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Early enteral nutrition reduces mortality in trauma patients requiring intensive care: A meta-analysis of randomised controlled trials
Injury, Int. J. Care Injured 42 (2011) 50–56
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Injury journal homepage: www.elsevier.com/locate/injury
Early enteral nutrition reduces mortality in trauma patients requiring intensive care: A meta-analysis of randomised controlled trials Gordon S. Doig a,*, Philippa T. Heighes b, Fiona Simpson a, Elizabeth A. Sweetman b a b
Intensive Care, Northern Clinical School, University of Sydney, Sydney, NSW 2006, Australia Royal North Shore Hospital, Intensive Care Unit, St. Leonards, NSW 2065, Australia
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 11 June 2010
Introduction: To determine whether the provision of early standard enteral nutrition (EN) confers treatment benefits to adult trauma patients who require intensive care. Materials and methods: MEDLINE and EMBASE were searched. Hand citation review of retrieved guidelines and systematic reviews was undertaken and academic and industry experts were contacted. Methodologically sound randomised controlled trials (RCTs) conducted in adult trauma patients requiring intensive care that compared the delivery of standard EN, provided within 24 h of injury, to standard care were included. The primary analysis was conducted on clinically meaningful patient-oriented outcomes, which included mortality, functional status and quality of life. Secondary analyses considered vomiting/ regurgitation, pneumonia, bacteraemia, sepsis and multiple organ dysfunction syndrome. Meta-analysis was conducted using an analytical method known to minimise bias in the presence of sparse events. The impact of heterogeneity was assessed using the I2 metric. Results: Three RCTs with 126 participants were found to be free from major flaws and were included in the primary analysis. The provision of early EN was associated with a significant reduction in mortality (OR = 0.20, 95% confidence interval 0.04–0.91, I2 = 0). No other outcomes could be pooled. A sensitivity analysis and a confirmatory analysis conducted using a different analytical method confirmed the presence of a mortality reduction. Conclusion: Although the detection of a statistically significant reduction in mortality is promising, overall trial quality was low and trial size was small. The results of this meta-analysis should be confirmed by the conduct of a large multi-center trial. ß 2010 Elsevier Ltd. All rights reserved.
Keywords: Early enteral nutrition Trauma Intensive care unit Critical care Meta-analysis Systematic review
Introduction Recently published clinical practice guidelines recommend initiating enteral nutrition (EN) in the trauma patient ‘as early as feasible’.41 Whilst clinical practice guidelines may reduce inappropriate variability in the delivery of care by promoting awareness of interventions of proven benefit and discouraging ineffective care, they do not always result in practice change.6,19,54 Practice change is more likely to occur if guideline recommendations are supported by clear evidence of patient benefit.18,43 Previously published meta-analyses have assessed the effectiveness of early EN in various patient groups including acutely
* Corresponding author at: Royal North Shore Hospital, Intensive Care Unit, Pacific Hwy, St. Leonards, NSW 2065, Australia. Tel.: +61 2 9926 8656; fax: +61 2 9439 8418. E-mail addresses: [email protected] (G.S. Doig), [email protected] (P.T. Heighes), [email protected] (F. Simpson), [email protected] (E.A. Sweetman). 0020–1383/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2010.06.008
hospitalised medical patients,33 critically ill patients,9 burns patients,52 patients undergoing elective intestinal surgery 30 and patients with pancreatitis.36 Although the provision of early EN has been demonstrated to significantly reduce infectious complications in acutely hospitalised patients,33 and to significantly reduce mortality in critically ill patients9 and patients undergoing elective intestinal surgery,30 there have been no meta-analyses published with a primary focus on the trauma patient.22 The purpose of this project was to identify and synthesise the current evidence from methodologically sound randomised controlled trials (RCTs) conducted in adult trauma patients requiring intensive care to determine whether the provision of early standard EN confers a treatment benefit, on average, in the identified studies. Materials and methods Literature search MEDLINE (http://www.PubMed.org) and EMBASE (http:// www.EMBASE.com) were searched using appropriately broad
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Medical Subject Heading and EMTREE terms for nutritional support and critical illness. The MEDLINE terms used to identify the nutritional support literature included: nutrition therapy, nutritional support, nutrition phenomena, nutrition processes, nutrition disorders and nutrition assessment. These were mapped to the EMTREE terms: diet therapy, nutritional support, nutritional disorder, nutritional assessment, nutritional deficiency, feeding behaviour, nutritional status and overnutrition. These nutrition searches were crossed with the following terms to identify the critical care literature: critical, intensive, intensive care, intensive care unit/s, intensive therapy, critically ill, critical illness, and critical care. All search concepts were crossed with phrases optimised to detect RCTs.21,53 Academic and industry experts were contacted and reference lists of identified systematic reviews and evidence-based guidelines were hand searched. The search was not restricted by language. Complete details of the search process are available upon request. The search close out date was 2 February 2010. Study selection All controlled trials comparing primary feeding interventions were identified.12,25 Early EN was defined as the provision of a standard EN formula via any feeding tube route within 24 h of initial injury. A standard EN formula was considered to be any formula not supplemented with additional glutamine, arginine or other immune enhancing ingredients. Appropriate comparison groups were accepted to include all forms of standard care, including standard EN provided later than 24 h after injury. Trials reporting mortality, quality of life and/or physical function as outcomes,42 conducted in adult trauma populations requiring intensive care, were eligible for inclusion. The need for intensive care was determined using objective criteria, as reported in Table 1.10 Only methodologically sound RCTs were eligible for inclusion in the primary analysis (http://clinicalevidence.bmj.com/ceweb/ about/appraisal.jsp, visited 6 March 2009). Major methodological flaws were defined a priori as pseudo-randomisation (clear failure to maintain allocation concealment) and excessive (>10%) loss to follow-up.16 Publications based on subgroups of patients from larger published trials were not eligible for inclusion if the larger trial’s patient population was already deemed eligible. Methodological quality appraisal All included trials were appraised on the reporting of three key methodological criteria: (1) the maintenance of allocation
