Clinical question
Should supplementation with protein, arginine, zinc and micronutrients versus no supplementation/standard supplements be used to promote healing in adults with PIs?
Context
Population:
Intervention:
Comparison:
Main Outcomes:
Setting:
Conflicts on Interest:
Adults who have a pressure injury
Protein, arginine and micronutrient supplement
Standard diet or standard supplement or placebo
Any clinical setting
Hierarchy of outcome measures:
Outcome 1: Time to healing
Outcome 2: Complete healing (total/percent healed)
Outcome 3: Change in wound size (% change)
Outcome 4: Pain
Outcome 5: If infected at baseline, changes in signs and symptoms of infection
No Guideline Governance Group members of Core Review Group members had a conflict of interest
Evidence to Decision Framework
(Click on the individual judgements for more information)
Summary of Judgements
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Yes
Moderate
Small
Very low
No important uncertainty or variability
Probably favors the intervention
Moderate costs
Very low
No included studies
Probably increased
Varies
Varies
1. Problem:
Is the problem (pressure injuries) a priority?
JUDGEMENT
No
Probably No
Probably Yes
Yes
Varies
Don’t Know
RESEARCH EVIDENCE
Treating pressure injuries to achieve healing is a priority to most individuals who experience a PI. In 2021, the Guideline Governance Group undertook a stakeholder survey on priority issues to address in the guideline. Receiving clinical guidance on nutritional interventions for treating pressure injuries (PIs) was rated as the highest priority by clinicians (median ranking 5/5) and people with or at risk of PIs and their informal carers (median ranking 5/5). Clinical guidance on nutritional interventions for treating PIs was rated as a high priority by researchers (median ranking 4/5) and industry representatives (median ranking 4/5).
In an earlier survey conducted by the previous Guideline Governance Group in 2018,(Haesler, Pittman et al. 2022) 71.8% (275/383) of individuals with or at risk of PIs and 65.3% (555/850) of informal carers rated receiving information on diet and hydration as important or very important.
2. Desirable Effects:
How substantial are the desirable anticipated effects?
JUDGEMENT
Trivial
Small
Moderate
Large
Varies
Don’t Know
RESEARCH EVIDENCE
| Outcome | Energy, protein and, micronutrient supplement |
No supplement |
Difference | Relative effect |
|---|---|---|---|---|
| Number completely healed | 7/30 (23.3%) | 5/31 (16.1%) | 40 more per 1000 (from 382 fewer to 347 more) |
RR 1.25 (0.49-3.15) |
| Change in PI surface area (cm2) | -- | -- | Mean difference 2cm2 lower (range 4.54 lower to 0.53 higher) |
-- |
Outcome 1: Complete PI healing
A meta-analysis (Langer, Wan et al. 2024) of two RCTs (Cereda, Gini et al. 2009, van Anholt, Sobotka et al. 2010) provided evidence on the effectiveness supplementation with protein, arginine, zinc and micronutrients for complete PI healing versus a standard hospital diet or placebo supplements.** The supplements were taken for 8 to 12 weeks. In one study the majority of participants were being tube fed,(Cereda, Gini et al. 2009) but in the second study, being malnourished was an exclusion criteria (van Anholt, Sobotka et al. 2010). The analysis showed that energy, protein and micronutrient supplementation might be associated with more PIs achieving complete healing (relative risk [RR] 1.25, 95% CI 0.49 to 3.15), which translates to 40 more per 1000 PIs (from 82 fewer to 347 more) achieving complete healing. However, there is very low certainty in this result. The certainty was downgraded once for risk of bias because the highest weighted study had some concerns with respect to risk of bias and was also downgraded twice for imprecision due to the confidence interval including the value indicating null effect, as well as a small number of events and low number of participants (Langer, Wan et al. 2024).
Outcome 2: Change in PI surface area (cm2)
The meta-analysis (Langer, Wan et al. 2024) of two RCTs (Cereda, Gini et al. 2009, van Anholt, Sobotka et al. 2010) provided evidence on the effectiveness supplementation with protein, arginine, zinc and micronutrients for change in PI surface are versus a standard hospital diet or placebo supplements. The studies were the same as those reported above for Outcome 1. The analysis showed that energy, protein and micronutrient supplementation might be associated with more a mean difference of 2cm2 lower (4.54cm2 lower to 0.53cm2 higher) in surface area, noting that the mean PI area ranged from 3.34 to 12.28 cm2. There is very low certainty in this result due to downgrading once for risk of bias because the highest weighted study had some concerns with respect to risk of bias and was also downgrading twice for imprecision due to the wide confidence interval and small number of events and participants (Langer, Wan et al. 2024).
