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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References

The role of nutrition in the management of diseases has often centred on correcting apparent nutrient deficiencies or meeting estimated nutritional requirements of patients. Nutrition has traditionally been considered a supportive measure akin to fluid therapy and rarely it has been considered a primary means of ameliorating diseases. Recently, however, further understanding of the underlying mechanisms of various disease processes and how certain nutrients possess pharmacological properties have fuelled an interest in exploring how nutritional therapies themselves could modify the behaviour of various conditions. Nutrients such as omega-3 fatty acids, antioxidants and certain amino acids such as arginine and glutamine have all been demonstrated to have at least the potential to modulate diseases. Developments in the area of critical care nutrition have been particularly exciting as nutritional therapies utilising a combination of approaches have been shown to positively impact outcome beyond simply proving substrate for synthesis and energy. Application of certain nutrients for the modulation of diseases in veterinary patients is still in early stages, but apparent successes have already been demonstrated, and future studies are warranted to establish optimal approaches. This review describes the rationale of many of these approaches and discusses findings both in human beings and in animals, which may guide future therapy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References

Nutrition plays a critical role in the proper development and maintenance of optimal health in animals. This becomes particularly apparent when nutrient imbalances lead to pathological changes, such as dilated cardiomyopathy in cats with taurine deficiency (Pion and others 1987) or rickets in dogs with calcium, phosphorus or vitamin D imbalances (Hazewinkel 1989, Schoenmakers and others 2000). For many years, the focus of veterinary nutrition has been on determining particular nutrient requirements and preventing nutrition-related diseases. More recently, the field of clinical nutrition has shifted to developing strategies for the management of chronic diseases, such as chronic renal disease (Jacob and others 2002, Elliott 2006, Ross and others 2006), dermatological conditions (Miller 1989, Codner and Thatcher 1990), enteropathies (Guilford 1996, Marks and Fascetti 2000) and cardiac disease (Roudebush and Freeman 2000, Anderson 2006). Nutritional strategies have largely focused on altering the composition of foods to alleviate stresses on certain organ systems. However, the most exciting development in clinical nutrition has been the appreciation that certain nutrients could alter the behaviour of certain diseases by directly modulating pathophysiological processes. The direction of clinical nutrition is heading towards exploiting pharmacological effects of certain nutrients to modulate disease. Successes of such approaches in veterinary medicine have already been appreciated in the areas of chronic renal disease (Brown and others 1998, 2000, Bauer and others 1999) and cardiac disease (Kittleson and others 1997, Freeman and others 1998, 2001, Sanderson and others 2001). In human beings, critical care nutrition is the focus of intensive research as there is mounting evidence that certain nutrients such as glutamine, omega-3 fatty acids and antioxidants can positively impact both morbidity and mortality in severely affected populations. It is hoped that a greater understanding of how these nutrients impart such beneficial effects may lead to developments of novel strategies for modulating various diseases in small animals.

