J Nutr Health Aging

EFFICACY OF A DISEASE-SPECIFIC NUTRITIONAL SUPPORT FOR PRESSURE

ULCER HEALING: A SYSTEMATIC REVIEW AND META-ANALYSIS
E. CEREDA1, J.C.L. NEYENS 2, R. CACCIALANZA1, M. RONDANELLI MD3, J.M.G.A. SCHOLS4
1. Servizio di Dietetica e Nutrizione Clinica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 2 Maastricht University, CAPHRI, School of Public Health and Primary Care,
Department Health Services Research, The Netherlands; 3 Department of Public Health, Experimental and Forensic Medicine, Section of Human Nutrition, Endocrinology and Nutrition
Unit, University of Pavia, Pavia, Italy; 4 Faculty of Health, Medicine and Life Sciences / Dept. HSR and Dept. Family Medicine / School for Public Health and Primary Care (Caphri),
Maastricht University, Maastricht, the Netherlands. Corresponding author: Emanuele Cereda MD, PhD, Servizio di Dietetica e Nutrizione Clinica, Fondazione IRCCS Policlinico San
Matteo, Viale Golgi 19, 27100 Pavia, Italy, Tel.: +39 0382 501615 ; Fax: + 39 0382 502801, E-mail: [email protected]

Abstract: Objectives: The aim of this systematic review was to summarize the evidence on the efficacy of
high-calorie, high-protein nutritional formula enriched with arginine, zinc, and antioxidants (disease-specific
support) in patients with pressure ulcers (PUs). Methods: Randomized controlled trials in English published
from January 1997 until October 2015 were searched for in electronic databases (EMBASE, Medline, PubMed,
and CINAHL). Studies comparing a disease-specific nutritional support (oral supplements or tube feeding)
to a control nutritional intervention enabling the satisfaction of energy requirements regardless of the use of
high-calorie formula or placebo or no support for at least 4 weeks were considered eligible. Study outcomes
were the percentage of change in PU area, complete healing and reduction in the PU area ≥40% at 8 weeks,
and the percentage of change in area at 4 weeks. Results: A total of 3 studies could be included in the meta-
analysis. Compared with control interventions, formulas enriched with arginine, zinc and antioxidants resulted
in significantly higher reduction in ulcer area (-15.7% [95%CI, -29.9, -1.5]; P=0.030; I2=58.6%) and a higher
proportion of participants having a 40% or greater reduction in PU size (OR=1.72 [95%CI, 1.04, 2.84]; P=0.033;
I2=0.0%) at 8 weeks. A nearly significant difference in complete healing at 8 weeks (OR=1.72 [95%CI, 0.86,
3.45]; P=0.127; I2=0.0%) and the percentage of change in the area at 4 weeks (-7.1% [95%CI, -17.4, 3.3];
P=0.180; I2=0.0%) was also observed. Conclusions: This systematic review shows that the use of formulas
enriched with arginine, zinc and antioxidants as oral supplements and tube feeds for at least 8 weeks are
associated with improved PU healing compared with standard formulas.

Key words: Pressure ulcers, malnutrition, nutritional support, healing, arginine.

Introduction of energy and proteins include the provision of at least 30-35

kcal/kg/day and 1.25-1.5 grams of protein/kg/day (11). Besides,
Pressure ulcers (PUs) are a major, albeit underestimated, based on the publication of different small trials (13-16), the
health care problem around the world (1). Although prevalence role of supplementation with specific nutrients – arginine,
varies across the different healthcare setting, PUs affect zinc and antioxidants - involved in wound healing has been
approximately 10–20% of patients and negatively affect highlighted in the guidelines. However, these studies were
patient’s prognosis, medical resource use and healthcare costs at high risk of bias due to the small sample size and did not
(1-3). standardize for the protein and calorie content of the formula
Nutritional support has become a relevant strategy in used. The independent role of these nutrients in the healing of
the multidisciplinary care of patients with pressure ulcers PUs has been appropriately investigated in a recent high-quality
(PUs) (4, 5). Malnutrition has been found closely linked trial (17). Interestingly, the secondary analysis of this trial’s
to PUs (5-7) and, more important, studies have shown that data has shown that the use of a disease-specific nutritional
PU patients are characterized not only by increased energy formula is also cost-effective (18).
expenditures but also by the incapacity to cover their protein- Indeed, the grade of evidence and strength of
calorie requirements (8). The importance of calories in PU recommendations depend on the evaluation of several factors
healing has been adequately addressed by previous research associated with the quality of published trials: the risk of bias,
and it is now recognized (5, 9-11). Accordingly, PU patients consistency of results across the available studies, precision of
have increased energy requirements are often malnourished. the results, directness, and likelihood of publication bias, dose-
Therefore, nutritional screening, assessment and support should response, and strength of the association, as well as plausible
be systematically considered. confounders influencing the efficacy. Accordingly, the
International guidelines (4, 11, 12) have progressively conduction of meta-analysis is justified (19, 20) as it reasonably
recognized the role of nutritional support in the management of enables clarifying the efficacy of available treatments. To better
PU patients and a last edition has been released by the National evaluate the role of disease-specific formulae in the healing of
Pressure Ulcer Advisory Panel (NPUAP), European Pressure PUs, we conducted a systematic review and meta-analysis of
Ulcer Advisory Panel (EPUAP) and Pan Pacific Pressure Injury studies investigating the efficacy of a high-calorie nutritional
Alliance (PPPIA). Specific recommendations on the amount support enriched with specific micronutrients and comparing it
Received July 26, 2016
Accepted for publication August 30, 2016
1
J Nutr Health Aging

