Targeted Nutritional Strategies
Most surgeons now recognize that good attention to nutrition, including its effects on antioxidant and inflammatory status, can have a major positive impact on the outcome of a surgical procedure (Calder 2004). A comprehensive nutritional program begun in the weeks prior to surgery and continued at the earliest possible postoperative moment is known to increase survival, reduce complications, minimize length of hospital stay, keep costs down, and significantly enhance quality of life (Ellis 1991).
Immunonutrition aims to provide the proper nutrient mix to boost healthy immune function while suppressing the exaggerated inflammatory response (Chen 2005a; Grimble 2005). A variety of nutrient formulas and routes of delivery have been tested. The most promising results come from nutrient formulas provided by mouth or feeding tube (enteral route) rather than intravenous feedings. Such feedings reduce atrophy of the intestinal lining and prevent the increase in gut permeability that is a consequence of the inflammatory response (Mangiante 2005).
Patients given enteral (orally administered) supplements have been shown to have fewer infections (Fukushima 2004), shorter stays in intensive care, and fewer overall hospital days (Grimble 2005). They have improved wound healing compared with patients receiving standard nutrition (Farreras 2005). Starting immunonutrition supplements up to 5 days before surgery may provide even greater benefits (Sax 2005), including beneficial immune system effects (Matsuda 2006), fewer postoperative infections (Moskovitz 2004), and reduced costs (Braga 2005).
Omega-3 fatty acids. While many different mixtures of nutrients have been used in immunonutrition, several main components appear to provide maximum benefit. The goal of reducing exaggerated inflammatory response to surgery is met through the inclusion of omega-3 fatty acids, largely derived from fish oils (Grimble 2005). These fatty acids can shift the production of cytokines away from those that stimulate inflammation (Heller 2000). They also make cell and mitochondrial membranes more resistant to oxidant stress (Ates 2004), which reduces tissue damage and prevents amplification of the inflammatory response. Most effective immunonutrient supplements contain substantial quantities of omega-3 fatty acids.
Amino acids. The amino acids arginine, glutamine, and taurine are conditionally essential amino acids, which means that under certain stressful conditions (including trauma and surgery), the body cannot synthesize them in normal amounts; it must therefore rely on external supplemental sources (Kendler 2006; Sole 2002).
- Arginine. Arginine provides a substrate for nitric oxide production, which enhances blood flow by relaxing blood vessels (Grimble 2005). It also stimulates and activates immune system cells (Fukushima 2004). Trauma and surgery increase levels of the enzyme arginase, which reduces arginine levels (Bansal 2005). Arginine supplementation, alone or in combination, has been observed to enhance wound healing (Moskovitz 2004) and prevent pressure ulcers (Singer 2002).
- Glutamine. Glutamine is a major component of proteins produced during clotting (Weisel 2005). Supplementation with glutamine also speeds wound healing (Peng 2004).
- Taurine. Taurine is required for mitochondrial energy production and efficient utilization of other nutrients (Jeejeebhoy 2002). It has been documented to improve cardiac surgery outcomes by protecting heart muscle against ischemic damage (Keith 2005).
Ribonucleic acids. Ribonucleic acids (RNA) are crucial to protein synthesis in wound healing, as well as the expression of gene products of immune system cells. While the precise mechanism is unknown, immunonutritional supplements containing RNA appear to improve immune responses and more rapidly overcome immune depression induced by surgery (Kemen 1995). Like other nutrient combinations, these supplements are effective when given both preoperatively (Matsuda 2006) and in the early postoperative period (Farreras 2005).
More than 170 studies have been published on various immunonutrient combinations that have shown positive results (Grimble 2005). Patients given a preoperative formula containing omega-3 fatty acids and arginine had significantly improved systemic immune responses, gut oxygen levels, and gut perfusion compared with control patients (Braga 2002). In a different study, patients supplemented with arginine, glutamine, and omega-3 fatty acids had higher postoperative total protein and immunoglobulin levels, higher levels of infection-fighting white blood cells, and lower levels of pro-inflammatory cytokines and tumor necrosis factor than unsupplemented controls, demonstrating these supplements enhanced host defenses while modulating the exaggerated inflammatory response (Chen 2005b).
Wound healing is also improved by immunonutritional mixtures. A 2005 study demonstrated that a postoperative formula containing arginine, omega-3 fatty acids, and RNA increased protein synthesis in surgical wounds, and supplemented patients experienced fewer wound healing complications than unsupplemented control patients (Farreras 2005). Enhancement of host defenses by immunonutritional supplements (Ates 2004) results in fewer postoperative complications, such as pneumonia (Klek 2005) and pressure ulcers (Singer 2002).