concealment; (2) the use of any form of blinding and; (3) the completeness of patient follow-up.25 Outcomes The primary outcomes of interest included mortality, quality of life and physical function.42 In addition, vomiting/regurgitation, pneumonia, bacteraemia, sepsis and multiple organ dysfunction syndrome (MODS) were eligible for evaluation as secondary outcomes. All phases of study selection, methodological quality appraisal and data abstraction were undertaken by at least three reviewers. At each phase, majority decisions prevailed. Statistical analysis Analysis was conducted using a fixed effects model50 with the odds ratio (OR) metric.7 Because data was sparse with multiple zero-cells, the Peto method was used to calculate the OR metric.2 The presence of an inconsistent treatment effect between studies (heterogeneity) was assessed using a formal x2 test of study treatment effect interaction50 and was quantified using the I2 metric.23 In the presence of important heterogeneity (heterogeneity P < 0.10 or I2 metric >50%),20 stratified analyses were planned to investigate potential sources of heterogeneity.14 Analysis was conducted using RevMan Version 4.2 for Windows (The Cochrane Collaboration1, Oxford, England, 2003). A twotailed P 0.05 was accepted to indicate statistical significance whilst a two-tailed P > 0.05 but 0.10 was accepted to indicate a trend towards significance. Sensitivity analysis To assess the robustness of the underlying assumptions, a sensitivity analysis was conducted including all studies that were identified to be on-topic but were judged to be methodologically ‘unsound’. Results Literature search Four thousand two hundred and seventeen unique abstracts were identified. Contact with academic and industry experts, hand searching of abstracts (EAS, FS and GSD) and reference lists of published guidelines and systematic reviews (PH, FS and GSD), resulted in the retrieval of 701 citations for detailed eligibility review.
Table 1 Objective criteria of critical illness. A study was determined to have been conducted in a critically ill patient population if the manuscript reported (1) The patients were recruited in an ICU or (2) The inclusion criteria described were such that the patients would normally be cared for in an ICU (e.g. all patients were receiving invasive mechanical ventilatory support) or (3) The patients were suffering from a condition that usually requires care in an ICU (e.g. severe thermal burns of >40–50% TBSA, multi trauma that required urgent laparotomy) or (4) The patients had an average ICU length of stay of greater than two days or (5) A majority of the patients received a therapy that is delivered in the ICU (e.g. invasive mechanical ventilation) or (6) A severity of illness score was reported that was commensurate with the patients being critically ill A study was judged not to involve a critically ill patient population if none of the above criteria were met and: (1) The patients had simple operative procedures that would not normally require admission to an ICU (e.g. simple gastrectomy or hemi-colectomies) or (2) The exclusion criteria were such that patients with complicating medical conditions that might require admission to an ICU, such as cardiac failure, renal failure, diabetes or liver impairment, were not enrolled or (3) The course of the patients’ care was reported as uncomplicated (e.g. routine surgery, oral intake day one and then discharge from hospital day five or six) ICU, intensive care unit; TBSA, total burn surface area.
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[(Fig._1)TD$IG]
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Fig. 1. Flow diagram of the study selection process. EN = enteral nutrition, N = number of full text citations, RCT = randomised controlled trial.
Study selection The results of the detailed eligibility review of the 701 citations (EAS, PH, FS and GSD) are presented in Fig. 1. Thirty-three clinical trials appeared to address questions regarding the timing of the delivery of EN in appropriate patient groups and 13 of these trials were found to be conducted in trauma patients requiring intensive care. Of these 13 trials, nine were excluded for the following reasons: Four trials failed to explicitly report mortality outcomes11,17,24,44; four trials evaluated the impact of early immunoenhanced EN, not standard EN28,38,40,48 and; one trial commenced ‘early’ EN an average of 39 12 h post-injury.13 The remaining four trials provided early standard EN within 24 h of injury.5,26,27,39 Complete details of eligible trials are presented in Table 2.
None of the four eligible trials reported using any form of blinding. Three of the eligible trials reported mortality outcomes on all randomised patients such that an intention-to-treat analysis could be conducted.5,26,27 One trial failed to report outcomes on 12 of 75 (16%) randomised patients.39 Due to the presence of excessive loss to follow-up and the resultant inability to conduct an intention-to-treat analysis, this study did not qualify for inclusion in the primary analysis. However, this study was considered in a sensitivity analysis. Included trial characteristics The three trials included in the primary analysis randomised a total of 126 patients, with a median of 38 patients and a range from 36 to 52 patients.
Methodological quality appraisal
Patient-oriented outcomes
All four eligible trials failed to report sufficient detail on the method of randomisation such that it was unclear whether allocation concealment was maintained.
All included trials reported mortality however none reported quality of life and none reported direct measures of physical function.
