Ageing Research Reviews 11 (2012) 278–296

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Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Review

Systematic review and meta-analysis of the effects of high protein oral

nutritional supplements
A.L. Cawood a,b,∗ , M. Elia a , R.J. Stratton a
a
Institute of Human Nutrition, University of Southampton, Southampton, UK
b
Medical Affairs, Nutricia Ltd, Trowbridge, UK

a r t i c l e i n f o a b s t r a c t

Article history: Disease-related malnutrition is common, detrimentally affecting the patient and healthcare economy.
Received 2 September 2011 Although use of high protein oral nutritional supplements (ONS) has been recommended to counteract the
Received in revised form 4 December 2011 catabolic effects of disease and to facilitate recovery from illness, there is a lack of systematically obtained
Accepted 14 December 2011
evidence to support these recommendations. This systematic review involving 36 randomised controlled
Available online 22 December 2011
trials (RCT) (n = 3790) (mean age 74 years; 83% of trials in patients >65 years) and a series of meta-analyses
of high protein ONS (>20% energy from protein) demonstrated a range of effects across settings and patient
Keywords:
groups in favour of the high protein ONS group. These included reduced complications (odds ratio (OR)
Meta-analysis
Protein
0.68 (95%CI 0.55–0.83), p < 0.001, 10 RCT, n = 1830); reduced readmissions to hospital (OR 0.59 (95%CI
Supplement 0.41–0.84), p = 0.004, 2 RCT, n = 546); improved grip strength (1.76 kg (95%CI 0.36–3.17), p < 0.014, 4 RCT,
Nutrition n = 219); increased intake of protein (p < 0.001) and energy (p < 0.001) with little reduction in normal food
Oral nutritional supplements intake and improvements in weight (p < 0.001). There was inadequate information to compare standard
ONS (<20% energy from protein) with high protein ONS (>20% energy from protein). The systematic
review and meta-analysis provides evidence that high protein supplements produce clinical benefits,
with economic implications.
© 2011 Elsevier B.V. All rights reserved.

1. Introduction delays recovery from illness, increases complications, and resource

The prevalence of disease related malnutrition is common
across all health and social care settings including hospitals, care
homes, and sheltered housing (Waitzberg et al., 2001; Stratton
et al., 2003; Kruizenga et al., 2003; Russell and Elia, 2009; Elia
and Russell, 2009a). Overall, more than 3 million people in the UK
are malnourished or at risk of malnutrition, with people aged over
65 years accounting for about 1.3 million of these (Elia and Russell,
2009b). Despite this, malnutrition continues to remain undetected
and undertreated (Elia and Russell, 2009b) causing a variety of
detrimental effects at enormous cost to the individual and health-
care system (Elia and Stratton, 2009). This is because malnutrition
not only predisposes to disease, but it also adversely affects dis-
ease outcome in a variety of ways. For example, impaired immunity
predisposes to infections and the ability of the body to recover
from infections, muscle weakness and immobility predispose to
falls, venous thromboembolism and pressure ulcers. Malnutrition
∗ Corresponding author at: Institute of Human Nutrition (MP113), Southampton
General Hospital, Tremona Road, Southampton SO16 6YD, UK.
Tel.: +44 07738 024718.
E-mail addresses: A.L.Cawood@soton.ac.uk (A.L. Cawood), elia@soton.ac.uk
(M. Elia), rjs@soton.ac.uk (R.J. Stratton).
use, such as frequency of hospital admissions and length of hospital
stay (Elia, 2006).
Since reduced dietary intake is a major cause of malnutri-
tion, various authorities including NICE (National Institute for
Health and Clinical Excellence) (NICE, 2006) recommend improv-
ing dietary intake using a range of nutrition support strategies,
including dietary counselling, oral nutritional supplements (ONS)
and artificial nutritional support. Many of these strategies not only
aim to increase energy but also the contribution of protein to total
energy intake and there are several reasons for this. First, the intake
of protein is believed to be inadequate in a sizeable proportion of
the free living population, especially older people (65 years and
over), where 20% of the population do not meet the Reference Nutri-
ent Intake (RNI) for protein in the UK (Finch et al., 1998). Inadequate
protein intake is even more likely to occur in patients with disease-
related malnutrition because appetite is often poor due to the
effects of a wide range of diseases, including infective, malignant,
and traumatic conditions. Second, patients with disease-related
malnutrition tend to be sedentary, ingesting less food with less
protein and other nutrients, which means that nutrient deficien-
cies including protein are more likely to occur (WHO, 2007). If a
normal protein intake was to be maintained in the face of reduced
energy intake, protein would need to account for a greater pro-
portion of total dietary energy, which should be considered when

1568-1637/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.arr.2011.12.008
 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296
Citations excluded on the basis of
title/abstract which did not conform to
the inclusion/exclusion criteria.
(n=11018)
Studies excluded (n=96)
Reasons for exclusion:
Not high protein (n=47)
Not RCT (n=12)
Other reasons (n=37)
Fig. 1. Summary of systematic review stages and processes.
making recommendations about the composition of dietary intake
in disease-related malnutrition. Third, a protein intake above nor-
mal may be desirable in patients with illnesses and disabilities for
at least two reasons. One reason, is to counteract increased protein
losses, which may occur in people with protein losing enteropathy
(e.g. Crohn’s disease and colitis), transudative wounds including
burns, and the catabolic effects of inflammatory disease. The other
is the need for protein to encourage repair of damaged tissues, such
as wounds, including pressure ulcers, and to facilitate whole body
repletion. For example, at a fixed energy intake whole body accre-
tion of lean tissue can be facilitated by increasing protein intake
(Elia, 2003).
The above considerations have led to advice to moderately
increase the protein content of the diet particularly in older individ-
uals (Paddon-Jones et al., 2008), either by food fortification, protein
supplements or by use of commercially available ONS rich in pro-
tein to support patients with disease-related malnutrition. There
is limited evidence for the clinical effectiveness of dietary advice
(Baldwin and Weekes, 2009), however a number of systematic
reviews and meta-analyses consistently indicate beneficial clini-
cal effects when using ONS (Stratton and Elia, 2007). None of the
previous ONS reviews have specifically investigated the role of high
protein supplements (>20% energy from protein) on dietary intake,
changes in body composition and functionally/clinically relevant
outcomes, such as complications, mortality and length of hospital
stay. Given the arguments raised above, beneficial effects might be
expected; however, high protein intake has also been implicated in
producing some adverse effects like being linked with osteoporo-
sis and renal failure as well as encephalopathy in patients with
advanced liver disease (Department of Health, 1992; Institute of
Medicine, 2005). Therefore, this systematic review was undertaken
to examine whether high protein ONS have beneficial effects in
clinical practice and the extent to which these are associated with
increased protein intake.
2. Materials and methods
The review was planned, conducted and reported following
published guidelines. These include those issued by the Cochrane
279
Formulate study question
Retrieve potentially relevant
citations
Evaluate citation title/ abstract.
NO
Does it fulfil inclusion criteria?
(n=11142)
YES
Evaluate full study text. Does
NO it fulfil inclusion criteria?
(n=132)
YES
Studies included in systematic
review (n= 36)
Data extraction, quality
assessment, synthesis of
evidence
Collaboration (The Cochrane Collaboration, 2009), the UK National
Health Service Centre for Reviews and Dissemination (CRD) (Centre
for Reviews and Dissemination, 2009), and the PRISMA guidelines
(Moher et al., 2009). Fig. 1 illustrates the principle stages and pro-
cesses undertaken.
2.1. Identification and selection of studies for the systematic
literature review
Potential studies were identified by searching electronic
databases that were last accessed 4th January 2010. The databases
searched included PubMed, Cochrane, Clinical Evidence Database,
National Electronics Library for Health guidelines finder, Turning
Research into Practice, Cinahl, and National Service Frameworks.
The search terms used included both single words and combina-
tions of words; sip, adult, nutrition, support, oral, feed, supplement,
enteral, liquid, formula, protein. Bibliographies were checked and
experts were consulted for any additional studies.
Studies available as full papers (conference proceedings were
excluded) were deemed eligible if they conformed to the predeter-
mined inclusion and exclusion criteria (Table 1). Only randomised
controlled trials (RCT) qualified for review and any other study
types were not included. Subjects eligible for inclusion were adults,
of any nutritional status (well nourished and malnourished) and
based in any setting. No restrictions were placed on sample size.
Suitable interventions were those studies using high protein ONS
of any consistency (ready made liquid, powder, puddings), for any
duration, that contained two or more macronutrients, as well as a
range of micronutrients. A high protein oral nutritional supplement
was defined as the ONS containing at least 20% of energy provided
from protein (Lochs et al., 2006; Regulations (EC) No. 1924/2006,
2006). The intervention could provide some or the entire daily
requirement for energy and could be nutritionally complete or
incomplete with respect to individual nutrients. No restrictions
were placed on studies with regard to year of publication, or type of
comparator (e.g. placebo, routine care, normal diet, dietary advice,
ONS not high in protein). Throughout the review the comparator
arm was termed ‘control’, unless another ONS was given as the
comparator and these were termed ‘standard ONS’ (ONS not high
280 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296

Table 1
Summary of inclusion and exclusion criteria used to evaluate studies for the systematic review.