Omega-3 fatty acids

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References

As inflammation plays a crucial role in many diseases, manipulation of the inflammatory cascade by changing the composition of inflammatory precursors has become an important target of therapy. Potent proinflammatory eicosanoids, leucotrienes and thromboxanes of the 2 and 4 series are produced from arachidonic acid (AA) metabolism of certain polyunsaturated fatty acids (namely the omega-6 fatty acids). Provision of omega-3 fatty acids in the diet or as supplements is aimed at displacing and substituting omega-6 fatty acids in membranes. When these are metabolised by AA, they yield eicosanoids of the 3 and 5 series, which are less vasoactive and less proinflammatory (Fig 1). Studies on mice, rats, dogs and human beings have demonstrated that omega-3 fatty acids also increase renal blood flow, improve glomerular filtration rate (Patrono and Dunn 1987), reduce systemic hypertension (Radak and Huster 1991, Mori 2006) and favourably alter leucocyte activity, lipid mediator generation and cytokine production (Mayer and others 2006). Although omega-3 fatty acid supplementation is being incorporated into diets designed for dogs and cats with osteoarthritis, the evidence supporting these approaches are derived from in vitro work in other species (Curtis and others 2002, Curtis and others 2004) or are only available in abstract form (Bartges and others 2001, Roush and others 2005). While manipulation of the inflammatory response through omega-3 fatty acids supplementation was thought to be more feasible with chronic inflammatory conditions (for example, atopy, cardiac disease, osteoarthritis and chronic renal disease), there have been recent breakthroughs in improving outcome in acute and severe conditions, such as sepsis and acute lung injury in human beings (Gadek and others 1999, Pontes-Arruda and others 2006). In a landmark study, Gadek and others (1999) demonstrated that an enteral tube feed diet enriched with eicosapentaenoic acid (EPA), γ-linolenic acid (GLA) and antioxidants administered to patients with acute respiratory distress syndrome was associated with a significant improvement in oxygenation parameters, ventilator-free days, reduction in intensive care unit hospitalisation and reduced new organ failures. In a more recent study, Pontes-Arruda and others (2006) also demonstrated that an enteral diet enriched with EPA, GLA, docosahexaenoic acid and vitamins E and C administered to patients with severe sepsis or septic shock and requiring mechanical ventilation also experience dramatic positive results. The authors were able to demonstrate reductions in 28 day mortality from 52 per cent in the control population to 33 per cent in study population. Absolute risk reduction for mortality was 19·4 per cent, and the number of patients needed to be treated to save an additional life at 28 days was five. These findings are particularly exciting as previous studies had not demonstrated a clear benefit of omega-3 fatty acids in septic populations. It is believed that the immunomodulatory effects of omega-3 fatty acids are at least partly responsible for the benefits demonstrated. Especially formulated enteral diets enriched with omega-3 fatty acids and antioxidants are now available in the market and are intended for use in mechanically ventilated human patients, and this practice is quickly becoming the standard of care. The use of enteral diets enriched with fish oils in critically ill veterinary populations has not been reported but merits further evaluation as these studies suggest a great potential to benefit such patients.

image

Figure 1. The most common types of fatty acids found in cell membranes are omega-6 fatty acids, which produce more potent inflammatory mediators when metabolised (leucotrienes and eicosanoids of the 2 and 4 series). Supplementation with omega-3 fatty acids results in the production of less intense inflammatory mediators (leucotrienes and eicosanoids of the 3 and 5 series) when metabolised

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Antioxidants

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References

Oxidative stress is recognised to be a prominent and common feature of many disease processes, including neoplasia, heart disease, trauma, burns, severe pancreatitis, sepsis and critical illness (Nathens and others 2002, Du and others 2003, Berger 2006). During various pathophysiological states, particularly those typified by an inflammatory response, cells of the immune system such as neutrophils, macrophages and eosinophils substantially contribute to reactive oxygen species (ROS) production (McMichael 2007). With the depletion of normal antioxidant defences, the host is more vulnerable to free radical species and prone to cellular and subcellular damage (for example, DNA and mitochondrial damage). Moreover, oxidative stress is associated with the triggering of apoptosis in several organ systems such as the liver and cardiovascular system and also involved in the pathophysiology of multiple organ failure (Kurose and others 1997, Berger 2006, Crimic and others 2006, Eaton 2006).

Replenishment of antioxidant defences attempts to lessen the intensity of the signals that eventually leads to multiple organ dysfunction. Antioxidants can be classified in three different systems: (1) antioxidant proteins such as albumin, haptoglobin and ceruloplasmin, (2) enzymatic antioxidants such as superoxide dismutase, glutathione peroxidase and catalase and (3) non-enzymatic or small molecule antioxidants such as ascorbate (vitamin C), alpha-tocopherol (vitamin E), glutathione, selenium, lycopene and beta-carotene. N-acetylcysteine is a powerful progenitor of glutathione and has been associated with very positive results in several patient populations (Henderson and Hayes 1994, Suter and others 1994). Treatment with N-acetylcysteine not only scavenges ROS but also enables continual production of glutathione and even blocks transcription of inflammatory cytokines (Henderson and Hayes 1994).

Antioxidants such as selenium have also been associated with promising results in human beings with systemic inflammatory response syndrome when used alone, but this has only been confirmed in small clinical trials (Angstwurm and others 1999). Antioxidant vitamins (vitamins C and E) are becoming ubiquitous in immune-enhancing diets (IEDs) and in fact it is difficult to identify studies that do not include antioxidant vitamins in test formulations. Given the consistent evidence that oxidative stress is quite prevalent in critically ill populations, it is not surprising that antioxidant therapy be included in dietary management of critically ill patients.