Other Nutrients That Enhance Surgical Outcomes
In addition to immunonutrients, supplementation with many other biologically active materials can help prepare a person for surgery. Ensuring that the body is replete with antioxidants is one easy and powerful way to avoid antioxidant depletion during surgery (Pechan 2004). Maximizing anti-inflammatory status and boosting immune function to achieve proper balance of host defense against infection while minimizing exaggerated inflammatory response to surgery is another. Also, ensuring adequate protein intake prior to surgery is an important way of providing the soon-to-be-healing body with building blocks of new tissue. All of these effects can be achieved with a reasonable program of supplementation in the weeks prior to surgery.
Amino acids. In addition to being a good source of immunonutrition, amino acids are the building blocks of proteins, which are the chief components of structural tissue. Enzymes that catalyze all biological processes are also proteins. Surgery dramatically increases the daily requirement of protein, particularly if there is substantial blood loss. Supplements containing amino acids or whole proteins have been shown in animal models and human trials to enhance surgical outcomes (Collins 2005; MacKay 2003; Scholl 2001). Supplements may improve wound healing (Collins 2005), reduce the rate and severity of pressure ulcers (Frias 2004; Bourdel-Marchasson 2000; Breslow 1993), and improve fat mass (a good thing following surgery) (de Luis 2005).
Almost all known vitamins are essential in each of the phases of surgery, either as vital cofactors in protein or nucleic acid synthesis for rapidly healing tissue or as potent antioxidants that can minimize tissue damage and the heightened inflammatory response caused by surgery. Blood levels of many of the vitamins are markedly reduced during surgery, and there is good evidence for both pre- and postoperative supplementation.
Vitamin C. Vitamin C is an antioxidant required for protein synthesis, making it indispensable in wound and fracture healing; fractures in animal models heal faster when they receive vitamin C supplementation (Sarisozen 2002; Yilmaz 2001). In humans, vitamin C contributes to the strength of healing wounds and reduces the degree and severity of postoperative pressure ulcers (Desneves 2005; Frias 2004; MacKay 2003).
Vitamin E. Vitamin E is a potent antioxidant and fat-soluble vitamin found in large amounts in skin, where it may improve wound healing and scar appearance (Chen 2005; MacKay 2003). By scavenging reactive oxygen species, vitamin E can reduce tissue damage caused by free radicals, thereby reducing surgically induced inflammation. Like vitamin A, vitamin E levels are depleted during surgical procedures, especially those that require use of a heart-lung machine (Schindler 2003). In animal models, supplements containing vitamin E promote fracture healing (Turk 2004; Sarisozen 2002) and mitigate the deleterious effects of hyperbaric (high pressure) oxygen (Patel 2005). In humans, vitamin E also assists in the healing of bone necrosis following radiation treatment (Delanian 2005). Vitamin E, administered directly into coronary blood vessels during open-heart surgery, has been shown to reduce reperfusion oxidative injury to cardiac muscle cells (Canbaz 2003).
Because vitamin E can inhibit platelet aggregation, vitamin E supplementation should be considered on a case-by-case basis (well in advance of surgery) to determine whether the benefit exceeds the risk. Another way to enhance vitamin E function without direct vitamin E supplementation is to consider alpha-lipoic acid, which has been shown to support vitamin E’s antioxidant function in patients undergoing hyperbaric oxygen treatment (Alleva 2005).
Lipoic acid. Lipoic acid is an effective antioxidant that may have a role in preoperative care. In a rat model of skin injury, pretreatment with lipoic acid sped the healing of skin wounds by protecting skin cells from oxidant damage (Lateef 2005). In humans, lipoic acid helped combat free radical damage caused by high tissue concentrations of oxygen (Alleva 2005).
Vitamin A. Vitamin A is essential for surgical patients; it stimulates the production of transforming growth factor beta-1, which accelerates skin and intestinal wound healing (Yuen 2004). Supplements containing vitamin A have been especially useful in the prevention of pressure ulcers (Singer 2002) and treatment of burn patients (Grau 2005). Vitamin A has also been shown to mitigate the effects of inflammation caused by radiation treatments that often accompany cancer surgery (Ehrenpreis 2005).
In addition to vitamins, a number of other micronutrients and conditionally essential nutrients, many with antioxidant or anti-inflammatory effects, have been found to improve surgical outcomes and prevent complications.
Omega-3 fatty acids. Omega-3 fatty acids have already been mentioned as key components of immunonutrient formulas. Fish oil supplements have independently been documented to reduce the exaggerated inflammatory response caused by surgery, producing decreased cytokine levels (Aiko 2005; Babcock 2005; Bansal 2005). Supplementation with fish oil rich in omega-3 fatty acids reduced infection rates and showed promise for shortening length of hospital stay (Heller 2000). The same group of investigators also demonstrated postoperative improvements (in liver and pancreatic function) in cancer patients supplemented with fish oil (Heller 2004). Cancer patients given 5 days of omega-3 supplementation before their surgery had dramatically reduced blood levels of inflammatory mediators in the postoperative days (Nakamura 2005). In a 2004 study, preoperative supplementation with fish oil demonstrated a decrease in deaths following surgery (Tsekos 2004). This study also showed a lower requirement for mechanical ventilation postoperatively and shorter length of hospital stay in the group supplemented preoperatively.
