN or PN) may make little or no difference to mortality in hospital (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.80 to 1.77; 361 participants; 6 studies; low‐certainty evidence), or mortality within 30 days (RR 1.02, 95% CI 0.92 to 1.13; 3148 participants; 11 studies; low‐certainty evidence). It is uncertain whether one feeding route rather than the other reduces mortality within 90 days because the certainty of the evidence is very low (RR 1.06, 95% CI 0.95 to 1.17; 2461 participants; 3 studies). One study reported mortality at one to four months and we did not combine this in the analysis; we reported this data as mortality within 180 days and it is uncertain whether EN or PN affects the number of deaths within 180 days because the certainty of the evidence is very low (RR 0.33, 95% CI 0.04 to 2.97; 46 participants).

No studies reported number of ICU‐free days up to day 28, and one study reported number of ventilator‐free days up to day 28 and it is uncertain whether one feeding route rather than the other reduces the number of ventilator‐free days up to day 28 because the certainty of the evidence is very low (mean difference, inverse variance, 0.00, 95% CI ‐0.97 to 0.97; 2388 participants).

We combined data for adverse events reported by more than one study. It is uncertain whether EN or PN affects aspiration because the certainty of the evidence is very low (RR 1.53, 95% CI 0.46 to 5.03; 2437 participants; 2 studies), and we found that one feeding route rather than the other may make little or no difference to pneumonia (RR 1.10, 95% CI 0.82 to 1.48; 415 participants; 7 studies; low‐certainty evidence). We found that EN may reduce sepsis (RR 0.59, 95% CI 0.37 to 0.95; 361 participants; 7 studies; low‐certainty evidence), and it is uncertain whether PN reduces vomiting because the certainty of the evidence is very low (RR 3.42, 95% CI 1.15 to 10.16; 2525 participants; 3 studies).

Enteral nutrition versus enteral nutrition and parenteral nutrition

We found that one feeding regimen rather than another (EN or combined EN or PN) may make little or no difference to mortality in hospital (RR 0.99, 95% CI 0.84 to 1.16; 5111 participants; 5 studies; low‐certainty evidence), and at 90 days (RR 1.00, 95% CI 0.86 to 1.18; 4760 participants; 2 studies; low‐certainty evidence). It is uncertain whether combined EN and PN leads to fewer deaths at 30 days because the certainty of the evidence is very low (RR 1.64, 95% CI 1.06 to 2.54; 409 participants; 3 studies). It is uncertain whether one feeding regimen rather than another reduces mortality within 180 days because the certainty of the evidence is very low (RR 1.00, 95% CI 0.65 to 1.55; 120 participants; 1 study).

No studies reported number of ICU‐free days or ventilator‐free days up to day 28. It is uncertain whether either feeding method reduces pneumonia because the certainty of the evidence is very low (RR 1.40, 95% CI 0.91 to 2.15; 205 participants; 2 studies). No studies reported aspiration, sepsis, or vomiting.

Authors' conclusions

We found insufficient evidence to determine whether EN is better or worse than PN, or than combined EN and PN for mortality in hospital, at 90 days and at 180 days, and on the number of ventilator‐free days and adverse events. We found fewer deaths at 30 days when studies gave combined EN and PN, and reduced sepsis for EN rather than PN. We found no studies that reported number of ICU‐free days up to day 28. Certainty of the evidence for all outcomes is either low or very low. The 11 studies awaiting classification may alter the conclusions of the review once assessed.

Plain language summary

Delivery of nutrition (food) to critically ill adults other than by the person eating and swallowing the food/nutrition

Background

Critically ill adults in the intensive care unit (ICU) are at an increased risk of malnutrition because the body responds to serious illness or injury by increasing the metabolic rate. Also, the person's feeding routine may be disrupted because they are unconscious or too ill to feed themselves or eat normally. This means alternative ways to ensure people receive adequate nutrition must be used. People may be given artificial nutrition in three ways: enteral feeding (through a tube placed into the stomach or small intestine; parenteral feeding (through a tube inserted into a vein whereby nutrients enter the bloodstream directly); or by a combination of both routes. This review compared the effects of these routes.

Study characteristics

The evidence is current to 3 October 2017. We included 25 studies with 8816 participants who had trauma, emergency, medical or postsurgical conditions and were in the ICU. Eleven studies are awaiting classification (because we did not have enough details to assess them) and two studies are ongoing. Included studies compared enteral feeding with parenteral feeding, or with combined enteral and parenteral feeding.

Key results

Studies reported the number of people who died from any cause at different time points. We found no evidence that enteral feeding compared to parenteral feeding or compared to a combination of routes was more or less likely to reduce the number of deaths in hospital, within 90 days and 180 days. We found evidence from three small studies that fewer people died within 30 days when feeding was given through combined enteral and parenteral routes. No studies reported number of ICU‐free days up to day 28 (i.e. length of stay in the ICU by taking account of expected participant loss because of death) and one study reported that the feeding route did not affect the number of ventilator‐free days.

We found no evidence that enteral feeding compared to parenteral feeding was likely to increase or decrease cases of aspiration (the entry of materials such as food from the digestive system to the lungs) or pneumonia (swelling of the tissue in one or both lungs that is usually caused by a bacterial infection). Enteral nutrition may reduce sepsis (a life‐threatening condition that arises when the body's response to infection causes injury to its own tissues and organs), although evidence was from studies of people with different conditions (such as trauma, medical, or postsurgical conditions). We found that fewer participants vomited if they were given parenteral feeding rather than enteral feeding, although there were few studies with very few reported events.

Certainty of the evidence

It was not possible for researchers to mask the ICU staff to the type of feeding route, which may have biased the findings, and study authors did not consistently report good study methods. People in each study had different types of critical illness (such as trauma, medical, or postsurgical conditions) which may have affected how they responded to the type of feeding route, and there were limited data for many of our measurements. We believed that the certainty of the evidence was low or very low.

Conclusion

We found insufficient evidence to determine with confidence whether one feeding route was better at reducing the number of deaths, the number of ventilator‐free days, and side effects. No studies reported number of ICU‐free days up to day 28. Evidence was of low and very low certainty, and we could not be confident in the findings of our review.

Summary of findings

Background

Description of the condition

Malnutrition is associated with increased mortality and morbidity to include susceptibility to infectious complications, such as pulmonary infections, urinary infections, wound infections, and sepsis, and susceptibility to non‐infectious complications, such as respiratory failure and cardiac arrhythmias (Correia 2003; Mogensen 2015).

Acute and chronic illness, trauma, and inflammation induce stress‐related catabolism, increasing the metabolic rate at which the body breaks down food. In addition to this, drug‐related side effects may affect ingestion and lead to loss of appetite or nausea and vomiting, or both, and it has been suggested that hospital routines and lack of awareness among nursing staff may affect nutritional care (Norman 2008). Critically ill people, who may be unconscious, unable to feed themselves or unable to receive oral nutritional support, or both, are at increased susceptibility to malnutrition.

Nutritional support is a complex aspect of care for critically ill people. This systematic review aimed specifically to address the route of delivery that will optimize uptake of nutrition. It did not deal with supplementation of specific nutrients as a number of these are reviewed already (Allingstrup 2016; Dushianthan 2016; Tao 2014).

Description of the intervention

Enteral nutrition (EN) refers to the delivery of a nutritionally complete feed via a tube into the stomach, duodenum, or jejunum (NICE 2006). This method is suitable for people who have inadequate oral intake but a functional gastrointestinal tract, and some evidence suggests that it is an effective method of providing nutrition to particular patient groups (e.g. people with sepsis (Elke 2013); people with acute pancreatitis (Al‐Omran 2010)). EN may help to maintain the function and integrity of the gut barrier (Altintas 2011; King 1999; Kyle 2006), and is associated with increased immunoglobulin A production, which in turn may provide increased protection against airway infections. However, critically ill people may not tolerate enteral feeding well, and side effects such as nausea and vomiting may occur (Harvey 2015), and non‐occlusive bowel necrosis (Marvin 2000). In addition, high volumes of gastric residual may allow bacteria to colonize, and increase the risk of aspiration and complications, such as ventilator‐associated pneumonia (Altintas 2011), although one study assessing monitoring of gastric residual volume showed no difference in ventilator‐associated pneumonia with absence of monitoring (Reignier 2013). Furthermore, EN can be disturbed by patient care and diagnostic interventions, particularly among people receiving respiratory support (Corley 2017), and this may affect the capacity for EN to maintain nutritional goals (Kyle 2006; Seres 2013). Some benefit has been found from placing the tube into the duodenum or jejunum rather than the stomach (Alkhawaja 2015).

Parenteral nutrition (PN) is unphysiological and bypasses the gastrointestinal tract and portal venous system. It delivers a nutritionally complete feed intravenously via a central or peripheral venous catheter, and may be used as an alternative for people in need of nutritional support. It confers the advantage of ease of administration to the person (Seres 2013), often with no further intervention needed to provide nutritional support when all components are administered via an 'all in one bag' system. Whilst interrupting feeding during patient care is not necessary, PN may increase the risk of overfeeding (Singer 2009). PN is associated with a higher rate of hyperglycaemia; subsequently, people may require glycaemic control alongside PN. Earlier studies have reported increased susceptibility to infectious complications, such as catheter‐related bloodstream infections (Peter 2005).

PN may be used to supplement EN to achieve target energy requirements when EN alone is inadequate (Singer 2011).