Recent studies have also identified significant benefits of high-dose parenteral ascorbate therapy in human beings with severe conditions, such as major trauma, burns, sepsis and critical illness (Metnitz and others 1999, Nathens and others 2002, Du and others 2003, Berger 2006, Crimic and others 2006, Heyland and others 2006). In disorders where a dysfunctional endothelium plays a major role such as in cardiovascular diseases or sepsis, supraphysiological doses of ascorbate has been demonstrated to reduce the bioavailability of nitric oxide (NO), inhibit NO synthase induction and improve vasomotor responsiveness (Harrison 1997, Biesalski and McGregor 2007). Interestingly, until recently, high doses of ascorbate were thought to paradoxically have a pro-oxidative effect; however, this does not appear to be the case (Valko and others 2005, McGregor and Biesalski 2006). It is unknown whether a similar approach would be beneficial to animals with serious conditions, although a study did demonstrate attenuation of ischaemia-reperfusion injury in a canine model of renal transplantation (Lee and others 2006).

Despite the clear importance of oxidative stress in various diseases in companion animals, investigations evaluating the effect of antioxidants on disease processes are limited. Positive results have been demonstrated in experimental models of oxidative stress, including in conditions such as congestive heart failure (Harker-Murray and others 2000), acute pancreatitis (Shabanov and others 2006), gastric dilatation-volvulus (Badylak and others 1990, Lantz and others 1992, Guilford and others 1995), renal transplantation (Lee and others 2006), gentamicin-induced nephrotoxicity (Varzi and others 2007) and acetaminophen toxicity (Webb and others 2003). Recent studies evaluating antioxidants in naturally occurring disease such as chronic valvular disease (Freeman and others 2006) and renal insufficiency (Yu and Paetau-Robinson 2006) have also been positive and support the need for further evaluation.

Special amino acids

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References

Amino acids fulfil a vast array of functions in the body. They primarily serve as building blocks for protein synthesis and participate in various chemical reactions. Certain amino acids also serve as an energy source for certain cells; perhaps, the most pertinent example being glutamine, which is the preferred fuel source for enterocytes and cells of the immune system (Heyland and Dhaliwal 2005). During disease states, the body undergoes marked alterations in substrate metabolism that could lead to a deficiency in these amino acids. In the response to stress, there may be a dramatic increase in demand by the host of particular amino acids, such as arginine and glutamine. In health, these amino acids are adequately synthesised by the host. However, during periods following severe trauma, infection or inflammation, the demand for these amino acids cannot be met by the host and they become “conditionally essential” and must be obtained from the diet. Given the importance of these amino acids, the sudden depletion in these important substrates led to the hypothesis that dietary supplementation of these amino acids during disease would improve outcome.

An exciting development in this area has been the demonstration that supplementation of amino acids such as glutamine yielded positive results beyond restoration of a deficient state (Montejo and others 2003, Heyland and Dhaliwal 2005). In fact, it has been recognised that glutamine must possess pharmacological effects because positive responses have been demonstrated in a dose-dependent manner and in the absence of deficiency in both human beings and experimental animal models (Heyland and Dhaliwal 2005). These positive responses include cellular expression of heat shock proteins, which enable cells to withstand a great deal of injury and remain viable and functional. The relationship between glutamine and expression of heat shock proteins is well documented in rodent models of shock and sepsis (Wischmeyer and others 2001, Singleton and others 2005). This effect does not appear to be limited to rodent models as a recent study has also demonstrated a similar beneficial effect in critically ill human patients (Ziegler and others 2005).

The recognition that amino acids may possess pharmacological properties beyond serving as building blocks or energy sources generated a great deal of interest in exploiting the potential of using nutrients to modulate disease. An obvious target for this approach was in serious diseases where nutritional intake is poor and dysregulation of the immune response is present. With decreased enteral nutrition, enterocytes are deprived of luminal nutrients they require. This leads to gut atrophy and disruption of the gastrointestinal barrier, which leads to the possibility of bacterial translocation or gut-derived sepsis (Hulsewe and others 2004, Balzan and others 2007). As the gastrointestinal tract is in fact the largest immune organ, dysregulation of the immune response further compromises the host and leads to multiple organ dysfunction. Given the relationship between critical illness and gut atrophy, supplementation with the gastrointestinal tract’s preferred energy source, glutamine, is an attempt at restoring the integrity and function of this vital organ system.