** Regimens are described in the data extraction tables. Product names may have changed.
3. Undesirable Effects:
How substantial are the undesirable anticipated effects?
JUDGEMENT
Trivial
Small
Moderate
Large
Varies
Don’t Know
| Outcome | Protein, arginine, zinc and micronutrient supplement |
No supplement placebo |
Difference | Relative effect |
|---|---|---|---|---|
| Adverse GI tract events | 16/22 (72.7%) | 13/21 (61.9%) | 105 more per 1000 (from 142 fewer to 489 more) |
RR 1.17 (0.77 to 1.79) |
Outcome: Adverse GI events
Adverse gastrointestinal events
The forest plot(Langer, Wan et al. 2024)included one RCT (van Anholt, Sobotka et al. 2010) reporting adverse gastrointestinal (GIT) effects associated with protein, arginine, zinc and micronutrient supplementation. Compared to not taking a supplement, there was a non-significant higher rate of GIT events associated with the intervention (72.7% vs 61.9%, RR 1.17, 95% CI 0.77 to 1.79, p=0.45). This translated to 100 more individual per 1,000 experiencing an adverse GIT event (from 68 fewer to 555 more). However, there is very low certainty in this result. The certainty was downgraded once for risk of bias of the included study, and twice for imprecision due to the confidence interval including the value indicating null effect, as well as a small number of events and low number of participants (Langer, Wan et al. 2024).
4. Overall certainty of evidence: What is the overall certainty of the evidence of effects?
JUDGEMENT
Very low
Low
Moderate
High
No included studies
RESEARCH EVIDENCE
| Outcome | Relative Importance | Certainty of Evidence |
|---|---|---|
| Complete healing | CRITICAL | VERY LOW |
| Change in PI surface area (cm2) | CRITICAL | VERY LOW |
Outcome 1: PI occurrence
There is no core outcome set specific to pressure injury healing. To determine the relative importance of outcome measures, the GGG reviewed literature (Gottrup, Apelqvist et al. 2010, Augustin, Schmitt et al. 2014, Driver, Gould et al. 2017, Driver, Gould et al. 2019, Miranda, Deonizio et al. 2021, Raepsaet, Alves et al. 2023, Gupta, Goldstone et al. 2024, Zhang, Zhang et al. 2024), on PI and wound healing outcome measures and, in 2021, undertook a survey of stakeholders regarding their perspective on the importance of commonly reported wound healing outcomes. Based on the review and survey, the GGG prioritized consideration of the following five outcome measures of interest when evaluating evidence for interventions to support PI healing. These clinical outcomes were supported by all surveyed stakeholder groups as critically important to making decisions about the evidence, and are wound agnostic (Gupta, Goldstone et al. 2024), frequently reported in PI research (Miranda, Deonizio et al. 2021), and relevant to both clinical practice and quality of life for individuals with a PI (Driver, Gould et al. 2017, Driver, Gould et al. 2019).
Priority for outcome measures was:
Time taken to heal
Complete healing
Percent change in wound size
Wound-related pain
Change sin signs and symptoms of infection (if infected at baseline)
Certainty of evidence for complete PI healing was very low. The certainty was downgraded once due to highest weighted study being at some concern regarding overall risk of bias, and downgraded twice for imprecision due to 95% CI overlaps the null effect, as well as a small number of events and low number of participants. (Langer, Wan et al. 2024)
Certainty of evidence for change in PI surface area (cm2)very low. The certainty was downgraded once due to highest weighted study being at some concern regarding overall risk of bias, and downgraded twice for imprecision due to wide confidence interval and small number of participants. (Langer, Wan et al. 2024)
5. Values:
Is there important uncertainty about or variability in how much people value the main outcomes?
JUDGEMENT
Important uncertainty or variability
Possibly important uncertainty or variability
Probably no important uncertainty or variability
No important uncertainty or variability
RESEARCH EVIDENCE
In a Delphi survey (Lechner, Coleman et al. 2022) that developed a core outcomes et for PI prevention trials, the outcome of PI occurrence was rated as being of critical important (score of 7-9) by all types of stakeholders (health professionals, people with or at risk of a PI and their informal carers, industry representatives and researchers). Greater than 90% of the 158 participants rated this outcome measure as critically important (Lechner, Coleman et al. 2022).
