Metabolism and Nutrition of the Surgical Patient

During states of health, the body's neuroendocrine system is in a constant state of flux in order to maintain homeostasis. Alterations in host substrate metabolism and endocrine pathways have been documented in both human and veterinary patients with critical illness and neoplasia [1-6]. In general, stressors such as injury, neoplasia, infection, anesthesia, and surgery can adversely influence the body's physiologic adaptive mechanisms and disturb homeostasis (Fig. 5.1). The changes observed in metabolic pathways are intimately related to changes in the body's hormonal axes, including suppression of thyroid hormone activity and host release of glucocounterregulatory hormones, including cortisol and glucagon. Activation of the hypothalamic-pituitary-adrenal axis, thyroid axis, renin-angiotensin-aldosterone system, and release of proinflammatory cytokines during states of illness and injury can lead to protein and calorie depletion, negative nitrogen balance, organ dysfunction, suppressed immunity, delayed wound healing, changes in resting energy requirements, and increased morbidity and mortality [7-8]. Nutritional intervention is one modality that should be considered in all cases of critically ill and surgical patients to help restore homeostasis and aid in the healing and recovery process.

Figure 5.1. Activation of the stress response.

Stressed Versus Non-Stressed Starvation

In healthy patients, starvation occurs as a result of lack of available nutrients. This differs greatly from the "stressed starvation" that occurs in the face of illness and injury.

During non-stressed starvation, adaptations occur that favor utilization of fat for energy, sparing carbohydrate for glucose-dependent tissues and diverting host amino acids and protein to healing processes [5,9]. In healthy animals, hepatic glycogenolysis initially is utilized to maintain a state of euglycemia [10]. In dogs, hepatic glycogen becomes depleted within 48 to 72 hours [11] and physiologic adaptations are utilized to break down muscle protein and provide gluconeogenic precursors such as alanine and glutamine for gluconeogenesis [10,12]. During non-stressed starvation, pyruvate becomes transaminated and is transported to the liver as alanine, where it becomes deaminated to pyruvate for gluconeogenesis. The kidney and the gastrointestinal tract also contribute alanine for gluconeogenesis, sparing muscle protein for other purposes. Skeletal muscle stores of alanine can become depleted during prolonged stressed starvation and can lead to dyshomeostasis and loss of function [13]. Obviously, continued proteolysis can result in lack of available amino acids for de novo protein synthesis and wound healing.

As starvation becomes more prolonged, down-regulation of the patient's metabolic rate and muscle proteolysis occurs, and the body adapts by reverting to lipolysis and fat oxidation for energy purposes. Muscle lactate, rather than muscle amino acids, are shuttled to the liver for gluconeogenesis by the Cori cycle (Fig. 5.2) Although energy is formed in this process, it is largely an inefficient process by which the body maintains euglycemia.

Figure 5.2. Protein metabolism.

Stressed Starvation

Lack of adequate nutrient intake is of particular importance in surgical patients and those with a variety of illnesses due to maladaptive responses that occur. Inadequate nutrient intake is common in veterinary patients during the pre- and post-operative periods. Many animals either cannot, or will not, voluntarily consume their nutritional requirements as a result of nausea, pain, facial masses or trauma, or anxiety. Food is often withheld in preparation for anesthesia and surgery. Sometimes, inadequate food orders can contribute to a decrease in nutrient intake, even in the realm of a hospital environment [14]. Suppression of resting energy expenditure occurs because of down-regulation of the hypothalamic-pituitary-adrenal axis. However, the release of proinflammatory cytokine mediators, including interleukin-1, interleukin-2, interleukin-10, and tumor necrosis factor (TNF), combined with the glucose counterregulatory hormones cortisol and glucagon has been implicated to play a role in the catabolic stress response [15-17]. Continued proteolysis in ongoing starvation leads to negative nitrogen balance.