Despite the very important role of glutamine in health and disease, trials evaluating the therapeutic use of glutamine have yielded mixed results (Bertolini and others 2003, Heyland and Samis 2003, Fuentes-Orozco and others 2004, Hulsewe and others 2004). A possible reason for conflicting results may relate to the form of glutamine used in the various trials. The most consistent positive effects have been associated with glutamine administered parenterally to critically ill surgical patients (Powell-Tuck and others 1999, Labow and Souba 2000). Unfortunately, parenteral glutamine is not widely available. While there are many trials supporting enteral glutamine for use in trauma and burn patients, the evidence is perhaps not as convincing. Supplementation of glutamine to burn and trauma patients has yielded some modest positive results in terms of decreased risk of infectious complications and decreased inflammatory response, but these trials were limited by their relative small sizes (Wilmore 2001, Bastian and Weimann 2002, Windle 2006). Furthermore, while glutamine is touted as the preferred fuel source of enterocytes and therefore could help support gut integrity, enteral administration of this amino acid does not seem to consistently improve circulating plasma glutamine concentrations.

Immune-enhancing diets

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References

Formulating diets to modulate the host immune response has led to the concept of “immune-enhancing diets”, and this is a major focus of current critical care nutrition (Montejo and others 2003). IEDs often contain several nutrients known to play important roles in ensuring that the host is able to deal with various pathophysiological processes, such as inflammation and oxidative stress. Such nutrients include glutamine, arginine, omega-3 fatty acids and antioxidants. These IEDs supplements are usually supplied as powders that can be easily dissolved in the patient’s drink or enteral formula and are therefore very convenient for clinical practice. One concern, however, is that since it is the pharmacological effects of these nutrients that it is being sought, then it is a specific therapeutic dose of these nutrients, not their mere presence, that is required to ensure a positive response. Nevertheless, little attention is being paid to the doses found in such products. Perhaps, more concerning is that conflicting results in many clinical trials and even meta-analyses have resulted in little consensus on the efficacy of such treatments (Heyland and others 2001, Heyland and Samis 2003, Montejo and others 2003).

A major critique of many such clinical trials is that IEDs are frequently supplied as cocktails, making isolation of effects attributed to a specific nutrient difficult. It is also possible that a side effect of one supplement could negate the positive effect of another. Another major critique is that many trials have used very heterogeneous populations of patients and only through ad hoc subgroups analyses can certain relationships be demonstrated (Sacks and others 2003). Yet, fewer trials evaluate a single nutrient in a set population, or those that do, lack adequate sample size. Because of these confounding factors, the apparent successes of IEDs must be interpreted with caution. Despite the fact that recent trials do show promise in the use of IEDs in severely affected patient populations, there is no consensus on the efficacy of this approach.

If one only considers trials evaluating the supplementation of a single nutrient on a particular condition, the strongest evidence is for the use of arginine in elective surgical patients (Sacks and others 2003). The role of arginine in healing is well known and has been associated with lower infectious complication rates. However, arginine has also been linked with possibly causing harm in septic patients and therefore the wisdom of supplementing arginine to all critically ill patients should be questioned (Stechmiller and others 2004). As arginine is a precursor to NO, the effects on vasomotor tone in an already cardiovascularly challenged individual may explain the negative effects of arginine supplementation to septic patients (Stechmiller and others 2004).

Veterinary data

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References

To date, there is a paucity of veterinary information evaluating the role of nutrients used specifically to modulate disease. While correction of particular deficiencies, for example, taurine deficiency, can have very positive effects, the use of IEDs in animals has not been well documented. The use of omega-3 fatty acid supplementation has been evaluated in dogs with chronic inflammatory diseases, such as atopy, but this approach has not been evaluated in dogs with acute and serious diseases. A recent trial did demonstrate a marked improvement of arrhythmias in asymptomatic boxers with arrhythmogenic right ventricular cardiomyopathy when these dogs were supplemented with omega-3 fatty acids (Smith and others 2007). Antioxidant therapy has been evaluated in experimental models of gastric dilatation-volvulus, but no trial has evaluated its efficacy in naturally occurring disease or shown significant benefits (Lantz and others 1992, Guilford and others 1995). Studies evaluating antioxidant therapy in cats have also yielded mixed results. Supplementation of vitamin E alone does not prevent oxidative injury (development of Heinz body anaemia) in cats fed onion powder or propylene glycol (Hill and others 2001), but the same group of investigators later showed that supplementation of vitamin E with cysteine in cats decreased the production of methaemoglobinaemia following acetaminophen challenge (Hill and others 2005).