Selection criterion Inclusion criteria Exclusion criteria

Population - Adults 18 years and over - Animal studies

- Any nutritional status (well nourished or malnourished) - Developing world
- Based in any setting (hospital, community) - Pregnancy and lactation
- Any sample size - Sports studies

Intervention - All randomised controlled trials using multi-nutrient high protein (≥20% of - Dietary counselling only
total energy from protein) ONS of any consistency (including those - Parenteral nutrition only
simultaneously using or comparing with dietary counselling and/or standard
diet and/or standard ONS.)
- ONS can be nutritionally complete or incomplete and provide some or all the - Enteral tube feeding
entire daily requirement
- Any duration of intervention - ONS with <2 macronutrients, no
micronutrients, <20% energy from protein

Other - English language - Language other than English

- Full papers only - Abstract only
- Conference proceedings

ONS, oral nutritional supplement.

in protein; <20% energy from protein). Studies that were not pub-
lished in English were excluded from the review. Once the titles and
abstracts of all studies had been checked and potentially relevant
papers had been identified, full articles were obtained and evalu-
ated by one researcher; a second researcher verified the decisions.
The quality of individual studies was assessed using the JADAD
scale (Jadad et al., 1996), and was conducted by one researcher
and verified by a second assessor. Any discrepancies were resolved
by discussion. The JADAD score is based on a highest score of 5,
which can only be achieved by well-conducted double blind RCTs,
with adequate description of drop-outs and the appropriate use of
methods for randomisation and blinding.
Studies were classified according to the setting in which the
intervention was given (Tables 2 and 3). These are defined as: (i)
hospital; intervention given only in the acute hospital setting, (ii)
community; intervention given outside of the acute hospital, in the
community including outpatients, community hospitals, rehabili-
tation hospitals, nursing homes, residential homes, GP surgeries,
free living and (iii) hospital and community; intervention given in
both the hospital and community setting.
2.2. Data extraction and outcome measures
A pre-determined data collection table was designed to capture
study characteristics and outcome data. Outcome measures sought
included clinical and health care use (e.g. complications, mortality,
length of stay, readmissions to hospital), functional (e.g. strength,
quality of life, activities of daily living) and nutritional (e.g. intake,
weight, appetite, and body composition). Following extraction of
data from eligible studies, meta-analysis was conducted where
appropriate and feasible, for comparable trials with numerically
consistent outcome measures (trials reporting the same outcomes
in the same way). Outcomes that could not be meta-analysed are
described in the text.
2.3. Statistical methods
Meta-analysis and meta-regression was performed using Com-
prehensive Meta-Analysis v2 (Biostat, Englewood, NJ, USA) using
the random effects model, except where otherwise stated. For
the fixed effect model heterogeneity was reported using the I2
statistic (Higgins and Thompson, 2002; Higgins et al., 2003). Data
was presented as either difference in means and 95% confidence
intervals (95%CI) or odds ratio (OR) and 95%CI. Overall signifi-
cance was assumed at p < 0.05. Forest plots were used to present
meta-analysis data. Details of the statistical methods associated
with meta-analysis and meta-regression are described elsewhere
(Borenstein et al., 2009).
3. Results
3.1. Overall search findings (n = 36 RCT)
A total of 11142 studies were identified by the search strat-
egy (Fig. 1). Following evaluation of the title and or abstract, 132
papers were potentially relevant and obtained in full. Upon read-
ing the full text of these, 36 studies were deemed eligible for
inclusion (n = 3790) mean age 74 years (range 42–86 years); 64%
female (range 15–100%) (McEvoy and James, 1982; Stableforth,
1986; Efthimiou et al., 1988; Knowles et al., 1988; Otte et al.,
1989; Delmi et al., 1990; Tkatch et al., 1992; Volkert et al., 1996;
Schurch et al., 1998; Yamaguchi et al., 1998; Krondl et al., 1999;
Lauque et al., 2000; Bourdel-Marchasson et al., 2000; Espaulella
et al., 2000; Benati et al., 2001; Houwing et al., 2003; Bruce et al.,
2003; Bonnefoy et al., 2003; Steiner et al., 2003; Eneroth et al.,
2004; Tidermark et al., 2004; Neumann et al., 2004; Carlsson et al.,
2005; Seidner et al., 2005; Teixido-Planas et al., 2005; Ravasco
et al., 2005a, 2005b; Bunout et al., 2006; Rosendahl et al., 2006;
Gariballa et al., 2006; Olofsson et al., 2007; Gariballa and Forster,
2007a, 2007b; Norman et al., 2008; Botella-Carretero et al., 2008;
de Luis et al., 2008b). The other 96 studies were rejected from the
systematic review due to the ONS not being high protein (n = 47)
(Lewis et al., 1987; Williams et al., 1989; Nayel et al., 1992; Hirsch
et al., 1993; Woo et al., 1994; Gray-Donald et al., 1995; Saudny-
Unterberger et al., 1997; Keele et al., 1997; Gariballa et al., 1998;
Hoh et al., 1998; Kuhlmann et al., 1999; McCarthy and Weihofen,
1999; Beattie et al., 2000; Le Cornu et al., 2000; Verma et al.,
2000; Berneis et al., 2000; Lawson et al., 2000; Macfie et al., 2000;
Fiatarone Singh et al., 2000; Forli et al., 2001; Potter et al., 2001;
Payette et al., 2002; Caglar et al., 2002; Beck et al., 2002; Wouters-
Wesseling et al., 2002, 2003, 2005, 2006; Roberts et al., 2003;
Lauque et al., 2004; Smedley et al., 2004; Bunout et al., 2004; Young
et al., 2004; Desneves et al., 2005; Collins et al., 2005; Price et al.,
2005; Miller et al., 2005, 2006; Raffoul et al., 2006; Rosendahl et al.,
2006; Persson et al., 2007; Arias et al., 2008; Plank et al., 2008;
Chapman et al., 2009; Manders et al., 2009; McMurdo et al., 2009;
Hung and Tarng, 2009), study not a RCT (n = 12) (Johnson et al.,
1993; McCarter et al., 1998; Creutzberg et al., 2000; Bos et al., 2000,
2001; Planas et al., 2005; Tepaske et al., 2007; Hommel et al., 2007;
Heyman et al., 2008; Mantovani et al., 2008; de Luis et al., 2008a;
Iizaka et al., 2010), or for other reasons (n = 37) which included inap-
propriate ONS (no compositional information, variety of ONS used
Table 2
Trial characteristics of studies comparing high protein ONS with control in alphabetical order.

Trial, population, setting & Jadad Supplement (S) (S) E density (S) prescribed Comparator/control Duration of Follow up No (S) No (C) Mean age
primary outcome score (C) intervention

Benati 2001 1 High protein 2.5 kcal/ml 500 kcal Normal hospital 2 weeks 15 days 5 5 82 years
Pressure Ulcers supplement (2 arms 37 g P diet
Hospital use a high protein 30 En%P
Pressure ulcer healing supplement data
shown for treatment B
from paper)
Bonnefoy 2003 3 Diepal Labs, 1 kcal/ml 400 kcal Placebo 9 mo 9 mo 30 27 83 years
Frail elderly in care Villefranche sur Saone, 30 g P
Community France 30 En%P
Fat free mass & muscle
power
Botella-Carretero 2008 3 Resource 1.25 kcal/ml 500 kcal Standard diet – – 30 30 84 years
Elderly post hip fracture Hiperproteico; 37.6 g P

A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296

Hospital – Community Novartis Medical 30 En%P
Nutritional status Nutrition, Spain
(Compare 2 arms only
from paper: Group 2
ONS, Group 3 Control)
Bourdel-Marchasson 2000 2 Variety used from 1 kcal/ml 400 kcal Std diet 1800 kcal/d 15 days or until 15 days 295 377 83 years
Critically ill Jacquemarie-Sante, 30 g P (calculated) discharge
Hospital France; Nutricia, 30 En%P
Pressure ulcer incidence France
Clintec-Sopharga,
France
Bruce 2003 1 Sustagen Hospital Plus, 1.5 kcal/ml 352 kcal Routine care 28 days 6 mo 50 59 84 years
Hip Fracture Mead Johnston 17.6 g P
Hospital – Community 20 En%P
Weight & clinical outcomes
Carlsson 2005 1 Fortimel, Nutricia 1 kcal/ml 200 kcal Routine care 6 mo 6 mo 16 14 83 years
Hip fracture 20 g P
Hospital – Community 40 En%P
Appetite and intake
Delmi 1990 1 250 ml supplement 1 kcal/ml 254 kcal Hospital diet Mean 32 days 6 mo 27 32 82 years
Hip Fracture provided by 20.4 g P
Hospital – Community Sandoz-Wander, 32 En%P
Clinical outcomes Switzerland
Efthimiou 1988 1 Carnation Build Up 1.13 kcal/ml 2–4 sachets Normal diet 3 mo 9 mo 7 7 57 years
COPD powder, Nestle 1 sachet + 0.5 pint 640–1280 kcal
Community whole milk 36–75 g P
Nutritional status & function 320 kcal, 18 g P 22.5 En%P
Eneroth 2004 5 Fortimel, Nutricia 1 kcal/ml 400 kcal Placebo 6 mo 6 mo (1 & 26 27 75 years
Foot ulcers 40 g protein 2 years)
Community 40 En%P
Wound healing
Espaulella 2000 5 Clinical Nutrition SA, 0.75 kcal/ml 149 kcal Placebo 60 days 6 mo 85 86 83 years
Hip Fracture Mataro, Spain 20 g P
Hospital – Community 54 En%P
Clinical outcomes
Gariballa 2006 4 400 ml 2.48 kcal/ml 995 kcal Placebo 6 weeks 6 mo 223 222 77 years
Acute Illness 49.75 g P (calculated)
Hospital – Community 20 En%P
Clinical outcomes (comm with author)

281
 282
Table 2 (Continued)

Trial, population, setting & Jadad Supplement (S) (S) E density (S) prescribed Comparator/control Duration of Follow up No (S) No (C) Mean age
primary outcome score (C) intervention

Gariballa 2007a 4 400 ml 2.48 kcal/ml 995 kcal Placebo 6 weeks 6 mo 106 119 76 years
Acute Illness 49.75 g P (calculated)
Hospital – Community 20 En%P
Quality of life (comm with author)
Gariballa 2007b 4 400 ml 2.48 kcal/ml 995 kcal Placebo 6 weeks 6 mo 106 119 76 years
Acute Illness 49.75 g P (calculated)
Hospital – Community 20 En%P
Depressive symptoms (comm with author)
Houwing 2003 2 Cubitan, Nutricia 1.25 kcal/ml 500 kcal Placebo 4 weeks or until 51 52 81 years
Hip Fracture 40 g P discharge (mean
Hospital 32 En% P 11.8 days)
Pressure ulcer incidence
Knowles 1988 2 Sustacal Mead Johnson 1 kcal/ml To increase TEI by Normal diet 8 weeks 16 weeks 13 12 69 years
COPD 50%
Community 24 En%P

