The Potential Role of Zinc Supplementation on Pressure Injury Healing in Older Adults: A Review of the Literature

Introduction. Compromised nutritional status is common among older adults (aged ≥ 65 years) and is a risk factor for pressure injuries (PIs), which may lead to poor clinical outcomes. The aim of this review was to determine whether or not poor PI healing in older adults is a result of suboptimal zinc status. Methods. A literature search was performed in PubMed from 2001 to 2016 using the key words: “zinc status,” “pressure ulcer,” “pressure ulcers in older adults,” “wound healing,” and “zinc sulfate.” Inclusion criteria consisted of adequate sample size, nonacute setting, clinical trial or observational study, sound methodology, and generalizable findings for primary and secondary outcomes, which included food intake, oral nutritional supplement (ONS) consumption, risk for malnutrition, nutrient loss from wound exudate, and lab values. Results. Of 41 total studies, 10 satisfied the inclusion criteria and investigated PI in older adults versus nutritional intake. Both standard and specialty ONS interventions, which contain additional fortification, improve outcomes, though findings are inconsistent regarding formulations preferable for the treatment of older adults. Monitoring for nutritional deficiencies, including Zn, is essential for optimal patient outcomes. Discussion. Recently, Zn in combination with ONS containing additional kilocalories, protein, and other trace elements, has been investigated for PIs. Although both standard and specialty ONS interventions improve outcomes, findings are inconsistent regarding preferable formulations for the treatment of older adults. Monitoring for nutritional deficiencies, including Zn, is essential for optimal patient outcomes. Unreliability of biomarkers for frank Zn deficiency make diagnosis uncommon, and oral Zn sulfate administration has not shown significant effects on PI outcomes in the past. Conclusion. This population benefits from the clinical application of supplementation with preparations containing Zn, added calories, protein, and other trace elements. This improves outcomes, decreases healing time, and mitigates comorbidities.

The development of pressure injuries (PIs) is a significant problem in health care settings. Pressure injury prevalence varies from 8.52% to 32.2% in long-term care (LTC) and 2.9% to 19.1% in home-care patients, and stage 1 and 2 PIs make up the majority of skin lesions.^1,2 Approximately 2.5 million patients are treated annually for PIs in US health care facilities, and an estimated $11 billion is spent annually on PI treatment.^3,4 There are 88.3% US LTC residents aged ≥ 65 years, and 45.2% aged ≥ 85 years.⁵ This population is prone to compromised skin integrity.² Additionally, they are susceptible to nutrition-related risk factors including a decreased appetite and altered thirst; dysphagia, self-feeding deficits, or other eating problems; and unintentional weight loss.⁶ These risk factors contribute to malnutrition and nutritional deficiencies, which include zinc (Zn) deficits. A cross-sectional study⁷ found that Zn deficiency in older adults was associated with risk for malnutrition. Consequently, nutritional deficiencies and malnutrition associated with aging further increase the chances of developing a skin injury or delayed wound healing.^6,8 

Pressure injuries are defined as “localized damage to the skin and/or underlying soft tissue usually over a bony prominence or related to a medical or other device.”² There are 3 stages of wound development and healing. The first, the inflammatory phase, increases fluid and cell influx to the wound location to provide needed oxygen and nutrients to enhance regenerative processes, and, consequently, results in decreased immunity and increased susceptibility to infections.^8,9 The second, the proliferative phase, also is considered the building phase⁸; this phase consists of the synthesis of collagen, reticulin, and elastin from fibroblasts for new tissue growth.⁸ The final stage is the remodeling phase, where cellular activity and the number of blood vessels in the area return to normalcy.^8,10 In order to support the immune response during the first 2 phases, nutritional needs increase from 25 kcal/kg to 30 kcal/kg energy and 0.8 g/kg to 1.0 g/kg protein daily to 25 kcal/kg to 35 kcal/kg and 1.2 g/kg to 1.5 g/kg for PIs.⁸ 

Repositioning programs for pressure relief, selection of mattresses, and wound care are important considerations in PI treatment.¹¹ Currently, there are more than 3000 non-nutritional products on the market for adjuvant therapeutic use.¹¹ Nutritional interventions can include oral vitamins/minerals, therapeutic diets, and oral nutritional supplementation (ONS). Considering the connections between nutritional deficiencies, risk of malnutrition, and PI development, close nutrition monitoring along with appropriate interventions should be considered to improve wound healing outcomes.