Coenzyme Q10. Coenzyme Q10 (CoQ10) is an antioxidant molecule intimately involved in intracellular energy management. Like other antioxidants, its levels plummet sharply during surgery, presumably because of rapid consumption by oxidant species (Pechan 2004). Diminished levels of CoQ10 and other conditionally essential antioxidants may also worsen cardiac output, especially in people with preexisting heart disease (Sole 2002). Poor cardiac output results in poor perfusion of other organs, can delay healing, and set the stage for other complications. Preoperative treatment with CoQ10 can restore cardiac muscle function and protect against hypoxic (low oxygen) damage (Keith 2005; Rosenfeldt 2005). One study of a supplement containing CoQ10, taurine, and carnitine demonstrated improved cardiac blood volumes in cardiac surgery patients (Jeejeebhoy 2002).
Zinc. Zinc is a mineral that functions as an important coenzyme in the production of collagen (chief protein in healing wound tissue); in addition, it has an important antioxidant function in skin (Rostan 2002). The earliest sign of zinc deficiency in humans is often the development of skin breakdown, and topical zinc treatments have been used for centuries with good effect (Schwartz 2005). Animals made zinc deficient have slower rates of collagen accumulation in wounds and diminished wound strength, while zinc supplementation prior to creation of the wound (preoperatively) increased the strength of the healing wound (Kaplan 2004; Iriyama 1982). Quantitative studies of the effects of zinc supplementation in mice demonstrate that adequate zinc has an antioxidant function and hastens wound healing, while deficiency or very high doses delay healing (Lim 2004; Cario 2000). Zinc may help in the healing, not only of skin wounds, but also bone; a study demonstrated that zinc supplementation hastened the healing of leg fractures in rats (Igarashi 1999).
In studies of patients with pressure ulcers, supplementation with a combination of zinc, arginine, and vitamin C produced significant improvement in treated patients compared with controls given placebo (Desneves 2005; Frias 2004). A similar supplement was shown to delay the onset of pressure ulcers in a group of patients recovering from hip surgery (Houwing 2003). This combination is now widely recognized for patients undergoing surgery of any kind (Singer 2002).
Melatonin. Melatonin is a pineal gland hormone with antioxidant functions (Macchi 2004). It appears to fundamentally affect a variety of brain functions related to relaxation, sleep, and anxiety; also, its natural secretion is perturbed by surgery (Guo 2002) and anesthesia (Karkela 2002). These disturbances may contribute to the well-known phenomena of postoperative delirium (Shigeta 2001) and “ICU psychosis,” in which patients become agitated, confused, and combative while in intensive care. Melatonin supplementation has been suggested in this setting (Miyazaki 2003).
Melatonin has recently been demonstrated to be as effective at reducing anxiety before a procedure as the commonly used benzodiazepine drug midazolam (Acil 2004). As a premedication, melatonin has the added advantage of not producing postoperative impairments in mental function, as do the benzodiazepines (Samarkandi 2005). There is emerging clinical evidence that melatonin may positively modify surgically induced general inflammation. In a study of newborns, melatonin given postoperatively significantly reduced inflammatory cytokine levels (Gitto 2004).
Curcumin. Curcumin is a major component of turmeric. It is an antioxidant and potent inhibitor of nuclear factor-kappa B, which plays a central role in “translating” inflammatory stimuli into activation of the inflammatory response. There has been tremendous interest in the role of nuclear factor-kappa B inhibition as a means of reining in overactive inflammatory reactions in sepsis, cancer, and autoimmune diseases (Maheshwari 2006).
A study of topical curcumin delivered in a collagen-based film demonstrated enhanced wound healing and tissue proliferation in wounds covered with the film, as well as more-efficient free radical scavenging than in wounds covered with a non-curcumin-containing film (Gopinath 2004). In an animal model of radiation-induced impaired wound healing, pretreatment with curcumin enhanced wound closure compared with controls (Jagetia 2004). This study has profound implications for human cancer surgeries often complicated by the effects of radiation treatment.
Curcumin has also demonstrated powerful antioxidant effects on skin cells in culture, protecting cells against damage caused by hydrogen peroxide (Phan 2001). These mechanisms together may explain the more rapid healing of experimentally-produced surgical wounds in animals treated with curcumin (Sidhu 1998, 1999). There is limited research on the effect of curcumin in the context of surgery, but it has been observed to be safe and well-tolerated in human trials as an anti-inflammatory and chemoprotective agent (Holt 2005; Cheng 2001).