NUTRITIONAL SUPPORT AND PRESSURE ULCERS

Table 1
Characteristics of the studies included in quantitative synthesis

Reference Country; setting Study size Malnutrition(%) Study duration Active Control Method used Results *
(active / control) (weeks) intervention intervention in outcome - Mean difference in
[energy ; [energy and assessment reduction in area at 8
proteins] proteins] weeks (%)
- Reduction in area
≥40% at 8 weeks (n)
- Complete healing at
8 weeks (n)
- Mean difference in
reduction in area at 4
weeks (%)
Cereda, 2009 Italy (multi-cen- N=30 (15/15) 90% 12 Oral: standard oral Oral: standard oral Tracing the peri- -24.4% (95%CI, -37.5,
ter); diet + 2 specific diet + 2 standard meter onto sterile, -11.3) ‡
long-term care ONS § per day ONS/day transparent block Active, n=10; Control,
institutions Tube: specific Tube: standard paper and counting n=8
formula # (1000 and high-protein the blocks Active, n=2; Control,
mL/day) + stan- formula as ne- n=0
dard formula as cessary -6.5% (95%CI, -22.8,
necessary [29.5 kcal/kg/day; 9.8) ‡
[30 kcal/kg/day; 1.2 g/kg/day]
1.5 g/kg/day]
Van Anholt, Multi-country; N=43 (22/21) 0% 12 Standard oral diet Standard oral Measuring the 7.3% (95%CI, -18.7,
2010 hospitals + 3 specific ONS diet + 3 bottles maximum length 33.2) †
and § per day [not of non-caloric and width of the Active, n=15; Control,
long-term care reported] placebo/day ulcer with a ruler n=15
institutions [not reported] and assuming the Active, n=6; Control,
surface area of the n=5
ulcer has an ellipse -1.6% (95%CI, -26.7,
form 23.5) †
Cereda, 2015 Italy (multi-cen- N=200 100% 8 Standard oral diet Standard oral diet Tracing the -18.7% (95%CI,
ter); (101/99) + 2 specific ONS + 2 isocaloric, perimeter onto -31.8, -5.7) ‡
long-term care § per day isonitrogenous sterile, transparent Active, n=71; Control,
institutions [27.5 kcal/kg/day; ONS/day paper and using n=54
and 1.5 g/kg/day] [27.0 kcal/kg/day; the VISITRAKTM Active, n=17; Control,
home-care 1.5 g/kg/day] system (resolution n=10
services 0.1 cm2; precision -10.2% (95%CI, -27.0,
of -0.2%–3.3%) 6.5) ‡
Abbreviations: ONS, oral nutritional supplements; 95%CI, 95% confidence interval; * According to multiple imputation of missing outcomes; ‡ Estimates adjusted for pressure ulcer (PU)
area at baseline, PU stage, setting of care, and recruiting center.; † Estimates adjusted for pressure ulcer (PU) area at baseline, PU stage, and recruiting center; § Approximate additional
amount of specific nutrients per each ONS: arginine 3 g; zinc, 4 mcg; copper, 600 mcg; manganese, 1.2 mg; selenium, 40 mcg; vitamin E, 30 mg; vitamin C, 200 mg; # Approximate
additional amount of specific nutrients per 1 litre of formula: arginine 8.5 g; zinc, 8 mcg; copper, 200 mcg; manganese, 0.5 mg; selenium, 40 mcg; vitamin E, 60 mg; vitamin C, 250 mg.

