In this study, ICU patients who received nutritional support enriched with fish oil (eicosapentaenoic acid) and micronutrients had significantly less progression of existing pressure ulcers than did patients who received an isonitrogenous, nutrientsufficient formula. In addition, decreases in CRP concentrations were greater in the study group than in the control group.
Wound healing refers to the complex and dynamic process of restoring cellular structures and tissue layers after injury and/or infection. The wound healing process in humans can be divided into 3 phases: inflammatory, proliferative, and remodeling. The role of the initial inflammatory phase is isolation and removal of the injurious or infectious agent and removal of cellular debris (endogenous debridement) before tissue reconstruction. The reparative stages (ie, the proliferative and remodeling phases), involve a shift in the predominant cellular activity from phagocyte-mediated inflammation and catabolism to epithelial and mesenchymal anabolic processes. In the proliferative phase, fibroblasts, smooth muscle cells, and endothelial cells infiltrate the wound as epithelial cells begin to cover the site of injury. Finally, the collagen matrix continually undergoes reabsorption and deposition to remodel and strengthen the wound, constituting the remodeling phase of healing.[12,13]
Thus, healing of significant wounds is a metabolically demanding process, requiring considerable quantities of calories and amino acids.[1,5,14] Continuous administration of calories and protein is also important for appropriate wound healing in acute illness. In our study, both groups of patients received similar and adequate amounts of protein and calories to support wound healing. Nevertheless, the effect on pressure ulcers occurred solely in patients who received the nutritional formula enriched with eicosapentaenoic acid and micronutrients. We did not assess the specific contribution of the multivitamins and minerals. Interestingly, we previously showed that the use of the same nutritional formula in critically ill patients with acute respiratory distress syndrome did not result in higher serum levels of vitamins.
Although the inflammatory phase is an essential physiological response, excessive release of proinflammatory molecules may exacerbate tissue injury. Indeed, the depiction of inflammation as a double-edged sword, as in response to infection, is also applicable to wound healing. Several lines of evidence support the notion that self-resolving inflammation is a normal and necessary prerequisite to fibroblast activation and net matrix synthesis, whereas an inflammatory response that is excessive in magnitude and duration hampers the transition from the inflammatory phase to the reparative phases of tissue repair.[12,18] Impaired healing of chronic venous ulcers, wounds associated with diabetes, and trauma-induced wounds may be attributed in part to an injurious inflammatory response.
In our study, the interventional nutritional formula prevented progression of pressure ulcers and was associated with reduced concentrations of the acute-phase reactant CRP. Previous studies have shown that supplementation with ω-3 acids results in decreases in CRP levels. Thus, supplemented parenteral nutrition resulted in a decrease in CRP levels in severe acute pancreatitis and was associated with a decrease in the hyperinflammatory response and attenuation of systemic disease sequelae. In addition, fish-oil supplementation lowered CRP levels in patients with end-stage renal disease. Although our findings do not firmly establish a causative association, the temporal sequence of these effects suggests that ω-3 PUFAs may have attenuated the inflammatory response in a manner that minimizes tissue injury while avoiding suppression of those components of inflammation necessary for subsequent wound healing. Dampening the magnitude of the inflammatory response might facilitate resolution of inflammation and transition to wound healing. Indeed, novel lipid mediators derived from ω-3 PUFAs, the resolvins and protectins, promote the resolution of inflammation. These mediators are synthesized during the later stages of inflammation (ie, after the classic eicosanoids), at which time they enhance macrophage engulfment of apoptotic neutrophils and the efflux of macrophages to local lymph nodes.[24,25] Recently, resolvins were shown to enhance resolution of inflammation and microbial clearance in experimental critical illness. Thus, ω-3 PUFAs have pleiotropic properties during inflammation through production of weaker eicosanoids (eg, leukotriene B5 vs leukotriene B4), inhibition of nuclear factor kB, and direct promotion of resolution. Determining whether resolvins and protectins directly induce the wound-healing macrophage phenotype would be of interest.
In addition to its content of long-chain ω-3 PUFAs, our study formula contained higher concentrations of certain micronutrients, some of which are operative in wound healing, than did the control formula. However, on the basis of the micronutrient dose necessary to improve wound healing in supplementation trials, most likely the quantitive difference in micronutrients was insufficient to facilitate tissue repair independently of fish oil. However, a synergistic cytoprotective and anti-inflammatory effect is possible, and antioxidant nutrients are vital to prevent PUFA peroxidation. The relative roles of ω-3 PUFAs and individual micronutrients in promoting healing of pressure ulcers therefore requires further research.
Of note, the cost of the study formula (enteral and parenteral components) was significantly higher for the study group ($99.60/d) than for the control group ($44.20/d). However, pressure ulcers are a major burden on health care systems. Thus, the costs of treatment of pressure ulcers in the United States are on the order of $500 to $40 000 per ulcer, depending on the stage of the ulcer. In the United Kingdom, the total cost for a patient with a full-thickness ulcer has been estimated at £30 000 (€36 376). Finally, an Australian study indicated that in 2001 to 2002, costs for bed days lost were a median of AU $285 million in Australian public hospitals. We did not perform a cost analysis in our study. However, these figures for other countries suggest that an intervention, such as ours, that decreases the incidence of pressure ulcers may have an important economic impact and negate the added costs of the intervention.
Although our clinical and laboratory end points were significant, our study has several limitations. All assessments of pressure ulcers were completed by a single investigator, a situation that might have introduced an element of bias. Treatment allocation was known by the participants and some of the care providers, and the study included a relatively small number of patients. For example, the investigator who assessed ulcer severity knew the allocation because he is an active member of the ICU staff. Our patients, in both groups, received 80% of their measured energy requirements via the enteral route. This route was used largely because of technical reasons and has been described by others. On the other hand, the target was achieved for patients receiving parenteral nutrition. Finally, we did not firmly establish a causative association between the anti-inflammatory effect of the formula and the subsequent improvement in pressure ulcer status. Larger clinical trials are necessary to establish whether the presence of grade II pressure ulcers may benefit from enriched nutrition in the ICU.
Am J Crit Care. 2012;21(4):102e-109. © 2012 American Association of Critical-Care Nurses