A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296

Muscle performance
Krondl 1999 2 235 ml can, Boost, 1 kcal/ml 235 kcal Normal diet 16 weeks 16 weeks 35 36 70 years
Healthy Elderly Mead Johnson. 11.75 g P
Community 20 En%P
Nutritional status and QOL
Lauque 2000 2 Clinutren, Nestle. Soup, HP; 300–500 kcal Routine care 60 days 60 days 13 22 85 years
Elderly in care Soup (200 kcal, 10 g P) Dessert: 15–40 g P
Community Fruit (120 kcal, 7.5 g P) 1 kcal/ml (calculated)
Nutritional status and Dessert (150 kcal, 12 g Fruit: 0.6 kcal/ml 20–32 En%P
strength P)
(2 groups reported; B risk of HP (200 kcal, 15 g P)
MN no supps; C risk of MN
supps)
McEvoy 1982 2 Build Up, Nestle – 644 kcal Std Hosp diet 4 weeks 4 weeks 26 25 –
Acutely Ill Elderly 36.4 g P
Hospital 23 En%P
Nutritional status
Norman 2008 3 Fresubin Protein 1.5 kcal/ml 900 kcal Dietary Counselling 3 mo 3 mo 48 53 53 years
GI disease Energy Drink, Fresenius 60 g P
Community 27 En%P
Function & body composition
Olofsson 2007 2 Fortimel 1 kcal/ml 200 kcal Routine care Until discharge 4 mo 102 97 82 years
Hip Fracture 10 g P ∼34 days
Hospital 20 En%P (comm with
Complications (comm with author) author)
Otte 1989 4 Novo, Denmark. 1 kcal/ml 400 kcal Placebo 13 weeks 13 weeks 13 15 55 years
Emphysema 20 g P (calculated)
Community 20 En% P
Nutritional status
Ravasco 2005a 3 Oral nutrition 1 kcal/ml 400 kcal Ad lib. diet 49 days 3 mo 25 25 60 years
Head and neck cancer commercial 40 g P
Community supplements 40 En%P
Outcomes (Compare 2 arms only
from paper (G2 + G3))
Ravasco 2005b 3 Oral nutrition 1 kcal/ml 400 kcal Ad lib. diet 42 days 3 mo 37 37 58 years
Colorectal cancer commercial 40 g P
Community supplements 40 En%P
Outcomes (Compare 2 arms only
from paper (G2 + G3))
Table 2 (Continued)

Trial, population, setting & Jadad Supplement (S) (S) E density (S) prescribed Comparator/control Duration of Follow up No (S) No (C) Mean age
primary outcome score (C) intervention

Rosendahl 2006 5 – 1 kcal/ml 194 kcal Placebo 13 weeks 6 mo 50 50 84 years

Dependant elderly in care (Compare 2 arms only 14.8 g P
Community from paper Con + P; 30 En%P
Balance and strength Con + Placebo)
Schurch 1998 4 Meritene 3.85 kcal/g 250 kcal Isocaloric placebo 6 mo 12 mo 41 41 81 years
Hip Fracture (Sandoz) powder 20 g P 5 days per week
Hospital – Community 32 En%P
Bone metabolism
Seidner 2005 4 Abbott Laboratories. 1.3 kcal/ml 310 kcal Placebo 6 mo 6 mo 59 62 42 years
Ulcerative colitis 16.1 g P
Community 21 En%P
Disease activity (Plus Fish oil, Soluble
Fibre &Antioxidants)

A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296

Stableforth 1986 1 Carnation Instant 1.2 kcal/ml 320 kcal Routine care 10 days 10 days 24 34 82 years
Hip Fracture Breakfast (Nestle) Per 18.5 g P
Hospital 100 ml: 6.2 g P, 13.3 g 23 En%P
Nitrogen and Calorie balance CHO, 3.7 g Fat
Steiner 2003 5 Respifor, Nutricia 1.5 kcal/ml 570 kcal Placebo 7 weeks 7 weeks 42 43 67 years
COPD 28 g P
Community 20 En%P
Exercise performance
Teixido-Planas 2005 3 ProtenPlus Fresenius, 1 kcal/ml 200 kcal Routine care 12 mo 6 mo 35 30 58 years
Peritoneal Dialysis Germany 20 g P 12 mo
Community 40 En%P
Nutritional parameters
Tidermark 2004 2 Fortimel, Nutricia 1 kcal/ml 200 kcal Routine care 6 mo 6 mo 20 20 84 years
Hip Fracture 20 g P 12 mo
Community 40 En%P
Body composition, ADL and
QOL
Tkatch 1992 1 250 ml ONS. 1 kcal/ml 254 kcal Placebo 38.2 days 7 mo 33 29 82 years
Hip Fracture Sandoz-Wander, 20.4 g P
Hospital-Community Switzerland 32 En%P
Clinical outcome
Volkert 1996 3 Variety used Soup: Hospital 500 kcal Normal diet 6 mo 6 mo 20 26 86 years
Elderly admitted to acute Soups (7 g P) and sweet 1.22 kcal/ml 30 g P
care drinks (8 g P) per Drinks: 24 En%P
Hospital – Community 100 ml 1.2–1.28 kcal/ml Community
Functional status 250 kcal
15 g P
24 En%P
Yamaguchi 1998 1 237 ml 1.27 kcal/ml 300 kcal Placebo Up to 18 mo 6 mo 30 32 78 years
Homebourd elderly receiving 40 g CHO 15 g P 12 mo
meals 15 g P 20 En%P 18 mo
Community 9 g fat (6 mo data
Nutritional intake used in
Fig. 4)

Abbreviations: S, supplement; C, comparator/control; P, protein; CHO, carbohydrate; En%P, % energy from protein; ADL, activities of daily living; QOL, quality of life; comm with author, data not available in the paper, but obtained
through personal communication with the author.
Comparator/control (C) – description of the control arm, described in table as described in text of reference.

283
284 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296

not all high protein, other treatments used in addition to ONS),

Mean age

77 years

76 years

83 years
ineligible study population, conference proceedings only (Gegerle
et al., 1986; Evans et al., 1987; Arnold and Richter, 1989; Rogers
et al., 1992; Hubsch et al., 1992; Habicht et al., 1995; D’antoni et al.,
1996; Jensen and Hessov, 1997a, 1997b; Champagne et al., 1998;
Schwenk et al., 1999; Riso et al., 2000; Gianotti et al., 2002; Isenring
No (C)

et al., 2004; Irvine et al., 2004; Flakoll et al., 2004; Ballard et al.,
50

16

24
2005; Gonzalez-Espinoza et al., 2005; Tiengou et al., 2006; Eneroth
et al., 2006; Kwon Lee et al., 2006; de Luis et al., 2007; Helminen
et al., 2007; Lundholm et al., 2007; Nielsen et al., 2007; Holm et al.,
No (S)

2008; Sattler et al., 2008; Beck et al., 2008; Lockwood et al., 2008;
50

14

22
Portier et al., 2008; Cereda et al., 2009; Moretti et al., 2009; Hoffman
et al., 2009; Murakami et al., 2009; Okamoto et al., 2009; Sundell
et al., 2009; Tang et al., 2009).
Follow up

12 mo

3 mo

3 mo

3.2. Description of studies included in the systematic review

(n = 36 RCT)

The 36 studies eligible for the systematic review are shown in

Tables 2 and 3. In these studies ONS were given in hospital (6 RCT
intervention
Duration of

(McEvoy and James, 1982; Stableforth, 1986; Bourdel-Marchasson

10 weeks

28 days

et al., 2000; Benati et al., 2001; Houwing et al., 2003; Olofsson

12 mo

et al., 2007); n = 1093), hospital and community (11 RCT (Delmi

et al., 1990; Tkatch et al., 1992; Volkert et al., 1996; Schurch et al.,
1998; Espaulella et al., 2000; Bruce et al., 2003; Carlsson et al., 2005;
Gariballa et al., 2006; Gariballa and Forster, 2007a, 2007b; Botella-
Ensure, Ross Labs,

Carretero et al., 2008); n = 1540) or community (19 RCT (Efthimiou

Comparator (C)

et al., 1988; Knowles et al., 1988; Otte et al., 1989; Yamaguchi

et al., 1998; Krondl et al., 1999; Lauque et al., 2000; Bonnefoy
233 kcal

245 kcal

250 kcal
13 En%P

17 En%P

14 En%P
10.5 g P

et al., 2003; Steiner et al., 2003; Eneroth et al., 2004; Tidermark

7.6 g P

8.8 g P

USA

et al., 2004; Neumann et al., 2004; Seidner et al., 2005; Teixido-

Planas et al., 2005; Ravasco et al., 2005a, 2005b; Bunout et al.,
2006; Rosendahl et al., 2006; Norman et al., 2008; de Luis et al.,
2008b); n = 1157) settings. Studies had intervention and follow up
periods ranging from as little as 2 weeks to a maximum of 1 year.
(S) prescribed

The total number of patients studied in a single trial ranged from

10 to 672 patients. High protein ONS had differing energy densities
237 kcal

205 kcal

240 kcal
27 En%P

21 En%P

25 En%P
15.7 g P

10.7 g P

(0.75–3.85 kcal/ml) and the percentage energy from protein ranged

15 g P

from 20–54%. The prescribed daily energy and protein intake from
Abbreviations: S, supplement; C, comparator/control; P, protein; En%P, % energy from protein.

the supplement ranged from 149 to 995 kcal and 10–60 g respec-
Trial characteristics of studies comparing high protein ONS with ONS not high in protein.

tively. The populations studied were mostly elderly including those

with hip fractures, pressure ulcers, chronic obstructive pulmonary
(S) E density

0.9 kcal/ml

disease (COPD), cancer, gastro-intestinal disease, and a range of

critical and acute illnesses (Tables 2 and 3). Most studies (Table 2)
(33 RCT, n = 3614) compared high protein ONS with a control arm
–

(Bourdel-Marchasson et al., 2000; Benati et al., 2001; Bruce et al.,

2003; Bonnefoy et al., 2003; Carlsson et al., 2005; Botella-Carretero
Boost HP, Mead

et al., 2008; McEvoy and James, 1982; Stableforth, 1986; Efthimiou

Supplement (S)

Glucerna SR,

Laboratories

et al., 1988; Knowles et al., 1988; Otte et al., 1989; Delmi et al.,
Ministry of

1990; Tkatch et al., 1992; Volkert et al., 1996; Schurch et al., 1998;
Johnson
Chilean

Abbott
Health

Yamaguchi et al., 1998; Krondl et al., 1999; Lauque et al., 2000;