Research findings are unclear regarding sufficient caloric intake needed to meet the energy requirements of critically ill people, and no evidence currently supports the assumption that these people benefit from a normocaloric intake (80% to 100% of energy requirements) rather than permissive underfeeding (less than 70% of energy requirements) (Marik 2016). Similarly, a target time for initiation of nutrition has been debated by researchers, with large randomized controlled trials (RCTs) (e.g. the EDEN (Early versus delayed enteral feeding to treat people with acute lung injury or acute respiratory distress syndrome) study (ARDS Clinical Trials Network 2012); the EPaNIC (Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients) study (Casaer 2011)), providing evidence that conflicts with European nutrition guidelines (ESPEN; Singer 2009), which advise early feeding during critical illness (Casaer 2014). Whilst this review aimed specifically to address the route of nutrition, both caloric intake and initiation time are also important considerations.

Why it is important to do this review

The most current American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines recommend use of EN over PN (Taylor 2016), suggesting a reduction in infectious morbidity and length of stay in the intensive care unit (ICU) for people given EN. This is comparable with guidelines of the European Society for Parenteral and Enteral Nutrition (ESPEN) (Kreymann 2006; Singer 2009), and the UK National Institute for Health and Care Excellence (NICE) (NICE 2006). However, these guidelines reflect only research findings of small RCTs published prior to these guidelines, and current evidence contradicts some outcomes, for example, risk of infectious complications with PN.

It is highly debated if, how, and when nutritional support may contribute to improved patient outcomes (Casaer 2014; Preiser 2015; Schetz 2013). Nutrition for critically ill people has global relevance, achieving benefits for the patient and reducing impact on healthcare resources. This review aimed specifically to consider whether the route of delivery of nutrition is a significant factor in the treatment of critically ill adults, and incorporates recent findings to assess both evidence of benefit and risk of adverse events.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included all randomized controlled trials (RCTs), including quasi‐randomized studies (e.g. studies in which the method of assignment was based on alternation, date of birth, or medical record number) and cluster‐randomized studies.

Types of participants

We included all adults, over 16 years of age, who had been in an ICU for at least 24 hours.

We included participants admitted for all conditions, except acute pancreatitis as this patient group is reviewed elsewhere (Al‐Omran 2010). We aimed to include studies that had a mixed population that included acute pancreatitis, if fewer than 50% of participants had acute pancreatitis; we aimed to contact study authors to request additional information if necessary.

We included trauma, emergency, medical, and elective postsurgical participants. We included mechanically ventilated and non‐mechanically ventilated participants.

If studies included participants of which not all were in the ICU, we included the study if study authors reported that more than 75% of participants were in the ICU.

Types of interventions

We included studies that compare EN versus PN, and studies that compared EN versus EN and PN. These represent two comparison groups; we analysed separately data from studies comparing EN versus PN and studies comparing EN versus EN and PN.

We included EN that was given via a tube into the stomach, duodenum, or jejunum, and PN that was given via a central venous catheter or a peripheral venous catheter. We anticipated that the protocol used to administer nutrition would differ between studies. We included EN and PN initiated early or delayed, and given to meet a normocaloric or hypocaloric goal.

Types of outcome measures

We aimed to establish whether one type of feeding method reduced the rate of mortality among study participants and considered data gathered at different time points, up to 180 days. Length of stay in the ICU was an important outcome for this review topic. Given that rates of mortality may be high in the included population, and to avoid the effect of death on this outcome, we planned to report data presented as ICU‐free days. Similarly, we planned to assess duration of mechanical ventilation as the number of ventilator‐free days. These outcomes account for the number of days that a person is alive or is no longer using mechanical ventilation; therefore, a participant who has died would be counted as having zero ICU‐free or ventilator‐free days. Adverse events represent an important outcome for this review, and EN and PN may lead to different adverse events. For each adverse event reported by study authors, we collected data during the study follow‐up period.

Primary outcomes

Mortality (measured: in‐hospital, within 30 days, within 90 days, and within 180 days).

Secondary outcomes

Number of ICU‐free days up to day 28.
Number of ventilator‐free days up to day 28.
Adverse events as reported by study authors (to include hyperglycaemia, aspiration pneumonia, catheter‐related bloodstream infections, and gastrointestinal events).

Search methods for identification of studies

Electronic searches

We identified RCTs through literature searching with systematic and sensitive search strategies as outlined in Chapter 6.4 of the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). We applied no restrictions to language or publication status.

We searched the following databases for relevant trials:

Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 9);
MEDLINE (OvidSP, 1946 to 3 October 2017);
Embase (OvidSP, 1974 to 3 October 2017).

We developed a subject‐specific search strategy in MEDLINE and used that as the basis for the search strategies in the other listed databases. The search strategy was developed in consultation with the Information Specialist. Search strategies can be found in Appendix 1; Appendix 2; and Appendix 3.

We scanned the following trial registries for ongoing and unpublished trials (8 January 2018):

World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp/en/);
ClinicalTrials.gov (clinicaltrials.gov).

Searching other resources

We carried out citation searching of identified included studies in Web of Science (apps.webofknowledge.com), on 24 March 2017 and conducted a search of grey literature through Opengrey (www.opengrey.eu./), on 27 April 2017. We scanned reference lists of relevant systematic reviews to search for additional trials. We did not contact study authors or organizations to ask if they were aware of other completed or ongoing studies.

Data collection and analysis

Two review authors (SL and OSR) independently completed all data collection and analyses before comparing results and reaching consensus. We consulted with a third review author (AS) to resolve conflicts when necessary.

Selection of studies

We used reference management software to collate the results of searches and to remove duplicates (Endnote). We used Covidence software to screen results of the search of titles and abstracts and identify potentially relevant studies (Covidence). We sourced the full texts of all potentially relevant studies and considered whether they meet the inclusion criteria (see Criteria for considering studies for this review). We reviewed abstracts at this stage and included these in the review only if they provided sufficient information and relevant results that included denominator figures for each intervention/comparison group. We recorded the number of papers retrieved at each stage and reported this information using a PRISMA flow chart. We reported in the review brief details of closely related but excluded papers.

Data extraction and management

We used Covidence software to extract data from individual studies (Covidence). A basic template for data extraction forms is available at www.covidence.org. We adapted this template to include the following information.

Methods: type of study design; setting; dates of study; funding sources.
Participants: number of participants randomized to each group; baseline characteristics (to include "Acute Physiology and Chronic Health Evaluation II" (APACHE II) scores, whether mechanically ventilated and length of time in the ICU before study commencement).
Interventions: details of intervention and comparison nutrition (kilocalories per kilogram received, time of initiation, duration of delivery, use of glycaemic controls).
Outcomes: all relevant review outcomes as measured and reported by study authors.
Outcome data: results of outcome measures.

We considered the applicability of information from individual studies and the generalizability of data to our intended study population (i.e. the potential for indirectness in our review). If we found associated publications from the same study, we created a composite dataset based on all eligible publications.

Assessment of risk of bias in included studies

Two review authors (SL and OSR) independently assessed study quality, study limitations, and the extent of potential bias by using the Cochrane ’Risk of bias’ tool (Higgins 2011). We considered the following domains.

Sequence generation (selection bias).
Allocation concealment (selection bias).
Blinding of participants, personnel, and outcome assessors (performance and detection bias).
Incomplete outcome data (attrition bias).
Selective outcome reporting (reporting bias).
Other: use of concomitant drugs.

We anticipated that it would not be feasible for studies to blind participants and personnel and, in the absence of any description of personnel blinding, we assumed that no blinding occurred. However, we anticipated that it was feasible to blind outcome assessors and we considered risk of detection bias (outcome assessor blinding) by each outcome. We considered whether investigators used standard criteria for diagnosis of outcomes, for example, aspiration pneumonia or ventilator‐acquired pneumonia, which may be subject to clinician bias.

For each domain, we judged whether study authors had made sufficient attempts to minimize bias in their study design. We made judgements using three measures; high, low, and unclear risk of bias. We recorded this judgement in ’Risk of bias’ tables and presented a summary ’Risk of bias’ figure.

Measures of treatment effect

We collected dichotomous data for mortality and adverse events, and continuous data for number of ICU‐free days and number of ventilator‐free days. We reported dichotomous data as risk ratios (RR) to compare groups, and continuous data as a mean difference (MD). We reported 95% confidence intervals (CI).

Unit of analysis issues

(See Differences between protocol and review.) We conducted separate analysis for the comparison arms PN, and EN and PN; this method avoided double‐counting in multi‐arm studies.

In the event of cluster trials, we would have defined the unit of allocation as the ICU or the hospital rather than the individual participant and analysed data accordingly, calculating effect estimates using the generic inverse variance method (Higgins 2011).

Dealing with missing data

In the event that study authors did not account for missing data, we would have contacted them for information. We considered data to be complete if losses were reported and explained by study authors and we combined no incomplete data in the meta‐analysis.

Assessment of heterogeneity

We assessed whether evidence of inconsistency was apparent in our results by considering heterogeneity. We assessed clinical heterogeneity by comparing similarities in our included studies between study designs, participants, interventions, and outcomes, and used the data collected as stated under Data extraction and management. We assessed statistical heterogeneity by calculating the Chi² test or I² statistic and judged any heterogeneity above an I² value of 60% and a Chi² P value less than or equal to 0.05 to indicate moderate to substantial statistical heterogeneity (Higgins 2011).

In addition to looking at statistical results, we considered point estimates and overlap of CIs. If CIs overlap, then results are more consistent. Combined studies may show a large consistent effect but with significant heterogeneity. Therefore, we planned to interpret heterogeneity with caution (Guyatt 2011a).