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Table 2 Characteristics of eligible studies. Study
Patient population
Early EN intervention
Control intervention
Chuntrasakul 1996
Severe trauma (ISS >20 and <40) Mean ISS 29 1.5
Immediately after resuscitation or surgery: 30 mls/h 3/4 strength EN (TraumacalTM) via NGT, concentration increased over time. Goals estimated using modified Harris-Benedict equation. TPN was added if goals were not met
5% dextrose/NSS for maintenance. Oral intake commenced upon return of bowel sounds
Kompan 1999
Multiple trauma (ISS > 25) Mean ISS 33.6 10 Mean APACHE II 11.5 5.8
Immediately after resuscitation: EN (JevityTM) started at 20 ml/h via NGT. Increased to 50% of estimated goal on Day 1, 75% of estimated goal on Day 2 and 100% of goal on Day 3. Estimated goal was set at 25–35 nonprotein kcal/kg per day and 0.2–0.3 g nitrogen/kg per day at 72 h post-ICU admission. TPN was added to meet estimated requirements
Same protocol as Early EN except EN begun a median 41.4 (33.9–53.6 range) hours after trauma. Note: 50% of goal received via TPN for first 24 h before EN was begun
Kompan 2004
Multiple trauma (ISS > 20) Mean APACHE II 11.3 4.8
Immediately after resuscitation: Same protocol as Kompan 1999 except goal set at an average of 25 nonprotein kcal/kg
Same protocol as Early EN except EN begun 38.5 15.6 h after trauma. Note: 50% of goal received via TPN for first 24 h before EN was begun
Moore 1986
Major abdominal trauma (ATI > 15)
Within 12–18 h of surgery: EN (Vivonex HN at 1/4 strength) via NJT at 50 ml/h. Rate and concentration increased at 8 h intervals to target (full strength solution 125ml/h ) at 72 h
5% dextrose (approx. 100 g/day) during first 5 days post-op and then TPN if not tolerating oral diet at that time
APACHE, Acute Physiology and Chronic Health Evaluation Score; ATI, Abdominal Trauma Index; EN, enteral nutrition; ICU, intensive care unit; ISS, Injury Severity Score; NCJ, needle catheter jejunostomy; NGT, naso-gastric tube; NJT, naso-jejunal tube; NPO, nil per os (no oral intake); NSS, normal saline solution; TPN, total parenteral nutrition.
[(Fig._2)TD$IG]
Fig. 2. Primary analysis of trials reporting intention-to-treat mortality. CI = confidence interval, EN = enteral nutrition, OR = odds ratio.
Hospital discharge mortality was reported in one trial26 whilst two trials reported intensive care unit (ICU) discharge mortality.5,27 As shown in Fig. 2, meta-analysis of the RCTs included in the primary analysis revealed a statistically significant reduction in mortality in favour of early standard EN provided within 24 h of injury (OR = 0.20, P = 0.04, I2 = 0).
difference in the incidence of MODS (12/17 early EN patients vs. 13/19 delayed, P = 0.82) however severity of MODS demonstrated a trend towards fewer failed organ systems in patients receiving early standard EN (2.5 0.7 vs. 3.1 0.8 organ failures per patient, P = 0.057). Sensitivity analysis
Complications and major ICU infections Vomiting/aspiration No included trials reported the incidence of vomiting or aspiration. Pneumonia One included trial reported the incidence of pneumonia.27 The incidence of pneumonia was significantly lower in patients receiving EN within 24 h of injury (9/27 vs. 16/25, P = 0.050). Bacteremia No included trials reported the incidence of bacteraemia as an outcome. Sepsis No included trials reported the incidence of sepsis as an outcome. Multiple organ dysfunction syndrome (MODS) One included trial reported the incidence and severity (number of failed organs per patient) of MODS.26 There was no significant
A sensitivity analysis was conducted including the poorer quality Moore study.39 The sensitivity analysis demonstrated a significant reduction in mortality attributable to early standard EN (OR = 0.26, P = 0.04, I2 = 0). Discussion We undertook an extensive literature search to identify RCTs evaluating the effectiveness of early standard EN, provided within 24 h of injury, in trauma patients requiring ICU care. Our primary conclusions were based on trials that were free from major methodological flaws. Four clinical trials conducted in patients with severe multiple trauma and major abdominal injury met our selection criteria. Meta-analysis revealed a statistically significant reduction in mortality attributable to the provision of standard EN within 24 h of injury. Individual trials reported statistically significant reductions in pneumonia and a trend towards a reduction in severity of MODS attributable to the provision of early standard EN.
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Benefits of EN within 24 h of injury Laboratory studies have established the physiological benefits attributable to the provision of EN in trauma. This meta-analysis is the first to demonstrate these physiological benefits translate into improvements in survival. The provision of EN in the critically ill trauma patient is accepted to preserve physical gut barrier function, and maintain gut associated lymphoid tissue mass and function.29,31 By maintaining the host defence functions of the intestine, translocation of bacteria from the gut into the blood stream, and consequent systemic infectious complications, are reduced.15,49 The provision of EN also down-regulates the systemic immune response to bacterial translocation which reduces overall oxidative stresses and moderates the expression of the systemic inflammatory response syndrome37 and subsequent progression to MODS.3 The appropriate provision of EN may also reduce aspiration related complications such as pneumonia.4 Two eligible trials reported significant reductions in infectious complications in patients receiving early EN,27,39 potentially attributable to a decrease in bacterial translocation or aspiration. Although neither of these trials recorded the incidence and severity of MODS, a third eligible trial reported a trend (P = 0.057) towards a reduction in the severity of MODS in patients receiving early EN.26 The progressive failure of multiple organ systems is a leading cause of morbidity and mortality in critical illness and a reduction in the onset or severity of MODS could be expected to translate into a mortality benefit.34,51 Early EN: within 24 h or 48 h of injury? Based on the findings of previous publications9,35,45 we were explicitly interested in the results of trials that provided standard EN within 24 h of injury. Because others have defined the timeframe for the provision of early EN as within 48 h post-injury or ICU admission,41 we framed our literature search such that articles that employed any timeframe to define early EN could be identified. Our literature search identified only one trial that satisfied all eligibility criteria and defined early EN as within 48 h of injury.13 This trial enrolled and randomised 52 blunt trauma patients to receive early standard EN an average of 39 12 h post-injury or delayed EN, which was provided 90 12 h post-injury. Outcomes were reported on 38 patients, with two deaths in each group (2/19 vs. 2/19). Because this trial fails to show any suggestion of benefit in favour of standard EN provided within 48 h of injury, this publication does not provide any compelling reason to extend the definition of early EN from less than 24 h from injury to 48 h. Selection of analytic method The purpose of conducting a meta-analysis of previously published RCTs is to obtain a more definitive and precise answer to a research question. Decisions regarding the selection of metrics,7 models50 and issues arising due to heterogeneity14 can influence the overall validity of the conclusions of a meta-analysis. Mounting methodological evidence suggests the selection of the appropriate analytical method is also important.2,46 Two of the clinical trials included in our meta-analysis reported zero deaths in patients receiving early EN.26,27 Events in the control arms of these two trials were also relatively rare. The majority of commonly used analytical methods were developed using large sample theory. When outcomes are infrequent and RCTs report zero events in one arm of a trial, the two most commonly used analytical methods, the random effects method of DerSimonian and Laird8 and the fixed effects method of Mantel and Haenszel,32
