Systematic review and meta-analysis: the clinical and physiological effects of fibre-containing enteral formulae

Transcription

1 Alimentary Pharmacology & Therapeutics Systematic review and meta-analysis: the clinical and physiological effects of fibre-containing enteral formulae M. ELIA*, M. B. ENGFER, C.J.GREEN &D.B.A.SILKà *Institute of Human Nutrition, Southampton General Hospital, Southampton, UK; Clinical Nutrition Division, Royal Numico, Schiphol, the Netherlands; àdepartment of Academic Surgery, St Mary s Hospital, London, UK Correspondence to: Dr M. Elia, Institute of Human Nutrition, University of Southampton, Southampton General Hospital, Mailpoint 113, Tremona Road, Southampton SO16 6YD, UK. m.elia@soton.ac.uk Publication data Submitted 30 August 2007 First decision 17 September 2007 Resubmitted 3 October 2007 Accepted 3 October 2007 SUMMARY Background Enteral nutrition can be associated with gastrointestinal side effects and fibre supplementation has been proposed as a means to normalize bowel function. Aim To evaluate systematically the effects of fibre supplementation of enteral feeds in healthy volunteers and patients both in the hospital and community settings. Methods Electronic and manual bibliographic searches were conducted. Controlled studies in adults or children, comparing fibre-supplemented vs. fibre-free formulae given as the sole source of nutrition for at least 3 days, were included. Results Fifty-one studies (including 43 randomized-controlled trials), enrolling 1762 subjects (1591 patients and 171 healthy volunteers) met the inclusion criteria. Fibre supplementation was generally well tolerated. In the hospital setting, the incidence of diarrhoea was reduced as a result of fibre administration (OR 0.68, 95% CI: ; 13 randomizedcontrolled trials). Meta-regression showed a more pronounced effect when the baseline incidence of diarrhoea was high. In both patients and healthy subjects, fibre significantly reduced bowel frequency when baseline frequency was high and increased it when it was low, revealing a significant moderating effect of fibre. Conclusions The review indicates that the fibre-supplemented enteral formulae have important physiological effects and clinical benefits. There is a need to use a consistent approach to undertake more studies on this issue in the community setting. Aliment Pharmacol Ther 27, ª 2008 The Authors doi: /j x

2 SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF FIBRE-CONTAINING ENTERAL FORMULAE 121 INTRODUCTION Enteral nutrition (oral or tube feeding) is required when oral intake is insufficient or is likely to be absent for a period of more than 5 7 days. 1 It is used in the in-patient and out-patient settings in a wide range of disease states, with the majority of patients requiring nutritional support for around 1 month. 2 The duration of enteral feeding will depend upon the nature of the underlying condition. For example, patients recovering from surgery may require short-term enteral feeding whereas those in chronic-care facilities may depend on long-term enteral nutrition, usually tube feeding, over many months. There is an ongoing debate regarding the definition of fibre, which includes either in its entirety, or as a major component, the polysaccharides of plant cell walls. 3 The properties of fibres depend on their chemical as well as physical characteristics. Physiological approaches to definitions have been based on the consideration of nondigestibility of carbohydrates in the small intestine, with the plant cell wall polysaccharide being the dominant component. The solubility of fibre determines to some extent its physiological properties such as water-holding capacity. Nevertheless, this categorization may be too simplistic as it neglects the metabolism in the colon. 4 The degree of fermentability may be equally relevant for the health effects of fibres. In general, well-fermented fibres are soluble, whilst less well-fermented fibres are insoluble. However, there are some exceptions, e.g. insoluble soy polysaccharides, especially when finely ground, may be well-fermented. In addition, certain fibre types, the so-called prebiotics, have the ability to stimulate the growth of specific types of colonic bacteria. 5 An attempt has also been made to link the definition of fibre to health benefits, and as a healthy diet encompasses a large variety of fibres, it seems reasonable to consider the use of a mixture of fibres in enteral feeds. Dietary fibre was omitted from the early commercial enteral formulae, mainly on account of its effects on increasing viscosity and sedimentation. These technological issues have largely been overcome and several fibre-supplemented enteral formulae are now available, although doubts remain about their role, tolerability and efficacy. Gastrointestinal symptoms are observed in enterally fed patients, which can be influenced by various factors such as the nature and application of the feed (composition, temperature and flow rate), the disease state and or the medication. Lack of fibre in enteral formulae has been suggested to be a cause of impaired bowel function. 6 For example, in the acute hospital setting, especially critical care units, diarrhoea is reported to be a frequent complication of enteral feeding, 7 and the aim of fibre supplementation in this situation would be to reduce diarrhoea. However, in patients receiving long-term enteral feeding, constipation is probably the most frequently reported gastrointestinal problem. 8 The principal role of fibre supplementation in this situation is to prevent constipation, which may otherwise require large amounts of laxatives or even manual evacuation. Fibre can speed up gastrointestinal transit time, increase faecal bulk and reduce constipation. 9, 10 Fibre may also have other beneficial effects, such as improvement in gut barrier function, which prevents translocation of bacteria and toxins from the gut into the systemic circulation, 11 an increase in turnover or regeneration of epithelial cells, 12 and effects on fluid and electrolyte absorption. 13 Conversely, fibre is sometimes perceived as a factor leading to tolerance problems including bloating, flatulence and diarrhoea. 14, 15 Clinical trials that have examined the effects of fibre-supplemented formulae on gastrointestinal function in patients have shown variable results. 16 This inconsistency might be on account of the differences in patient types, types of intervention, end point definitions and lack of evaluation of the confounding factors. Studies performed in healthy volunteers could help establish overarching principles that apply to both health and disease, avoiding the confounding effects of disease, drug administration, and immobility, all of which may be present in a clinical setting. The effects of fibre supplementation in enteral nutrition have been evaluated in two recently published systematic reviews. 17, 18 The first by Yang et al. included only seven randomized-controlled trials (RCTs) published prior to 2003 (two of which included additional supplementation with probiotics) and did not include an analysis of the effects of fibre supplementation in healthy subjects. 17 The outcome parameters examined were restricted to the occurrence of diarrhoea, infection and length of hospital stay in hospitalized patients. The review by del Olmo et al. (English abstract only) included 25 studies published before the end of 2002, 18 focussing on incidence of diarrhoea and constipation, use of laxatives and frequency of bowel movements. The meta-analyses