Assessment of reporting biases

We attempted to source published protocols for each of our included studies by using clinical trials registers. We compared published protocols with published study results to assess the risk of selective reporting bias. If we identified sufficient studies reporting on an outcome (i.e. more than 10 studies (Higgins 2011)), we planned to generate a funnel plot to assess risk of publication bias in the review; an asymmetrical funnel plot may suggest publication of only positive results (Egger 1997).

Data synthesis

We completed meta‐analyses of outcomes for which we had comparable effect measures from more than one study, and when measures of heterogeneity indicated that pooling of results was appropriate. We did not pool studies that had a high level of clinical heterogeneity and moderate to high statistical heterogeneity indicated by I² statistics and Chi² P values. We used the statistical calculator provided in Review Manager to perform meta‐analysis (Review Manager 2014).

For dichotomous outcomes, for example, mortality rate, we calculated the RR using summary data presented in each trial. We used the Mantel‐Haenszel effects model. If events had been extremely rare (one per 1000), we would have used the Peto odds ratio (Higgins 2011). For continuous outcomes, we aimed to use the MD. We used a fixed‐effect statistical model. In the event of finding evidence of moderate statistical or clinical heterogeneity, we would have investigated this by performing subgroup analyses, as below, and analysed data using a random‐effects model to incorporate unexplained heterogeneity.

We calculated CIs at 95% and used a P value less than or equal to 0.05 to judge whether a result was statistically significant. We considered imprecision in the results of analyses by assessing the CI around an effects measure; a wide CI would suggest a higher level of imprecision in our results. A small number of identified studies may also reduce precision (Guyatt 2011b).

Subgroup analysis and investigation of heterogeneity

Study designs may differ in relation to time of initiation of feeding and target energy requirements given to participants. Therefore, we considered these subgroups for each of our outcomes. We used cut‐offs for time of feeding from the most recent ASPEN guidelines (Taylor 2016), and cut‐offs for target energy requirements from Marik 2016. Critically ill people who are elderly may have different nutritional requirements and metabolism (ASPEN 2002), leading to different responses to EN and PN methods as compared with younger participants. We did not supply a cut‐off age for this subgroup but aimed to separate participants described as 'frail elderly' by study authors from remaining participants. Heterogeneity may be introduced by the types of procedures that participants have undergone or by their reason for admission; people who have had abdominal or bowel surgery and people admitted with gastrointestinal complications may have greater difficulty with ingestion and digestion. In summary, we aimed to perform subgroup analysis as follows.

Early initiation of feeding (less than 48 hours) versus late initiation of feeding (48 hours or greater).
Normocaloric intake (to match 80% to 100% of energy expenditure) versus hypocaloric intake (less than 70% of energy expenditure).
'Frail elderly' versus other participants.
Gastrointestinal medical or surgical participants versus non‐gastrointestinal medical or surgical participants.

We performed subgroup analysis only when study authors reported outcome data for identified subgroups. In the absence of numerical data, we planned to present qualitative analysis of these factors as a possible source of heterogeneity.

We aimed to perform subgroup analyses on the following outcomes: mortality, number of ICU‐free days up to day 28, and number of ventilator‐free days up to day 28.

Sensitivity analysis

We explored the potential effects of decisions made as part of the review process as follows.

We excluded all studies that we judged at high or unclear risk of selection bias.
We assessed decisions made regarding missing data, excluding studies that provided incomplete data.
We conducted meta‐analysis using the alternate meta‐analytical effects model (fixed‐effect or random‐effects).

We compared effect estimates from the above results with effect estimates from the main analysis. We aimed to report differences that altered interpretation of effects.

We aimed to perform sensitivity analyses on the following outcomes: mortality, number of ICU‐free days up to day 28, and number of ventilator‐free days up to day 28.

'Summary of findings' table and GRADE

Two review authors (SL and OSR) independently used the GRADE system to assess the certainty of the body of evidence associated with the following outcomes (Guyatt 2008):

mortality (at time points: in‐hospital, 30 days, 90 days, 180 days);
number of ICU‐free days up to day 28;
number of ventilator‐free days up to day 28;
adverse events as reported by study authors (aspiration, sepsis, pneumonia, and vomiting).

The GRADE approach appraises the certainty of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Evaluation of the certainty of a body of evidence considers within‐study risk of bias, directness of the evidence, heterogeneity of the data, precision of effect estimates, and risk of publication bias.

We constructed two 'Summary of findings' tables using the GRADE profiler software for the following comparisons in this review (www.guidelinedevelopment.org/):

EN versus PN for adults in the ICU;
EN versus EN and PN for adults in the ICU.

We reached consensus without consulting a third review author.

Results

Description of studies

Results of the search

We screened 4173 titles and abstracts, of which we identified 1369 through forward and backward citation searches. We screened titles from clinical trials registers and grey literature searches. We assessed 147 full texts for eligibility. See Figure 1.

Included studies

See Characteristics of included studies table.

We included 25 studies (37 publications), with 8816 participants (Abdulmeguid 2007; Abrishami 2010; Adams 1986; Altintas 2011; Bauer 2000; Bertolini 2003; Borzotta 1994; Casaer 2011; Cerra 1988; Chiarelli 1996; Dunham 1994; Engel 1997; Fan 2016; Gencer 2010; Hadfield 1995; Harvey 2014; Heidegger 2013; Justo Meirelles 2011; Kudsk 1992; Peterson 1988; Radrizzani 2006; Rapp 1983; Xi 2014; Young 1987). Two studies were quasi‐randomized (Altintas 2011; Fan 2016), and the remaining studies were RCTs. We found no cluster‐randomized studies. Reports for Bertolini 2003 and Radrizzani 2006 were for the same study, but participants were divided according to criteria for sepsis (severe sepsis in Bertolini 2003; and non‐severe sepsis in Radrizzani 2006), and we included them as separate studies for the purpose of this review. We included one study for which we could only source the abstract (Abdulmeguid 2007); we sourced the full text of all remaining studies.

Study population

Participants had a wide variety of primary diagnoses but all were critically ill. Sixteen studies reported that participants were mechanically ventilated (Abdulmeguid 2007; Adams 1986; Altintas 2011; Bertolini 2003; Borzotta 1994; Cerra 1988; Chiarelli 1996; Dunham 1994; Harvey 2014; Heidegger 2013; Justo Meirelles 2011; Kudsk 1992; Radrizzani 2006; Rapp 1983; Wischmeyer 2017; Xi 2014); nine studies did not describe mechanical ventilation status as part of the inclusion or exclusion criteria (Abrishami 2010; Bauer 2000; Casaer 2011; Engel 1997; Fan 2016; Gencer 2010; Hadfield 1995; Peterson 1988; Young 1987).

Study setting

All studies were conducted in the ICU (Abdulmeguid 2007; Abrishami 2010; Adams 1986; Altintas 2011; Bauer 2000; Bertolini 2003; Casaer 2011; Cerra 1988; Chiarelli 1996; Dunham 1994; Fan 2016; Gencer 2010; Hadfield 1995; Harvey 2014; Heidegger 2013; Justo Meirelles 2011; Kudsk 1992; Peterson 1988; Radrizzani 2006; Rapp 1983; Wischmeyer 2017; Xi 2014), or assumed to be in the ICU (Borzotta 1994; Engel 1997; Young 1987). Eight studies were undertaken in the USA (Adams 1986; Borzotta 1994; Cerra 1988; Dunham 1994; Kudsk 1992; Peterson 1988; Rapp 1983; Young 1987); three were in Italy (Bertolini 2003; Chiarelli 1996; Radrizzani 2006); two were in the UK (Hadfield 1995; Harvey 2014); two were in Turkey (Altintas 2011; Gencer 2010); two were in China (Fan 2016; Xi 2014); and one each in Iran (Abrishami 2010); France (Bauer 2000); Belgium (Casaer 2011); Germany (Engel 1997); Switzerland (Heidegger 2013); and Brazil (Justo Meirelles 2011). One international study was undertaken in Belgium, Canada, France, and the USA (Wischmeyer 2017). One study did not report the country in which it was conducted (Abdulmeguid 2007).

Intervention and comparisons

Seventeen studies compared an EN feeding protocol to a PN feeding protocol (Abdulmeguid 2007; Adams 1986; Altintas 2011; Bertolini 2003; Borzotta 1994; Cerra 1988; Engel 1997; Gencer 2010; Hadfield 1995; Harvey 2014; Justo Meirelles 2011; Kudsk 1992; Peterson 1988; Radrizzani 2006; Rapp 1983; Xi 2014; Young 1987); Engel 1997 was a multi‐arm study with two EN groups (one standard EN formula and one formula supplemented with arginine, omega‐3 fatty acid, nucleotide, and selenium). Six studies compared an EN feeding protocol to a protocol in which EN was supplemented with PN (Abrishami 2010; Bauer 2000; Casaer 2011; Chiarelli 1996; Heidegger 2013; Wischmeyer 2017). Two studies compared EN versus PN and versus combined EN and PN (Dunham 1994; Fan 2016).

Study authors reported initiation of both EN and PN within 48 hours of ICU admission in 13 studies (Adams 1986; Altintas 2011; Bauer 2000; Bertolini 2003; Dunham 1994; Engel 1997; Fan 2016; Harvey 2014; Justo Meirelles 2011; Kudsk 1992; Peterson 1988; Radrizzani 2006; Wischmeyer 2017). One study reported that all participants were given PN within 24 to 36 hours and that EN was initiated in one group at four days (Chiarelli 1996). One study reported that initiation of EN in one group was after at least 14 days of fasting, and study authors did not state at which time point PN was initiated (Xi 2014). Two studies initiated supplemental PN after all participants had been given EN for three days (Casaer 2011; Heidegger 2013). The remaining five study authors did not report time of initiation of feeding (Abdulmeguid 2007; Abrishami 2010; Gencer 2010; Hadfield 1995; Young 1987).