Currently, there are only two published trials that have evaluated the use of glutamine in dogs and cats. In a trial of cats treated with methotrexate, enteral glutamine offered no intestinal protection in terms of reducing intestinal permeability (Marks and others 1999). Another trial evaluating the effects of enteral glutamine on plasma glutamine concentrations and prostaglandin E2 concentrations in radiation-induced mucositis showed no measurable benefit (Lana and others 2003). Possible reasons for the apparent failures in both of these trials could be attributed to inadequate doses used or because of the form used, enteral, was not effective in these conditions.

Chan and others (2006) recently evaluated the amino acid profile of critically ill dogs (for example, dogs with septic peritonitis, acute pancreatitis and trauma) and found that in respect to amino acids with immune-enhancing implications, only arginine was significantly lower than controls (median plasma arginine was 64·0 mmol/l [range 0·0 to 251·8 mmol/l] versus 117·6 mmol/l [64·8 to 165·9 mmol/l]; P<0·001). Differences in glutamine concentrations could not be demonstrated between these same two populations (median glutamine 591·9 mmol/l [range 132·0 to 1286·0 mmol/l] versus 706·5 mmol/l [168·8 to 942·3 mmol/l; P=0·132]). However, almost 30 per cent of critically ill dogs had plasma glutamine that were below the reference range (417 to 739 mmol/l) (unpublished data). Although our findings are interesting, further investigation is necessary before any recommendation for supplementation can be made. While there is a possibility that supplementation may confer positive effects, regardless of glutamine status in dogs and cats, such relationships have not yet been demonstrated.

Summary

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References

There is increasing evidence that nutrients such as omega-3 fatty acids, antioxidants and certain amino acids can have very positive effects in various diseases, even in companion animals. Whether relative deficiency of specific amino acids occur in dogs and cats with critical illnesses is uncertain and may be a key factor in determining whether supplementation merits further evaluation. An as-of-yet untested concept is the formulation of special veterinary diets incorporating these key nutrients to elicit the desired therapeutic response. Although the concept of IEDs would appear to make physiological sense, a major challenge for the formulation of these immune-enhancing cocktails is determining the necessary dosages. Despite very encouraging results in human beings, there are very few dose-finding trials to guide the proper formulation of these diets. An important consideration for development of these strategies for companion animals is that there are species differences that will most likely impact the requirements and kinetics of particular nutrients. For example, arginine is always an essential amino acid in the cat, but this is not true in either dogs or human beings.

Conclusions

Despite the many pitfalls discussed, nutritional modulation of diseases appears to be potentially useful strategy for companion animals. However, until trials can elucidate which specific nutrients and what dosages confer beneficial effects to particular patient populations, a certain degree of scepticism is advised. Of particular concern is the distinct possibility that significant species differences may reduce the usefulness of IEDs in veterinary patients. Before recommendations for the use of IEDs in veterinary patients can be made, many questions must be answered including whether actual or relative deficiencies in key nutrients occur in critically ill patients. In the event that supplementation of these nutrients is shown to be helpful, optimal doses and formulations must then be evaluated. Based on our current understanding and the paucity of data available in veterinary patients, there is currently little support for the widespread use of IEDs in the treatment of critically ill cats and dogs. There is stronger data supporting the use specific components of IEDs such as omega-3 fatty acids and antioxidants in animals. However, as our understanding of the interactions between nutrients and disease processes grows, we may yet identify a particular cocktail of nutrients that could modulate even serious diseases. Based on the progress being made in the area of clinical nutrition, it is quite evident that there should be a greater appreciation for the role nutrients play in ameliorating diseases and how treatment strategies for certain conditions in companion animals may one day heavily depend on nutritional therapies.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids
  5. Antioxidants
  6. Special amino acids
  7. Immune-enhancing diets
  8. Veterinary data
  9. Summary
  10. References
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