3 122 M. ELIA et al. combined findings from patient groups with those from healthy volunteers. Neither of the reviews examined whether the effects of fibre were dependent on the dose and type of fibre administered. In view of the various limitations of the previously published work, we felt a need to undertake a more comprehensive and up-to-date systematic review, applying more extensive statistical methods (including meta-analysis and meta-regression). The present review was undertaken to examine the potential clinical benefits, physiological effects and tolerance of fibre-containing feeds compared with standard fibrefree feeds. Studies performed in healthy subjects and patients with acute and or chronic conditions were considered. The decision was taken a priori not to combine patients and healthy subjects in the same meta-analysis, although any concepts emerging from healthy volunteers would be considered in the light of results emerging from patient populations. The final objective was to identify knowledge gaps in the published literature and to propose areas requiring further research. METHODS Research design and methods The main aim of the systematic review was to evaluate the effect of fibre-supplemented enteral feeds on objective and subjective measures of gastrointestinal function in both healthy volunteers and patient populations. The review was planned, conducted and reported following published guidelines. These include those issued by the Cochrane Collaboration 19 and the QUORUM guidelines. 20 Identification and retrieval of studies Potentially relevant studies were identified by searching the electronic databases PubMed, Embase and Biosys, accessed in July Two separate searches were performed focussing on different search terms. The first search concentrated on fibre and enteral nutrition and search terms included fibre (any spelling), enteral nutrition, clinical nutrition, artificial nutrition, medical food, tube feed, sip feed and oral nutritional supplement. The second search focussed on fibre types ( fibre subgroup search) and search terms comprised soy polysaccharides, resistant starch, oligofructose, oligosaccharides, inulin, pectin, arabic gum, guar gum, acacia, cellulose, pea* and oat*. Bibliographies of identified trials and relevant articles were checked and experts consulted for any additional studies. Study selection criteria, data extraction and outcome measures Studies were deemed eligible for inclusion in the review if they conformed to predetermined inclusion and exclusion criteria. Subjects eligible for inclusion were healthy volunteers or patients >1 year of age of any nutritional status (well nourished and malnourished) and based in any setting (e.g. hospital, care home and at home). Studies in which patients did not receive oral- or tube feeding as their main source of nutrition were excluded. Studies including a self-selected (SS) diet arm were included to allow comparison with fibre-free fibre-containing enteral feeds. However, studies involving infant formulae and studies that did not involve a fibre-free period were excluded. Although priority was given to RCTs, non-rcts and observational cohort studies were also admissible. Epidemiological dietary intake studies, animal or in vitro studies, literature reviews, observational case studies and acute studies (<3 days) were excluded. No other restrictions were placed on studies with regard to year of publication, format, language (providing an English abstract was available) and source. Following the identification of potentially relevant studies based on title and abstract, full articles were obtained and evaluated by one researcher. A second independent assessor verified the validity of inclusion exclusion decisions. Disputes as to eligibility were referred to the authors panel. A predetermined data extraction table was designed to capture study characteristics and outcome data and allow the assimilation of data from all study designs. Both subjective (incidence of diarrhoea constipation, stool consistency and gastrointestinal symptoms) and objective (transit time, stool weight and bowel frequency) outcome measures were considered. Quality assessment The methodological quality of individual studies was assessed by one researcher and verified by a second assessor using the two scales which are commonly

4 SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF FIBRE-CONTAINING ENTERAL FORMULAE 123 adopted by health technology appraisal groups worldwide. The first method was the one developed by Jadad et al., 21 an objective grading system which awards a score of 0 5 and assesses randomization (0 2 points), double blinding (0 2 points), and withdrawals and dropouts (0 1 point). The second was a six-point scale adapted from the Quality of Evidence Quality Assessment (AHCPR) scale. 22 A high JADAD score is deemed to be of better quality. The converse is true for the AHCPR scale, where a lower score is indicative of higher quality. Synthesis of data and statistical methods Meta-analyses were conducted using a fixed effects model, which combines treatment estimates of effect size assuming that there is no heterogeneity between study results. Heterogeneity was investigated using the I 2 statistic. 23, 24 A mean treatment difference was considered to be statistically significant if the 95% confidence interval (CI) did not span the value of zero. Forest plots were used to present the effect size of each meta-analysis. Funnel plots to investigate publication bias are deemed inappropriate when a small number of studies are involved. Therefore, such plots and associated statistics (Begg and Mazumdar s rank correlation and Egger s regression intercept method) were only used when 10 or more studies were included in the meta-analyses, 25 although 10 studies are still considered to be an inadequate number by many investigators. 26 Linear meta-regression was undertaken. Like ordinary regression, meta-regression examines the extent to which a putative explanatory variable accounts for the variability or heterogeneity in results. Unlike ordinary regression, where the unit is an individual subject, in meta-regression the unit is an individual study. Studies are weighted so that the more precise ones have more influence in meta-regression analysis. In the figures of meta-analyses and meta-regressions, the area of the symbols is proportional to the weight of the studies. All meta-analyses and meta-regressions were performed using COMPREHENSIVE META ANALYSIS Version 2.0 (Biostat, Englewood, NJ, USA). A P-value of <0.05 (two-tailed) was considered to be statistically significant. In the forest plots the squares indicate point estimates of treatment effect, with the size of the square representing the weight attributed to each study and the horizontal bars indicating 95% CI. RESULTS Overall search findings In total, 339 references were identified by systematic search of literature: 276 references from the fibre and enteral nutrition search and 63 references from the fibre subgroup search. Upon examination of the abstracts and or full texts, 247 and 61 papers were excluded, respectively, leaving 31 papers. Cross-referencing and expert consultations identified a further 20 papers, giving a total of 51 studies, which complied with the inclusion criteria and were therefore included in the review (Figure 1). Of the 51 studies included in the review, 38 were available as full papers and 13 as abstracts. RCTs accounted for 43 of 51 (84%) studies, scoring the highest grade of 1 according to the Quality of Evidence Scale. 22 However, the methodology of individual RCTs in individual cases was often poorly described (with regard to method of randomization, blinding and recording the fate of withdrawals) with only one study 15 scoring the top grade of 5 on the Jadad scale. The remaining RCTs scored 4, 10, , 8, , , 1 14, or 0. 63, 64 Eight studies were either nonrandomized or there was insufficient information to conclude whether they were randomized from the details available in the publication Patient subgroups The 51 studies were divided into subgroups, with studies involving healthy volunteers (13 studies, 171 subjects) considered separately from those in patients (38 studies, 1591 patients). The patient studies were further subdivided on the basis of the setting, whether adult or paediatric populations were considered, and based on underlying condition. The details of the subgroups are reported in Table 1. Route of formula administration In the 13 studies conducted in healthy volunteers, subjects were fed via the oral route. 9, 10, 15, 34, 43 47, 56, 61, 62, 72 In the patient studies (n = 38), enteral nutrition was administered via various routes:

5 124 M. ELIA et al. Figure 1. Protocol of included and excluded papers in the literature search. 1 In 18 of 38 (47%) studies, feeding was administered 28 31, 35, 36, 39, 40, 42, 49, 50, 53, 58, via a nasogastric tube; 60, 65, 66, 68, 71 2 In three of 38 (8%) studies, feeding was administered via a nasojejunal tube needle catheter jejunostomy tube; 14, 33, 38 3 In three of 38 (8%) studies, a variety of tube feeding routes was used 8, 27, 37 and 4 In 14 of 38 (37%) studies, the route of tube feeding was not explicitly 32, 41, 48, 51, 52, 54, 55, 57, 59, stated. 63, 64, 67, 69, 70 Reported end points Diarrhoea and constipation were the most frequently reported clinical end points. Stool bowel frequency, transit time, stool weight, stool consistency, shortchain fatty acids (SCFA) and stool microflora were the most commonly reported physiological parameters. Tolerance was reported as a range of subjective end points and laxative use was also reported as it is often regarded as an indicator of bowel function. The frequency of the main end points reported in

6 SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF FIBRE-CONTAINING ENTERAL FORMULAE 125 Table 1. Demographics of study groups Study subgroups Mean number of patients study (range) Mean treatment duration, days (range) Adults 9, 10, 15, 34, 43 47, 61, 62 Healthy volunteers (n = 13): RCTs 13 (8 22) 10 (7 21) Non-RCTs 67, , 39, 40, 48, 49, 64 Intensive care unit () critically ill* (n = 11): RCTs 51 (9 100) 11 (4 18) Non-RCTs 68, 69 Surgical post-operative (n = 8): RCTs 28, 29, 38, 50, 55, 57, 59, (16 100) 9 (5 15) 37, 42, 53, 56, 58 Medical (n = 6): RCTs 56 (11 155) 14 (5 28) Non-RCT 65 Chronic care (n = 6): RCTs 8, 14, 35, 36, 52, (7 28) 24 (7 49) Paediatrics Acute medical (n = 2): RCTs 51, (31 112) 18 (15 21) 27, 41 Chronic care (n = 5): RCTs Non-RCTs 66, 70, (11 20) 93 (14 300) * Including studies with mainly patients and septic patients. RCT, randomized-controlled trial. the 51 studies that have been included, is reported in Table 2. Several other end points, such as plasma glucose levels, 10, 33, 50 mineral retention 44, 71 or cholesterol levels 33, 53, 54 were reported in a small number of studies only and were therefore not considered further. Amount and type of fibre sources in the studies included Over 15 different fibre sources administered either as a sole fibre source or as part of a mixture, were employed in the studies included (Table 3). polysaccharide was the most frequently studied fibre source, followed by a mixture of six different fibres (Nutricia Multi Fibre, Nutricia, Zoetermeer, The Netherlands; used in 16% of all studies). In 65% of the studies a single fibre source was used, in 8% of studies a mixture of two sources, in 4% a mixture of five sources and in 6% of studies insufficient details were reported. A number of studies investigated the effects 9, 32, 34 of different fibre sources. Overall, there was considerable variability between the studies in the amount of fibre administered daily (Table 3). The actual daily fibre intake was not explicitly reported in 18 studies, 10, 29 31, 35, 36, 41, 48, 55, 57, 59, 60, 63, 64, 68 70, 72 however, it was possible in several cases to calculate the actual intake based on information reported in the article. Wherever available, the amount of fibre intake was based on actual fibre analysis by various methods, e.g. by the methods of AOAC, 4, 73 and Southgate. In all other cases, data on fibre intake was used as stated in the article. Fructooligosaccharides (FOS and inulin) were assumed to be part of the total fibre intake. Of the 51 studies which reported the fibre source, 26 studies administered fibre as an integrated constituent of the formula 8, 15, 29 32, 35, 36, 39, 41, 46, 50, 52 54, 56 60, 63, 64, 66, compared with 20 studies where the fibre source was added to the 9, 10, 14, 27, 28, 33, 34, 37, 38, 40, 42 44, 47, 49, 51, 55, 61, feed. 65, 67 In the study by Slavin et al., patients received three different fibre regimens over the course of the study, one of which was an integrated formula compared with two, where the fibre was added to the feed. 45 In seven studies (four conducted in healthy volunteers 44, 45, 61, 72 and three in patients 29, 66, 71 ) subjects received different amounts of fibre during different treatment phases, allowing the effect of the amount of fibre on bowel function to be studied. Considering the studies enrolling healthy volunteers, they compared: 30 and 60 g of soy polysaccharides day, 45 20, 30 and 40 g day of either cellulose day 61 or soy polysaccharide 44 and low moderate high levels of fibre. 72 Patient-enrolled studies compared high (14 g L) with moderate (7 g L) levels of soy polysaccharide 29 or administered an increase in daily fibre intake from 15 to 21 g during the final study 66, 71 period.

