The effectiveness of trace element supplementation following severe burn injury: A systematic review protocol

Abstract

Review question/objective The objective of this review is to assess the effectiveness of trace element supplementation on clinically meaningful outcomes following severe burn injury in children and adults. More specifically, the objectives are to assess the effectiveness of selenium, copper and zinc supplementation on mortality, length of intensive care unit (ICU) hospital stay, wound healing and infection rates (wound and nosocomial) in patients who have sustained a severe burn injury. Background In the United States (US) it has been estimated that each year around 450,000 people seek medical treatment for burn injuries and 3,400 people die as a direct result of fire and burns.1 According to the 2013 American Burn Association National Burn Repository Report, fire/flame and scalds are the most commonly documented cause of burn injury (43.2% of reported hospital burn injury admissions).2 Pneumonia is the most commonly reported clinical complication related to burn injury with an incidence of 5.9% in fire/flame injury admissions, with an increased frequency of patients who require mechanical ventilation for four or more days.2 The average length of hospital stay for patients who survive a burn injury requiring hospital admission, is just over one day per percent of the total body surface area burned.2 The mortality rate for patients admitted from fire/flame injury is reported as 6.2%, with three weeks being the average length of stay for patients with less than 70% burns who do not survive. For this patient group there is an average daily hospital charge of US$13,000 more than patients who did survive their admission.2 Longer term economic costs of burn injury are also important factors to recognize, with reportedly only 50-67% of people who are actively employed at their time of burn injury returning to paid employment.3 Physical rehabilitation from burn injury is often more prolonged than that of other types of injury, however similar physical outcomes and functioning can be expected following burn injury.3 Psychological rehabilitation is not as ‘clear cut' as physical rehabilitation, with a 39% prevalence in psychiatric disorders, major depression, anxiety disorders, and post-traumatic stress disorder (PTSD) predominantly, one to four years post-injury.3 The development of PTSD appears to be related to pain scores shortly after burn injury rather than the severity of the burn injury.3 This is important as negative burn perceptions, as a result emotional distress and concerns with appearance, are associated with a lengthened time to healing.3 Nutrition support following severe burns injury is recognized as an essential part of burn injury management.4 Pronounced inflammatory responses, endocrine, metabolic and immune system disturbances are observed following a severe burn injury.4,5 It is recognized that nutritional deficiencies exacerbate complications of severe burns injury such as infections, delayed wound healing and muscle catabolism, with infective complications such as wound sepsis and pneumonia remaining a major cause of mortality following hospitalization due to burn injury.4,5 Trace element deficiencies are part of the sequelae following severe burn injuries,5,6 with a recent survey of American Burn Association Burn Centers indicating that 92% of responding centers routinely supplement patients with vitamins and/or minerals.7 Despite this prevalence of vitamin and mineral supplementation following burns injury, variation exists in the supplements administered between centers. Trace elements, such as copper, selenium and zinc play an important physiological role in immune function as well as wound healing; however they are acutely depleted following severe burn injury.5,6 The mechanism of trace element deficiency following burn injury appears to be multi-modal. Trace elements are thought to be primarily lost through extensive exudative losses following injury and repeated surgeries.5,6 It has been reported that 5-10% of total body zinc stores and 20-40% of total body copper stores are lost within seven days of a severe burn injury, with concomitant increases in urinary excretion of these metals following burn injury contributing significantly.8 Trace element losses also occur through thermal destruction of skin and removal of burn eschar. The reported antagonistic relationship between endogenous selenium and the silver used in burn dressings may also contribute to observable losses of selenium.6,8 Selenium performs it's antioxidant role as an essential component of the active site of the enzyme glutathione peroxidase (GSH-Px),8 which contributes to the first line antioxidant defenses in both the intra- and extra-cellular milieu.5 Depleted endogenous stores of antioxidants have been associated with an increase in free radical generation and heightened systemic inflammatory responses.9 In the critically ill population, this is associated with increased morbidity and mortality.9 As the rate limiting step in the biosynthesis of GSH-Px, selenium deficiency directly influences these responses.8 Selenium also has identified roles in tissue oxygenation, protection against lipid per-oxidation, phagocytic activity of neutrophils,8 activation and regulation of thyroid hormones, DNA synthesis and cell viability and proliferation.9 Similarly, the trace elements copper and zinc also promote wound healing as a component of several metalloenzymes.6,8 Copper is a component of lysyl oxidase, which is necessary for cross linking of collagen fibres;8 this is important for wound healing rates and healed wound integrity. Copper is also a component of superoxide dismutase;6,8 when copper levels are low, synthesis of superoxide dismutase is decreased. This process is associated with oxidative damage as a result of inflammation.8 Zinc is required for the function of over 200 metalloenzymes, as well as for normal cell replication and growth.8 Immune function is also influenced by zinc status, with deficiency leading to thymic atrophy, loss of T-helper cell function and alterations to the normal profiles of serum immunoglobulins.8 Currently, many international evidence-based nutrition support guidelines available for clinicians provide global recommendations for the ICU setting.10-12 These guidelines are commonly adopted for burn injury patients as specific guidance for this sub-population may or may not be available. More often, recommendations for burns injury patients are extrapolated from critical care data. The critical care population is recognized as a heterogeneous group. Burn injury however, is a specific sub-group, characterized by the severe hypermetabolic, inflammation, endocrine and immune responses. These combine to have a pronounced effect on nutritional requirements and therefore evidence-based recommendations for nutritional supplementation in burn injury should be separated from the ‘general' critical care population. A recently published set of recommendations for nutritional therapy in major burns stated that micronutrient substitution, including zinc, copper and selenium, be included for both adults and children.13 This was provided as Grade C evidence (based on the GRADE methodology [Grade of Recommendation, Assessment, Development and Evaluation14]), with strong agreement between experts.13 Details on duration for this supplementation were provided, however recommended dosages were lacking.13 A search for systematic reviews on this topic of MEDLINE and the Cochrane and JBI Libraries failed to identify any existing publications. As a result, this review will examine the current evidence regarding the effectiveness of trace element supplementation in burn injury patients, with an aim to elucidate ideal trace element dosages, route of administration and timing for administration.