Espaulella et al., 2000; Houwing et al., 2003; Steiner et al., 2003;
Eneroth et al., 2004; Tidermark et al., 2004; Seidner et al., 2005;
Teixido-Planas et al., 2005; Ravasco et al., 2005a, 2005b; Rosendahl
et al., 2006; Gariballa et al., 2006; Olofsson et al., 2007; Gariballa
Jadad
score

and Forster, 2007a, 2007b; Norman et al., 2008). Three studies

2

(Table 3) (n = 176) compared high protein ONS with standard ONS

(containing less than 20% energy from protein); all based in the
community (Neumann et al., 2004; Bunout et al., 2006; de Luis et al.,
Bone mineral density
Elderly, osteoporosis

2008b).
Clinical outcomes
Diabetes, elderly
setting & primary

Nutritional and

When assessing the quality of the studies (JADAD), 8 stud-

Trial, population,

Neumann 2004
Hip Fracture
Community

Community

Community

ies scored 1 (Stableforth, 1986; Efthimiou et al., 1988; Delmi

parameters
Bunout 2006

De Luis 2008

metabolic

et al., 1990; Tkatch et al., 1992; Yamaguchi et al., 1998; Benati

outcome

et al., 2001; Bruce et al., 2003; Carlsson et al., 2005), 10 stud-

Table 3

ies scored 2 (McEvoy and James, 1982; Knowles et al., 1988;

Krondl et al., 1999; Lauque et al., 2000; Bourdel-Marchasson et al.,
 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296
2000; Houwing et al., 2003; Tidermark et al., 2004; Neumann
et al., 2004; Bunout et al., 2006; Olofsson et al., 2007); 8 studies
scored 3 (Volkert et al., 1996; Bonnefoy et al., 2003; Teixido-
Planas et al., 2005; Ravasco et al., 2005a, 2005b; Norman et al.,
2008; Botella-Carretero et al., 2008; de Luis et al., 2008b), 6 stud-
ies scored 4 (Otte et al., 1989; Schurch et al., 1998; Seidner et al.,
2005; Gariballa et al., 2006; Gariballa and Forster, 2007a, 2007b);
and 4 studies scored 5 (highest quality) (Espaulella et al., 2000;
Steiner et al., 2003; Eneroth et al., 2004; Rosendahl et al., 2006)
(Tables 2 and 3).
3.3. Outcomes from studies comparing high protein ONS with
control (n = 33 RCT)
3.3.1. Clinical and Health Care Use
Twenty RCT (n = 2580) comparing high protein ONS with a con-
trol arm reported clinical outcomes (Table 4) (Otte et al., 1989;
Delmi et al., 1990; Tkatch et al., 1992; Volkert et al., 1996; Schurch
et al., 1998; Lauque et al., 2000; Bourdel-Marchasson et al., 2000;
Espaulella et al., 2000; Houwing et al., 2003; Bruce et al., 2003;
Eneroth et al., 2004; Tidermark et al., 2004; Teixido-Planas et al.,
2005; Ravasco et al., 2005a, 2005b; Rosendahl et al., 2006; Gariballa
et al., 2006; Olofsson et al., 2007; Norman et al., 2008; Botella-
Carretero et al., 2008).
3.3.1.1. Complications. Eleven RCT reported data on complications
(n = 1892) mean age 79 years (52–84 years), 73% female, prescribed
daily intake 149–995 kcal, 10.0–49.8 g protein, 0.5–6 months (Otte
et al., 1989; Delmi et al., 1990; Tkatch et al., 1992; Bourdel-
Marchasson et al., 2000; Espaulella et al., 2000; Houwing et al.,
2003; Eneroth et al., 2004; Tidermark et al., 2004; Gariballa et al.,
2006; Olofsson et al., 2007; Botella-Carretero et al., 2008). Popula-
tions included elderly patients with hip fracture, leg and pressure
ulcers, and those with acute illness (Table 4). ONS was prescribed
in hospital (3 RCT (Bourdel-Marchasson et al., 2000; Houwing et al.,
2003; Olofsson et al., 2007), n = 974), community (3 RCT (Otte et al.,
1989; Eneroth et al., 2004; Tidermark et al., 2004), n = 121) and
both hospital and community settings (5 RCT (Delmi et al., 1990;
Tkatch et al., 1992; Espaulella et al., 2000; Gariballa et al., 2006;
Botella-Carretero et al., 2008), n = 797). A range of complications
were recorded including pressure ulcers, wounds, fracture not heal-
ing, infections, or a combination of complications. In all but one
trial (Botella-Carretero et al., 2008) complications were fewer in
the ONS than control group. In one of the eleven studies (Tkatch
et al., 1992) results were expressed as number of complications, this
paper reported less complications in the ONS group and a signifi-
cantly favourable clinical course for patients in the high protein ONS
group compared to control (48% vs. 20%; p < 0.005). In the remaining
ten studies (mean age 79 years (55–84 years), 72% female), results
were expressed as number of patients with a complication. These
were pooled for meta-analysis (Fig. 2) and showed that high protein
ONS significantly reduced the incidence of complications compared
to control (OR 0.68 (95% CI 0.55–0.83), p < 0.001, n = 1830, random
effects model, 10 RCT). This corresponds to an average of 19% abso-
lute reduction in complications. Three studies showed significant
results in their own right. The summary effect remained significant
when subgroup analysis was carried out according to setting: hos-
pital trials (OR 0.69 (95% CI 0.53–0.89), p = 0.005, n = 932, random
effects model, 3 RCT); community trials (4 starting in hospital) (OR
0.66 (95% CI 0.47–0.93), p = 0.017, n = 846, random effects model, 7
RCT). A further 3 RCT (Schurch et al., 1998; Ravasco et al., 2005a,
2005b) reported data on nausea and vomiting which can sometimes
be considered a complication. When the additional three RCTs
reporting nausea/vomiting as an outcome variable were included
in the meta-analysis the overall results remained similar (OR 0.74
285
(95% CI 0.60–0.90), p = 0.004, n = 2098, random effects model, 13
RCT).
3.3.1.2. Mortality. Fifteen RCT (n = 2216) reported mortality data
(mean age 78 years (53–86 years), 72% female, prescribed daily
intake 149–995 kcal; 10.0–60.0 g protein; 15 days to 12 months)
(Table 4) (Delmi et al., 1990; Tkatch et al., 1992; Volkert et al.,
1996; Schurch et al., 1998; Lauque et al., 2000; Bourdel-Marchasson
et al., 2000; Espaulella et al., 2000; Eneroth et al., 2004; Tidermark
et al., 2004; Teixido-Planas et al., 2005; Rosendahl et al., 2006;
Gariballa et al., 2006; Olofsson et al., 2007; Norman et al., 2008;
Botella-Carretero et al., 2008). Populations included hip fracture,
foot ulcers, dialysis, GI disease, elderly with a range of condi-
tions, critically and acutely ill. ONS was given in the hospital
(2 RCT (Bourdel-Marchasson et al., 2000; Olofsson et al., 2007);
n = 871); community (6 RCT (Lauque et al., 2000; Eneroth et al.,
2004; Tidermark et al., 2004; Teixido-Planas et al., 2005; Rosendahl
et al., 2006; Norman et al., 2008); n = 394) and hospital and com-
munity settings (7 RCT (Delmi et al., 1990; Tkatch et al., 1992;
Volkert et al., 1996; Schurch et al., 1998; Espaulella et al., 2000;
Gariballa et al., 2006; Botella-Carretero et al., 2008); n = 951). Mor-
tality was recorded from 15 days to 7 months after the start of the
intervention, with the majority of trials (10/15) reporting mortal-
ity at 6 months. Only one study (Schurch et al., 1998) reported
the cause of death for some but not all of the patients who
died.
None of the 15 RCT reported significant differences in mortality
rates between the two groups; the overall mortality rate across
groups was 8.2%. Meta-analysis showed that high protein ONS had
no significant effect on mortality compared to control (OR 1.23 (95%
CI 0.91–1.66), p = 0.177, n = 2216, random effects model).
3.3.1.3. Length of stay. Nine RCT (n = 1227) reported data on
length of stay (mean age 82 years (77–84 years), 83% female, pre-
scribed daily intake 149–995 kcal; 10.0–49.8 g protein; 28 days to
6 months) (Bruce et al., 2003; Botella-Carretero et al., 2008; Delmi
et al., 1990; Espaulella et al., 2000; Gariballa et al., 2006; Schurch
et al., 1998; Olofsson et al., 2007; Tidermark et al., 2004; Tkatch
et al., 1992). The patient populations included hip fracture and
acute illness, with ONS given in the hospital setting (1 RCT (Olofsson
et al., 2007); n = 199), community setting (1 RCT (Tidermark et al.,
2004); n = 40), and both the hospital and community setting (7
RCT (Delmi et al., 1990; Tkatch et al., 1992; Schurch et al., 1998;
Espaulella et al., 2000; Bruce et al., 2003; Gariballa et al., 2006;
Botella-Carretero et al., 2008); n = 988) (Table 4). Four of the pri-
mary studies (Delmi et al., 1990; Tkatch et al., 1992; Schurch
et al., 1998; Olofsson et al., 2007) reported significant reductions in
length of hospital stay in favour of the ONS group, and the remaining
studies showed no significant difference between the groups.
Six studies (mean age 82 years, 79% female) reported mean
length of stay and for one study mean length of stay was obtained
from the author (Tidermark et al., 2004). Two studies reported
median length of stay (Delmi et al., 1990; Tkatch et al., 1992).
Meta-analysis of the seven studies reporting mean length of stay,
with measures of dispersion showed that high protein ONS reduced
length of stay compared with control although not significantly
(−2.65 (95% CI −6.22 to 0.94) days, p = 0.146, n = 1128, random
effects model, 7 RCT). This corresponds to about a 10% reduction
in length of hospital stay in favour of the ONS group. When the
two studies reporting median length of stay were included in the
meta-analysis (by assuming that the difference between means is
equal to the difference between medians, and that standard error
of the difference was calculated from the p value) the overall sum-
mary results were significant (−3.77 (95% CI −7.37 to −0.17) days,
p = 0.040, n = 1227, random effects model, 9 RCT).
286 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296

Table 4
Table summarising complications, mortality, length of stay and health care use.