Outcomes

All studies, except Engel 1997, reported participant deaths; some studies did not clearly report time points and some studies reported deaths as participant losses with mortality as a reason for withdrawal from the study. No studies reported data for number of ICU‐free days up to day 28, and one study reported data for number of ventilator‐free days up to day 28 (Harvey 2014). Study authors reported adverse events which were: mechanical (Borzotta 1994; Casaer 2011; Harvey 2014); metabolic (Borzotta 1994; Fan 2016; Harvey 2014); gastrointestinal (Adams 1986; Altintas 2011; Bauer 2000; Borzotta 1994; Casaer 2011; Cerra 1988; Chiarelli 1996; Fan 2016; Harvey 2014); and infective (Abdulmeguid 2007; Adams 1986; Altintas 2011; Borzotta 1994; Casaer 2011; Engel 1997; Fan 2016; Gencer 2010; Justo Meirelles 2011; Heidegger 2013; Kudsk 1992; Rapp 1983; Wischmeyer 2017; Xi 2014; Young 1987).

Funding sources

Study authors reported funding sources in 11 studies (Abrishami 2010; Adams 1986; Bertolini 2003; Borzotta 1994; Casaer 2011; Hadfield 1995; Harvey 2014; Heidegger 2013; Radrizzani 2006; Rapp 1983; Wischmeyer 2017). Three studies noted no involvement in trial management from funders (Casaer 2011; Heidegger 2013; Radrizzani 2006); remaining studies reported no details of funders' involvement.

Excluded studies

We excluded 99 articles after reading the full text. We reported details of 32 of these studies in Characteristics of excluded studies. Of these 32 studies, we excluded studies in which the setting was not reported and we could not assume it was the ICU (Arefian 2007; Baigrie 1996; Braga 1996; Braga 1998; Braga 2001; Chen 2004; DiCarlo 1999; Dong 2010; Hermann 2004; Kim 2012; Klek 2008; Klek 2011; Malhotra 2004; McArdle 1981; Moore 1989; Reynolds 1997; Ryu 2009; Sand 1997; Suchner 1996; Van Barneveld 2016; Xiao‐Bo 2014; Yu 2009; Zhang 2016; Zhu 2012), or too few participants were in the ICU (Woodcock 2001). We excluded two studies of participants with acute pancreatitis (Abou‐Assi 2002; Pupelis 2001). One study compared EN versus PN in people in the ICU (Zhang 2005), but reported that participants in the EN group were also given PN as required for the first three to four days and it was therefore ineligible for our review, and one study was described as an RCT but not all participants randomized to the control group received EN (Doig 2013). We excluded one study that compared early‐goal directed nutrition (EGDN) versus EN in people in the ICU; the EGDN group were given EN supplemented with PN; however, the supplemented PN was only given if required to meet feeding goals and study authors did not report which participants had and did not have PN (Allingstrup 2017). One study compared EN versus PN but feeding took place for only one day in the ICU and feeding was continued for an additional six days on the ward (Fujita 2012). We excluded one abstract that had not been published as a full report (Zanello 1992); the abstract included no outcomes of interest and was published in 1992.

Studies awaiting classification

We were unable to assess eligibility in 11 studies (Braga 1995; Cao 2014; Chen 2011; NCT00522730; NCT01802099; Ridley 2015; Soliani 2001; Theodorakopoulou 2016; Xiang 2006; Xiu 2015; Yi 2015). We identified one study in clinical trials registers that was completed without published results (NCT00522730). From database searches we identified one protocol for a terminated study (NCT01802099), and one study that had been completed but not published (Ridley 2015). We were unable to source full texts for three trials and could not assess eligibility from abstracts (Braga 1995; Chen 2011; Soliani 2001). Four trials were published only as abstracts with insufficient information to assess eligibility (Cao 2014; Theodorakopoulou 2016; Xiu 2015; Yi 2015), and one study report requires translation before we assess eligibility (Xiang 2006). See Characteristics of studies awaiting classification table.

Ongoing studies

We identified two ongoing studies from clinical trials registers (NCT00512122; NCT02022813). See Characteristics of ongoing studies table.

Risk of bias in included studies

We have included a summary of risk of bias assessments in Figure 2 and Figure 3. Blank spaces in the risk bias summary figures indicate that study authors did not report the review outcome.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. Blank spaces in tables indicated that study authors did not report the review outcome.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Blank spaces in tables indicate that study authors did not report the review outcome.

Allocation

All studies were described as randomized and nine studies provided sufficient information on the method of randomization (Bertolini 2003; Borzotta 1994; Casaer 2011; Harvey 2014; Heidegger 2013; Kudsk 1992; Peterson 1988; Radrizzani 2006; Wischmeyer 2017). Two studies randomized participants according to hospital record number (Altintas 2011; Fan 2016), and we judged these to have high risk of bias. The remaining 14 studies reported insufficient information on method of randomization and we recorded these as having unclear risk of bias (Abdulmeguid 2007; Abrishami 2010; Adams 1986; Bauer 2000; Cerra 1988; Chiarelli 1996; Dunham 1994; Engel 1997; Gencer 2010; Hadfield 1995; Justo Meirelles 2011; Rapp 1983; Xi 2014; Young 1987).

Ten studies described adequate allocation concealment methods, and we judged these to have low risk of selection bias (Altintas 2011; Bertolini 2003; Borzotta 1994; Casaer 2011; Harvey 2014; Heidegger 2013; Kudsk 1992; Peterson 1988; Radrizzani 2006; Wischmeyer 2017) The remaining 15 studies reported no description of methods to conceal allocation and we recorded these as having unclear risk of bias (Abdulmeguid 2007; Abrishami 2010; Adams 1986; Bauer 2000; Cerra 1988; Chiarelli 1996; Dunham 1994; Engel 1997; Fan 2016; Gencer 2010; Hadfield 1995; Justo Meirelles 2011; Rapp 1983; Xi 2014; Young 1987).

Blinding

One study reported that participants in the enteral group were given a placebo parenteral solution and we judged this study to have low risk of performance bias (Bauer 2000). One study reported that personnel were not blinded to the intervention group (Heidegger 2013). The remaining studies did not report whether attempts had been made to blind personnel; adequate blinding would involve intrusive procedures (e.g. central line placement or nasogastric tube placement) and if these procedures were not described we assumed that blinding had not occurred (Abdulmeguid 2007; Abrishami 2010; Adams 1986; Altintas 2011; Bertolini 2003; Borzotta 1994; Casaer 2011; Cerra 1988; Chiarelli 1996; Dunham 1994; Engel 1997; Fan 2016; Gencer 2010; Hadfield 1995; Harvey 2014; Justo Meirelles 2011; Kudsk 1992; Peterson 1988; Radrizzani 2006; Rapp 1983; Wischmeyer 2017; Xi 2014; Young 1987). We judged these studies, and Heidegger 2013, to have high risk of performance bias.

We did not believe that lack of blinding of outcome assessors would influence data for the mortality outcome and we judged all studies to have low risk of detection bias for mortality, regardless of whether study authors reported blinding of outcome assessors. Three studies adequately reported blinding of outcome assessors for the remaining review outcomes and we judged these to have low risk of detection bias (Casaer 2011; Dunham 1994; Heidegger 2013). Nineteen studies reported insufficient details of outcome assessor blinding and we judged these to have unclear risk of detection bias (Abdulmeguid 2007; Adams 1986; Altintas 2011; Bauer 2000; Bertolini 2003; Borzotta 1994; Cerra 1988; Chiarelli 1996; Engel 1997; Fan 2016; Gencer 2010; Harvey 2014; Justo Meirelles 2011; Kudsk 1992; Peterson 1988; Rapp 1983; Wischmeyer 2017; Xi 2014; Young 1987). Three studies included data only for mortality and our assessment of detection bias was limited to this outcome (Abrishami 2010; Hadfield 1995; Radrizzani 2006). We noted whether studies had included criteria for diagnoses of outcomes and we were not concerned that lack of information or type of measurement tools had introduced risk of clinician bias.

Incomplete outcome data

We judged 21 studies to have low risk of attrition bias, as there appeared to be no reported losses (Abdulmeguid 2007; Adams 1986; Altintas 2011; Bertolini 2003; Chiarelli 1996; Engel 1997; Fan 2016; Gencer 2010; Hadfield 1995; Justo Meirelles 2011; Rapp 1983; Wischmeyer 2017; Xi 2014), or losses were few and adequately explained by study authors (Abrishami 2010; Bauer 2000; Casaer 2011; Cerra 1988; Dunham 1994; Harvey 2014; Kudsk 1992; Radrizzani 2006). Four studies had a large number of losses or losses were unevenly distributed between groups and we were unclear whether these losses could influence outcome data (Borzotta 1994; Heidegger 2013; Peterson 1988; Young 1987).

Selective reporting

We were able to source prospective clinical trials registration reports for four studies, of which we judged three studies to have low risk of reporting bias (Casaer 2011; Harvey 2014; Wischmeyer 2017). We noted changes to the clinical trials registration documents after completion of the study with regard to data collection time points and we could not be certain whether these changes may have introduced bias to the results; we judged this study to have an unclear risk of selective reporting bias (Heidegger 2013). We were unable to judge reporting bias for the remaining 21 studies because study authors did not report clinical trials registration reports or published protocols (Abdulmeguid 2007; Abrishami 2010; Adams 1986; Altintas 2011; Bauer 2000; Bertolini 2003; Borzotta 1994; Cerra 1988; Chiarelli 1996; Dunham 1994; Engel 1997; Fan 2016; Gencer 2010; Hadfield 1995; Justo Meirelles 2011; Kudsk 1992; Peterson 1988; Radrizzani 2006; Rapp 1983; Xi 2014; Young 1987).