to a control one providing an adequate amount of calories and

proteins. Study Selection
We included only randomized, clinical trials that: 1)
Methods addressed the efficacy of a high-calorie disease-specific
nutritional support compared to a control nutritional
The review was conducted following the indications of intervention enabling the satisfaction of energy requirements,
Preferred Reporting Items for Systematic reviews and Meta- regardless of the use of high-calorie formula or placebo or no
Analyses (PRISMA) statement (21). support; 2) included patients with PUs; 3) and lasted at least
4 weeks. A disease-specific support was defined as any type
Search Strategy of intervention providing micronutrients putatively involved
Two investigators (EC, JN) independently conducted an in the healing process (e.g. arginine, zinc and antioxidants). A
electronic literature search using EMBASE, Medline, PubMed, study duration of 4 weeks was chosen following recent reviews
and CINAHL. The selection was limited to English-language that suggested that efficacy of nutritional support could not be
publications made from January 1997 (year of introduction of adequately evaluated for short-term interventions (5, 22).
wound-specific nutritional formula) until October 2015. Any When necessary, we contacted authors asking for further
disagreement was resolved by consensus with a third author information when data could not be meta-analyzed (e.g. no
(RC). A description of the strategy used in the identification mean difference in the reduction in PU area or no data on
of potentially relevant publication is provided in the complete healing were provided), 2) or other relevant
Supplementary Appendix. Reference lists of included articles information was missing (e.g. estimate boundaries).
and of those relevant to the topic were also reviewed.

2
J Nutr Health Aging

THE JOURNAL OF NUTRITION, HEALTH & AGING©

Data Extraction (n=1) (25).

Two authors (EC, JN) independently extracted data from
the selected studies on a standardized record form. Any Study and Patient Characteristics
disagreement was resolved by consensus with a third author The characteristics of the studies meta-analyzed are
(MR). The following information were extracted: 1) study summarized in Table 1. The trials (15-17) included a total of
population characteristics; 2) country; 3) clinical setting 273 participants (disease-specific, N=138; control, N=135);
in which the study was performed; 4) duration and type of they were all multicentre, mainly conducted in a long-term
interventions; 5) efficacy outcomes. care setting and substantially of good quality (Table 2)
although for two studies (15, 16) it was necessary to retrieve
Outcomes additional information (random sequence generation [2 studies]
The primary outcome was the percentage of change in ulcer and allocation concealment [1 study]) from the authors to
area at 8 weeks. Secondary outcome measures included: a fully evaluate the risk of bias. They included old patients
reduction in the area of 40% or greater and complete healing at (age at baseline assessment >70 years) with moderate-severe
8 weeks; the percentage of change in the area at 4 weeks. PUs (stage II, III and IV). In two trials participants were
Risk of Bias Assessment characterized by a severe impairment of nutritional status (15,
Assessment of bias was performed using the Cochrane 17), while in one malnutrition was listed among exclusion
Collaboration criteria (23). Accordingly, the following issues criteria (16). Finally, two studies were focused exclusively
were evaluated: random sequence generation, allocation on patients able to drink oral nutritional supplements while in
concealment, blinding of participants and personnel, blinding one study 65% of participants were tube-fed (15). In all the
of outcome assessment, incomplete outcome data, selective studies a nutritional formula enriched with arginine, zinc and
reporting, and differences in baseline features between antioxidants from the same industry was used.
treatment arms. Risk of bias was independently graded by two
reviewers as follows: low risk, high risk, and unclear risk. Any Figure 1
discrepancies between raters were resolved through consensus. Flow diagram of systematic review of literature
Finally, authors of included articles were contacted to obtain
additional information on unclear reporting.

Statistical Analysis
The meta-analysis was performed using the software
Comprehensive Meta-Analysis, version 2.2.064 (Biostat,
Englewood, NJ - http://www.meta-analysis.com/index.php),
establishing the level of significance at a 2-tailed P<0.05.
For continuous end points (the percentage of reduction
in area at 8 and 4 weeks) we computed the pooled mean
difference between interventions using fully-adjusted estimates.
However, for categorical outcomes (reduction in the area ≥ 40%
and complete healing at 8 weeks) risk ratios were calculated
using the number of events. For all the outcomes we pooled
estimates calculated using according to the multiple imputation
of missing outcomes. All estimates were provided along with
95% confidence interval (95%CI).