Trial and population Complications no. complications/total complications Mortality no. deaths/total Length of stay (LOS) and health
deaths care use

Botella-Carretero 2008 Range of complications including UTI, respiratory S 0/30a Mean and SD read off grapha
Elderly post hip fracture infection, wound infection, pressure ulcersa C 0/30 S 13.5 ± 4.5 days
Hospital – Community S 17/30 (57%) C 11.5 ± 5.5 days
C 15/30 (50%) (NS) (NS)
Time to resolution of complications
S 6.8 ± 8.8 days
C 7.7 ± 5.0 days (NS)
Bourdel-Marchasson 2000 Pressure ulcersa 15 daya –
Critically ill S 118/295 (40%) S 25/295
Hospital C 181/377 (48%) C 22/377
No statistics reported p = 0.18
Bruce 2003 – – Mean + SDa
Hip Fracture S 17.7 ± 9.4 days
Hospital – Community C 16.6 ± 9.2 days NS

Delmi 1990 Range of complications including pressure ulcers and 6 moa Total median LOSa
Hip Fracture infections at 6 moa S 6/27 S 24 days (13–157)
Hospital – Community S 4/27 (15%) C10/32 C 40 days (10–259) p < 0.02
C 10/32 (31%) p < 0.05
Eneroth 2004 Wound not healed @ 6 moa 6 moa –
Foot ulcers S 14/26 (54%) S 1/26
Community C 17/27 (63%) NS C 1/27
Espaulella 2000 Range of complications @ 6 mo including delirium, UTI, 6 moa Mean + SDa
Hip Fracture bed soresa S 17/80 S 16.4 ± 6.6 days
Hospital – Community S 44/80 (55%) C 10/81 NS C 17.2 ± 7.7 days
C 57/81 (70%) (p = 0.04)
Range of complications during hospitalisation
S 26/85
C 39/86 (NS)
Gariballa 2006 Infections @ 6 moa 6 moa Mean + SD Length of staya
Acute Illness S 21/222 (10%) S 32/222 S 9.4 ± 7 days
Hospital – Community C 26/223 (12%) p = 0.4 C 19/223 p = 0.1 C 10.1 ± 8 days p = 0.2
Readmissions
S 65/222 (29%)
C 89/223 (40%) p = 0.02

Houwing 2003 Pressure ulcersa – –

Hip Fracture S 27/51 (53%)
Hospital C 30/52 (58%) p = 0.42
Lauque 2000 – 60 daysa –
Elderly in care S 0/13
Community C 0/22
Norman 2008 – 3 moa 3 mo Readmissions
GI disease S 0/38 S 10/38 (26%)
Community C 0/42 C 20/42 (48%)
p = 0.041

Olofsson 2007 During hospitalisation S 6/102 died in hospital S 3/102 Length of staya
Hip Fracture no. with Delirium died after discharge S 27.4 ± 15.9
Hospital S 48/83 C 7/97 died in hospital C 39.8 ± 41.9
C 54/74 p = 0.022 C 6/97 died after discharge p = 0.019
no. with Constipation
S 30/83 Totala
C 37/74 S 9/102
no. with Decubitus ulcers C 13/97
S 7/83 No statistics reported
C 14/74 p = 0.054
no. with UTIa
S 27/83 (33%)
C 37/74 (50%)
Otte 1989 Exacerbationsa – –
Emphysema S 3/13 (23%)
Community C 4/15 (27%) Stats not reported
Ravasco 2005a Reduction in symptoms @ 3 mo – During radiotherapy drugs
Head and neck cancer S 67% improved (17/25) prescribed for
Community C 51% improved (13/25) 61% of group S
p < 0.0001 68% group C

Ravasco 2005b Reduction in nausea and vomiting @ 3 mo – During radiotherapy

Colorectal cancer S 62% improved (23/37) antiemetic drugs prescribed for
Community C 51% improved (19/37) 49% of group S
p < 0.0001 68% group C
Reduction in diarrhoea @ 3 mo During radiotherapy
S 59% improved (2/37) anti-diarrheals prescribed for
C 19% improved (7/37) 53% of group S
p < 0.0001 78% group C
 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296 287

Table 4 (Continued)

Trial and population Complications no. complications/total complications Mortality no. deaths/total Length of stay (LOS) and health
deaths care use

Rosendahl 2006 – 6 moa –

Elderly S 2/50
Community C 1/50 No statistics reported
Schurch 1998 Nausea and Diarrhoea 6 moa Ortho ward
Hip Fracture S 6/41 S 4/41 S 18 ± 1.4 days
Hospital – Community C 5/41 C 3/41 C 16.9 ± 0.9 days
Rehab hosp
S 42.2 ± 6.6 days
C 53.0 ± 4.6 days p < 0.018
Total LOSa
S 60.2 ± 6.6 days
C 69.9 ± 4.6 days (assumed SD)

Teixido-Planas 2005 – 6 moa –

Peritoneal Dialysis S 0/35
Community C 1/30
Tidermark 2004 Fracture healing complication 6 moa Median reported in paper NS
Hip Fracture S 4/20 S 1/20 S 20 (5–356) days
Community C 7/20 C 1/20 C 27 (5–197) days
Infections No statistics reported Contacted author for mean and
S 3/20 SD
C 5/20 Mean + SDa
For meta-analysisa S 20 ± 88 days
S 7/20 (35%) C 27 ± 48 days
C 12/20 (50%)
No statistics reported
Tkatch 1992 Range of complications including infections & pressure 7 moa Median
Hip Fracture ulcers @ 7 mo S 3/33
Hospital – Community S 26/33 C 4/29 NS 1st Hospital
C 47/29 Note: Author states S deaths S 23.5 days
No. of complications rather than no. of patients with a immediately post op before C 24.7 days
complication, unable to include in meta-analysis. benefit of S 2nd Hospital
Favourable clinical course S 78.6 days
S 16/33 (48%) C 91.8 days
C 6/29 (20%) p < 0.05 7 moa
S 69.4 days
C 101.6 days p < 0.05

Volkert 1996 – 6 moa –

Elderly S 4/35
Hospital – Community C 8/37

Abbreviations: S, supplement group; C, comparator/control group; NS, not significant; mo, months; UTI, urinary tract infection; no., number; (–) no data available in reference.
a
Included in meta analysis.

3.3.1.4. Readmissions. Two RCT (n = 546) reported data on hospi-
tal readmissions at 3–6 months (mean age 65 years (53–77 years),
47% female, prescribed daily intake 900–995 kcal, 49.8–60.0 g pro-
tein, 6 weeks to 3 months) (Table 4) (Gariballa et al., 2006; Norman
et al., 2008). The patient populations were GI disease and acutely
ill elderly with a wide variety of conditions, one with intervention
based in the community (Norman et al., 2008) (n = 101) and one in
both the hospital and community settings (Gariballa et al., 2006)
(n = 445). Each study reported a significant difference in readmis-
sions between groups, one from 40% (89/223) in the control to 29%
(65/222) in the ONS group (Gariballa et al., 2006) and the other from
48% (20/42) in the control to 26% (10/38) in the ONS group (Norman
et al., 2008) (Fig. 3). Meta-analysis of only two studies with similar
interventions and outcomes was undertaken using the fixed effect
model. This showed that high protein ONS, when taken in both set-
tings had a significant effect on hospital readmissions compared to

Study Setting Statistics for each study Comp / Total Odds ratio and 95% CI
Odds Lower Upper
ratio limit limit Z-Value p-Value ONS Control
Botella-Carretero et al 2008 Hospital-Community 1.308 0.473 3.615 0.517 0.605 17 / 30 15 / 30
Bourdel-Marchasson et al 2000 Hospital 0.722 0.530 0.983 -2.071 0.038 118 / 295 181 / 377
Delmi et al 1990 Hospital-Community 0.383 0.104 1.402 -1.450 0.147 4 / 27 10 / 32
Eneroth et al 2004 Community 0.686 0.229 2.057 -0.672 0.501 14 / 26 17 / 27
Espaulella et al 2000 Hospital-Community 0.515 0.269 0.985 -2.006 0.045 44 / 80 57 / 81
Gariballa et al 2006 Hospital-Community 0.792 0.431 1.454 -0.754 0.451 21 / 222 26 / 223
Houwing et al 2003 Hospital 0.825 0.379 1.796 -0.485 0.628 27 / 51 30 / 52
Olofsson et al 2007 Hospital 0.482 0.252 0.921 -2.210 0.027 27 / 83 37 / 74
Otte et al 1989 Community 0.825 0.147 4.628 -0.219 0.827 3 / 13 4 / 15
Tidermark et al 2004 Community 0.359 0.100 1.294 -1.566 0.117 7 / 20 12 / 20
0.676 0.548 0.832 -3.683 0.000 282 / 847 389 / 931
0.01 0.1 1 10 100