7 126 M. ELIA et al. End point reported Number of studies reporting end point (not all study results were eligible for further analysis) Table 2. End points reported in included studies Diarrhoea (n = 23) Healthy volunteers n =3 13 Patients n =20 38 Constipation (n = 17) Healthy volunteers n =4 13 Patients n =13 38 Stool bowel frequency (n = 29) Healthy volunteers n =10 13 Patients n =19 38 Transit time (n = 14) Healthy volunteers n =9 13 Patients n =5 38 Faecal mass (n = 18) Healthy volunteers n =10 13 Patients n =8 38 Stool consistency (n = 24) Healthy volunteers n =5 13 Patients n =19 38 Laxative use (n = 10) Patients n =10 38 Microflora (n = 4) Healthy volunteers n = Patients n =3 38 SCFA (n =8) Healthy volunteers n =5 13 Patients n =3 38 Tolerance (n = 26)* Healthy volunteers n =5 13 Patients n = , 43, 46 8, 28 32, 37 41, 53, 56 58, 60, 63, 64, 68, 69 10, 43, 46, 61 8, 14, 28 30, 33, 35, 38, 41, 50, 56, 58, 60 9, 10, 15, 34, 43, 45 47, 61, 62 8, 14, 27, 35, 36, 41, 42, 49 56, 60, 65, 66, 70 9, 34, 43, 45, 46, 61, 62, 67, 72 8, 27, 41, 52, 53 9, 10, 15, 34, 45, 46, 61, 62, 67, 72 8, 39, 42, 52, 53, 55, 58, 66 10, 34, 43, 45, 47 14, 27, 32, 33, 36, 37, 39, 40, 49 52, 54 56, 65, 66, 69, 70 8, 27, 35, 49, 52, 54, 56, 63, 66, 70 14, 35, 65 9, 10, 15, 34, 47 14, 35, 65 15, 34, 43, 46, 62 8, 14, 27, 29, 33, 35, 38, 40 42, 48, 51 53, 55 58, 63, 68, 70 * Tolerance was defined as the incidence of gastrointestinal symptoms and included nausea, vomiting, flatulence, abdominal cramps and bloating. The incidence of diarrhoea and constipation were considered as separate end points. SCFA, short chain fatty acids. Bowel-related outcomes Diarrhoea. There was widespread inter-study variation in the quantification of diarrhoea in the studies that were reviewed. Twenty-two studies defined diarrhoea and the definitions reported can be grouped into four categories: 1 Number of liquid stools was used in nine of 22 8, 33, 37, 38, 49, 51, 58, 64, 69 (41%) studies; 2 Diarrhoea score was used in eight of 22 (36%) 28, 30 32, 39, 40, 48, 63 studies; 3 Scale based on frequency consistency in four of 22 (18%) studies 10, 50, 60, 70 and 4 Scale based on frequency volume in one of 22 (5%) studies. 29 Some studies reported a diarrhoea-related end point without explicitly providing a definition for diarrhoea. 41, 55, 56, 68 Only two of the studies conducted in healthy volunteers reported the incidence of diarrhoea. Increased watery stools were observed in the fibre-free and the guar gum groups compared with subjects treated with feeds supplemented with soy polysaccharide 34 or Nutricia Multi Fibre. 46 A meta-analysis was undertaken of the incidence of diarrhoea (defined as number of patients with diarrhoea) in the hospitalized patients participating in RCTs (16 data sets from 13 RCTs; Table 2; n = 338 in fibre group and n = 345 in fibre-free group). Incidence of diarrhoea was found to be significantly reduced as a result of fibre administration [odds ratio (OR) 0.68;

8 SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF FIBRE-CONTAINING ENTERAL FORMULAE 127 Table 3. Fibre sources used in studies Fibre source* Studies evaluating fibre source (%) Number of fibres Mean fibre intake (range; g day) polysaccharides (n = 20) 8, 9, 27 30, 34, 36, 39, 44, 45, 52, 55, 58, 59, 64, 66, 67, 69, (6 35) polysaccharides, alpha-cellulose, arabic gum, inulin, oligofructose, resistant starch (Nutricia Multi Fibre; n =8) 35, 41, 46, 54, 57, 59, 63, 70 Guar gum, hydrolysed (n =7) 10, 31, 33, 34, 38, 43, (15 42) polysaccharides oat (n =2) 50, à 28.8 Pectin (n =2) 32, Psyllium (n =2) 37, Oat, soy, gum arabic, carboxymethylcellulose, FOS (n =2) 32, Inulin (n =1) Cellulose (n =1) Oat (n =1) Galactomannan (n =1) FOS (n =1) Carrot (pectin cellulose) (n =1) FOS pea (n =1) oligosaccharides (n =1) Ispaghula husk (n =1) Oat, soy, gum arabic, carboxymethylcellulose, FOS, pectin (n =1) Not reported (n =3) 62, 68, * Some studies examined more than one fibre source. As reported in the articles, amount of total dietary fibre was used whenever available. Majority of patients in study received Nutricia Multi Fibre. à Initial dose given. FOS, fructooligosaccharide. 95% CI: ; P = 0.03, Figure 2, overall results]. There was no evidence of publication bias (Begg and Mazumdar s rank correlation, P = 0.39; Eggers s regression intercept method, P = 0.71), although there was significant heterogeneity between the studies (test of overall heterogeneity, I 2 = 38%, P = 0.05). This heterogeneity resulted from the studies (I 2 = 44%; P = 0.09) rather than the non- studies (five surgical, one medical and one paediatric; I 2 = 0%, P = 0.50). Thus the incidence of diarrhoea in the studies was variable, ranging from 9 92% in the fibrefree groups. Subgroup analyses (Figure 2) revealed a significant reduction in the incidence of diarrhoea in the non- studies (OR 0.42, 95% CI: ; P = 0.001; eight data sets from seven RCTs, n = 185 in fibre group and n = 183 in fibre-free group) and in the surgical studies alone (data not reported). However, this effect was attenuated when patients were analysed as a distinct group (OR 0.98, 95% CI: ; P = 0.93; eight data sets from six RCTs, n = 153 in fibre group and n = 162 in fibre-free group). The 16 datasets were divided into eight studies with the highest (>30%) and lowest (<30%) incidence of diarrhoea in the fibre-free group. A significant reduction was found in the incidence of diarrhoea in the high incidence group (OR 0.61, 95% CI: ; I 2 = 49%, P = 0.06), but not in the low incidence group (OR 0.88, 95% CI: ; I 2 = 38%, P = 0.06). A meta-regression of the 16 data sets indicated that the extent to which the incidence of diarrhoea was reduced by fibre supplementation was related to the incidence of diarrhoea in the group receiving a fibrefree diet [Figure 3: intercept, 0.62 log OR; slope (log OR proportion of patients with diarrhoea) )3.4 (S.E. 0.91); z = )2.2, P = ]. Thus, beneficial effects were more likely to occur when the incidence of diarrhoea was high. This effect was maintained when the [intercept, 1.3 log OR; slope )3.5 (S.E. 1.3); P = 0.008] and non- subgroups [intercept, 0.37 log OR; slope )2.9 (S.E. 1.3); P = 0.001] were analysed separately. This type of meta-regression is subject to a