Results * compared different (non disease-specific) protein-calorie regimens (n=3)

The search identified 1249 non duplicate potentially eligible Study outcomes
studies. After excluding 1225 papers through title and abstract For all the trials fulfilling inclusion criteria for quantitative
review, 24 full text articles were examined. Altogether, 9 synthesis it was possible to collect data on the outcomes
studies were included in the qualitative synthesis and 3 in considered. In primary analysis, based on all trials, the use
meta-analysis (Figure 1) (15-17). A description of the articles of a disease specific nutritional support was associated with
excluded (13,14,24-27) is provided in the Supplementary a significantly higher reduction in ulcer area (Figure 1) and
Table 1. Particularly, study were excluded due to the following a higher proportion of participants having a 40% or greater
reasons: short duration (n=2) (14, 29); outcome data not reduction in PU size at 8 weeks (Table 3). Besides, we observed
available (n=2) (13, 24); inclusion of patients with different a nearly significant difference in complete healing at 8 weeks
types of chronic wounds (n=1) (26); lack of a control group and the percentage of change in the area at 4 weeks with

3
J Nutr Health Aging

NUTRITIONAL SUPPORT AND PRESSURE ULCERS

Table 2
Risk of bias of RCTs included in quantitative synthesis

Reference Evaluation of the Random sequence Allocation conceal- Blinding of Incomplete Selective outcome Differences
study based on generation ment (selection patients and outcome data reporting in baseline
(selection bias) bias) outcome assessors (attrition bias) (reporting bias) characteristics
(performance and between arms
detection bias)
Cereda, 2009 Manuscript review ↑ ? ↑ ↑ ↑ More patients with
multiple PUs in
the disease-specific
group
Request to the ↑ ↑ ↑ ↑ ↑
authors
Van Anholt, 2010 Manuscript review ? ? ↑ ↑ ↑ None
Request to the ↑ ↑ ↑ ↑ ↑
authors
Cereda, 2015 Manuscript review ↑ ↑ ↑ ↑ ↑ None
Request to the ↑ ↑ ↑ ↑ ↑
authors
Risk of bias - rating: ↑ low; ↓ high; ?, unclear.

Table 3
Secondary efficacy end points

END POINT Analysis # Disease-specific Control Treatment effect P-value Heterogeneity

[95%CI] (I2 [P-value])
Total (N) Events (N) * Total (N) Events (N) *
Reduction in area ≥40% at week 8 ‡ Primary 138 96 135 77 1.72 [1.04, 2.84] 0.033 0.0% [0.520]
Sensitivity 116 81 114 62 1.94 [1.13, 3.34] 0.016 0.0% [0.883]
Complete healing at week 8 ‡ Primary 138 25 135 15 1.72 [0.86, 3.45] 0.127 0.0% [0.655]
Sensitivity 116 19 114 10 1.95 [0.87, 4.37] 0.106 0.0% [0.482]
Difference in percentage of reduction in Primary 138 -- 135 -- -7.1% [-17.4, 3.3] 0.180 0.0% [0.847]
ulcer area at week 4 †
Sensitivity 116 -- 114 -- -8.3% [-19.6, 3.2] 0.156 0.0% [0.751]
Abbreviations: 95%CI, 95% confidence interval; * According to multiple imputation of missing outcomes; ‡ Odds ratio (95%CI) [disease-specific vs. control]; † Mean difference (95%CI)
[disease-specific vs. control]; # Primary analysis was based on estimates from all studies, while sensitivity analysis was limited to those from trials including malnourished participants

no heterogeneity (I2=0.0% for all). These findings were of a disease-specific formula enriched with arginine, zinc
substantially confirmed by sensitivity analysis (Table 3) and antioxidants in the nutritional support of PU patients.
refitted on studies including malnourished patients (15, 17). Accordingly, it strengthens the recent recommendations
Particularly, in respect to the primary outcome we observed an included in the NPUAP-EPUAP-PPPIA international guidelines
increase in the pooled effect size with no heterogeneity (Figure released in 2014 (11). Interestingly, the use of this formula has
1). been found to be also cost-effective, as it enables reducing the
intensity of local care (18).
Publication Bias Results on efficacy are consistent with and expand
Visual inspection of funnel plots showed that publication those of a previous meta-analysis (31) reporting a trend to
bias was unlikely. improved healing from the use of a disease-specific formula.
Unfortunately, the analysis was based on the findings
Discussion of small trials (13-16, 26) and did not consider those of the
OligoElement Sore Trial (OEST), a large trial with a low risk
Despite the wide availability of nutritional formulae, many of bias specifically addressing the independent role of specific
of which are marketed for specific disease conditions, there is nutrients in wound healing (18). Arginine is a semiessential
limited evidence supporting their efficacy and use in clinical amino acid contributing to protein anabolism (e.g collagen
practice (28-30). This is an important issue as these formula synthesis), cellular growth. As a donor of nitric oxide, it can
are usually more expensive than standard ones. Our meta- also increase tissue blood flow, improve immune response and
analysis reasonably supports as Grade A evidence for the use induce the mobilization of endothelial progenitor cells from