Zinc plays a vital role in protein metabolism, regulation of gene expression, immunity, and the inflammatory response, all of which play an important role in wound healing. A deficit of Zn may delay processes in all phases of wound healing.¹² The purpose of this review is to determine whether there is a body of evidence to support the hypothesis of poor PI healing (as measured by both surrogate measures and biomarkers) in older adults is a result of suboptimal Zn status.

Zinc plays a significant role in several biochemical and physiological functions.¹³ These functions include but are not limited to: control of gene transcription and translational regulation vital for deoxyribonucleic acid repair, transcriptional regulation, and protein metabolism, as well as catalytic enzyme activity for many biological processes in intermediary metabolism and insulin signaling.^14–16 Zinc also plays a role in immunocompetence. Without adequate Zn availability, T-helper and B-helper cells fail to reach maturation, subsequently leading to lymphopenia along with impaired natural killer cell and phagocytic cell function.¹⁴ Suboptimal Zn levels impair secretion of cytokines, regulation of interferon gamma, tumor necrosis factor, and production of interleukin-2¹⁴; these are vital for immune response.¹⁴ Most relevant to this literature review is the need for Zn for normal functioning of anabolic processes for growth, tissue maintenance, and wound healing.¹⁷ 

The recommended dietary allowance (RDA) for Zn in adults (≥ 19 years) is 8 mg/d to 11 mg/d, and the American Society for Parenteral and Enteral Nutrition has suggested that nutritional needs are further increased for critically ill patients.^17,18 Dietary sources of Zn can be found in meat products, such as oysters, organ meats, fish, and beef.¹⁵ In contrast, some plant-based foods may be good sources of Zn, but are less bioavailable due to the presence of phytate, iron, and fiber, which inhibit Zn absorption.¹⁷ The third National Health and Nutrition Examination Survey found 57.5% of the advanced age population (≥ 71 years) consumed inadequate levels of Zn in their diet, and advanced age contributes to decreased dietary Zn intake below recommended guidelines (≤ 77% RDA).⁵ Additionally, Zn is primarily transported from the small intestine, and intestinal absorption decreases with aging.¹³ Consequently, it is difficult to assess the adequacy of dietary Zn levels in older adults due to reduced intakes and absorption. Surrogate measures (eg, dietary assessment of a patient’s overall nutritional status) should be evaluated when considering a possible Zn deficiency. These assessments include inadequate intake, reduced absorption, increased losses, or increased nutrient needs.¹⁷

With respect to intracellular concentrations, Zn homeostasis is maintained via multiple feedback controls to preserve tight regulation and adequate levels. There is no site for storage; Zn is recycled through an internal reservoir or “pool.”^17,19 A further obstacle in evaluating Zn status is lack of a reliable biomarker.¹³ Although plasma Zn concentrations are the most widely used biomarker to assess Zn status, it is an insensitive marker for deficiency.²⁰ Many factors can result in false positive hypozincemia, such as hypoalbuminemia, that have an impact on the validity of these test results.^17,20 The normal range for plasma Zn level range is 12 µmol/L to 18 µmol/L (78 µg/dL–118 µg/dL).¹² It can also be measured by urinary Zn, but has little validity due to several factors affecting its loss in urine aside from Zn status.²⁰ The pancreas, prostate, and mammary glands have unique Zn requirements for metabolic processes, but measuring Zn from tissue biopsies is not used in practice.²¹ Several other biochemical markers have been considered but have not been found to be useful indicators of Zn status.¹⁷ A potential biomarker that may be useful in future research is the copper to zinc ratio (CZr), which has been a suggested biomarker for physical and functional decline associated with aging. Though the role of this marker is to predict mortality rather than evaluate Zn status, it may be useful in determining associations with immobility and risk of development in PIs in the aged population.²² Future research is needed to validate the use of this measure. As a result, it is difficult to assess Zn status from biochemical markers. Despite being unable to measure the efficiency of Zn absorption and imprecise measures of Zn status using plasma Zn, the International Zinc Nutrition Consultative Group currently recommends monitoring Zn status by assessing plasma Zn concentration and dietary intakes, though alternative indicators are under investigation.²³  