may produce severely biased treatment effect estimates.2,46 Both the Exact method and the ‘one-step, assumption free’ fixed effects method of Peto55 are known to be minimally biased when outcome events are rare.2,46 The Peto method is implemented in software widely accessible to all researchers (RevMan, The Cochrane Collaboration1, Oxford, England, 2003), thus we conducted our primary analysis using this technique. Because many methodologists may consider the Exact method to be more definitive, we elected to confirm the results of our primary analysis obtained using the Peto method by conducting an additional analysis using the Exact method (StatXact 5.0, Cytel Software Corporation, Cambridge, USA). The Exact method revealed a significant reduction in mortality attributable to the provision of early EN (ORExact = 0.14, 95% CI 0.01–0.97), which was entirely consistent with the findings obtained using the Peto method. Strengths and limitations We conducted an extensive and exhaustive literature search that was not restricted to the English language. Although it is unlikely that published studies were missed, we did not explicitly search the grey literature to identify conference abstracts of unpublished studies.1 It is likely our literature search identified all eligible trials. We undertook a formal sensitivity analysis and also confirmed our primary analysis using a second analytical method. The formal sensitivity analysis included RCTs with major methodological flaws identified during our current search whilst the confirmatory analysis was conducted using the Exact method. The results of the sensitivity analysis and the confirmatory analysis did not differ significantly from the results of the primary analysis: both demonstrated a statistically significant reduction in mortality attributed to the provision of standard EN within 24 h of injury. Overall, the RCTs included in our meta-analysis were small and of poor quality however, none of the RCTs included in our primary analysis had major methodological flaws. Furthermore, the patient outcomes reported in each trial were limited to ICU or hospital discharge mortality, which may not fully capture the mortality experience of the trauma patient.47 There is a pressing need for the conduct of a multi-center adequately powered clinical trial in this field, equivalent to a Food and Drug Administration (FDA) Phase III licensing trial. We strongly recommend such a trial should report patient survival beyond 90 days post-injury and collect quality of life and physical function information. The composition of standard EN formula used, nutritional goals set, use of supplemental parenteral nutrition and comparator interventions appeared to differ between included trials (Table 2). Because there is no evidence of statistical heterogeneity and the magnitude of the observed treatment effect is consistent across all included trials, it is valid to obtain an overall summary estimate despite these apparent differences.7,23,50 Within the constraints of the patient groups and interventions evaluated in the included trials, the presence of a reasonably consistent treatment effect in the face of differences in study design suggests that the benefits of early EN may be independent of the composition of standard EN formula used, nutritional goals set, use of supplemental parenteral nutrition and comparator interventions. This hypothesis should be confirmed in a subsequent multi-center clinical trial. Conclusions Meta-analysis conducted on the methodologically sound clinical trials identified by our systematic review of the literature revealed a statistically significant reduction in mortality attributable to the provision of standard EN within 24 h of injury. These
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findings are robust: the results of the confirmatory and sensitivity analyses did not differ significantly from the primary analysis. Due to the constraints of the included trials, we recommend the use of judicious clinical judgement in applying these findings to clinical practice. The primary findings of this meta-analysis need to be confirmed by the conduct of a large-scale multi-centre Level I (FDA Phase III) clinical trial. Authors’ contributions GSD and FS conceived and designed the study, managed the project, conducted the statistical analysis, interpreted the results and drafted the manuscript. GSD had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. PTH and EAS contributed to study design, managed the project, interpreted the results and helped draft the manuscript. Guarantor Gordon S Doig PhD (Epidemiology and Biostatistics) was responsible for and conducted all analyses. He had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of interest statement GSD has received academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd. and speakers honoraria from Baxter Healthcare Pty Ltd. FS has received academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd. and speakers honoraria from Pharmatel-Fresenius Kabi Pty Ltd. EAS has received an academic research grant from Baxter Healthcare Pty Ltd. PTH declares no competing interests. Ethics Ethics approval was not required to conduct this integrative meta-epidemiological study. Funding source The conduct of this study was not funded. References 1. Benzies KM, Premji S, Hayden KA, Serrett K. State-of-the-evidence reviews: advantages and challenges of including grey literature. Worldviews Evid Based Nurs 2006;3:55–61. 2. Bradburn MJ, Deeks JJ, Berlin JA, Russell LA. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 2007;26:53–77. 3. Carrico CJ, Meakins JL, Marshall JC, et al. Multiple-organ-failure syndrome. Arch Surg 1986;121:196–208. 4. Chen YC. Critical analysis of the factors associated with enteral feeding in preventing VAP: a systematic review. J Chin Med Assoc 2009;72:171–8. 5. Chuntrasakul C, Siltharm S, Chinswangwatanakul V, et al. Early nutritional support in severe traumatic patients. J Med Assoc Thai 1996;79:21–6. 6. Cook DJ, Greengold NL, Ellrodt AG, Weingarten SR. The relation between systematic reviews and practice guidelines. Ann Intern Med 1997;127:210–6. 7. Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med 2002;21:1575–600. 8. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. 9. Doig GS, Heighes PT, Simpson F, et al. Early enteral nutrition, provided within 24 hours of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials. Intensive Care Med 2009;35(12):2018–27. 10. Doig GS, Simpson F, Delaney A. A review of the true methodological quality of nutritional support trials conducted in the critically ill: time for improvement. Anesth Analg 2005;100:527–33.