4
J Nutr Health Aging

THE JOURNAL OF NUTRITION, HEALTH & AGING©

Figure 2
Forest plot of the percentage of change in ulcer area at 8 weeks in participants receiving disease-specific vs control nutritional
support. In the plots, the squares indicate point estimates of effect (mean difference), with the size of the square representing
the weight attributed to each study and the horizontal bars indicating 95%CI. Sensitivity analysis is based on studies including
malnourished participants

the bone marrow. Zinc is an important co-enzyme of enzymes size due to unavailability of non-malnourished patients. In
involved in protein and DNA synthesis, immune function, agreement with this, the OEST study has found that about 90%
and cellular proliferation. Antioxidants are also relevant in of PU patients are malnourished (17). Therefore, PU patients
any chronic inflammatory condition. Particulalry, vitamin are likely malnourished and nutritional support should be
C plays an important role in cellular immunity, fibroblast systematically considered.
proliferation and the synthesis of collagen (32, 33). Previous The following limitations are acknowledged. First, despite
trials were not able to demonstrate a positive effect for these using multiple database we searched only for English-language
single micronutrients and the failure was likely due to the lack full-text articles. Second, only 3 high-quality trials have been
of concomitant energy supply (17, 31). included in the present meta-analysis. Other studies have
The present meta-analysis has shown that nutritional considered the use of a disease-specific nutritional support
support should be at least 8-week long and primarily directed in PU patients (13, 14, 24-27). Although they did not fulfill
to malnourished patients as these reasonably more likely to criteria for inclusion in quantitative synthesis they have all
be characterized by low values of several nutrients. Although shown a positive effect of supplementation with nutrients
van Anholt et al. have reported a significant difference in PU playing a role in wound healing (arginine + different
healing over time (faster improvement in the initial phases combination of other nutrients) on mixed healing outcomes
of the study with a reduction in the intensity of care) in non- (Pressure Ulcer Scale for Healing [PUSH]; complete healing;
malnourished patients, at 8 weeks the reduction in PU area time to complete healing; improved tissue viability). On
appeared to be comparable to that obtained in the placebo the other hand, the limited number of studies included in
group (16). Interestingly, this was the only trial – among those quantitative synthesis highlights the important methodological
included in quantitative synthesis – in which a significant limitations in this research area. Besides, we cannot exclude
difference in protein-calorie support between treatment arms that multiple separate micronutrient supplements provided in
was present. Besides, a less accurate method of assessment of combination with a high-calorie, high-protein formula have the
ulcer area was used and not description of how pressure (a key same effectiveness of a all-in-one oral nutritional supplement.
estrinsic factor for PU) was managed (e.g. mattresses/overlays, Third, complete healing is an important outcome in wound care.
repositioning protocol, etc...). It is also worth mentioning that However, most available studies did not consider a support
the study was stopped before reaching the estimated sample until complete healing and have included it as a secondary

5
J Nutr Health Aging

NUTRITIONAL SUPPORT AND PRESSURE ULCERS

outcome measure. Besides, it should be recognized that all Supplementary Appendix