Due to risk of poor dietary intakes and decreased efficiency in Zn absorption with aging, monitoring Zn status for older patients with PIs should be part of clinical practice for optimal wound healing outcomes. In the event of deficit, nutritional interventions should be instituted. These nutritional interventions include standard ONS, specialty ONS formulas, Zn sulfate, and potentially L-carnosine (CAR) and its Zn complex, polaprezinc (PLZ).

Search strategies included the use of the following Medical Subject Heading (MeSH) terms in PubMed: “zinc status,” “pressure ulcer,” “pressure ulcers in older adults,” “wound healing,” and “zinc sulfate.” PubMed was chosen for its comprehensive database of peer-reviewed journals in all aspects of medical and allied health, often encompassing the contents of several other databases used for queries of medical, nursing, and dietetics research. A total of 41 full-text journal articles, books, and credible web-based content were evaluated. The inclusion criteria comprised adequate sample size, sound methodology, generalizability of findings, and adherence to MeSH categorization. Articles between 2006 and 2016 were selected. One article from 2001 was selected that investigated adverse effects of supplementation, and another article from 1968 was reviewed in order to incorporate contrasting information on oral Zn supplementation effects alone. Inclusion criteria consisted of LTC and home-care populations, as well as articles investigating chronic wounds, including PIs and healing progression. A large number of papers reporting on intensive care units and home-health settings were excluded. Exclusion was due to the short duration of the study or insufficient follow-up, with no ability to consider the course of wound healing. For comparative purposes, 1 study from intensive care, home health, and dietary Zn alone were evaluated.^24,25 Lack of research measuring nutrient loss from PI wound exudate in the elderly was found, but 1 study was included that investigated select vitamin and trace element loss from wound exudates in adults.²⁶ The use of topical Zn as an intervention was also excluded, as this is not ingested and therefore not considered a nutritional intervention. Search results were narrowed by English language, timeframe, and peer review.

A total of 10 studies were analyzed and evaluated. These findings include 4 observational studies^25-28 and 6 clinical trials^29-34 (eTables 1, 2, respectively). Outcome assessments were analyzed including nutritional status, Zn biomarkers, micronutrient measurement in wound exudate, and PI healing. These findings included Braden Pressure Ulcer Risk Assessment Score (BPURAS), Pressure Ulcer Scale for Healing tool (PUSH), and other skin assessments, subjective global assessment, Patient-Generated-Subjective Global Assessment, and micronutrient biomarkers in plasma and wound exudate. 

Three observational studies^25,26,28 found relationships between inadequate oral intakes, including Zn, with PIs, suggesting there is a connection between malnutrition and both PI development and healing. The fourth study²⁷ determined micronutrients are also lost from wound exudate. Of the clinical trials, three^29,30,32 concluded wound-specific ONS formulas in combination with standard PI care are superior to standard ONS formulas for wound healing outcomes. However, Bauer et al³² did not find one formula to be preferable over the other. 

No studies were found using Zn tissue measurements or the CZr ratio per exclusion criteria. Also, studies that use oral Zn sulfate as the intervention have not been conducted within the last 10 years. All intervention trials of ONS followed wound care protocols in all groups. Oral nutritional supplementation intervention studies^29-34 that met criteria contained several nutrients in addition to Zn that were also known to be beneficial for wound healing. These studies demonstrate dietary inadequacies are likely in older adults with PIs, and nutritional interventions are beneficial in improving wound healing. 