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Early enteral nutrition reduces mortality in trauma patients requiring intensive care: A meta-analysis of randomised controlled trials Gordon S. Doig a,*, Philippa T. Heighes b, Fiona Simpson a, Elizabeth A. Sweetman b a b
Intensive Care, Northern Clinical School, University of Sydney, Sydney, NSW 2006, Australia Royal North Shore Hospital, Intensive Care Unit, St. Leonards, NSW 2065, Australia
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 11 June 2010
Introduction: To determine whether the provision of early standard enteral nutrition (EN) confers treatment benefits to adult trauma patients who require intensive care. Materials and methods: MEDLINE and EMBASE were searched. Hand citation review of retrieved guidelines and systematic reviews was undertaken and academic and industry experts were contacted. Methodologically sound randomised controlled trials (RCTs) conducted in adult trauma patients requiring intensive care that compared the delivery of standard EN, provided within 24 h of injury, to standard care were included. The primary analysis was conducted on clinically meaningful patient-oriented outcomes, which included mortality, functional status and quality of life. Secondary analyses considered vomiting/ regurgitation, pneumonia, bacteraemia, sepsis and multiple organ dysfunction syndrome. Meta-analysis was conducted using an analytical method known to minimise bias in the presence of sparse events. The impact of heterogeneity was assessed using the I2 metric. Results: Three RCTs with 126 participants were found to be free from major flaws and were included in the primary analysis. The provision of early EN was associated with a significant reduction in mortality (OR = 0.20, 95% confidence interval 0.04–0.91, I2 = 0). No other outcomes could be pooled. A sensitivity analysis and a confirmatory analysis conducted using a different analytical method confirmed the presence of a mortality reduction. Conclusion: Although the detection of a statistically significant reduction in mortality is promising, overall trial quality was low and trial size was small. The results of this meta-analysis should be confirmed by the conduct of a large multi-center trial. ß 2010 Elsevier Ltd. All rights reserved.
Keywords: Early enteral nutrition Trauma Intensive care unit Critical care Meta-analysis Systematic review
Introduction Recently published clinical practice guidelines recommend initiating enteral nutrition (EN) in the trauma patient ‘as early as feasible’.41 Whilst clinical practice guidelines may reduce inappropriate variability in the delivery of care by promoting awareness of interventions of proven benefit and discouraging ineffective care, they do not always result in practice change.6,19,54 Practice change is more likely to occur if guideline recommendations are supported by clear evidence of patient benefit.18,43 Previously published meta-analyses have assessed the effectiveness of early EN in various patient groups including acutely
* Corresponding author at: Royal North Shore Hospital, Intensive Care Unit, Pacific Hwy, St. Leonards, NSW 2065, Australia. Tel.: +61 2 9926 8656; fax: +61 2 9439 8418. E-mail addresses: [email protected] (G.S. Doig), [email protected] (P.T. Heighes), [email protected] (F. Simpson), [email protected] (E.A. Sweetman). 0020–1383/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2010.06.008
hospitalised medical patients,33 critically ill patients,9 burns patients,52 patients undergoing elective intestinal surgery 30 and patients with pancreatitis.36 Although the provision of early EN has been demonstrated to significantly reduce infectious complications in acutely hospitalised patients,33 and to significantly reduce mortality in critically ill patients9 and patients undergoing elective intestinal surgery,30 there have been no meta-analyses published with a primary focus on the trauma patient.22 The purpose of this project was to identify and synthesise the current evidence from methodologically sound randomised controlled trials (RCTs) conducted in adult trauma patients requiring intensive care to determine whether the provision of early standard EN confers a treatment benefit, on average, in the identified studies. Materials and methods Literature search MEDLINE (http://www.PubMed.org) and EMBASE (http:// www.EMBASE.com) were searched using appropriately broad
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Medical Subject Heading and EMTREE terms for nutritional support and critical illness. The MEDLINE terms used to identify the nutritional support literature included: nutrition therapy, nutritional support, nutrition phenomena, nutrition processes, nutrition disorders and nutrition assessment. These were mapped to the EMTREE terms: diet therapy, nutritional support, nutritional disorder, nutritional assessment, nutritional deficiency, feeding behaviour, nutritional status and overnutrition. These nutrition searches were crossed with the following terms to identify the critical care literature: critical, intensive, intensive care, intensive care unit/s, intensive therapy, critically ill, critical illness, and critical care. All search concepts were crossed with phrases optimised to detect RCTs.21,53 Academic and industry experts were contacted and reference lists of identified systematic reviews and evidence-based guidelines were hand searched. The search was not restricted by language. Complete details of the search process are available upon request. The search close out date was 2 February 2010. Study selection All controlled trials comparing primary feeding interventions were identified.12,25 Early EN was defined as the provision of a standard EN formula via any feeding tube route within 24 h of initial injury. A standard EN formula was considered to be any formula not supplemented with additional glutamine, arginine or other immune enhancing ingredients. Appropriate comparison groups were accepted to include all forms of standard care, including standard EN provided later than 24 h after injury. Trials reporting mortality, quality of life and/or physical function as outcomes,42 conducted in adult trauma populations requiring intensive care, were eligible for inclusion. The need for intensive care was determined using objective criteria, as reported in Table 1.10 Only methodologically sound RCTs were eligible for inclusion in the primary analysis (http://clinicalevidence.bmj.com/ceweb/ about/appraisal.jsp, visited 6 March 2009). Major methodological flaws were defined a priori as pseudo-randomisation (clear failure to maintain allocation concealment) and excessive (>10%) loss to follow-up.16 Publications based on subgroups of patients from larger published trials were not eligible for inclusion if the larger trial’s patient population was already deemed eligible. Methodological quality appraisal All included trials were appraised on the reporting of three key methodological criteria: (1) the maintenance of allocation
