One amino acid above others can help with wound healing …

Arginine Heals Bedsores
…Whatever your age

By Will Block

U nless you have a loved one who is (or has been) laid-up in the hospital recently or who is in a nursing home, you’re not likely to have thought about pressure ulcers. But you’re certain to think about them if you find yourself in convalescence, from an accident, an operation, or worse yet, a disease. Pressure ulcers—also known as decubitus or bedsores (BS)—are injuries to skin and underlying tissue resulting from prolonged pressure on the skin. BS present a major clinical challenge, are physically debilitating, and place the patient at risk of serious comorbidities such as septic shock (see “Arginine Helps Fight Septic Shock” in the April 2015 issue).

Pressure Ulcers Are a Part of the Geriatric Syndrome

Each year, more than 2.5 million people in the United States develop BS.1 To put that into context, BS are often mentioned as one of the geriatric syndromes, together with urinary incontinence, functional decline, falls, and low self-esteem.


Bedsores present a major clinical
challenge, are physically debilitating
and place the patient at risk of serious
comorbidities such as septic shock.

Yet many bedsores still do not heal
and often become a chronic wound
that may even lead to death.


The effect of BS on patient quality of life has been recognized as a serious problem for many years, and the need for robust and effective management of BS is a significant national health-care issue. Numerous interventions have been tried for the treatment of BS, including special dressings and pressure-relieving devices, yet many BS do not heal and often become chronic wounds that may even lead to death.

Arginine Formula Significantly Improves Bedsores

A new paper has found that an energy-dense, protein-rich oral formula enriched with arginine, zinc, and antioxidants for 8 weeks significantly improves BS.2

To date, trials on specific nutritional supplements (including arginine) for the treatment of BS have been small, inconsistent in their formulations, or unsuccessful in controlling for total supplement calorie or protein content.

The researchers of the new trial (called the OligoElement Sore Trial) set out to evaluate whether supplementation with arginine, zinc, and antioxidants within a high-calorie, high-protein formula improves pressure ulcer healing. The multicenter, randomized, controlled, blinded trial, used long-term care and home care services as its milieu.


To the researchers’ knowledge, this
was the first study supporting the
usefulness of this mixture of specific
nutrients in wound healing.


Altogether, 200 adult malnourished patients with stage II, III, and IV BS were selected. These patients were given an energy-dense, protein-rich oral formula enriched with arginine, zinc, and antioxidants (400 mL/day) or an equal volume of an equivalent caloric, nitrogenous formula for 8 weeks.

Of the most significant nutrients, this formula provided 6 g of arginine, 900 mg of calcium, 18 mg of zinc, 2.7 mg of copper, 128 mcg of selenium, 76 mg of vitamin E, and 500 mg vitamin C, per day in four 100 ml servings (see Table 1 below).

Primary and Secondary Endpoints: Measures of Success

The primary end point was the percentage of change in BS area at 8 weeks. Secondary end points included complete healing, reduction in the BS area of 40% or greater, incidence of wound infections, the total number of dressings at 8 weeks, and the percentage of change in area at 4 weeks.

Supplementation with the enriched formula (n = 101) resulted in a greater reduction in BS area (mean reduction, 60.9%) than with the control formula (n = 99) (45.2%). A more frequent reduction in area of 40% or greater at 8 weeks was also seen.

Overall Improvement

The researchers concluded that among malnourished patients with BS, 8 weeks of supplementation with an oral nutritional formula enriched with arginine, zinc, and antioxidants improved BS healing.

Arginine Demonstrated to Aid Wound Healing

Diabetes impairs wound healing, and there are few therapeutic options to reverse it. However, previous work has demonstrated the importance of nitric oxide for successful wound healing. In diabetes, nitric oxide (NO) synthesis is reduced. Furthermore, the amino acid L-arginine is the only substrate for NO synthesis. Consequently, in 2002, Adrian Barbul, MD, et al hypothesized that L-arginine supplementation enhanced wound healing by restoring NO synthesis.1


Arginine supplementation restores
impaired healing in wounds by
normalizing the NO pathway
without affecting arginase activity.