The elderly adult population is at risk for compromised skin integrity, inadequate dietary intakes, reduced Zn absorption, and malnutrition. As a result, PI development is a common yet detrimental complication that can lead to poor clinical outcomes. Although Zn deficiency is difficult to diagnose due to lack of sensitive Zn biomarkers, studies^25,26,28 indicate Zn status is likely to be compromised in older adults with PIs. Recognizing these conditions in this target population is vital in initiating nutritional interventions as Zn plays an important role in wound healing for collagen synthesis and improved immune response. The use of both standard and specialty ONS as nutritional interventions should be considered for PI wound healing.

Identifying nutrient inadequacies. Both macronutrient and micronutrient oral intakes were found to be suboptimal in the majority of older patients with PIs. Two observational studies^25,28 that measured oral intakes demonstrated food intake alone is inadequate in meeting sufficient nutrient intakes for both caloric targets and Zn intake in older adults with PIs. Raffoul et al²⁵ found target energy consumption was variable through food intake 76% ± 21%, and the addition of ONS provided 35% ± 12% of energy requirements.²⁵ Prior to the onset of offering ONS, plasma Zn levels measured a median of 9.4 µmol/L, below the normal range, and improved slightly (P = .07) by day 10 after ONS consumption.²⁵ These findings suggest ONS acceptance reduces these energy and mineral intake deficits. Similarly, Wojcik et al²⁶ found that only 59% of subjects met their energy requirements, and 41% met estimated protein needs for wound healing without supplementation.²⁶ Additionally, intakes of Zn were least likely to meet Estimated Average Requirement compared to other mineral biomarkers measured; 45.5% of subjects had inadequate Zn intake with food alone.²⁶ Alternatively, only 22.2% of subjects accepting the ONS consumed inadequate Zn levels, indicating a measurable improvement.²⁶ These improvements in nutrient consumption, including higher protein intakes, were associated with higher BPURAS scores.²⁶ These findings suggest older adults with PIs are at risk for a number of nutrient deficiencies including Zn, which may impair the wound healing process. 

An observational study²⁷ investigated vitamin and trace element losses from wound exudates and found 0.5 mg Zn loss from open abdominal wounds and 0.3 mg Zn loss from soft-tissue wounds over 24 hours.This loss accounts for 5% and 3% of the RDA for Zn, respectively.²⁷ While this study did not focus on the older adult population with PIs, it is important to consider because nutrient loss may also occur from wound exudate in PIs. These studies support the aforementioned premise that older adults with PIs are prone to inadequate dietary intakes, as well as nutrient losses from wound exudate, which increases risk for malnutrition, a condition that is associated with increased severity in PIs.^25-27 Though identifying Zn deficiency may be difficult, interventions for PI healing should consider this possible insufficiency in addition to the other known factors. 

Effects of Zn in ONS for treatment of wounds. Nutritional interventions for PIs are beneficial in order to decrease wound-healing time.^29-34 Heyman et al²⁹ studied how ONS containing fortification of several nutrients providing additional protein, arginine, vitamins C and E, and Zn, in addition to standard wound care in the aged is supported in use for the reduction in PI area and optimal for wound healing. The use of specialized ONS designed to improve wound healing versus standardized ONS remains controversial. Cereda et al³⁰ concluded that specialized ONS formula enriched with arginine, Zn, and antioxidants was superior to standard ONS and resulted in a greater reduction in PI area with a mean reduction of 60.9% compared to 45.2%, respectively. Another clinical trial³¹ found that ONS enriched with high protein, arginine, Zn, and vitamin C and standard nutrition formula both improve PI healing, but the enriched ONS had higher rates of PI healing as measured by PUSH score and ulcer area (P < .05). It is a preferable formula for wound healing.³¹ Serum Zn levels were also monitored.³¹ There was a 107.5 µg/dL ± 106.6 µg/dL Zn increase from baseline to week 12 in the treatment group, whereas serum Zn dropped 32.5 µg/dL ± 87.1 µg/dL in the control, suggesting nutritional inadequacies are more efficiently replete with the treatment formula.³¹ 

In contrast, a study investigating a wound-specific ONS enriched with immune-enhancing nutrients including arginine, Zn, and vitamin C, versus standard high protein ONS found the standard ONS formula was more beneficial in improving PUSH scores and healing (P = .044).³² At the same time, nutrition status and quality of life remained similar between both groups.³³ These variable findings in the literature should prompt health care clinicians to implement an appropriate plan of care based on individual needs to most effectively treat each patient.  