Favours ONS Favours CON

Fig. 2. Meta-analysis showing significantly lower rate of complications with high protein ONS.
288
60
48%
Readmissions (%)
40%
40
* *
29%
26%
20
0 between the groups with mean changes in the control and ONS
6
08
0
20
20
al
al
et
et
la
an
al
m
ib
or
ar
G
Fig. 3. Significant reductions in readmissions with high protein ONS.
control (OR 0.59 (95% CI 0.41–0.84), p = 0.004, n = 546 (heterogene-
ity I2 = 0.0%) (same OR for random effects model)). Taking the
number of readmissions in the control group as reference, ONS
reduced the overall readmissions by 30%.
3.3.2. Functional
Nineteen RCT (n = 2009) reported data on functional outcomes
(mean age 73 years (53–86 years), 62% female, prescribed daily
intake 149–995 kcal; 11.8–60.0 g protein; 28 days to 9 months)
(Efthimiou et al., 1988; Knowles et al., 1988; Otte et al., 1989;
Volkert et al., 1996; Schurch et al., 1998; Krondl et al., 1999; Lauque
et al., 2000; Espaulella et al., 2000; Bruce et al., 2003; Bonnefoy
et al., 2003; Steiner et al., 2003; Tidermark et al., 2004; Ravasco
et al., 2005a, 2005b; Rosendahl et al., 2006; Gariballa et al., 2006;
Gariballa and Forster, 2007a, 2007b; Norman et al., 2008). Popula-
tions included elderly with a range of diseases, respiratory, a range
of acute illnesses, cancer, hip fracture, and GI disease. Intervention
was based in both the community (12 RCT (Efthimiou et al., 1988;
Knowles et al., 1988; Otte et al., 1989; Krondl et al., 1999; Lauque
et al., 2000; Bonnefoy et al., 2003; Steiner et al., 2003; Tidermark
et al., 2004; Ravasco et al., 2005a, 2005b; Rosendahl et al., 2006;
Norman et al., 2008; n = 680) and hospital and community settings
(7 RCT (Volkert et al., 1996; Schurch et al., 1998; Espaulella et al.,
2000; Bruce et al., 2003; Gariballa et al., 2006; Gariballa and Forster,
2007a, 2007b); n = 1329). Functional outcomes were categorised
into strength, activities of daily living (ADL), quality of life (QOL),
breathlessness and mobility.
3.3.2.1. Strength. Nine RCT reported markers of strength
(Efthimiou et al., 1988; Knowles et al., 1988; Otte et al., 1989;
Schurch et al., 1998; Lauque et al., 2000; Bonnefoy et al., 2003;
Steiner et al., 2003; Tidermark et al., 2004; Norman et al., 2008;
n = 467). These included; muscle power (Bonnefoy et al., 2003)
respiratory muscle function (Knowles et al., 1988; Otte et al., 1989;
Norman et al., 2008), and handgrip strength (Efthimiou et al.,
1988; Schurch et al., 1998; Lauque et al., 2000; Steiner et al., 2003;
Tidermark et al., 2004; Norman et al., 2008). In the six studies that
reported handgrip strength, one did not report any data (Schurch
et al., 1998) but stated there were no differences. For the other
five studies (n = 275), all reported mean changes that were greater
in the ONS group than the control. In 4 of the 5 studies (n = 174)
strength decreased in the control group. A meta-analysis could be
undertaken on four of the RCT (mean age 65 years (53–84 years),
A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296
60% female) (Efthimiou et al., 1988; Steiner et al., 2003; Tidermark
High Protein ONS et al., 2004; Norman et al., 2008); three reporting mean and SD
Control of the change; and one in which the SD of the change in the ONS
p<0.05
* group was calculated from the available data and assumed to be
the same in the control group. A significant effect in favour of the
ONS group was found (1.76 kg (95%CI 0.36–3.17), p = 0.014, n = 219,
random effects model, 4 RCT).
3.3.2.2. Activities of daily living. Seven RCT reported activities of
daily living assessed by the Barthel index (4 RCT) (Volkert et al.,
1996; Espaulella et al., 2000; Gariballa et al., 2006; Gariballa and
Forster, 2007a), and Katz scores (3 RCT) (Schurch et al., 1998; Bruce
et al., 2003; Tidermark et al., 2004). Data were not amenable to
meta-analysis. Most (5 RCT) reported non-significant differences
group being similar. Two RCT (Schurch et al., 1998; Tidermark et al.,
2004) reported significant improvements in activities of daily living
in the ONS group.
3.3.2.3. Quality of life. Six RCT (n = 561) used questionnaires to
assess quality of life including SF36 (Krondl et al., 1999; Gariballa
and Forster, 2007a; Norman et al., 2008), EuroQol (Tidermark
et al., 2004), and EORTC QLQ-C30 (European Organization for the
Research and Treatment of Cancer Quality of Life Questionnaire
Version 3) (Ravasco et al., 2005a, 2005b). In all three studies that
used SF36, domain scores were significantly better in the ONS
than control group (2/8 domains significantly improved in the ONS
group, with no significant differences in control group (Krondl et al.,
1999); significant difference in favour of ONS between the groups in
3/8 domains (Gariballa and Forster, 2007a) and 8/8 domains signif-
icantly improved in the ONS group compared to 3/8 in the control
(Norman et al., 2008)). For the one study that used EuroQol, index
scores were higher at 6 and 12 months in the ONS group compared
to control but there were no significant differences. For the 2 stud-
ies that used a cancer specific questionnaire there was a significant
improvement from baseline in all domains for the ONS group.
3.3.2.4. Breathlessness/dyspnoea. Three studies reported breath-
lessness, but meta-analysis was not possible. In one study
(Efthimiou et al., 1988) there was a significant improvement in
breathlessness in the ONS group which remained virtually unal-
tered in the control group. In the second study (Otte et al., 1989)
the changes in dyspnoeic score did not differ between groups and
in the third study, there were significant changes within each group
but no significant differences between groups (Steiner et al., 2003).
3.3.2.5. Mobility. Three studies reported mobility by walk tests and
one by shuttle test. In 6 min (Efthimiou et al., 1988; Bonnefoy et al.,
2003) and 12 min walking tests (Otte et al., 1989), there was no
significant difference in the distance walked between the groups.
In the study involving a shuttle test (Steiner et al., 2003) there was
also no significant difference between ONS and control group. Apart
from one study (Bonnefoy et al., 2003), which involved elderly
patients in retirement homes, all other studies involved patients
with respiratory disease.
3.3.3. Nutritional
3.3.3.1. Total intake. Fifteen RCT (n = 1473) reported data on total
energy and protein intake (mean age 71 years (53–86 years), 60%
female, prescribed daily ONS intake 200–900 kcal; 11.8–60.0 g pro-
tein; 15 days to 12 months) (Stableforth, 1986; Efthimiou et al.,
1988; Knowles et al., 1988; Delmi et al., 1990; Volkert et al., 1996;
Yamaguchi et al., 1998; Krondl et al., 1999; Lauque et al., 2000;
Bourdel-Marchasson et al., 2000; Steiner et al., 2003; Carlsson et al.,
2005; Teixido-Planas et al., 2005; Ravasco et al., 2005a, 2005b;
Norman et al., 2008). Populations included hip fracture, elderly
 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296
with a range of conditions, respiratory, cancer, critically ill, dial-
ysis and GI disease. ONS was consumed in the community (10 RCT
(Efthimiou et al., 1988; Knowles et al., 1988; Krondl et al., 1999;
Lauque et al., 2000; Norman et al., 2008; Ravasco et al., 2005a,
2005b; Steiner et al., 2003; Teixido-Planas et al., 2005; Yamaguchi
et al., 1998); n = 582), hospital (2 RCT (Stableforth, 1986; Bourdel-
Marchasson et al., 2000); n = 730) and hospital and community
setting (3 RCT (Carlsson et al., 2005; Delmi et al., 1990; Volkert
et al., 1996); n = 161).
Twelve RCT (n = 1242) reported changes in total energy intake
from baseline to the end of the intervention period (Efthimiou et al.,
1988; Knowles et al., 1988; Delmi et al., 1990; Yamaguchi et al.,
1998; Krondl et al., 1999; Lauque et al., 2000; Bourdel-Marchasson
et al., 2000; Steiner et al., 2003; Carlsson et al., 2005; Teixido-
Planas et al., 2005; Ravasco et al., 2005a, 2005b). In all but one
study the increase from baseline in the ONS group was greater than
the control group (Fig. 4) and significantly so according to meta-
analysis (314 kcal (95% CI 146–482), p < 0.001, n = 1242, 12 RCT
random effects model). Eleven of these were community studies
(2 started in hospital) (hospital trial excluded (Bourdel-Marchasson
et al., 2000)) which also showed significant improvements in favour
of the ONS group (349 kcal (95% CI 210–488), p < 0.001, n = 672,
random effects model, 11 RCT).
Ten RCT (n = 1152) reported changes in total protein intake from
baseline to the end of the intervention period (Efthimiou et al.,
1988; Delmi et al., 1990; Yamaguchi et al., 1998; Krondl et al.,
1999; Lauque et al., 2000; Bourdel-Marchasson et al., 2000; Steiner
et al., 2003; Carlsson et al., 2005; Ravasco et al., 2005a, 2005b).
In all but one study the increase from baseline in the ONS group
was greater than the control group and significantly so according
to meta-analysis (22 g (95% CI 10–34 g), p < 0.001, n = 1152, random
effects model, 10 RCT). When split for setting the effect on protein
intake only remained significant in community trials (2 started in
hospital) (25 g (95% CI 16–33 g), p < 0.001, n = 480, random effects
model, 9 RCT) (hospital trial excluded (Bourdel-Marchasson et al.,
2000)).
3.3.3.2. Effect of ONS on oral food intake and appetite. One study
reported that there was no significant difference in appetite
between the two groups (Carlsson et al., 2005), and 5 studies
reported that supplements high in protein did not reduce volun-
tary food intake (Otte et al., 1989; Delmi et al., 1990; Yamaguchi
et al., 1998; Lauque et al., 2000; Norman et al., 2008). Only two of
the studies reported oral food intake separately from ONS intake
(Delmi et al., 1990; Lauque et al., 2000) before and after the inter-
vention. Total energy intake increased in both of them by an amount
corresponding to 99.6% (Delmi et al., 1990) and 65.4% (Lauque et al.,
2000) of the ONS energy ingested. When adjusted for changes that
occurred in the control group (oral food intake alone) the corre-
sponding results were 99.6% and 70.7% respectively. These studies
did not report on measures of disease severity and it was not possi-
ble to examine the impact of this on food intake within and between
studies. However, being randomised controlled studies patients
with disease were included in both the intervention and control
groups of the study. Similar calculations were not possible in a
further two studies which did not report baseline data (Bourdel-
Marchasson et al., 2000; Norman et al., 2008).
3.3.3.3. Weight and body composition. Twelve RCT (n = 1244)
reported data on weight (mean age 72 years (53–86 years), 68%
female, prescribed daily intake 200–995 kcal; 10.0–60.0 g protein;
28 days to 12 months) (McEvoy and James, 1982; Efthimiou et al.,
1988; Otte et al., 1989; Volkert et al., 1996; Lauque et al., 2000;
Bruce et al., 2003; Steiner et al., 2003; Tidermark et al., 2004;
Teixido-Planas et al., 2005; Gariballa et al., 2006; Olofsson et al.,
2007; Norman et al., 2008). Populations included hip fracture,
289
elderly with a range of conditions, respiratory, acute illness, GI dis-
ease and dialysis. Intervention occurred in the community (7 RCT
(Efthimiou et al., 1988; Otte et al., 1989; Lauque et al., 2000; Steiner
et al., 2003; Tidermark et al., 2004; Teixido-Planas et al., 2005;
Norman et al., 2008); n = 368), hospital (2 RCT (McEvoy and James,
1982; Olofsson et al., 2007); n = 250) and hospital and community
setting (3 RCT (Volkert et al., 1996; Bruce et al., 2003; Gariballa
et al., 2006); n = 626).
Five studies reported weight gain in the supplement group
and weight loss in the control group (McEvoy and James, 1982;
Efthimiou et al., 1988; Volkert et al., 1996; Lauque et al., 2000;
Steiner et al., 2003) (3 based in the community, 1 in hospital, and 1
hospital to community setting). Five studies reported weight gain
in both groups with greater weight gain in the supplement group
(Otte et al., 1989; Teixido-Planas et al., 2005; Gariballa et al., 2006;
Olofsson et al., 2007; Norman et al., 2008), and 2 studies (Bruce
et al., 2003; Tidermark et al., 2004) reported weight loss in both
groups with less weight lost in the supplement group (1 commu-
nity and 1 hospital to community). Overall the mean weight change
was greater in the high protein supplement group (2.1 kg; −1.3 to
11.0 kg) compared to control (−1.6 kg; −2.4 to 2.7 kg).
Three studies reported a significant improvement in weight in
the group consuming high protein ONS (McEvoy and James, 1982;
Otte et al., 1989; Steiner et al., 2003) (8 studies did not report any
statistics), and 5 RCT showed a difference in mean weight change
of more than 2 kg in the high protein supplement group compared
to control (McEvoy and James, 1982; Efthimiou et al., 1988; Volkert
et al., 1996; Lauque et al., 2000; Teixido-Planas et al., 2005).
Meta-analysis (12 RCT) (Fig. 5) showed that high protein ONS
significantly increased weight compared to control (1.7 kg (95% CI
0.8–2.7) p < 0.001, n = 1224, random effects model), this remained
significant when excluding those trials where the SD was not avail-
able so the largest SD from the other trials was used (1.4 kg (0.5–2.4)
p = 0.004, 5 RCT). When split for setting the effect on weight only
remained significant in community trials (10 RCT; 3 started in
hospital) (1.9 g (95% CI 0.8–3.0), p < 0.001, n = 973, random effects
model).
Ten RCT (n = 1149) reported information on measures of body
composition including triceps skinfold, fat mass measured by
DEXA, mid upper arm circumference (MUAC), mid arm muscle
circumference (MAMC), and bone mineral density (McEvoy and
James, 1982; Efthimiou et al., 1988; Knowles et al., 1988; Otte
et al., 1989; Schurch et al., 1998; Bonnefoy et al., 2003; Steiner
et al., 2003; Seidner et al., 2005; Gariballa et al., 2006; Gariballa
and Forster, 2007b; Norman et al., 2008). Six of these (n = 397;
prescribed daily intake 250–900 kcal; 16.1–60.0 g protein; 4 weeks
to 6 months) reported significant improvements over time with
ONS in measures of body composition including skin folds, MAMC,
MUAC, and BMI, with some papers reporting more than one mea-
sure (McEvoy and James, 1982; Efthimiou et al., 1988; Otte et al.,
1989; Schurch et al., 1998; Seidner et al., 2005; Norman et al.,
2008). Populations included respiratory disease, acutely ill elderly,
hip fracture, and GI disease. Intervention was based in the hos-
pital (1 RCT (McEvoy and James, 1982); n = 51), community (4
RCT (Efthimiou et al., 1988; Otte et al., 1989; Seidner et al., 2005;
Norman et al., 2008); n = 264) and hospital and community settings
(1 RCT (Schurch et al., 1998); n = 82). Significant improvement in
patients who received ONS versus control were seen for triceps
skinfold (McEvoy and James, 1982; Efthimiou et al., 1988), sum of
four skinfolds (Otte et al., 1989), mid arm muscle circumference
(Efthimiou et al., 1988) mid upper arm circumference (McEvoy and
James, 1982), fat mass as measured by DEXA (Steiner et al., 2003)
and bone mineral density (at lumbar spine, contralateral proxi-
mal femur and contralateral mid-femoral shaft) (Schurch et al.,
1998). Four studies (n = 118) reported changes in MAMC and were
meta-analysable (mean age 61 years (55–69 years), 45% female,
290 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296