6. Balance of Effects:
Does the balance between desirable and undesirable effects favour the intervention or the comparison?
JUDGEMENT
Favors the comparison
Probably favors the comparison
Does not favor either the intervention or the comparison
Probably favors the intervention
Favors the intervention
Varies
Don’t know
RESEARCH EVIDENCE
The desirable effects were moderate and the undesirable effects were small.
7. Resources Required:
How large are resource requirements (costs) of the intervention?
JUDGEMENT
Large costs
Moderate costs
Negligible costs and savings
Moderate savings
Large savings
Varies
Don’t know
RESEARCH EVIDENCE
In the Panel Group’s expert opinion, nutritional supplementation can be expensive, particularly for homeless people, people living in the community, people in long term institutional settings, and those without access to health insurance. This is a particular concern for people who require supplementation for longer duration. In acute care settings, particularly intensive care, nutritional supplements are usually funded within the costs of health care.
In the Guideline Governance Group’s expert opinion, the above costs represent moderate costs of implementing the nutritional supplementation
8. Certainty of evidence of required resources:
What is the certainty of evidence of resource requirements (costs) of the intervention?
JUDGEMENT
Very low
Low
Moderate
High
No included studies
RESEARCH EVIDENCE
There is no research evidence.
9. Cost Effectiveness: Does the cost-effectiveness of the intervention favour the intervention or the comparison?
JUDGEMENT
Favors the comparison
Probably favors the comparison
Does not favor either the intervention or the comparison
Probably favors the intervention
Varies
No included studies
RESEARCH EVIDENCE
No studies
10. Inequity:
What would be the impact of recommending the intervention on health inequity?
JUDGEMENT
Reduced
Probably reduced
Probably no impact
Probably increased
Increased
Varies
Don’t know
RESEARCH EVIDENCE
In the Panel Group’s expert opinion, people who are at higher risk of nutritional deficits are also more likely to be unable to access nutritional supplementation due to their social circumstances and the cost of interventions. This includes barriers to accessing a dietitian to evaluate the person’s nutritional needs. In the Guideline Governance Group’s expert opinion, recommending nutritional supplementation would likely increase health inequity. There are barriers to accessing supplementation for many people depending on their geographic location and the clinical context.
11. Acceptability:
Is the intervention acceptable to key stakeholders?
JUDGEMENT
No
Probably no
Probably yes
yes
Varies
Don’t know
RESEARCH EVIDENCE
In the Panel Group’s expert opinion, a wide range of factors influence acceptability of nutritional supplements. These include palatability of thickened supplements and altered foods (e.g. pureed or thickened) and the person’s ability to consume the volume of fluid required for some supplements.
In the Guideline Governance Group’s expert opinion, recommending nutritional supplementation would having varying acceptability from stakeholders.
12. Feasibility:
Is the intervention (limiting sitting time) feasible to implement?
JUDGEMENT
No
Probably no
Probably yes
yes
Varies
Don’t know
RESEARCH EVIDENCE
In the Panel Group’s expert opinion, barriers to implementation include access to a dietitian to ensure the intervention can be individualized to the person’s needs. Nutritional supplementation is not available in many clinical and geographic contexts, and in some contexts there are rigid referral mechanisms to access dietitians and nutritional interventions.
In the Panel Group’s expert opinion, people living in the community may be unable to implement the recommendation due to lack of relevant knowledge to select an appropriate supplement.
In the Guideline Governance Group’s expert opinion, the feasibility of implementing a recommendation to provide nutritional supplementation varies. In some contexts (e.g. most acute care settings) access to nutritional supplementation and the processes that support implementation (e.g. screening for nutritional deficits, dietician review, access to products) is highly feasible. In other contexts (e.g., community settings, low resource communities) implementing a recommendation to provide nutritional supplementation would not be feasible.