Using 36 male Sprague-Dawley rats (body weight, 225 to 250 g) separated in 4 groups: 20 rats were rendered diabetic 7 days prior to wounding by intraperitoneal streptozotocin injection. Streptozotocin is a naturally occurring chemical that is particularly toxic to the insulin-producing beta cells of the pancreas. Sixteen rats served as controls, while half of the animals of each group received 1 g/kg supplemental L-arginine administered by gavage twice daily.

The treatment was started 3 days before wounding. All rats underwent a dorsal skin incision and subcutaneous implantation of polyvinyl alcohol sponges. The rats were sacrificed 10 days after wounding, at which time wound breaking strength, hydroxyproline content of the sponges, nitrite/nitrate (NO(x)) concentration, arginase activity, and amino acid composition of the wound fluid and plasma were analyzed. Wound fluid NO(x) concentrations and wound breaking strength were significantly reduced in the diabetic group compared to the controls.

L-Arginine treatment restored diabetic NO(x) levels toward normal values and significantly enhanced wound breaking strength. Wound fluid arginase activity and ornithine concentrations were significantly lower in the diabetic animals but were unaffected by treatment.

The data showed that the impaired NO synthesis in the diabetic wound setting could at least partially be reversed by arginine supplementation. In view of previous results on the importance of NO for wound healing, the data suggest that arginine supplementation restores impaired healing in wounds by normalizing the NO pathway without affecting arginase activity.

Reference

  1. Witte MB, Thornton FJ, Tantry U, Barbul A. L-Arginine supplementation enhances diabetic wound healing: involvement of the nitric oxide synthase and arginase pathways. Metabolism. 2002 Oct;51(10):1269–73.

As per the Agency for Healthcare Research and Quality, BS are one of the patient safety indicators reflecting quality of care. Besides the quality of life downturn, pressure ulcers consume medical resources and increase healthcare costs.

Table 1. Nutrient Contents for 100 mL of the Intervention Formula
LEM1506table1_274.gif
(click on thumbnail for full sized image)

The mainstay of the multifaceted approach to reduce the development of BS is to avoid prolonged pressure at bony sites.


The efficacy of the nutrients in wound
healing is likely synergistic because
there is no evidence supporting an
independent effect when given alone.


Additionally, many other interventions are important, although their relative efficacy has not been established. For example, malnutrition is common in patients with BS, and is a factor that contributes to the development of BS and impairs their healing.

Negative Energy Balance Is a Factor

Also, patients with BS frequently have a negative energy balance—i.e., calories taken into the body through food and drink are inadequate to meet the needs of the body. Nutritional care in wound healing should be directed at ensuring adequate supply of proteins and calories.


In the current trial, adherence to
therapy was high because it was
integrated with daily care, was spread
throughout the day, and was not left
to the patient’s initiative and
capacity to take it.


As already mentioned, studies have suggested that supplementation with a nutritional formula enriched with arginine, zinc, and antioxidants may have healing benefits.3–8 Arginine is a semi-essential amino acid that improves protein anabolism (such as collagen) and cellular growth. It is a donor of nitric oxide, which increases tissue blood flow and acts as an immune response mediator. (See the sidebar above, “Arginine Demonstrated to Aid Wound Healing”)

Zinc is an essential mineral required for the catalytic activity of several enzymes. It contributes to protein and DNA synthesis, immune function, and cellular proliferation.

Antioxidants are also relevant in any chronic inflammatory condition. Among these, vitamin C is also actively involved in the synthesis of collagen and enhances fibroblast proliferation and cellular immunity.

Dealing with Malnourishment is Key

No previous trial evaluated the independent role of these nutrients in a readily available commercial formula designed to improve wound healing. In this case, the scientists performed a large, randomized study in malnourished patients with BS to investigate whether an oral nutritional supplement enriched with arginine, zinc, and antioxidants was beneficial to the healing of BS.