ONS
Energy Control

800

600

400
Mean change (kcal)

200

Ravasco et al 2005b
Ravasco et al 2005a
Marchasson et al

Lauque et al 2000

Teixido-Planas et

Yamaguchi et al
Carlsson et al

Krondl et al 1999
Knowles et al
Efthimiou et al

Steiner et al 2003
Delmi et al 1990
Bourdel-

1988
2005

al 2005
1998

1998
2000

-200

-400

-600
Protein ONS
Control
40

30
Mean change (g)

20

10

0
Ravasco et al 2005b
Ravasco et al 2005a
Efthimiou et al

Lauque et al 2000

Yamaguchi et al
Krondl et al 1999

Steiner et al 2003
Carlsson et al 2005

Delmi et al 1990
Marchasson et al
Bourdel-

1998

1998
2000

-10

-20

Fig. 4. Effect of high protein ONS versus control on intake of energy and protein (mean change in intake during intervention period (baseline to end of intervention). See
Table 2 for duration of intervention).

prescribed daily intake 400–664 kcal; 20–36 g protein; 4 weeks to et al., 2004), and length of rehabilitation stay (23.3 ± 1.3 days high
3 months). All reported changes in favour of ONS (mean difference protein ONS group; 28.0 ± 2.6 days standard ONS group (Neumann
compared to control; 0.47 cm; 95%CI 0.30–0.64, p < 0.05) (McEvoy et al., 2004)). Only 1 RCT (de Luis et al., 2008b) reported any sig-
and James, 1982; Efthimiou et al., 1988; Knowles et al., 1988; Otte nificant differences, with patients in the high protein ONS group
et al., 1989). achieving significant improvements in weight, BMI and fat mass
compared to those in the standard ONS group.
3.4. Studies comparing high protein ONS with standard ONS
(n = 3) 3.5. Long-term supplementation and follow-up

Three RCT (n = 176) all based in the community reported data Seven studies involved longer follow-up periods ranging from
comparing high protein ONS with standard ONS (ONS not high in 7 to 18 months (Tables 2 and 3) (Efthimiou et al., 1988; Tkatch
protein, <20% energy from protein) (Bunout et al., 2004; Neumann et al., 1992; Schurch et al., 1998; Yamaguchi et al., 1998; Bonnefoy
et al., 2004; de Luis et al., 2008b). Most outcomes reported across et al., 2003; Tidermark et al., 2004; Teixido-Planas et al., 2005),
these three trials were not significantly different, including mor- these studies had intervention periods ranging from 38 days to
tality (1 death in each group (Bunout et al., 2004), 6 deaths in each 18 months. Several of these studies reported clinical outcomes.
group (de Luis et al., 2008b)), admissions (2 admissions in the high Three studies (Tkatch et al., 1992; Schurch et al., 1998; Tidermark
protein ONS group, 1 admission in the standard ONS group (Bunout et al., 2004) reported a reduced length of stay in favour of ONS, with
et al., 2004)), falls (Bunout et al., 2004), body weight (Bunout et al., one being length of stay at 7 months (Tkatch et al., 1992). One study
2004), arm circumference (Bunout et al., 2004), mobility (Neumann that reported complications (fracture not healing and infections)
 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296 291

Study Setting Statistics for each study Difference in means and 95% CI
Difference Lower Upper
in means limit limit p-Value
Bruce et al 2003 Hospital-Community 0.400 -0.651 1.451 0.456
Efthimiou et al 1988 Community 4.900 -1.491 11.291 0.133
Gariballa et al 2006 Hospital-Community 1.000 -0.134 2.134 0.084
Lauque et al 2000 Community 2.700 -1.482 6.882 0.206
McEvoy et al 1982 Hospital 2.800 1.696 3.904 0.000
Norman et al 2008 Community 0.900 -1.708 3.508 0.499
Olofsson et al 2007 Hospital -0.400 -2.096 1.296 0.644
Otte et al 1989 Community 1.360 0.486 2.234 0.002
Steiner et al 2003 Community 1.210 -1.384 3.804 0.361
Teixido-Planas et al 2005 Community 8.280 5.305 11.255 0.000
Tidermark et al 2004 Community 1.130 -1.156 3.416 0.333
Volkert et al 1996 Hospital-Community 2.400 -0.419 5.219 0.095
1.743 0.785 2.702 0.000
-12.00 -6.00 0.00 6.00 12.00
Favours CON Favours ONS

Fig. 5. Meta-analysis showing significant improvement in weight with high protein ONS (7 RCT (Efthimiou et al., 1988; Volkert et al., 1996; Lauque et al., 2000; Steiner et al.,
2003; Teixido-Planas et al., 2005; Gariballa et al., 2006; Olofsson et al., 2007), no reported SD of weight change so assumed as SD 6.1 (highest of rest of group).