concealment; (2) the use of any form of blinding and; (3) the completeness of patient follow-up.25 Outcomes The primary outcomes of interest included mortality, quality of life and physical function.42 In addition, vomiting/regurgitation, pneumonia, bacteraemia, sepsis and multiple organ dysfunction syndrome (MODS) were eligible for evaluation as secondary outcomes. All phases of study selection, methodological quality appraisal and data abstraction were undertaken by at least three reviewers. At each phase, majority decisions prevailed. Statistical analysis Analysis was conducted using a fixed effects model50 with the odds ratio (OR) metric.7 Because data was sparse with multiple zero-cells, the Peto method was used to calculate the OR metric.2 The presence of an inconsistent treatment effect between studies (heterogeneity) was assessed using a formal x2 test of study treatment effect interaction50 and was quantified using the I2 metric.23 In the presence of important heterogeneity (heterogeneity P < 0.10 or I2 metric >50%),20 stratified analyses were planned to investigate potential sources of heterogeneity.14 Analysis was conducted using RevMan Version 4.2 for Windows (The Cochrane Collaboration1, Oxford, England, 2003). A twotailed P 0.05 was accepted to indicate statistical significance whilst a two-tailed P > 0.05 but 0.10 was accepted to indicate a trend towards significance. Sensitivity analysis To assess the robustness of the underlying assumptions, a sensitivity analysis was conducted including all studies that were identified to be on-topic but were judged to be methodologically ‘unsound’. Results Literature search Four thousand two hundred and seventeen unique abstracts were identified. Contact with academic and industry experts, hand searching of abstracts (EAS, FS and GSD) and reference lists of published guidelines and systematic reviews (PH, FS and GSD), resulted in the retrieval of 701 citations for detailed eligibility review.
Table 1 Objective criteria of critical illness. A study was determined to have been conducted in a critically ill patient population if the manuscript reported (1) The patients were recruited in an ICU or (2) The inclusion criteria described were such that the patients would normally be cared for in an ICU (e.g. all patients were receiving invasive mechanical ventilatory support) or (3) The patients were suffering from a condition that usually requires care in an ICU (e.g. severe thermal burns of >40–50% TBSA, multi trauma that required urgent laparotomy) or (4) The patients had an average ICU length of stay of greater than two days or (5) A majority of the patients received a therapy that is delivered in the ICU (e.g. invasive mechanical ventilation) or (6) A severity of illness score was reported that was commensurate with the patients being critically ill A study was judged not to involve a critically ill patient population if none of the above criteria were met and: (1) The patients had simple operative procedures that would not normally require admission to an ICU (e.g. simple gastrectomy or hemi-colectomies) or (2) The exclusion criteria were such that patients with complicating medical conditions that might require admission to an ICU, such as cardiac failure, renal failure, diabetes or liver impairment, were not enrolled or (3) The course of the patients’ care was reported as uncomplicated (e.g. routine surgery, oral intake day one and then discharge from hospital day five or six) ICU, intensive care unit; TBSA, total burn surface area.
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[(Fig._1)TD$IG]
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Fig. 1. Flow diagram of the study selection process. EN = enteral nutrition, N = number of full text citations, RCT = randomised controlled trial.
Study selection The results of the detailed eligibility review of the 701 citations (EAS, PH, FS and GSD) are presented in Fig. 1. Thirty-three clinical trials appeared to address questions regarding the timing of the delivery of EN in appropriate patient groups and 13 of these trials were found to be conducted in trauma patients requiring intensive care. Of these 13 trials, nine were excluded for the following reasons: Four trials failed to explicitly report mortality outcomes11,17,24,44; four trials evaluated the impact of early immunoenhanced EN, not standard EN28,38,40,48 and; one trial commenced ‘early’ EN an average of 39 12 h post-injury.13 The remaining four trials provided early standard EN within 24 h of injury.5,26,27,39 Complete details of eligible trials are presented in Table 2.
None of the four eligible trials reported using any form of blinding. Three of the eligible trials reported mortality outcomes on all randomised patients such that an intention-to-treat analysis could be conducted.5,26,27 One trial failed to report outcomes on 12 of 75 (16%) randomised patients.39 Due to the presence of excessive loss to follow-up and the resultant inability to conduct an intention-to-treat analysis, this study did not qualify for inclusion in the primary analysis. However, this study was considered in a sensitivity analysis. Included trial characteristics The three trials included in the primary analysis randomised a total of 126 patients, with a median of 38 patients and a range from 36 to 52 patients.
Methodological quality appraisal
Patient-oriented outcomes
All four eligible trials failed to report sufficient detail on the method of randomisation such that it was unclear whether allocation concealment was maintained.
All included trials reported mortality however none reported quality of life and none reported direct measures of physical function.