9 128 M. ELIA et al. Group by: Study name /non - Ward Fibre type Odds ratio and 95% CI Spapen et al Guenter et al Frankenfield & Beyer 1989 Dobb & Towler 1990 Schultz et al Schultz et al Schultz et al Hart & Dobb 1988 Khalil et al Reese et al Reese et al Homann et al de Kruif et al Richardson et al Belknap et al Hofman et al non - non - non - non - non - non - non - non - non - Overall Surgical Surgical Surgical Surgical Surgical Surgical Medical Paediatric Guar Fibre mixture* Pectin Fibre mixture* + pectin + oat (7 g/l )) (14 g/l ) Guar Psyllium Fibre mixture** Favours fibre Favours fibre-free Figure 2. Meta-analysis (fixed effect model) of the incidence of diarrhoea (proportion of patients with diarrhoea proportion of patients without diarrhoea) in tube-fed hospitalized patients participating in randomized-controlled trials. *Fibre mixture: oat, soy, gum arabic, carboxymethylcellulose, fructose oligosaccharides; **fibre mixture: soy polysaccharide, alpha-cellulose, arabic gum, inulin, oligofructose, resistant starch (Nutricia Multi Fibre). OR of <1.0 (favouring fibre) indicates that administration of a fibre-containing feed reduces the incidence of diarrhoea Log odds ratio Proportion with diarrhoea in fibre-free group Figure 3. Meta-regression of proportion of patients with diarrhoea in fibre-free group on log odds ratio for development of diarrhoea (proportion with diarrhoea proportion without diarrhoea). The horizontal dotted line indicates that fibre-containing feeds have no effect on the incidence of diarrhoea in comparison with fibre-free feeds, while values below the dotted line indicate that fibre decreases the proportion of patients with diarrhoea.

10 SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF FIBRE-CONTAINING ENTERAL FORMULAE 129 certain degree of bias 74 (regression to the mean, which increases the strength of the relationship), as a measurement error in the fibre-free group also appears to directly influence the dependent variable (treatment effect). However, the large variation in risk across trials (9 92% of patients had diarrhoea) would be expected to reduce this type of error. The level of fibre intake was reported in six of these 28, 30, 31, studies, ranging from 14.0 to 34.9 g day. However, no significant relationship was observed between the level of fibre intake during feeding and incidence of diarrhoea [intercept (log OR) )0.33; slope ; z = )0.24; P = 0.81; n = 135 in fibre group and n = 135 in fibre-free group]. A meta-analysis was also undertaken of seven studies, where the incidence of diarrhoea was defined as the percentage of days with diarrhoea, as opposed to the percentage of patients with diarrhoea as discussed 31, 40, 64 above. These studies included three in the, two medical, 37, 58 one paediatric 41 and one surgical 28 (n = 173 in fibre group, n = 170 in fibre-free group). This analysis showed that fibre reduced the duration of diarrhoea compared with the fibre-free group but the effect was not significant (OR 0.60, 95% CI: ; P = 0.09; test of heterogeneity, I 2 = 0%, P = 0.93). All but one of these studies were performed in adults with acute conditions and when this study 41 (enrolling children with chronic conditions) was excluded, meta-analysis of the remaining six studies (n = 157 in fibre group and 154 in control group), confirmed that fibre reduced the frequency of diarrhoea compared with the fibre-free group, although the effect was still not significant (OR 0.61, 95% CI: ; P = 0.11; test of heterogeneity, I 2 = 0%, P = 0.86). Antibiotic use. Antibiotic use was reported in a total 28 30, 32, 33, 37, 39, 40, 48 50, 54, 55, 63, 64 of 15 studies, although antibiotics may have been prescribed in other studies without reporting. The route of antibiotic administration was not explicitly stated in any of the studies. Nine studies reported the effect of antibiotic usage on diarrhoea incidence. While there was no effect on incidence of diarrhoea in four studies, 28, 32, 50, 54 five reported an increased incidence of diarrhoea in patients receiving antibiotic therapy. 29, 39, 40, 55, 64 Regarding any relationship between the particular antibiotic prescribed and the incidence of diarrhoea, the study by Frankenfield et al. reported that every subject who developed diarrhoea received a combination of clindamycin and gentamicin (plus ranitidine). 39 In a further study, subjects receiving cefazolin and metronidazole experienced a lower incidence of diarrhoea compared with subjects receiving other antibiotics. 29 Constipation. In total, 24 studies reported constipation as a clinical outcome (includes studies reporting laxative use). A variety of definitions was used in eight studies out of above, which reported: 1 Hard stool retains its shape, with difficulty in defecation ; 10 2 The development of infrequent hard stools ; 58 3 Absence of any bowel movement over a period 8, 28 of 72 h ; 4 Zero bowel frequency over 10-day study period ; 50 5 Intestinal evacuation less frequent over every 2 3 days, or increased flatus in combination with abdominal distension ; 38 6 Absence of bowel movements for more than 3 days or the inability to pass a bowel movement after straining or pushing for more than 10 min ; 33 7 Patients were classified as constipated if they required use of laxatives, suppositories or enemas. 29 Some studies reported a constipation-related end point without explicitly providing a definition for constipation. 30, 35, 41, 56, 60, 61 A meta-analysis of the incidence of constipation (reported in various ways) was possible on data from seven RCTs in the acute setting (two, 30, 33 three surgical 28, 50, 60 and two medical; 38, 56 n = 144 in fibre group, of which 23 had constipation, and 149 in fibrefree group, of which 36 had constipation). There was a nonsignificant trend for fibre to reduce the percentage of patients reporting constipation (test of overall effect, OR 0.57, 95% CI: ; P = 0.09; test of heterogeneity, I 2 = 0%; P = 0.51). The effect of fibre on laxative use for the treatment of constipation was reported in four studies in 49, 54, 56, 63 the acute setting. Following fibre supplementation, use of elimination aid was either significantly reduced 54, 56, 63 or unchanged. 49 Constipation was also considered to be a problem in the study of Vandewoude et al. (longer term medical patients) where patients were prescribed laxatives as required. 54