Baseline characteristics

Three studies reported some baseline imbalances between groups and we did not know if these differences could influence outcome data (Altintas 2011; Bertolini 2003; Radrizzani 2006). One study was an abstract and did not provide sufficient detail on baseline characteristics (Abdulmeguid 2007). We judged 21 studies to have low risk of bias for baseline characteristics because data for characteristics were comparable between groups (Abrishami 2010; Adams 1986; Bauer 2000; Borzotta 1994; Casaer 2011; Cerra 1988; Chiarelli 1996; Dunham 1994; Engel 1997; Fan 2016; Gencer 2010; Hadfield 1995; Harvey 2014; Heidegger 2013; Justo Meirelles 2011; Kudsk 1992; Peterson 1988; Rapp 1983; Wischmeyer 2017; Xi 2014; Young 1987).

Other potential sources of bias

We considered whether differences between intervention and comparison groups could have introduced bias; in particular we considered nutritional protocols, patient management and use of concomitant medication, and glycaemic controls. We noted some differences in 12 studies (Abdulmeguid 2007; Adams 1986; Bertolini 2003; Borzotta 1994; Chiarelli 1996; Dunham 1994; Gencer 2010; Hadfield 1995; Harvey 2014; Kudsk 1992; Radrizzani 2006; Young 1987). We were not able to judge if these differences influenced study outcome data and we reported these as having unclear risk of bias. We identified no other sources of bias in the remaining studies.

Effects of interventions

See: Table 1; Table 2

Summary of findings for the main comparison. Enteral versus parenteral nutrition for adults in the intensive care unit.

Enteral versus parenteral nutrition for adults in the intensive care unit
Patient or population: critically ill adults admitted to the ICU for trauma, emergency, or surgical care; population excluded people with acute pancreatitis  Setting: intensive care units in: Brazil, China, Germany, Iran, Italy, Turkey, UK, and USA  Intervention: EN  Comparison: PN
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)
	Risk with EN	Risk with PN
Mortality	In‐hospital mortality		RR 1.19  (0.80 to 1.77)	361  (6 studies)	⊕⊕⊝⊝  Low^a
	Study population
	229 per 1000  (154 to 340)	192 per 1000
	Mortality within 30 days		RR 1.02 (0.92 to 1.13)	3148  (11 studies)	⊕⊕⊝⊝  Low^b
	Study population
	304 per 1000  (274 to 336)	298 per 1000
	Mortality within 90 days		RR 1.06  (0.95 to 1.17)	2461  (3 studies)	⊕⊝⊝⊝  Very low^c
	Study population
	393 per 1000  (352 to 434)	371 per 1000
	Mortality within 180 days		RR 0.33 (0.04 to 2.97)	46  (1 study)	⊕⊝⊝⊝  Very low^d
	Study population
	130 per 1000	43 per 1000 (5 in 387)
Number of ICU‐free days up to day 28	–	–	–	–	Not measured
Number of ventilator‐free days up to day 28	Mean number of ventilator‐free days: 14.2 (SD ± 12.2)	Mean difference 0 days (0.97 fewer to 0.97 more)	N/A	2388  (1 study)	⊕⊝⊝⊝   Very low^d
Adverse events: aspiration (as reported by study authors at end of study follow‐up period)	Study population		RR 1.53  (0.46 to 5.03)	2437  (2 studies)	⊕⊝⊝⊝  Very low^e
	5 per 1000  (2 to 17)	3 per 1000
Adverse events: sepsis (as reported by study authors at end of study follow‐up period)	Study population		RR 0.59 (0.37 to 0.95)	361  (7 studies)	⊕⊕⊝⊝  Low^f
	123 per 1000  (77 to 199)	209 per 1000
Adverse events: pneumonia (as reported by study authors at end of study follow‐up period)	Study population		RR 1.10 (0.82 to 1.48)	415  (7 studies)	⊕⊕⊝⊝  Low^f
	314 per 1000  (234 to 423)	268 per 1000
Adverse events: vomiting (as reported by study authors at end of study follow‐up period)	Study population		RR 3.42  (1.15 to 10.16)	2525  (3 studies)	⊕⊝⊝⊝  Very low^g
	11 per 1000  (4 to 32)	3 per 1000
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EN: enteral nutrition; ICU: intensive care unit; N/A: not applicable; PN: parenteral nutrition; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence  High: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Enteral versus enteral and parenteral nutrition for adults in the intensive care unit
Patient or population: critically ill adults admitted to the ICU for trauma, emergency, or post‐surgical care; population excludes participants with acute pancreatitis  Setting: intensive care units in: France, Italy, Switzerland, Turkey, and USA  Intervention: EN  Comparison: EN + PN
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)
	Risk with EN	Risk with EN + PN
Mortality	In‐hospital mortality		RR 0.99 (0.84 to 1.16)	5111  (5 studies)	⊕⊕⊝⊝  Low^a
	Study population
	106 per 1000  (90 to 124)	107 per 1000
	Mortality within 30 days		RR 1.64 (1.06 to 2.54)	409  (3 studies)	⊕⊝⊝⊝  Very low^b
	Study population
	216 per 1000  (140 to 335)	132 per 1000
	Mortality within 90 days		RR 1.00 (0.86 to 1.18)	4760 (2 studies)	⊕⊕⊝⊝  Low^c
	Study population
	115 per 1000 (99 to 135)	115 per 1000
	Mortality within 180 days		RR 1.00  (0.65 to 1.55)	120 (1 RCT)	⊕⊝⊝⊝  Very low^d
	Study population
	400 per 1000 (260 to 620)	400 per 1000
Number of ICU‐free days up to day 28	–	–	–	–	Not measured
Number of ventilator‐free days up to day 28	–	–	–	–	Not measured
Adverse events: aspiration (as reported by study authors at end of study follow‐up period)	–	–	–	–	Not measured
Adverse events: sepsis (as reported by study authors at end of study follow‐up period)	–	–	–	–	Not measured
Adverse events: pneumonia (as reported by study authors at end of study follow‐up period)	350 per 1000 (228 to 538)	250 per 1000	RR 1.40 (0.91 to 2.15)	205 (2 studies)	⊕⊝⊝⊝ Very low^d
Adverse events: vomiting (as reported by study authors at end of study follow‐up period)	–	–	–	–	Not measured
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EN: enteral nutrition; ICU: intensive care unit; PN: parenteral nutrition; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence  High: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Study ID	Description of event	EN group (n/N)	PN group (n/N)
Mechanical events
Adams 1986	Clogged jejunostomy tube	9/23	N/A
	Disconnected line	N/A	1/23
	Line eroded into right upper lobe bronchus	N/A	1/23
	Malfunctioned line	N/A	7/23
Dunham 1994	Transpyloric tube occlusion	2/12	0/15
	Failure to intubate	0/12	0/15
	Withdrawal of tube by participant	1/12	N/A
Metabolic events
Adams 1986	Hepatic failure	1/23	1/23
	Acute renal failure	1/23	1/23
	Pancreatitis	2/23	1/23
Fan 2016	Hypoproteinaemia	22/40	32/40
Harvey 2014	Electrolyte disturbance	5/1197	8/1191
Gastrointestinal events
Adams 1986	Nausea, cramps, bloating	19/23	16/23
Adams 1986	Gastrointestinal bleeding	0/23	0/23
Dunham 1994	Gastric reflux	0/12	0/15
	Ileus	1/12	0/15
	Small bowel ileus	0/12	1/15
Fan 2016	Stress ulcer	7/40	19/40
Harvey 2014	Elevated liver enzymes	7/1197	3/1191
	Jaundice	1/1197	1/1191
	Ischaemic bowel	0/1197	1/1191
Xi 2014	Anastomotic leak	2/22	6/23
Infective events
Adams 1986	Persistent fever without obvious cause	1/23	5/23
Altintas 2011	Catheter infection	2/30	4/41
Borzotta 1994	Meningitis	2/28	0/21
	Sinusitis	3/28	6/21
	Bronchitis	6/28	6/28
	Clostridium difficile	2/28	4/21
	Peritonitis	0/28	1/21
Fan 2016	Intracranial infection	7/40	13/40
Fan 2016	Pyaemia	3/40	19/40
Gencer 2010	Pulmonary infection	2/30	2/30
Kudsk 1992	Empyema	1/51	4/45
Young 1987	Aspiration pneumonia	9/28	3/23
Young 1987	Infection (type of infection not described)	5/28	4/23