available trials were underpowered. Finally, at least another Search terms used in literature review
large confirmatory trial is probably required to provide definite
conclusions and recommendations in this area. “nutrition[MeSH Terms]) OR enteral*[MeSH Terms]) OR
In conclusion, the use of disease-specific formulas enriched oral*[MeSH Terms]) OR supplement*[MeSH Terms]) OR
with arginine, zinc and antioxidants as oral supplements and feed[MeSH Terms]) OR sip[MeSH Terms]) OR liquid[MeSH
Terms]) OR formula*[MeSH Terms]) OR protein[MeSH Terms]) OR
tube feeds for at least 8 weeks are associated with improved
arginine[MeSH Terms]) OR zinc[MeSH Terms]) OR vitamin C[MeSH
PU healing compared with standard formulas. The use of this Terms]) OR ascorbic acid[MeSH Terms]) OR vitamin E[MeSH
formula should be preferred to that of high-calorie, high-protein Terms]) OR antioxida*[MeSH Terms]))”
ones whenever available. Future studies should consider an AND
evaluation of its use in patients with other types of wounds. “decubitus[MeSH Terms]) OR pressure ulcer[MeSH Terms]) OR
pressure sore[MeSH Terms]) OR bed sore[MeSH Terms])”
Conflict of Interest Disclosures: The Authors certify that there are no affiliations AND
with, or involvement in, any organization or entity that has a direct financial interest in
the subject matter, or material, discussed in the manuscript. Dr. Cereda reports having
«1997/01/01»[Date - Publication]: «2015/10/01»[Date - Publication]
received (not for the present study and before 2010) consultancy and speaker honoraria AND
and investigator grants from the “Fondazione Grigioni per il Morbo di Parkinson”, the «English»[Language]
Fondazione IRCCS Policlinico San Matteo and Nutricia Italia.
* truncated terms.
Author Contributions: Dr. Cereda had full access to all of the data in the study and
take responsibility for the integrity of the data and the accuracy of the data analysis. Study
concept and design: Cereda, Schols. Acquisition of data: Cereda, Neyens, Caccialanza,
Rondanelli, Schols. Statistical analysis and interpretation of data: Cereda, Schols. Drafting
of the manuscript: Cereda. Critical revision of the manuscript for important intellectual
content: Cereda, Neyens, Caccialanza, Rondanelli, Schols. Obtained funding: Cereda,
Schols. Administrative, technical, or material support: Cereda, Neyens, Schols. Study
supervision: Schols. Additional Contributions: The authors wish to thank Dr Jennifer S
Hartwig for assistance in editing the manuscript.

Ethical standard: The study did not required the approval of the Ethics Committee.

Supplementary Table 1
Characteristics of the randomized trials undergoing qualitative review and excluded from quantitative synthesis

Reference Duration Sample size Experimental intervention Comparison Reason of exclusion

[servings/day (n)]
Benati, 2001 2 weeks N=36 Normal hospital diet + Normal hospital diet or diet Data on wound healing were
wound-specific ONS* [2] + high-calorie/high-protein presented only graphically
ONS (only for 16 patients); short
duration; data not available
Desneves, 2005 3 weeks N=16 Standard hospital diet + Standard hospital diet or Short duration; a significant
wound-specific ONS § [2] diet + high-calorie/high- imbalance in baseline features
protein ONS was also present
Benati, 2012 12 weeks N=50 Home standard tube feeding + Home standard tube feeding Data not available
specific supplements # [2]
Leigh, 2012 3 weeks N= 23 Standard hospital diet + No comparison Lack of a control group
wound-specific ONS § [1 vs. 2] receiving standard high-calorie
ONS
Bauer, 2013 8 weeks (4 weeks of support N=24 Oral diet + wound-specific Oral diet + standard Patients with different types of
+ 4 weeks of best wound ONS § [2] high-calorie ONS chronic wounds were included
and nutrition care) and pooled in the analysis
Wong, 2014 2 weeks N= 23 Normal hospital diet + standard Normal hospital diet + stan- Short duration
high-calorie ONS + specific dard high-calorie ONS
supplements # [2]
Abbreviations: ONS, oral nutritional supplement; * , Cubitan®, Nutricia (high-calorie formula enriched with wound-specific nutrients [arginine, zinc and antioxidants]) ; § , Resource
Arginaid®, Nestlé Health Science (high-calorie formula enriched with wound-specific nutrients [arginine, zinc and vitamin C]) ; # , AboundTM, Abbott (calorie-free supplement contai-
ning wound-specific nutrients [arginine, glutamine and β-hydroxy β-methylbutyrate]) ; Reference list: 1. Benati G, Delvecchio S, Cilla D, Pedone V. Impact on pressure ulcer healing of
an arginine-enriched nutritional solution in patients with severe cognitive impairment. Arch Gerontol Geriatr Suppl. 2001;7:43-7. 2. Desneves KJ, Todorovic BE, Cassar A, Crowe TC.
Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial. Clin Nutr. 2005 Dec;24(6):979-87. 3. Benati G, Gasparoni R,
Coppola D. Supplementation with arginine, glutamine and β-hydroxy β-methylbutyrate (βHMB) can improve pressure ulcer healing, reduce pain and frequency of dressing changes,
improving costs. Clin Nutr Suppl. 2012; 7(1):269. 4. Leigh B, Desneves K, Rafferty J, Pearce L, King S, Woodward MC, Brown D, Martin R, Crowe TC. The effect of different doses of
an arginine-containing supplement on the healing of pressure ulcers. J Wound Care. 2012 Mar;21(3):150-6. 5. Bauer JD, Isenring E, Waterhouse M. The effectiveness of a specialised oral
nutrition supplement on outcomes in patients with chronic wounds: a pragmatic randomised study. J Hum Nutr Diet. 2013 Oct;26(5):452-8. 6. Wong A, Chew A, Wang CM, Ong L, Zhang
SH, Young S. The use of a specialised amino acid mixture for pressure ulcers: a placebo-controlled trial. J Wound Care. 2014 May;23(5):259-60, 262-4, 266-9.