11 130 M. ELIA et al. Due to the paucity of data, it was not possible to meta-analyse the effect of fibre-supplemented feeds on constipation in patients with chronic conditions. For example, Schneider et al. reported that 53% of stable patients considered themselves constipated, although a comparison between intervention and fibre-free groups was not reported. 35 8, 29 Two studies showed no differences between those receiving the fibre-containing and fibre-free formulae with the study by Shankardass et al. being confounded by the use of laxatives. 8 Five studies in the chronic setting reported the use of laxatives enemas for the treatment of constipation, 8, 27, 35, 52, 66 with all but one study 35 reporting the effect of fibre supplementation on elimination aid use. Following fibre supplementation, use of elimination aid was either significantly reduced, 8 minimally reduced 52 27, 66 or unchanged. Bowel frequency. Healthy volunteers: Bowel frequency during administration of fibre-free and fibre-containing feeds was reported in 14 data sets derived from nine RCTs (n = 154, fibre-containing feed; n = 153, fibre-free feed). 9, 10, 15, 34, 43, 46, 47, 61, 62 In a metaanalysis (Figure 4), the fibre-containing feed significantly increased mean bowel frequency [test of overall effect, 0.14 (S.E. 0.05) times day, z = 2.8, P = 0.005; test of heterogeneity, I 2 = 26%, P = 0.17]. A funnel plot and associated statistical tests [Begg and Mazumdar s rank correlation (P = 0.17) and Egger s regression intercept method (P = 0.14)] did not suggest publication bias. The results remained significant when the study of Kies et al. was excluded from the analysis [test of overall effect, 0.12 (S.E. 0.05) times day, z = 2.2; P = 0.03]. The study of Kies et al. is unique in that four of the 18 healthy subjects given a feedcontaining cellulose (Sulka-floc), developed severe Study name Fibre type Bowel frequency (times/day) fibre - free group Difference in means and 95% CI Silk et al Fibre mixture* 1.20 Kapadia et al Kapadia et al Oat 0.90 Kapadia et al oligosaccharide 0.90 Lampe et al Guar 0.70 Lampe et al Zimmaro et al polysaccharide Pectin Whelan et al FOS + pea 0.60 Alam et al Guar 1.00 Meier et al Guar 1.15 Kies et al Cellulose (20 g) 1.49 Kies et al Kies et al L ü bke et al Cellulose (30 g) Celluose (40 g) Unknown Overall Favours fibre-free Favours fibre Figure 4. Meta-analysis (fixed effect model) comparing bowel frequency (times day) in healthy subjects receiving a fibrecontaining feed or a fibre-free feed. *Fibre mixture: soy polysaccharides, alpha-cellulose, arabic gum, inulin, oligofructose, resistant starch (Nutricia Multi Fibre); FOS: fructooligosaccharides. A value >0 (favouring fibre) indicates that administration of a fibre-containing feed increases bowel frequency compared with fibre-free feeds.

12 SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF FIBRE-CONTAINING ENTERAL FORMULAE 131 constipation with impaction, which required digital evacuation. 61 It is not clear if the reported frequency of bowel action included these evacuations. No such impactions were observed in subjects receiving a fibre-free feed. Meta-regression of these nine RCTs indicated that fibre supplementation increased bowel frequency in those in whom the frequency was low, and decreased it in those in whom it was high, and had little or no effect in those with an average frequency that was close to one bowel movement per day. This relationship was of borderline significance if the study by Kies et al. 61 was included [intercept (mean difference), 0.38 times day, slope )0.27 (S.E. 0.15); z = )1.8; P = 0.08]. However, a highly significant relationship was reported when this study was excluded from the analysis [Figure 5: intercept, 0.72 times day; slope 0.73 (S.E. 0.17); z = )3.8, P = ; 11 data sets from eight RCTs, n = 100 in fibre group and n = 99 in fibre-free group]. However, despite the observed strong relationships, these results should be regarded carefully, as they are subject to bias associated with regression to the mean, which tends to increase the strength of the relationships. Patients: Data were available from six studies (five RCTs) in patients (five adult and one paediatric patient population) requiring chronic care (n = 80 both in fibre-supplemented and fibre-free group). 8, 14, 41, 52, 53, 66 Supplementation of the enteral feed with fibre significantly increased bowel frequency [test of overall effect, 0.27 (S.E. 0.08) times day, z = 3.2, P = 0.001; test of heterogeneity, I 2 = 0%, P = 0.68]. When the meta-analysis was repeated following exclusion of the non-rct study 66 (five RCTs; n = 69 both in fibre and fibre-free groups), the effect of fibre in increasing bowel frequency remained significant [test of overall effect, 0.25 (S.E. 0.1) times day, z = 2.5, P = 0.01; test of heterogeneity, I 2 = 0%, P = 0.57]. Exclusion of the paediatric study 41 did not affect the result [test of overall effect, 0.25 (S.E. 0.10) times day, z = 2.6, P = 0.009; test of heterogeneity, I 2 = 0.00, P = 0.52]. Three RCTs enrolled patients with acute medical conditions (n = 95 in fibre group and 105 in fibre-free group). 42, 54, 65 Fibre supplementation led to a significant decrease in bowel frequency compared with fibre-free enteral feeds [overall test of effect, )0.22 (S.E. 0.08) times day, z = )2.7, P = 0.006], although the inter-study results showed significant heterogeneity (test of heterogeneity, I 2 = 72%, P = 0.03). An additional study in patients with head and neck cancer, 55 which could not be included in the above analysis due to lack of relevant information in the abstract, reported that fibre supplementation increased bowel frequency by 0.33 times day compared with the Difference in means Bowel frequency in fibre-free group (times/day) Figure 5. Meta-regression of bowel frequency (fibre-free group) on difference in mean values (bowel frequency on fibrecontaining feed ) bowel frequency in fibre-free feed) in healthy subjects. The horizontal dotted line indicates no difference in bowel frequency when a fibre-containing feed is compared with a fibre-free feed. Values above the dotted line (subjects having low bowel frequency) indicate that fibre-containing feeds increase bowel frequency and values below the line (subjects having a high frequency) report a decreased bowel frequency compared with a fibre-free feed.