References
Augustin, M., J. Schmitt, K. Herberger, L. Goepel, K. Heyer, J. Dissemond, A. Mayer, R. Aschoff, F. Beikert, M. Bischoff, C. Blome, J. Bunse, H. Diener, T. Eberlein, S. Eming, H. Fansa, F. Flesch, F. Gaiser, S. Gartner, S. Gass, V. Gerber, S. Glau, T. Goerge, V. Großkopf, C. Hampel-Kalthoff, B. Hartmann, J. Helfrich, T. Hirsch, D. Hochlenert, T. Horn, U. Imkamp, C. Janetzko, J. O. Jost, M. Jünger, R. Kaufmann, F. Kamperhoff, B. Lange-Asschenfeldt, S. Langer, M. May, K. C. Münter, R. Nagel, A. Nast, T. R. Neubert, A. D. Niederbichler, R. U. Peter, T. Petzold, K. Protz, A. Risse, E. Schäfer, K. Scharffetter-Kochanek, M. Schindzielorz, M. Schmidt, H. Schuster, A. Sindrilaru, M. Storck, W. Tigges, C. Tonn, E. Valesky, C. van Montfrans, W. Vanscheidt, A. von Lienen, K. Waldvogel-Röcker, T. Wild, C. C. Zouboulis and E. S. Debus (2014). "The German national consensus on wound documentation and outcomes: Rationale, working programme and current status." Wound Medicine 7: 8-13.
Cereda, E., A. Gini, C. Pedrolli and A. Vanotti (2009). "Disease-specific, versus standard, nutritional support for the treatment of pressure ulcers in institutionalized older adults: A randomized controlled trial." J Am Geriatr Soc 57(8): 1395-1402.
Driver, V. R., L. J. Gould, P. Dotson, L. L. Allen, M. J. Carter and L. L. Bolton (2019). "Evidence supporting wound care end points relevant to clinical practice and patients' lives. Part 2. Literature survey." Wound Repair Regen 27(1): 80-89.
Driver, V. R., L. J. Gould, P. Dotson, G. W. Gibbons, W. W. Li, W. J. Ennis, R. S. Kirsner, W. H. Eaglstein, L. L. Bolton and M. J. Carter (2017). "Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community." Wound Repair Regen 25(3): 454-465.
Gottrup, F., J. Apelqvist and P. Price (2010). "Outcomes in controlled and comparative studies on non-healing wounds: recommendations to improve the quality of evidence in wound management." J Wound Care 19(6): 237-268.
Gupta, R., L. Goldstone, S. Eisen, D. Ramachandram, A. Cassata, R. D. J. Fraser, J. L. Ramirez-GarciaLuna, R. Bartlett and J. Allport (2024). "Towards an AI-based objective prognostic model for quantifying wound healing." IEEE J Biomed Health Inform 28(2): 666-677.
Haesler, E., J. Pittman, J. Cuddigan, S. Law, Y. Y. Chang, K. Balzer, D. Berlowitz, K. Carville, J. Kottner, M. Litchford, Z. Moore, P. Mitchell and D. Sigaudo-Roussel (2022). "An exploration of the perspectives of individuals and their caregivers on pressure ulcer/injury prevention and management to inform the development of a clinical guideline." J Tissue Viability 31(1): 1-10.
Langer, G., C. S. Wan, A. Fink, L. Schwingshackl and D. Schoberer (2024). "Nutritional interventions for preventing and treating pressure ulcers." Cochrane Database Syst Rev 2: CD003216.
Lechner, A., S. Coleman, K. Balzer, J. J. Kirkham, D. Muir, J. Nixon and J. Kottner (2022). "Core outcomes for pressure ulcer prevention trials: results of an international consensus study." Br J Dermatol 187(5): 743-752.
Miranda, J. S., A. P. Deonizio, J. F. Abbade, H. A. Miot, L. Mbuagbaw, L. Thabane and L. P. F. Abbade (2021). "Quality of reporting of outcomes in trials of therapeutic interventions for pressure injuries in adults: a systematic methodological survey." Int Wound J 18(2): 147-157.
Raepsaet, C., P. Alves, B. Cullen, A. Gefen, J. L. Lázaro-Martínez, H. Lev-Tov, B. Najafi, N. Santamaria, A. Sharpe, T. Swanson, K. Woo and D. Beeckman (2023). "The development of a core outcome set for clinical effectiveness studies of bordered foam dressings in the treatment of complex wounds." J Tissue Viability 32(3): 430-436.
van Anholt, R., L. Sobotka, E. Meijer, H. Heyman, H. Groen, E. Topinková, M. van Leen and J. Schols (2010). "Specific nutritional support accelerates pressure ulcer healing and reduces wound care intensity in non-malnourished patients." Nutrition 26(9): 867-872.
Zhang, J., M. Zhang, C. Xu, J. Tian, D. Yang and B. Wang (2024). "Heterogeneous outcome selection and incomplete prespecification of outcomes in systematic reviews: A case study on pressure injury." Advin Skin Wound Care 37(9): 490-498.