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 In‐hospital mortality	6	361	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.80, 1.77]
2 Mortality at 30 days	11	3148	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.92, 1.13]
3 Mortality at 90 days	3	2461	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.95, 1.17]
4 Aspiration	2	2437	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.46, 5.03]
5 Pneumothorax	2	2437	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.19, 11.22]
6 Hyperglycaemia	2	2437	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.35, 0.93]
7 Vomiting	3	2525	Risk Ratio (M‐H, Fixed, 95% CI)	3.42 [1.15, 10.16]
8 Diarrhoea	6	363	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [1.72, 2.75]
9 Abdominal distension	3	2505	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.34, 6.96]
10 Sepsis	7	361	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.37, 0.95]
11 Pneumonia	7	415	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.82, 1.48]
12 Intra‐abdominal infection	3	202	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.07, 0.89]
13 Wound infection	3	155	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.55, 3.82]
14 Urinary tract infection	3	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.65, 3.40]
15 In‐hospital mortality: gastrointestinal (GI) medical/surgical vs non‐GI medical/surgical	6	361	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.80, 1.77]
15.1 GI medical/surgical	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.06, 13.74]
15.2 Non‐GI medical/surgical	5	263	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.80, 1.79]
16 Mortality at 30 days: GI medical/surgical vs non‐GI medical/surgical	10	3068	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.93, 1.14]
16.1 GI medical/surgical	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.71]
16.2 Non‐GI medical/surgical	9	3008	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.93, 1.15]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 In‐hospital mortality	5	5111	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.84, 1.16]
2 Mortality at 30 days	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.06, 2.54]
3 Mortality at 90 days	2	4760	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.86, 1.18]
4 Feeding tube obstruction	2	4662	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.70, 1.32]
5 Diarrhoea	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6 Pneumonia	2	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.91, 2.15]
7 Wound infection	2	4765	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.50, 0.92]
8 Bloodstream infection	2	4765	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.66, 1.01]
9 Urinary tract infection	3	4885	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.65, 1.17]
10 Airway infection	3		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Methods	RCT, 2‐arm, parallel design
Participants	Total number of randomized participants: 80 Inclusion criteria Critically ill, mechanically ventilated people in the ICU Exclusion criteria Not reported in abstract Baseline characteristics No details reported in abstract Country: not reported (published in Croatian journal) Setting: ICU
Interventions	EN group n = 40 Details: nutritional requirements based on Harris‐Benedict equation. Formula consisted of fat, carbohydrate, and protein. Identical to PN group PN group n = 40 Details: nutritional requirements based on Harris‐Benedict equation. Formula consisted of fat, carbohydrate, and protein. Identical to EN group
Outcomes	Serum glucose levels Nosocomial bloodstream infections Septic morbidity LOS in ICU and hospital Duration of mechanical ventilation Mortality
Notes	Funding/declarations of interest: not reported Study dates: not reported We were unable to source the full‐text of this study, and did not have the study authors' contact details to attempt contact.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details. Abstract only
Allocation concealment (selection bias)	Unclear risk	No details. Abstract only
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details. Abstract only. We assumed investigators made no attempts to blind personnel
Blinding of outcome assessment (detection bias)   All outcomes (except mortality)	Unclear risk	No details. Abstract only
Blinding of outcome assessment (detection bias)   Mortality	Low risk	No details. Abstract only. Lack of blinding unlikely to influence outcome data for mortality
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No details. Abstract only. Outcome data were well reported and we assumed there were no losses
Selective reporting (reporting bias)	Unclear risk	No details. Abstract only
Baseline characteristics	Unclear risk	Study authors described participants as matched on SAPS II, age, and primary diagnoses. No baseline characteristics tables or additional detail available
Other bias	Unclear risk	Study authors described nutritional formula of both groups as identical. Insufficient detail in abstract to make judgement on other sources of bias

Methods	RCT, single‐centre, 2‐arm, parallel design
Participants	Total number of randomized participants: 20 Inclusion criteria > 18 years of age, recent ICU admission (< 24 hours), having SIRS, APACHE II > 10, expected not to feed via oral route for ≥ 5 days Exclusion criteria People with high probability of death in next 7 days of admission Pregnant or lactating Having contraindications to EN Primary diagnoses SIRS Baseline characteristics EN group Age, mean (SD): 58.4 (± 5.07) years Gender: not reported APACHE II, median: 17.0 SOFA, median: 9.0 EN + PN group Age, mean (SD): 54.9 (± 5.16) years Gender: not reported APACHE II, median: 18.5 SOFA, median: 7.0 Country: Iran Setting: ICU
Interventions	EN group n = 10; 0 losses Details: nasogastric tube feeding for 7 days. Feeding formula was Fresubin Original (Fresenius Kabi, Germany) given in solution as 1 kcal/mL. Average 70 kg participant initially received 50 mL every 3 hours, increased with 50 mL increments to maximum 300 mL every 3 hours at rate of 100 mL/h. GRV threshold at 300 mL with delay of feeding for 3 hours if threshold was reached. Glycaemic management not reported. EN + PN group n = 10; loss of 1 participant on day 3 (move to different hospital); number analysed assumed to be 9. Details: EN as above. PN consisted of 500 mL of 10% AA solutions (B Braun, Germany), 500 mL of 50% dextrose, infused over 24 hours. Equivalent management of GRV. Duration of feeding for 7 days
Outcomes	Mortality (within 7 days) Analysis of inflammatory markers Length of ICU and hospital stay
Notes	Funding/declarations of interest: partly supported by grant from Tehran University of Medical Sciences Study dates: November 2007 to May 2009
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomized but no additional details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details and we assumed investigators made no attempts to blind personnel
Blinding of outcome assessment (detection bias)   Mortality	Low risk	No details. Lack of blinding unlikely to influence outcome data for mortality
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 participant moved to another hospital after 3 days, not clear whether data for this participant were sourced but small loss unlikely to influence outcome data
Selective reporting (reporting bias)	Unclear risk	No protocol or clinical trials registration reported. Therefore, not feasible to make judgement on selective outcome reporting bias
Baseline characteristics	Low risk	Appeared to be equivalent between groups
Other bias	Low risk	Glycaemic management equivalent for each group. No other sources of bias identified

Methods	RCT, multi‐centre, 2‐arm, parallel design
Participants	Total number of randomized participants: 36 Inclusion criteria > 18 years of age, in high level care, in need of artificial ventilation and nutrition for ≥ 4 days Exclusion criteria Motor GCS < 4 Pure cerebral disease Spinal trauma Referral from ICUs in which participants stayed > 24 hours Primary diagnoses All had severe sepsis or septic shock; some participants had respiratory failure, or respiratory plus cardiovascular failure Baseline characteristics EN group Age, mean (SD): 59.3 (± 17.6) years Gender, M/F: 11/7 SAPS II, median (IQR): 41 (39 to 46) SOFA, median (IQR): 7 (5 to 8) PN group Age, mean (SD): 59.0 (± 21.4) years Gender, M/F: 10/11 SAPS II, median (IQR): 43 (35 to 51) SOFA, median (IQR): 7 (6 to 8) Country: Italy Setting: 33 ICUs
Interventions	EN group n = 17; note 1 participant wrongly randomized to non‐septic group (see Radrizzani 2006) and then analysed in this report; ITT analysis. 18 participants analysed. Details: feeding initiated within 48 hours of ICU admission. Feeding started at 10 kcal/kg/day, rising to 25 to 28 kcal/kg/day by 4th day. Nutritional formula consisted of 55% carbohydrates, 25% fat, 21% protein, 1.3 kcal/mL, containing per 100 mL: L‐arginine 0.8 g, omega‐3 fatty acids 0.15 g, omega‐6 fatty acids 0.7 g, vitamin E 2.9 mg, β‐carotene 0.75 mg, zinc 2.2 mg, and selenium 7 μg (Perative Abbott). Caloric intake received, mean (SD): 19.1 (± 7.6) kcal/kg/day over the first 6 days PN group n = 19; note 2 participants wrongly randomized to non‐septic group (see Radrizzani 2006) and then analysed in this report; ITT analysis. 21 participants analysed Details: feeding protocol as for EN group. Nutritional formula consists of equivalent carbohydrates, fats, and proteins (59% carbohydrates, 23% fat, 18% protein) but does not appear to include additional vitamins/minerals Caloric intake received, mean (SD): 25.9 (± 6.4) kcal/kg/day over the first 6 days
Outcomes	Mortality at 28 days and in the ICU Length of ICU stay
Notes	Funding/declarations of interest: Abbott Italia Study dates: November 1999 to April 2001 Note: study was described as an interim analysis. It is the same study as Radrizzani 2006 but data included were for a subgroup of participants with sepsis only. Also, study authors considered the difference in caloric intake and differences in some baseline characteristics to be significant, and conducted an adjusted analysis after which they concluded that these factors were potentially confounding and subsequently ceased randomization into this study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Adequate sequence generation. Use of computer‐generated randomization code
Allocation concealment (selection bias)	Low risk	Adequate concealment. Quote: "The randomisation code was generated by a computer programme at the co‐ordinating centre and was revealed to investigators by telephone at the moment of randomisation, once baseline data collection was completed."
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details and we assumed investigators made no attempts to blind personnel
Blinding of outcome assessment (detection bias)   All outcomes (except mortality)	Unclear risk	Study authors reported that outcome data analysts were not blinded; study authors did not report whether outcome assessors were blinded
Blinding of outcome assessment (detection bias)   Mortality	Low risk	Lack of blinding unlikely to influence outcome data for mortality
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No apparent losses
Selective reporting (reporting bias)	Unclear risk	Clinical trials registration or prospectively published protocol not reported. Not possible to make assessment on reporting bias
Baseline characteristics	Unclear risk	Study authors noted an imbalance in baseline characteristics (PN group had more women, more participants aged > 60 years, more participants with cardiovascular and respiratory failure) and completed adjusted analysis for these variables. We were unclear whether these differences may affect results for our outcomes
Other bias	Unclear risk	Participants in PN group were given more calories in first 3 days because of study design and study authors completed adjusted analysis for this variable. Participants in EN group given additional supplements of minerals/vitamins which are not included in PN formula. We were unclear whether these differences may affect results for our outcomes