13 132 M. ELIA et al. fibre-free control group (z = 2.3, P = 0.02). The authors considered that results for both stool consistency and bowel frequency were confounded by antibiotic treatment. Although meta-analysis of combined results from 8, 14, 41, 42, 52 the acute and chronic studies (nine RCTs 55, 65 and one non-rct 66 ) reported that fibre-containing feeds had no significant overall effect on bowel frequency because of substantial variability between studies (test of heterogeneity, I 2 = 71%; P = 0.001; overall difference of 0.05 times day; z = )0.98; P = 0.33), meta-regression demonstrated a highly significant moderating effect of fibre on bowel frequency, analogous to that found in normal subjects. Fibre supplementation decreased bowel frequency in those with high bowel frequency, and increased it in those patients with low bowel frequency. The highly significant relationship was observed in analyses involving RCTs and non-rcts of adults and children [intercept, 0.39 times day, slope )0.71 (S.E. 0.18), z = )3.9, P < ], only RCTs of adults and children [n = 175 in fibre group and n = 189 in control group; intercept, 0.36 times day; slope )0.68 (S.E. 0.19); z = )3.6; P < ], and only RCTs of adults [n = 159 in fibre group and n = 173 in fibre-free (control) group; intercept, 0.47 times day; slope )0.91 (S.E. 0.23); z = )3.9, P = ]. Transit time. Healthy volunteers: A meta-analysis of 9, 34, 43, 45, 46, 61, data sets from seven RCTs (n = 175 both in the fibre-containing and fibre-free group) investigated the effect of fibre supplementation on whole gut transit time in healthy volunteers. Administration of a fibre-supplemented enteral feed resulted in significantly faster gastrointestinal transit (Figure 6: test of overall effect, )9.3 (S.E. 2.29) h, z = )4.0, P < 0.001]. The analysis showed no statistical indication of publication bias [Begg and Mazumdar s rank correlation (P = 0.13); Egger s regression intercept method (P = 0.67)]. There was significant heterogeneity between studies (I 2 = 55%, P = 0.007), which may reflect the variety of fibre sources used in the enteral feed between studies. With respect to the effects of fibre source on transit time, a significant reduction was reported with the administration of a feed containing six different types of fibres (Multi Fibre) compared with a fibre-free feed ( h vs h; P < 0.05, paired t-test). 46 Furthermore, a significant reduction in transit time was reported for studies administering soy polysaccharide (test of overall effect, )19.3 h, z = )5.5, P < 0.001; five data sets from three RCTs 9, 34, 45 with n = 66 in both fibre-free and fibre-supplemented group) or cellulose [test of overall effect, )12.7 h, z = )2.4, P = 0.017; three data sets from one RCT 61 (n = 54 in both fibre-free and fibre-supplemented group)]. The effects of oat, soy oligosaccharides and hydrolysed guar gum on transit time were not significant. 9, 43 A meta-regression vs. fibre dose showed that increased intake had a tendency to shorten transit time, however, results were not significant [intercept, )0.32 (S.E. 0.18), z = )1.7, P = 0.09]. Patients: Whole gut transit time was investigated in three RCTs (two in adults and one in a paediatric population 27, 41, 53 ), each of which administered a different fibre type (soy, oat and soy and fibre mixture). A combined meta-analysis of all studies reported no significant effect [test of overall effect, 1.7 (S.E. 6.4) h, z = 0.26, P = 0.79; test of heterogeneity, I 2 = 52%; P = 0.12; very similar tests of significance were obtained when standardized differences were used in the analysis]. On account of the limited number of studies, meta-regression was not performed. Faecal mass. Healthy volunteers: An analysis of 12 data sets from seven RCTs in healthy volunteers (n = 129 in fibre-supplemented and fibre-free 9, 10, 15, 34, 45, 46, 62 groups), reported that mean faecal mass was significantly increased following treatment with a fibre-containing feed compared with fibre-free feed: 109 (S.E. 26) g vs. 74 (S.E. 21) g, respectively [Figure 7: test of overall effect, 35 g, z = 6.2, P < 0.001; test of heterogeneity, I 2 =4% (P = 0.41)]. An increase in faecal mass of 1.1 g g (s.d. 0.5) of supplemented fibre was observed when the weighted mean results from each study were used. Using meta-regression, a statistically significant positive relationship was reported between faecal mass and fibre intake [intercept, 3.9 g; gradient, 0.98 (S.E. 0.41) g g fibre; z = 2.4, P = 0.02]. The increase in faecal mass was not significantly related to either study duration or the baseline faecal mass of the fibre-free control group. In a meta-analysis of five data sets from two RCTs 34, 61 (n = 76 in fibre-supplemented and fibre-free groups), fibre supplementation resulted in a variable increase in faecal dry weight compared with the