6
J Nutr Health Aging

THE JOURNAL OF NUTRITION, HEALTH & AGING©

References 18. Cereda E, Klersy C, Andreola M, Pisati R, Schols JM, Caccialanza R, D’Andrea
F; OligoElement Sore Trial (OEST) Study Group. Cost-effectiveness of a disease-
specific oral nutritional support for pressure ulcer healing. Clin Nutr. 2015;
1. Bernabei R, Manes-Gravina E, Mammarella F. Epidemiology of pressure ulcers doi:10.1016/j.clnu.2015.11.012. [Epub ahead of print]
[Epidemiologia delle piaghe da decubito]. G Gerontol 2011;59:237-243 19. Schünemann H, Brözek J, Guyatt G, Oxman A, editors. GRADE handbook for
2. Smith DM. Pressure ulcers in the nursing home. Ann Intern Med 1995;123:433-442. grading quality of evidence and strength of recommendations. The GRADE Working
3. Dealey C, Posnett J, Walker A. The cost of pressure ulcers in the United Kingdom. J Group. Updated October 2013. Available at: www.guideline development.org/
Wound Care 2012;21:261-2, 264, 266. handbook; 2013.
4. Smith ME, Totten A, Hickam DH, Fu R, Wasson N, Rahman B, Motu’apuaka M, 20. Scottish Intercollegiate Guidelines Network. Sign 50: A guideline developers´
Saha S. Pressure ulcer treatment strategies: a systematic comparative effectiveness handbook. Edinburgh: Scottish Intercollegiate Guidelines Network. Available at:
review. Ann Intern Med 2013;159:39-50. http://www.sign.ac.uk/
5. Posthauer ME, Banks M, Dorner B, Schols JM. The role of nutrition for pressure 21. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting
ulcer management: national pressure ulcer advisory panel, European pressure ulcer items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern
advisory panel, and pan pacific pressure injury alliance white paper. Adv Skin Wound Med 2009;151:W65–W94.
Care. 2015 Apr;28(4):175-88 22. Benati G, Bertone MS, Cereda E, Ciprandi G, Masina M, Pedrolli C, Sidoli O,
6. Shahin ES, Meijers JM, Schols JM, Tannen A, Halfens RJ, Dassen T. The Vertsonis G. Nutritional Treatment in Patients with Pressure Ulcers. Acta Vulnol
relationship between malnutrition parameters and pressure ulcers in hospitals and 2011;9(3):27-127
nursing homes. Nutrition 2010;26:886-889. 23. Higgins JPT, Altman DG, on behalf of the Cochrane Statistical Methods Group and
7. Litchford MD, Dorner B, Posthauer ME. Malnutrition as a Precursor of Pressure the Cochrane Bias Methods Group. Chapter 8: Assessing risk of bias in included
Ulcers. Adv Wound Care (New Rochelle). 2014 Jan 1;3(1):54-63. studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
8. Cereda E, Klersy C, Rondanelli M, Caccialanza R. Energy balance in patients with Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; 2011 [updated
pressure ulcers: a systematic review and meta-analysis of observational studies. J Am March 2011].
Diet Assoc 2011;111:1868-1876. 25. Benati G, Gasparoni R, Coppola D. Supplementation with arginine, glutamine and
9. Qaseem A, Humphrey LL, Forciea MA, Starkey M, Denberg TD; Clinical Guidelines β-hydroxy β-methylbutyrate (βHMB) can improve pressure ulcer healing, reduce
Committee of the American College of Physicians. Treatment of pressure ulcers: a pain and frequency of dressing changes, improving costs. Clin Nutr Suppl. 2012;
clinical practice guideline from the American College of Physicians. Ann Intern Med. 7(1):269
2015 Mar 3;162(5):370-9. 26. Leigh B, Desneves K, Rafferty J, Pearce L, King S, Woodward MC, Brown D,
10. Cereda E. Treatment of Pressure Ulcers. Ann Intern Med. 2015 Oct 20;163(8):646-7. Martin R, Crowe TC. The effect of different doses of an arginine-containing
11. National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel supplement on the healing of pressure ulcers. J Wound Care. 2012 Mar;21(3):150-6.