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Table 2 Characteristics of eligible studies. Study
Patient population
Early EN intervention
Control intervention
Chuntrasakul 1996
Severe trauma (ISS >20 and <40) Mean ISS 29 1.5
Immediately after resuscitation or surgery: 30 mls/h 3/4 strength EN (TraumacalTM) via NGT, concentration increased over time. Goals estimated using modified Harris-Benedict equation. TPN was added if goals were not met
5% dextrose/NSS for maintenance. Oral intake commenced upon return of bowel sounds
Kompan 1999
Multiple trauma (ISS > 25) Mean ISS 33.6 10 Mean APACHE II 11.5 5.8
Immediately after resuscitation: EN (JevityTM) started at 20 ml/h via NGT. Increased to 50% of estimated goal on Day 1, 75% of estimated goal on Day 2 and 100% of goal on Day 3. Estimated goal was set at 25–35 nonprotein kcal/kg per day and 0.2–0.3 g nitrogen/kg per day at 72 h post-ICU admission. TPN was added to meet estimated requirements
Same protocol as Early EN except EN begun a median 41.4 (33.9–53.6 range) hours after trauma. Note: 50% of goal received via TPN for first 24 h before EN was begun
Kompan 2004
Multiple trauma (ISS > 20) Mean APACHE II 11.3 4.8
Immediately after resuscitation: Same protocol as Kompan 1999 except goal set at an average of 25 nonprotein kcal/kg
Same protocol as Early EN except EN begun 38.5 15.6 h after trauma. Note: 50% of goal received via TPN for first 24 h before EN was begun
Moore 1986
Major abdominal trauma (ATI > 15)
Within 12–18 h of surgery: EN (Vivonex HN at 1/4 strength) via NJT at 50 ml/h. Rate and concentration increased at 8 h intervals to target (full strength solution 125ml/h ) at 72 h
5% dextrose (approx. 100 g/day) during first 5 days post-op and then TPN if not tolerating oral diet at that time
APACHE, Acute Physiology and Chronic Health Evaluation Score; ATI, Abdominal Trauma Index; EN, enteral nutrition; ICU, intensive care unit; ISS, Injury Severity Score; NCJ, needle catheter jejunostomy; NGT, naso-gastric tube; NJT, naso-jejunal tube; NPO, nil per os (no oral intake); NSS, normal saline solution; TPN, total parenteral nutrition.
[(Fig._2)TD$IG]
Fig. 2. Primary analysis of trials reporting intention-to-treat mortality. CI = confidence interval, EN = enteral nutrition, OR = odds ratio.
Hospital discharge mortality was reported in one trial26 whilst two trials reported intensive care unit (ICU) discharge mortality.5,27 As shown in Fig. 2, meta-analysis of the RCTs included in the primary analysis revealed a statistically significant reduction in mortality in favour of early standard EN provided within 24 h of injury (OR = 0.20, P = 0.04, I2 = 0).
difference in the incidence of MODS (12/17 early EN patients vs. 13/19 delayed, P = 0.82) however severity of MODS demonstrated a trend towards fewer failed organ systems in patients receiving early standard EN (2.5 0.7 vs. 3.1 0.8 organ failures per patient, P = 0.057). Sensitivity analysis
Complications and major ICU infections Vomiting/aspiration No included trials reported the incidence of vomiting or aspiration. Pneumonia One included trial reported the incidence of pneumonia.27 The incidence of pneumonia was significantly lower in patients receiving EN within 24 h of injury (9/27 vs. 16/25, P = 0.050). Bacteremia No included trials reported the incidence of bacteraemia as an outcome. Sepsis No included trials reported the incidence of sepsis as an outcome. Multiple organ dysfunction syndrome (MODS) One included trial reported the incidence and severity (number of failed organs per patient) of MODS.26 There was no significant
A sensitivity analysis was conducted including the poorer quality Moore study.39 The sensitivity analysis demonstrated a significant reduction in mortality attributable to early standard EN (OR = 0.26, P = 0.04, I2 = 0). Discussion We undertook an extensive literature search to identify RCTs evaluating the effectiveness of early standard EN, provided within 24 h of injury, in trauma patients requiring ICU care. Our primary conclusions were based on trials that were free from major methodological flaws. Four clinical trials conducted in patients with severe multiple trauma and major abdominal injury met our selection criteria. Meta-analysis revealed a statistically significant reduction in mortality attributable to the provision of standard EN within 24 h of injury. Individual trials reported statistically significant reductions in pneumonia and a trend towards a reduction in severity of MODS attributable to the provision of early standard EN.
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Benefits of EN within 24 h of injury Laboratory studies have established the physiological benefits attributable to the provision of EN in trauma. This meta-analysis is the first to demonstrate these physiological benefits translate into improvements in survival. The provision of EN in the critically ill trauma patient is accepted to preserve physical gut barrier function, and maintain gut associated lymphoid tissue mass and function.29,31 By maintaining the host defence functions of the intestine, translocation of bacteria from the gut into the blood stream, and consequent systemic infectious complications, are reduced.15,49 The provision of EN also down-regulates the systemic immune response to bacterial translocation which reduces overall oxidative stresses and moderates the expression of the systemic inflammatory response syndrome37 and subsequent progression to MODS.3 The appropriate provision of EN may also reduce aspiration related complications such as pneumonia.4 Two eligible trials reported significant reductions in infectious complications in patients receiving early EN,27,39 potentially attributable to a decrease in bacterial translocation or aspiration. Although neither of these trials recorded the incidence and severity of MODS, a third eligible trial reported a trend (P = 0.057) towards a reduction in the severity of MODS in patients receiving early EN.26 The progressive failure of multiple organ systems is a leading cause of morbidity and mortality in critical illness and a reduction in the onset or severity of MODS could be expected to translate into a mortality benefit.34,51 Early EN: within 24 h or 48 h of injury? Based on the findings of previous publications9,35,45 we were explicitly interested in the results of trials that provided standard EN within 24 h of injury. Because others have defined the timeframe for the provision of early EN as within 48 h post-injury or ICU admission,41 we framed our literature search such that articles that employed any timeframe to define early EN could be identified. Our literature search identified only one trial that satisfied all eligibility criteria and defined early EN as within 48 h of injury.13 This trial enrolled and randomised 52 blunt trauma patients to receive early standard EN an average of 39 12 h post-injury or delayed EN, which was provided 90 12 h post-injury. Outcomes were reported on 38 patients, with two deaths in each group (2/19 vs. 2/19). Because this trial fails to show any suggestion of benefit in favour of standard EN provided within 48 h of injury, this publication does not provide any compelling reason to extend the definition of early EN from less than 24 h from injury to 48 h. Selection of analytic method The purpose of conducting a meta-analysis of previously published RCTs is to obtain a more definitive and precise answer to a research question. Decisions regarding the selection of metrics,7 models50 and issues arising due to heterogeneity14 can influence the overall validity of the conclusions of a meta-analysis. Mounting methodological evidence suggests the selection of the appropriate analytical method is also important.2,46 Two of the clinical trials included in our meta-analysis reported zero deaths in patients receiving early EN.26,27 Events in the control arms of these two trials were also relatively rare. The majority of commonly used analytical methods were developed using large sample theory. When outcomes are infrequent and RCTs report zero events in one arm of a trial, the two most commonly used analytical methods, the random effects method of DerSimonian and Laird8 and the fixed effects method of Mantel and Haenszel,32