Methods	RCT, single‐centre, 3‐arm, parallel design
Participants	Total number of randomized participants: 38 Inclusion criteria Blunt traumatic event, GCS ≥ 5, ISS ≥ 15 No spinal neuropathy above 8th thoracic spinal level No major fluid restriction requirement Aged 18 to 60 years Able to undergo upper gastrointestinal endoscopy Respiratory insufficiency that mandated need for mechanical ventilation for ≥ 48 hours Excluded criteria If randomization did not take place within 30 hours after admission or admission did not occur within 12 hours after injury Primary diagnoses Blunt trauma injuries Baseline characteristics EN group Age: not reported Gender: not reported APACHE II: not reported GCS, mean (SD): 11 (± 5) ISS, mean (SD): 34 (± 18) PN group Age: not reported Gender: not reported APACHE II: not reported GCS, mean (SD): 12 (± 3) ISS, mean (SD): 38 (± 12) EN + PN group Age: not reported Gender: not reported APACHE II: not reported GCS, mean (SD): 11 (± 4) ISS, mean (SD): 37 (± 15) Country: USA Setting: trauma centre
Interventions	EN group n = 12; 0 losses Details: transpyloric tube placement, feeding started within 24 hours of randomization and continued for 7 days. Investigators used Harris Benedict formula BEE x 1.3 to calculate caloric intake. Aimed to provide 50% projected calories by 24 hours after randomization; and 100% by 48 hours. Formula was Traumacal (Mead‐Johnson), NPC given in form of lipids (30%) and carbohydrates (70%). Ratio of NPC to nitrogen was 105:1. Protein load was 1.75 g/kg/day. Mean caloric intake: 1789 calories/day for 7 days PN group n = 16; 1 participant died on 4th study day, not included in study analysis but we have included in review outcome data. Details: feeding started within 24 hours of randomization and continued for 7 days. Investigators used Harris Benedict formula BEE x 1.3 to calculate caloric intake. Aim to provide 50% projected calories by 24 hours after randomization; and 100% by 48 hours. Formula consisted of dextrose‐lipid‐AA mixture; soybean solution, multi‐vitamin mixture. Mixture was 6.7% AA and 23.1% dextrose, soybean solution provided 30% of the NPC. Mean caloric intake: 1961 calories/day for 7 days EN + PN group n = 10; 0 losses Details: feeding started within 24 hours of randomization and continued for 7 days. Investigators used Harris Benedict formula BEE x 1.3 to calculate caloric intake. Aim to provide 50% projected calories by 24 hours after randomization; and 100% by 48 hours. EN formula provided 50% of calories and PN formula provided 50% of calories. EN consisted of Traumacal (Mead‐Johnson), NPC given in form of lipids (30%) and carbohydrates (70%). PN formula consisted of dextrose‐lipid‐AA mixture; soybean solution, multi‐vitamin mixture. Mean caloric intake: 2030 calories/day for 7 days
Outcomes	Number of ventilator days Number of ICU days Total hospital stay Presence of ARDS Respiratory infection Any infection Renal failure Icterus Death Hospital and professional charges
Notes	Funding/declarations of interest: not reported Study dates: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomized but no additional details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details and we assumed investigators made no attempts to blind personnel
Blinding of outcome assessment (detection bias)   All outcomes (except mortality)	Low risk	Most outcome data were taken from the trauma registry. Quote: "All data from the trauma registry and the finance officers were blinded, since these sources had no knowledge of the patient's status relative to the research arm assigned."
Blinding of outcome assessment (detection bias)   Mortality	Low risk	Outcome assessors were blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 participant was not included in data for PN group due to death during 7‐day intervention period; we have included this event in review analysis. No other loss of data
Selective reporting (reporting bias)	Unclear risk	Clinical trials registration or prospectively published protocol not reported; not feasible to judge risk of selective outcome reporting bias
Baseline characteristics	Low risk	Some usual baseline characteristics not reported (age, gender) but other characteristics all appeared comparable
Other bias	Unclear risk	Target rate of nutrition the same. Unclear if differences in formula were equivalent

Study	Reason for exclusion
Abou‐Assi 2002	RCT. Compared EN vs PN. People with acute pancreatitis
Allingstrup 2017	RCT. Early‐goal directed nutrition vs EN. Adults in ICU. Participants in the early‐goal directed nutrition group were given EN and PN; however, PN was only given if required and therefore, we excluded this study because some participants in early‐goal directed nutrition group may not have had PN, and this information was not reported by study authors.
Arefian 2007	RCT. EN vs PN. People with trauma injuries. Study authors did not report that participants were in the ICU.
Baigrie 1996	RCT. EN vs PN feeding. People undergoing oesophagectomy or gastrectomy. Study did not report that participants were in the ICU.
Braga 1996	RCT. 3 study groups: EN vs enriched EN vs PN. People undergoing curative surgery for gastric or pancreatic cancer. Study did not report that participants were in the ICU.
Braga 1998	RCT. 3 study groups: EN vs enriched EN vs PN. People undergoing curative surgery for gastric or pancreatic cancer. Study did not report that participants were in the ICU.
Braga 2001	RCT. PN vs early EN feeding. People undergoing curative surgery for cancer of the upper gastrointestinal tract. Study did not report that participants were in the ICU.
Chen 2004	RCT. EN vs PN feeding. People in a burns unit not an ICU
DiCarlo 1999	RCT. 3 study groups: EN vs enriched EN vs PN. People undergoing curative surgery for cancer of the pancreatic head. Study did not report that participants were in the ICU.
Doig 2013	RCT. People admitted to the ICU. This trial assessed early PN in people with relative contraindications to EN, not all the participants randomized to the control group received EN.
Dong 2010	RCT. 3 study groups: EN vs PN vs combined EN with Shenmai injection. People with gastric cancer after surgery. Study aimed to assess postoperative fatigue. Decision made from English abstract; study did not report that participants were in the ICU.
Fujita 2012	RCT. EN vs PN. Participants were in the ICU but only for 1 day as part of standard management of participants after thoracic oesophagectomy. Feeding by EN or PN continued on the ward for 6 postoperative days.
Hermann 2004	RCT. Compared EN vs PN. People with acute myeloid leukaemia. Decision made from abstract as we were unable to source the full text; study did not report that participants were in the ICU
Kim 2012	RCT. EN vs PN. People after gastrectomy with gastric cancer. Study authors did not report that participants were in the ICU.
Klek 2008	RCT. 4 study groups: EN vs immuno‐modulating EN vs PN vs immuno‐modulating PN. Well‐nourished people undergoing resection for gastrointestinal cancer. Study did not report that participants were in the ICU.
Klek 2011	RCT. 4 study groups: EN vs immuno‐modulating EN vs PN vs immuno‐modulating PN. Malnourished people undergoing resection for gastrointestinal cancer. Study did not report that participants were in the ICU.
Malhotra 2004	RCT. Compared enteral nutrition with PN. People undergoing surgical intervention for peritonitis. Study setting was reported as a surgical unit, not an ICU.
McArdle 1981	RCT. Compared EN vs PN. People treated in a surgical clinic. Study did not report that participants were in the ICU.
Moore 1989	RCT. Compared EN vs PN. People with abdominal trauma. Study did not report that participants were in the ICU.
Pupelis 2001	RCT. > 50% of participants had pancreatitis
Reynolds 1997	RCT. Compared EN vs PN. People undergoing upper gastrointestinal surgery. Study did not report that participants were in the ICU.
Ryu 2009	RCT. Compared EN vs PN. People undergoing surgery for laryngeal or pharyngeal cancer. Study did not report that participants were in the ICU.
Sand 1997	RCT. Compared EN vs PN. People undergoing gastrectomy for gastric cancer. Study did not report that participants were in the ICU.
Suchner 1996	RCT. Compared EN vs PN. People with head trauma or need for craniotomy. Study did not report that participants were in the ICU.
Van Barneveld 2016	RCT. Compared EN vs PN. People undergoing surgery for rectal carcinoma. Study did not report that participants were in the ICU.
Woodcock 2001	RCT. Compared EN vs PN. People requiring adjuvant nutritional support but study authors reported that only 37.4% were in the ICU and we excluded the study as this was too few and the data for participants in the ICU were not separate.
Xiao‐Bo 2014	RCT. Compared EN vs PN. People undergoing oesophagectomy for oesophageal cancer. Study did not report that participants were in the ICU.
Yu 2009	RCT. Compared EN vs PN. People undergoing surgery for colorectal cancer. Decision made from English abstract only; study did not report that participants were in the ICU.
Zanello 1992	RCT. Compared EN vs PN. People in the ICU with severe trauma or severe postoperative complications. Published only as an abstract; insufficient information on outcomes and not possible to use data. Abstract was from 1992, and unlikely to be published as a full report.
Zhang 2005	RCT. Compared EN vs PN. People in the ICU after pericardial devascularization. We noted that participants in the EN group were all given PN as a supplement for the first 3 days and, therefore, we excluded this study.
Zhang 2016	RCT. Compared EN vs PN. People with burn‐induced fungal infection. Study did not report that participants were in the ICU.
Zhu 2012	RCT. Compared EN vs PN. People with acute stroke. Study did not report that participants were in the ICU.