Use of Zn as PLZ. Another avenue for possible nutritional interventions in wound healing is CAR, a dipeptide composed of β-alanine and L-histidine, and PLZ.³³ Because CAR has many biological functions linked to anti-aging activity, it is presumed to have an effect on age-related diseases including wound healing.³⁵ The first controlled clinical study³³ to investigate ONS for PI treatments in their respective groups, CAR and PLZ, along with a control group receiving no supplementation, resulted in significant improvements in PUSH scores in both treated groups (P = .02 vs. control; P = .009 vs. control, respectively). The PLZ treatment group experienced increases in serum Zn levels (P < .001), though serum copper had decreased (P < .001).³³ These findings suggest both CAR and PLZ may be potential treatments for PIs. Future research should involve larger sample sizes with randomized trial methods and special consideration to appropriate length of PLZ treatment in order to ensure safe dosing regimens. 

Use of Zn alone for wound healing. Due to its notable role in immunity and wound healing, clinical trials testing the effects of Zn sulfate as an oral supplement date back to the 1960s.³⁶ However, the study by Houston et al³⁴ where they used oral Zn as the sole intervention shows it is much less frequent, likely as a result of disappointing findings. Moreover, older patients receiving high doses of Zn sulfate (440 mg) experienced adverse effects attributed to the supplementation including infection, which required more treatment for antibiotic therapy and nausea/vomiting.³⁴ Recent studies have shown more promising results with wound healing by incorporating a variety of nutrients through ONS.

Cost-effectiveness in treatment. Another consideration to clinical care is cost-effective treatments. A clinical trial³⁷ completed a cost analysis on the difference in medical costs of PI care and cost effectiveness of a disease-specific nutritional formula enriched with arginine Zn and antioxidants versus a standard formula. Both groups had improved wound healing, though the experimental group had greater improvements in the reduction in PI area (P = .012). The specialty formula cost significantly more (P < .001), but the patients receiving this formula had reduced costs in non-nutritional wound care management of PIs (P = .001). This care included dressing materials, pressure-relieving mattresses, nursing expenses, and antibiotics.³⁷ As a result, the use of a specialized formula should not be discounted based on initial higher cost. 

This descriptive review had the following limitations: Zn as the primary nutrient under consideration, smaller sample sizes, and studies short in duration. Further research is needed to investigate variations in trace elements supplementation including the combination of minerals versus the addition of single minerals as supplements. Dosing regimens should also be considered when gauging efficacy. To further strengthen conclusions regarding trace element mixture administration, careful consideration of methodology and study design should be undertaken. This review has raised the question of whether or not the RDA for older adults should be re-evaluated in order to adjust for impaired absorption in Zn. Optimal Zn nutriture would improve the quality of life in older adults with wounds.

Monitoring patient risk and implementing appropriate nutritional interventions based on individual needs is vital for maintaining nutritional status, thereby optimizing patient outcomes. In conclusion, for older adults, the clinical application of supplementation of Zn along with calories, protein, and other nutrients in PIs improves outcomes, shortens healing time, and decreases comorbidities.

From Central Michigan University, Mt. Pleasant, MI

Address correspondence to:
Melissa Heintschel, MS, RD, LD
Central Michigan University
Department of HEV
1200 S Franklin Street
Mount Pleasant, MI 48859
Heint2mm@cmich.edu

Disclosure: The author discloses no financial or other conflicts of interest.