may produce severely biased treatment effect estimates.2,46 Both the Exact method and the ‘one-step, assumption free’ fixed effects method of Peto55 are known to be minimally biased when outcome events are rare.2,46 The Peto method is implemented in software widely accessible to all researchers (RevMan, The Cochrane Collaboration1, Oxford, England, 2003), thus we conducted our primary analysis using this technique. Because many methodologists may consider the Exact method to be more definitive, we elected to confirm the results of our primary analysis obtained using the Peto method by conducting an additional analysis using the Exact method (StatXact 5.0, Cytel Software Corporation, Cambridge, USA). The Exact method revealed a significant reduction in mortality attributable to the provision of early EN (ORExact = 0.14, 95% CI 0.01–0.97), which was entirely consistent with the findings obtained using the Peto method. Strengths and limitations We conducted an extensive and exhaustive literature search that was not restricted to the English language. Although it is unlikely that published studies were missed, we did not explicitly search the grey literature to identify conference abstracts of unpublished studies.1 It is likely our literature search identified all eligible trials. We undertook a formal sensitivity analysis and also confirmed our primary analysis using a second analytical method. The formal sensitivity analysis included RCTs with major methodological flaws identified during our current search whilst the confirmatory analysis was conducted using the Exact method. The results of the sensitivity analysis and the confirmatory analysis did not differ significantly from the results of the primary analysis: both demonstrated a statistically significant reduction in mortality attributed to the provision of standard EN within 24 h of injury. Overall, the RCTs included in our meta-analysis were small and of poor quality however, none of the RCTs included in our primary analysis had major methodological flaws. Furthermore, the patient outcomes reported in each trial were limited to ICU or hospital discharge mortality, which may not fully capture the mortality experience of the trauma patient.47 There is a pressing need for the conduct of a multi-center adequately powered clinical trial in this field, equivalent to a Food and Drug Administration (FDA) Phase III licensing trial. We strongly recommend such a trial should report patient survival beyond 90 days post-injury and collect quality of life and physical function information. The composition of standard EN formula used, nutritional goals set, use of supplemental parenteral nutrition and comparator interventions appeared to differ between included trials (Table 2). Because there is no evidence of statistical heterogeneity and the magnitude of the observed treatment effect is consistent across all included trials, it is valid to obtain an overall summary estimate despite these apparent differences.7,23,50 Within the constraints of the patient groups and interventions evaluated in the included trials, the presence of a reasonably consistent treatment effect in the face of differences in study design suggests that the benefits of early EN may be independent of the composition of standard EN formula used, nutritional goals set, use of supplemental parenteral nutrition and comparator interventions. This hypothesis should be confirmed in a subsequent multi-center clinical trial. Conclusions Meta-analysis conducted on the methodologically sound clinical trials identified by our systematic review of the literature revealed a statistically significant reduction in mortality attributable to the provision of standard EN within 24 h of injury. These
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findings are robust: the results of the confirmatory and sensitivity analyses did not differ significantly from the primary analysis. Due to the constraints of the included trials, we recommend the use of judicious clinical judgement in applying these findings to clinical practice. The primary findings of this meta-analysis need to be confirmed by the conduct of a large-scale multi-centre Level I (FDA Phase III) clinical trial. Authors’ contributions GSD and FS conceived and designed the study, managed the project, conducted the statistical analysis, interpreted the results and drafted the manuscript. GSD had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. PTH and EAS contributed to study design, managed the project, interpreted the results and helped draft the manuscript. Guarantor Gordon S Doig PhD (Epidemiology and Biostatistics) was responsible for and conducted all analyses. He had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of interest statement GSD has received academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd. and speakers honoraria from Baxter Healthcare Pty Ltd. FS has received academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd. and speakers honoraria from Pharmatel-Fresenius Kabi Pty Ltd. EAS has received an academic research grant from Baxter Healthcare Pty Ltd. PTH declares no competing interests. Ethics Ethics approval was not required to conduct this integrative meta-epidemiological study. Funding source The conduct of this study was not funded. References 1. Benzies KM, Premji S, Hayden KA, Serrett K. State-of-the-evidence reviews: advantages and challenges of including grey literature. Worldviews Evid Based Nurs 2006;3:55–61. 2. Bradburn MJ, Deeks JJ, Berlin JA, Russell LA. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 2007;26:53–77. 3. Carrico CJ, Meakins JL, Marshall JC, et al. Multiple-organ-failure syndrome. Arch Surg 1986;121:196–208. 4. Chen YC. Critical analysis of the factors associated with enteral feeding in preventing VAP: a systematic review. J Chin Med Assoc 2009;72:171–8. 5. Chuntrasakul C, Siltharm S, Chinswangwatanakul V, et al. Early nutritional support in severe traumatic patients. J Med Assoc Thai 1996;79:21–6. 6. Cook DJ, Greengold NL, Ellrodt AG, Weingarten SR. The relation between systematic reviews and practice guidelines. Ann Intern Med 1997;127:210–6. 7. Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med 2002;21:1575–600. 8. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. 9. Doig GS, Heighes PT, Simpson F, et al. Early enteral nutrition, provided within 24 hours of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials. Intensive Care Med 2009;35(12):2018–27. 10. Doig GS, Simpson F, Delaney A. A review of the true methodological quality of nutritional support trials conducted in the critically ill: time for improvement. Anesth Analg 2005;100:527–33.
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