In malnourished patients with BS
receiving nutritional support and
guideline-based wound care
management, the use of an enriched
arginine nutritional formula benefits
wound healing. Nutritional
intervention should be considered an
integral part of bedsores care.


Summarizing, the OligoElement Sore Trial found that the additional provision of arginine, zinc, and antioxidants given to patients with BS improved BS healing. To the researchers’ knowledge, this was the first study supporting the usefulness of this mixture of specific nutrients in wound healing. According to an English-language MEDLINE search through March 2014, the use of a high-calorie, high-protein experimental formula enriched with arginine, zinc, and antioxidants had been investigated in 4 randomized, controlled trials.3–8

No Standardization in Previous Studies

These previous studies did not standardize for the protein and calorie content of the formula they used nor did they sufficiently describe the interventions.

Nonetheless, very recent studies, which were not available when the current trial began, suggest that the lipid fraction in the experimental formula also plays a role—particularly the 2-fold greater content in polyunsaturated fatty acids in the studied formula. Two strengths of the current study is that specific micronutrients were given within the context of appropriate nutritional care, and both groups received a similar high-protein, high-calorie formula to promote new tissue synthesis. Likewise, the rate of patients who did not respond to wound care was similar in the two treatment groups.

Malnutrition is highly prevalent among patients with BS. A recent trial also demonstrated the effectiveness of this experimental formula in non-malnourished patients with BS.

The Importance of Nutritional Therapy, along with Supplements

Nutritional status can be influenced positively by nutritional therapy. However, in clinical trials addressing the efficacy of oral nutritional supplements, adherence to treatment is the major problem. Difficulties in oral nutritional supplement consumption can be overcome by ensuring that treatment is received. In the current trial, adherence to therapy was high because it was integrated with daily care, was spread throughout the day, and was not left to the patient’s initiative and capacity to take it.

In malnourished patients with BS receiving nutritional support and guideline-based wound care management, the use of a nutritional formula enriched with arginine, zinc, and antioxidants benefits wound healing. Nutritional intervention should be an integral part of BS care.

References

  1. Preventing Pressure Ulcers in Hospitals. The Agency for Healthcare Research and Quality. www.ahrq.gov/professionals/systems/hospital/pressureulcertoolkit/index.html Accessed: May 23, 2015.
  2. Cereda E, Klersy C, Serioli M, et al. A nutritional formula enriched with arginine, zinc, and antioxidants for the healing of pressure ulcers: a randomized trial. Ann Intern Med. 2015 Feb 3;162(3):167–74.
  3. 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. doi: 10.1111/jhn.12084. Epub 2013 Apr 30. PubMed PMID: 23627791.
  4. Sodergren MH, Jethwa P, Kumar S, Duncan HD, Johns T, Pearce CB. Immunonutrition in patients undergoing major upper gastrointestinal surgery: a prospective double-blind randomised controlled study. Scand J Surg. 2010;99(3):153–61.
  5. Cereda E, Gini A, Pedrolli C, Vanotti A. Disease-specific, versus standard, nutritional support for the treatment of pressure ulcers in institutionalized older adults: a randomized controlled trial. J Am Geriatr Soc. 2009 Aug;57(8):1395-402. doi: 10.1111/j.1532-5415.2009.02351.x. Epub 2009 Jun 25. PubMed PMID: 19563522.
  6. Beale RJ, Sherry T, Lei K, Campbell-Stephen L, McCook J, Smith J, Venetz W, Alteheld B, Stehle P, Schneider H. Early enteral supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: outcome of a randomized, controlled, double-blind trial. Crit Care Med. 2008 Jan;36(1):131–44.
  7. 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.
  8. Houwing RH, Rozendaal M, Wouters-Wesseling W, Beulens JW, Buskens E, Haalboom JR. A randomised, double-blind assessment of the effect of nutritional supplementation on the prevention of pressure ulcers in hip-fracture patients. Clin Nutr. 2003 Aug;22(4):401–5.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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