(Tidermark et al., 2004), also showed a reduction in favour of ONS.
One study also reported a significantly favourable clinical course in
hip fracture patients randomised to ONS (Tkatch et al., 1992). All
four studies reported mortality and meta-analysis of these showed
no significant effect (OR 0.84 (95%CI 0.31–2.25), p = 0.727). There
was also an improvement with ONS in handgrip strength in two
studies (Efthimiou et al., 1988; Tidermark et al., 2004), which was
significant in one of them (Efthimiou et al., 1988). Follow-up for
7–18 months did not identify any significant detrimental effects of
ONS either in primary studies or in meta-analyses.
3.6. Heterogeneity and potential effects on results
To address the potential effects of confounding variables con-
tributing to potential heterogeneity a matrix of meta-regressions
was undertaken in which a range of individual outcomes (complica-
tions, mortality, length of stay, readmissions to hospital, handgrip
strength, weight, MAMC, and change in energy and protein intake)
were used as the dependent variables and a range of confounding
variables (covariates or moderator variables) were used as inde-
pendent variables (ONS % energy from protein, prescribed energy
and protein from ONS, age, and duration of intervention). There
were no significant effects of the moderator variables in the meta-
regressions involving complications, mortality, or length of stay.
There were insufficient studies to undertake meta-regression for
readmissions. The only meta-regression that was significant for
mean change in hand grip strength was with the amount of pro-
tein prescribed (effect size 0.1 kg/g protein) (p = 0.01). For the mean
change in energy intake significant relationships were observed
with amount of protein and energy prescribed, which are subject
to potential problems with regression to the mean, and with dura-
tion of intervention, which was of borderline significance. There
was also a significant negative relationship with age (smaller dif-
ference with increasing age), but there was a tendency for the
prescription to be lower in the older age groups. Similarly, there
was a relationship of the mean change in protein intake with age,
but there was a tendency for prescribed protein intake to be lower
in the older population. In studies involving subjects with a mean
age of >65 years the mean unweighted protein intake was almost
twofold lower than in studies in which the mean age was <65 years
(24 vs. 45 g; p = 0.003). These smaller prescriptions were associ-
ated with smaller mean changes in weight with increasing age. In
addition, there was a highly significant relationship between dura-
tion of intervention and improvement in weight (0.4 kg/month;
p = 0.0004). This matrix of analyses has not made adjustments of
multiple testing.
4. Discussion
This is the first systematic review to examine the effect of
high protein ONS on clinical, functional and nutritional outcomes.
It demonstrates that high protein ONS produce multiple benefi-
cial effects with no outcomes that significantly favour the control
group, which is consistent with conclusions from other systematic
reviews that include all types of ONS (Koretz et al., 2007; Milne
et al., 2009). The duration of intervention with ONS ranged from
short to longer term (mean period of intervention 3 months) across
a wide range of patients with different conditions (elderly patients
33% of trials; hip fracture 33% of trials), varying nutritional status,
and different care settings (hospital and community). Therefore,
the review employed random effects meta-analyses with subgroup
analyses where appropriate.
A major finding of the systematic review was a significant over-
all reduction (19%) in a range of complications, which applied
to both hospital and community settings. The reduction in com-
plication rates which included those associated with healing of
surgical wounds, pressure ulcers and infection rates all depend on
inflammatory and immune function, which requires an adequate
supply of amino acids (Li et al., 2007) such as glutamine, which
acts as a major source of energy (Calder, 1995). When consider-
ing wound healing, studies show that recent nutritional intake
is important, even in patients without chronic protein-energy
malnutrition (Haydock and Hill, 1987). Since wound strength is
dependent on formation and deposition of the protein collagen,
amino acid availability may help facilitate healing. In addition, the
function of fibroblasts which produce collagen, and hepatic cells
which produce acute phase proteins, are influenced by amino acid
availability. It is not possible from this analysis to partition the ben-
efits between specific nutrients (e.g. vitamins, trace elements and
macronutrients), although individual amino acids have been impli-
cated in specific metabolic processes such as (i) arginine, which has
been implicated in the metabolic function of fibroblasts leading to
collagen formation and wound healing (Witte and Barbul, 2003;
Stratton et al., 2005; Arnold and Barbul, 2006), (ii) branched-chain
292 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296
amino acids, such as leucine have been implicated in stimulating
anabolism (Pasiakos and MCClung, 2011), and (iii) glutamine has
been implicated in a wide variety of processes, including effects on
anti-oxidants such as glutathione.
Some functional outcomes, such as handgrip strength were
found to be improved by ONS compared to the control group and
there were significant improvements in certain domains of quality
of life. Other functional outcomes such as activities of daily living,
breathlessness and walk tests were not found to be improved, but
the lack of sample size and power calculations may explain this
since none of the studies set out to examine functional outcomes
as the primary end point.
Given the improvements in the above outcomes, it is not sur-
prising that the use of high protein ONS were also associated with
a reduction in length of hospital stay and reduction in hospital
readmission rates, both of which have important economic impli-
cations. Any nutritional intervention that allows earlier discharge
or can keep patients out of the expensive hospital environment
is beneficial to the wider health economy. In particular readmis-
sions are a large economic driver in many countries including the
USA and UK. For example, an estimate of the national average cost
per episode per patient for a non-elective admission in England is
£2197 ($3499) (Curtis, 2010).
In patients with disease-related malnutrition who have an inad-
equate dietary intake due to poor appetite, the main purpose
of prescribing high protein ONS, often for a limited period of
time, is to increase protein intake, from a low intake to a more
desirable or normal intake. In the studies reviewed the intake
increased from a mean of 55–74 g/day. There was also a signif-
icant increase in total protein intake compared to the control
group, which accompanied an increase in total energy intake in
favour of the ONS group. Improved nutritional intake is consid-
ered to be a key component of the causal pathway leading to
clinical benefits, but it is not possible to separate if the effects
are due to the amount and quality of the protein ingested or
from the presence of vitamins, trace elements and other nutri-
ents present in ONS. This improved intake may explain the
significant increase in body weight and muscle mass (MAMC).
The increase in muscle mass, which requires deposition of pro-
tein, can also help explain the significant improvement in grip
strength.
Concerns are sometimes raised about the adverse effects of
excessive amounts of protein in clinical practice. For example
excessive administration of protein over prolonged periods has
been implicated as having adverse affects on osteoporosis and renal
failure. However, national dietary surveys show that a substantial
proportion of the population naturally ingests a diet high in protein
(>20% energy from protein) (Finch et al., 1998); 14% people aged
19–64 years (Henderson et al., 2003), 18% those aged 50–64 years
(Henderson et al., 2003) and 13% of people aged 65 years and over
(Finch et al., 1998). In fact the Food and Nutrition Board, Institute
of Medicine (USA) considers that a diet containing 10–35% energy
from protein in adults is acceptable (Institute of Medicine, 2005).
In the ONS studies several included a follow up period of more than
6 months of these there were no significant adverse effects. On the
contrary, they tended to indicate benefits, such as improved hand-
grip strength, improved clinical course and period of time spent
in hospital. The ONS used in the reported studies contained more
than 20% energy from protein, however the overall contribution of
protein from ONS plus food intake was not high in protein and only
increased from 15.5% (±1.6%) at baseline to 17.2% (±1.1%) at the
end of intervention. This is because ONS make a small but impor-
tant contribution to total protein intake. Analysis of mean data did
not allow us to examine in any detail the proportion of subjects
who consumed more than 20% of their total dietary intake in the
form of protein.
Research has suggested that protein ingested by healthy sub-
jects may be more satiating than other macronutrients (Elia and
Cummings, 2007), but there is little data in patients in clinical
practice. In the studies in which voluntary food intake could be
examined (Delmi et al., 1990; Lauque et al., 2000) there was a
significant increase in total protein and energy intake with little
suppression of normal food intake. Although disease and illness
severity can reduce intake, these results arose from studies in which
patients with disease were randomised to either an intervention or
control group. The finding that intake from high protein ONS has lit-
tle suppressive effect (or largely adds rather than replaces oral food
intake) is consistent with other systematic reviews of the effects of
all types of ONS (Stratton et al., 2003).
This systematic review included a heterogeneous group of stud-
ies, which we have attempted to address using three procedures:
we undertook subgroup analysis, for example according to setting,
we have used a random effects model rather than a fixed effect
model; and we have used meta-regression to examine the effects
of moderator variables such as age, duration of intervention and
prescribed amounts of protein and energy. In general no signifi-
cant effect of the moderator variables was found and in those that
did demonstrate an effect, such as the relationship between change
in protein intake and age, this was related to the lower protein
prescription in studies with older individuals. The finding that the
duration of intervention was related to weight gain is not surpris-
ing. The conclusions generally remain unaltered. Further insights
might have been obtained if more studies were available and if
it were possible to use multiple moderator variables rather than
just individual ones in meta-regression analysis. The conclusions,
of course, depend on the quality of the studies, which was variable.
There was insufficient information to come to any conclusions
about the merits of high protein ONS versus standard ONS. This is
because only three head to head RCTs were identified for review:
one involved healthy older subjects with femoral osteoporosis
(Bunout et al., 2006); another involved diabetics who were given
either high fat versus low fat ONS to examine the effects on glu-
cose control (de Luis et al., 2008b) (with only a small incidental
difference in % energy from protein (17% vs. 21%)); and the third
trial involved patients recovering from hip fracture (Neumann et al.,
2004), in which there was a non-significant decrease in length of
stay in favour of the high protein group. In addition, the studies
were insufficiently powered to examine certain outcomes such as
mortality.
Future studies to address such issues would probably require
large sample sizes because the difference in protein intake between
a high protein ONS and a standard ONS is less than the difference
between high protein ONS supplementation and no supplementa-
tion. In the absence of such information, judgement about whether
to use high protein supplements in preference to standard ONS
and/or normal food, depends on the likelihood of perceived ben-
efits that take into account a range of considerations including
the following: whether the patient has a low protein intake and
is suffering from the catabolic effects of disease or increased pro-
tein losses, and whether an additional supply of amino acids might
facilitate wound repair and other essential tissue functions. The
evidence base addressing many of these issues has evolved from
physiological and patho-physiological studies rather than from
randomised controlled trials of nutritional care.
Based on the findings of this systematic review and meta-
analysis use of multi nutrient ONS high in protein (provision
per day of ∼440 kcal (149–995 kcal); ∼29 g protein (10–60 g) for
∼88 days (10–360 days)), are associated with improvements in out-
come in a range of patient groups and health care settings. Specific
patient groups who may benefit include the acutely ill elderly,
respiratory, hip fracture patients, those with pressure ulcers
and other patient groups with increased protein requirements.
 A.L. Cawood et al. / Ageing Research Reviews 11 (2012) 278–296
When providing ONS in clinical practice patients nutritional status
and nutritional requirements (energy, protein and micronutrients)
should be considered, goals should be set and treatment effectively
monitored. In order to make more specific clinical recommenda-
tions about the value of high protein supplements (>20% energy
from protein) versus standard supplements (<20% energy from pro-
tein) adequately powered comparative clinical trials are needed as
previously described. It would also be valuable to have information
about the optimal type of protein needed in the supplements (e.g.
casein, whey and soy protein).
5. Conclusion
There are clinical, nutritional and functional benefits resulting
from high protein ONS use and the available evidence suggests lit-
tle suppression of normal food intake, with the ONS being mostly
additive to food intake. There is still a need to understand the mech-
anisms of action, the extent to which high protein ONS represent
an improvement over standard ONS, and their overall economic
impact, which is associated with reduced length of stay and reduced
hospital readmissions. A formal economic impact analysis taking
into account the cost of resource use as well as cost of treatment
requires to be done.
Disclosure statement
Both AC and RS are employed by Nutricia, Advanced Medical
Nutrition.
Acknowledgements
Personal communication from authors for extra data; Salah
Gariballa, Jan Tidermark, Birgitta Olofsson.
Rachel Freeman for literature searches.
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