and Pan Pacific Pressure Injury Alliance. Prevention and Treatment of Pressure 27. Bauer JD, Isenring E, Waterhouse M. The effectiveness of a specialised oral nutrition
Ulcers: Clinical Practice Guideline. Emily Haesler (Ed.). Cambridge Media: Perth, supplement on outcomes in patients with chronic wounds: a pragmatic randomised
Australia; 2014. study. J Hum Nutr Diet. 2013 Oct;26(5):452-8.
12. National Pressure Ulcer Advisory Panel (NPUAP), European Pressure Ulcer 28. Wong A, Chew A, Wang CM, Ong L, Zhang SH, Young S. The use of a specialised
Advisory Panel (EPUAP). Prevention and Treatment of Pressure Ulcers: Clinical amino acid mixture for pressure ulcers: a placebo-controlled trial. J Wound Care.
Practice Guideline. Washington, DC: National Pressure Ulcer Advisory Panel; 2009. 2014 May;23(5):259-60, 262-4, 266-9.
13. Benati G, Delvecchio S, Cilla D, Pedone V. Impact on pressure ulcer healing of an 29. Elia M, Ceriello A, Laube H, Sinclair AJ, Engfer M, Stratton RJ. Enteral nutritional
arginine-enriched nutritional solution in patients with severe cognitive impairment. support and use of diabetes-specific formulas for patients with diabetes: a systematic
Arch Gerontol Geriatr Suppl 2001;7:43–47. review and meta-analysis. Diabetes Care. 2005 Sep;28(9):2267-79.
14. Desneves KJ, Todorovic BE, Cassar A, Crowe TC. Treatment with supplementary 30. ESPEN Guidelines on Enteral Nutrition. Clin Nutr 2006;25:175-360.
arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled 31. McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig
trial. Clin Nutr 2005;24:979-987. C, McCarthy MS, Davanos E, Rice TW, Cresci GA, Gervasio JM, Sacks GS, Roberts
15. Cereda E, Gini A, Pedrolli C, Vanotti A. Disease-specific, versus standard, nutritional PR, Compher C; Society of Critical Care Medicine; American Society for Parenteral
support for the treatment of pressure ulcers in institutionalized older adults: A and Enteral Nutrition. Guidelines for the Provision and Assessment of Nutrition
randomized controlled trial. J Am Geriatr Soc 2009;57:1395-1402. Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine
16. van Anholt RD, Sobotka L, Meijer EP, Heyman H, Groen HW, Topinková E, (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.).
van Leen M, Schols JM. Specific nutritional support accelerates pressure ulcer JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211.
healing and reduces wound care intensity in nonmalnourished patients. Nutrition 32. Langer G, Fink A. Nutritional interventions for preventing and treating pressure
2010;26:867-872. ulcers. Cochrane Database Syst Rev. 2014 Jun 12;6:CD003216.
17. Cereda E, Klersy C, Serioli M, Crespi A, D’Andrea F; OligoElement Sore Trial 33. Stechmiller JK. Understanding the role of nutrition and wound healing. Nutr Clin
Study Group. A nutritional formula enriched with arginine, zinc, and antioxidantsnfor Pract 2010;25:61-68.
the healing of pressure ulcers: a randomized trial. Ann Intern Med. 2015 Feb 34. Doley J. Nutrition management of pressure ulcers. Nutr Clin Pract 2010;25:50-60.
3;162(3):167-74.

7
J Nutr Health Aging

NUTRITIONAL SUPPORT AND PRESSURE ULCERS

8
 Copyrights and Use Restrictions.

This document has been supplied under a The Copyright

Licensing Agency Ltd (“CLA”) Licence. It is protected by
copyright and it may not (even for internal purposes) be
further copied stored or on-copied electronically without
permission, save as may be permitted by law. The
recipient may print out a single paper copy of any
document received electronically.

Copyright notice for 640dfc50-dced-495c-ade3-7b9f5cf67021