Methods	RCT
Participants	77 people in a surgical ICU undergoing curative surgery for gastric or pancreatic cancer. Participants randomized into 3 groups: standard EN formula (n = 24), enriched EN formula with arginine, RNA, and omega‐3 fatty acids (n = 26), isocoloric TPN formula (n = 27)
Interventions	EN formula vs enriched EN formula vs isonitrogen‐isocaloric parenteral formula. EN started 12 hours following surgery. Infusion rate was gradually increased until full amount was achieved on postoperative day 4.
Outcomes	Serum level of total iron‐binding capacity, albumin, prealbumin, retinal‐binding protein, cholinesterase Delayed hypersensitivity response Lymphocyte subsets Monocyte phagocytosis Postoperative infections Length of stay Measurements were taken on postoperative days 1 and 8
Notes	We were unable to source the full text for this study and the abstract contained insufficient information to decide eligibility.

Methods	RCT
Participants	61 people in the NICU
Interventions	EN vs early PN and vs supplemental PN
Outcomes	Serum level of total protein, albumin, prealbumin, and transferrin
Notes	Abstract only with insufficient information to justify inclusion

Methods	RCT
Participants	147 elderly people in a RICU
Interventions	EN + PN vs EN vs PN
Outcomes	Energy metabolism Respiratory muscle strength Other short‐term outcomes: plasma albumin, haemoglobin, creatinine, nitrogen balance, and blood urea nitrogen
Notes	We were unable to source the full text for this study and the abstract contained insufficient information to decide eligibility.

Methods	RCT
Participants	15 participants in each group
Interventions	Nutrition delivered continuously for 5 days to provide daily energy supply corresponding to current resting energy expenditure as determined by indirect calorimetry. Formula consisted of 35% of total energy requirements as lipids, 15% as proteins (maximum 1.2 g/kg ideal bodyweight/day), and 50% as dextrose. There was a tight glucose control strategy to avoid hyperglycaemia.
Outcomes	Change in plasma concentration of triglycerides Total cholesterol HDL‐cholesterol Free fatty acids Apolipoproteins Lipoprotein Incidence of hyperglycaemia Alteration of liver function Gastrointestinal intolerance Gastrointestinal bleeding Septic complications Occurrence of new organ Dysfunction Length of stay in the ICU Mortality
Notes	Trial was listed as completed in clinical trials register. Awaiting full publication of report to assess inclusion

Methods	RCT
Participants	Adults, ≥ 18 years of age, requiring mechanical ventilation for > 48 hours, treated with a vasoactive drug via a CVC, eligible for nutritional support started within 24 hours after endotracheal intubation (or within 24 hours after ICU admission if intubation occurred before ICU admission)
Interventions	Early EN formula vs PN formula. EN group given EN for 8 days, then supplemental PN if required. PN group given PN for at least 72 hours, then weaned to EN if haemodynamically stable
Outcomes	Mortality (28 days) VAP Bacteraemia CVC‐related complications Urinary tract infections Soft tissue infections Nosocomial infections Bacteriological data Vomiting or regurgitation Diarrhoea Bowel ischaemia Mean caloric intake Volume of liquid feed SOFA scores ICU mortality 90‐day mortality Hospital mortality Mean changes in albumin Prealbumin and C‐reactive protein Liver dysfunction episode ICU length of stay Hospital length of stay Duration of mechanical ventilation Changes in mean bodyweight
Notes	Clinical trials registration ID: NCT0180299 Study terminated early due to Data Safety and Monitoring Board recommendation. Report of results prior to termination not yet published

Methods	Enrolled participants allocated to supplemental PN (via CVC) for 7 days post randomization or usual care with EN
Participants	Participants admitted to the ICU within 48‐72 hours, mechanically ventilated, ≥ 16 years of age, central venous access suitable for PN solution, ≥ 1 organ system failure related to their acute illness, renal dysfunction, intracranial pressure monitor or ventricular drain in situ, currently receiving extracorporeal membrane, currently has a ventricular assist device
Interventions	EN and supplemental PN formula vs standard EN formula
Outcomes	Mean energy amount delivered in calories Total protein amount delivered in first 7 days Total energy amount delivered in the ICU stay Total protein amount delivered in the ICU stay Total antibiotic usage SOFA scores Duration of mechanical ventilation Duration of ICU and hospital stay Mortality up to 180 days post randomization Functional and quality of life to 180 days post randomization
Notes	Clinical trials registration ID: NCT01847534

Methods	RCT
Participants	171 people undergoing major abdominal and urological surgery for neoplastic pathology. Aim was to assess the effectiveness and clinical outcomes of total PN.
Interventions	Total PN vs early EN vs early immuno‐EN
Outcomes	Nutritional and immunological markers Septic morbidity Mortality
Notes	We were unable to source the full text of this study, and its abstract contained insufficient information to decide whether participants were in the ICU.

Methods	RCT
Participants	148 participants in the ICU
Interventions	EN vs PN
Outcomes	Duration of mechanical ventilation ICU and hospital length of stay Mortality rate
Notes	Reported as an abstract only. Study authors did not report denominator figures for each group, and, therefore, there were no useable data.

Methods	RCT
Participants	42 critically ill people
Interventions	EN vs PN vs control
Outcomes	Partial pressure of arterial oxygen Partial pressure of arterial carbon dioxide White blood cell count Serum alanine aminotransferase Blood urea nitrogen Gastrointestinal haemorrhage
Notes	English abstract did not report review outcomes. Requires translation to assess full eligibility

Methods	RCT
Participants	335 people who were expected to survive for > 7 days and were admitted to multiple Chinese ICUs
Interventions	Supplemented EN vs supplemented PN
Outcomes	Energy targets Gastric retention Hypoglycaemia
Notes	This study was published only as an abstract that contained insufficient information to decide eligibility.

Methods	RCT
Participants	63 liver transplant recipients
Interventions	Early EN formula vs PN formula. EN started within 48 hours of transplant surgery
Outcomes	Aspartate aminotransferase Alanine aminotransferase Total bilirubin Urea nitrogen Proalbumin Length of stay Infection rate
Notes	This study was published only as an abstract that contained insufficient information to decide eligibility

PERMALINK

Enteral versus parenteral nutrition and enteral versus a combination of enteral and parenteral nutrition for adults in the intensive care unit

Sharon R Lewis

Oliver J Schofield‐Robinson

Phil Alderson

Andrew F Smith

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' table and GRADE

Results

Description of studies

Results of the search

1.

Included studies

Study population

Study setting

Intervention and comparisons

Outcomes

Funding sources

Excluded studies

Studies awaiting classification

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Baseline characteristics

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Enteral versus parenteral nutrition for adults in the intensive care unit.

Summary of findings 2. Enteral versus enteral and parenteral nutrition for adults in the intensive care unit.

Enteral nutrition versus parenteral nutrition

Primary outcome

1. Mortality

In hospital

1.1. Analysis.

Within 30 days

1.2. Analysis.

Within 90 days

1.3. Analysis.

Within 180 days

Trial name or title	Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients
Methods	Participants randomly divided into EN or EN and early PN group. Multi‐centre study
Participants	Inclusion criteria Adults admitted to any 1 of 5 ICUs NRS ≥ 3 at ICU admission Exclusion criteria DNR code or moribund at time of ICU admission Already enrolled in another trial Transferred from another ICU with an established nutritional therapy Ketoacidotic or hyperosmolar coma on admission BMI < 17 kg/m² Short bowel syndrome Known to be pregnant or nursing On mechanical ventilation at home NRS score < 3 Readmitted to ICU after randomization to the EPaNIC trial Not critically ill on admission
Interventions	EN group: withholding PN during the first week of ICU stay. Participants will receive exclusively EN. If EN is insufficient after 7th day of ICU stay, PN will be started. EN and early PN: PN will be started the morning of 3rd day of ICU stay. Amount of PN will be calculated to cover the caloric needs of the participant, based on EN energy intake during the previous 24 hours.
Outcomes	Length of stay in ICU Mortality Days to weaning from mechanical ventilation Need for renal replacement therapies Presence or absence of new kidney injury during ICU stay Days of vasopressor or inotropic support Presence or absence of signs of ICU liver disease Need for tracheotomy Presence or absence of hyperinflammation within 5 days of ICU admission Blood lipid profiles and albumin on days 1, 5, 10, and 15 after admission Presence or absence of bacteraemia, ventilator‐associated pneumonia, and wound infections Episodes of hypoglycaemic events Amount and type of calories delivered Muscle strength Rehabilitation/functionality
Starting date	August 2007
Contact information	Greet Van den Berghe, Katholieke Universiteit Leuven
Notes	Clinical trials registration ID: NCT00512122

Trial name or title	Impact of supplemental parenteral nutrition in ICU patients on metabolic, inflammatory and immune responses (SPN2)
Methods	RCT. Trial aims to investigate the underlying carbohydrate and protein metabolism changes, as well as the immune and inflammatory modulations associated with these interventions.
Participants	Inclusion criteria Adults in ICU Estimated duration of ICU stay > 5 days Estimated survival > 7 days Absence of contraindication to EN Need for mechanical ventilation Informed consent obtained from participants, close relative, or referring physician Exclusion criteria Refusal of the participant or next of kin < 18 years of age Non‐functional digestive tract Already receiving PN before day 3 Absence of a central venous catheter Women who are pregnant Admission after cardiac arrest or severe brain injury
Interventions	EN group: EN to be progressed as soon as possible to energy target measured on day 3, and verified on day 4, using the usual facilitators (prokinetics) Supplemental PN group: addition of supplemental PN to complete the gap between energy delivered by EN feeding and energy target measured on day 4
Outcomes	Glucose and leucine turnover Immune and inflammatory impact of optimized target feeding Overall complications and organ failures Length of mechanical ventilation Length of ICU and hospital stay
Starting date	April 2014
Contact information	Mette M Berger, Prof, Centre Hospitalier Universitaire Vaudois
Notes	Clinical trials registration ID: NCT02022813