14 SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF FIBRE-CONTAINING ENTERAL FORMULAE 133 Study name Fibre type Fibre intake (g/day) Difference in means and 95% CI Kies et al Kies et al Kies et al Silk et al Lampe et al Meier et al Kapadia et al Kapadia et al Lampe et al Slavin et al Slavin et al Slavin et al Kapadia et al L ü bke et al Cellulose Cellulose Cellulose Cellulose Fibre mixture* Fibre mixture* Guar Guar Guar Oat Oat (processed) oligosaccharide oligosaccharide Unknown Unknown Overall Favours fibre Favours fibre-free Figure 6. Meta-analysis (fixed effect model) comparing transit time (hours) in healthy subjects receiving fibre-containing feed or fibre-free feed. *Fibre mixture: soy polysaccharides, alpha-cellulose, arabic gum, inulin, oligofructose, resistant starch (Nutricia Multi Fibre). A negative value (favouring fibre-containing group) indicates that administration of a fibrecontaining feed reduces transit time compared with a fibre-free feed. fibre-free group [test of overall effect, 16.5 (S.E. 1.4), z = 11.8, P < 0.001; test of heterogeneity, I 2 = 92%; P < 0.001]. Three doses of cellulose (20, 30 or 40 g) were administered in one study 61 while the second study compared guar gum with soy polysaccharide (15 g in both treatment arms). 34 The observed increase in faecal dry weight was significantly related to the dose (15 40 g) of fibre administered (z = 6.8, P < ). The weighted mean increase in dry faecal mass was 0.59 (s.d. 0.25) g g of fibre added [the corresponding nonweighted value was 0.53 (s.d. 0.30) g g of fibre added]. In four RCTs a comparison of fibre-free feed with SS diet was performed. 9, 34, 45, 46 A meta-analysis of five data sets from these four RCTs reported that faecal mass was twofold greater in subjects ingesting a SS diet (n = 50), compared with those ingesting a fibre-free feed (n = 50) [weighted mean mass, 159 g day (s.d. 69) vs. 79 g day (s.d. 33)]. This corresponded to an approximate 5 g increase in faecal mass per gram of supplemented fibre (weighted value, 5.0 g g fibre; nonweighted mean value, 4.6 g g fibre). A meta-analysis of nine data sets (n = 99 in both 9, 34, 45, 46 treatment arms) based on these four RCTs reported that faecal mass was also increased following ingestion of a SS diet [154 (S.E. 6) g day] compared with a fibre-containing feed [112 (S.E. 6) g day; Figure 8: test of overall effect (difference in mean values), 42 (S.E. 8.4) g day, z = 5.0; P < 0.001; test of heterogeneity I 2 = 27%; P = 0.21]. This increase was observed even though the SS diets were reported to

15 134 M. ELIA et al. Study name Fibre type Fibre intake (g/day) Difference in means and 95% CI Silk et al Fibre mixture 30 Kapadia et al Kapadia et al Oat 30 Kapadia et al oligosaccharide 30 Lampe et al Guar 15 Lampe et al Whelan et al FOS + pea 26 Alam et al Guar 53 Slavin et al (processed) 30 Slavin et al Slavin et al L ü bke et al Unknown 20 Overall Favours fibre-free Favours fibre Figure 7. Meta-analysis (fixed effect model) comparing faecal mass (g day) in healthy subjects receiving a fibre-containing feed or a fibre-free feed. *Fibre mixture: soy polysaccharides, alpha-cellulose, arabic gum, inulin, oligofructose, resistant starch (Nutricia Multi Fibre); FOS: fructooligosaccharides. A positive value (favouring fibre) indicates that administration of a fibre-containing feed was associated with greater faecal mass (g day) compared with a fibre-free feed. contain approximately half the amount of fibre compared with the fibre-containing feeds (15.1 vs g day). Inter-study variation in the difference in fibre intake between treatment arms was observed and as this difference became smaller, a corresponding decrease in faecal mass was reported [meta-regression intercept, 70.9 g; gradient )1.7 (S.E. 0.60) g faeces g fibre; P = 0.003]. Patients: Faecal mass was reported in seven studies: six RCTs (three chronic care, 8, 52, 53 one 39 and two medical populations 42, 58 ) and one non-rct (chroniccare paediatric population; 66 total n = 75 in fibre group and n = 75 in fibre-free group). Mean faecal mass was greater in the fibre group compared with the fibre-free group in all of these studies with the exception of the study where faeces were reported to be watery and faecal mass decreased significantly over time. 39 A meta-analysis of all studies showed a significant increase in faecal mass following fibre supplementation of the feed [test of overall effect, 21.2 (S.E. 6.4) g day, z = 4.7, P < 0.001; test of heterogeneity, I 2 = 0%, P = 0.50]. A meta-analysis of the six RCTs only (n = 64 in fibre-free group; n = 64 in fibre group) confirmed the significant effect of fibre in increasing faecal mass [test of overall effect, 16.7 (S.E. 5.2) g day, z = 3.2, P = 0.001; test of heterogeneity, I 2 = 0%, P = 0.87]. Two RCTs reported a significant increase in dry faecal mass following administration of a fibre-containing feed. 53, 58 Medical patients in the study by Heymsfield et al. 58 received 8 g soy fibre day [dry faecal weight: 27 (s.d. 9) g day vs. 12 (s.d. 5) g day; P < 0.01], whereas the chronic-care patients in the study by Zarling et al. 53 received 28.8 g of oat and soy fibre day [dry faecal weight, 57 (s.d. 31) g day (faecal moisture content of 72%) vs. 32 (s.d. 25) g day (faecal moisture content of 74%), P < 0.05]. The effect of fibre supplementation on faecal moisture and ph showed considerable inter-study variation. 34, 66 Studies reported a significant increase, decrease 61, 65 or no effect 15, 52, 53 on faecal moisture levels. The effect was observed to be dependent on