During a variety of stressors, including anesthesia and surgery, activation of the sympathetic nervous system leads to the release of the catecholamine norepinephrine from peripheral nervous tissue and epinephrine from the adrenal medulla [10]. Activation of the hypothalamic-pituitary-adrenal axis leads to the release of cortisol from the adrenal cortex. Epinephrine indirectly stimulates hepatic glycogenolysis and gluconeogenesis. The actions of epinephrine also inhibit insulin release and promote the release of glucagon. An increase in glucagon relative to insulin helps to promote glycogenolysis, gluconeogenesis, and ureagenesis. Gluconeogenesis from muscle amino acids proceeds unchecked, and nitrogen utilization is increased relative to intake. Accelerated protein catabolism in stressed patients and urinary nitrogen loss contributes to protein-calorie malnutrition [17]. Negative nitrogen balance is characteristic of a catabolic state.

During stress, muscle protein appears to be the primary source of energy used for fuel, with approximately 25% of calories obtained from utilization of endogenous proteins [15]. In addition to endogenous nitrogen, amino acids are shuttled into the production of hepatic acute-phase protein synthesis during stress and illness. In canine surgical and critically ill patients, accelerated urinary nitrogen loss can occur even in the presence of enteral and parenteral nutritional supplementation [16]. As a result of diminished structure and functional protein synthesis, depressed immune function, impaired wound healing, and cardiorespiratory dysfunction can occur (Table 5-1) [18-20].

Impaired carbohydrate utilization can also occur during critical illness. Any stressor, including surgery and anesthesia, that results in the release of glucocounterregulatory hormones, namely epinephrine, cortisol, and glucagon, can lead to impaired carbohydrate metabolism and inefficient glucose utilization. Glucocounterregulatory hormone release during illness can increase the synthesis of pyruvate carboxylase and phosphoenolpyruvate carboxylase, enzymes that favor the conversion of three-carbon intermediates to glucose [21]. As a result, glucose entry into the tricarboxylic acid (TCA) cycle is limited, and favors the shuttling of glucose through other pathways, including the Cori cycle or glucose-alanine shuttle (Fig. 5-3) [21].

Figure 5.3. Energy metabolism.

Lipid Metabolism

Endogenous catecholamines released during stress promote lipolysis by increasing hormone-sensitive lipase in adipose tissue. Glycerol and free fatty acids are utilized as alternate energy sources, thus sparing endogenous amino acids for other purposes. Fatty acids are oxidized in the liver to the ketone bodies beta-hydroxybutyrate, acetone, and acetoacetate that can be utilized for energy purposes by some tissues, including the brain [22]. Glycerol released during lipolysis can also serve as a gluconeogenic precursor, further sparing muscle amino acids. In non-stressed starvation, lipolysis is a primary means by which euglycemia is achieved. However, during stress, peripheral insulin resistance can lead to catabolism in the face of lipolysis and hyperglycemia.

Resting Energy Expenditure

A patient's resting energy expenditure (REE) is the amount or number of calories (Kcal) expended by an animal in a postabsorptive state while resting in a thermoneutral environment [8]. Values used for REE and basal energy requirements (BER) in small animal patients have largely been obtained from healthy animals or extrapolated from those obtained from human subjects [23-24]. In human medicine, the precise measurement of resting energy expenditure has become fairly routine using bed-side indirect calorimetry units. In veterinary patients, relatively few studies have used similar methods to determine energy expenditure in small animal patients [23-27]. It was previously thought that all human and veterinary patients with illness and injury, including surgically induced trauma, were in a hypermetabolic state, and therefore required caloric intake in excess of their basal requirements [25]. This assumption led to the routine arbitrary use of an illness/injury/infection multiplication factor to apply to a patient's REE to determine the patient's actual daily caloric requirements. Indirect calorimetry analyses conducted in over 106 dogs with a variety of illnesses documented no significant increase in their resting energy expenditure compared with that of healthy controls [23]. Surgery and anesthesia, too, failed to increase a dog's REE [25-27]. In fact, research has demonstrated that an individual dog's REE can differ depending on the type, duration, and degree of illness; the REE may be increased, decreased, or normal [28]. Depending on the time that an individual patient's REE is measured, nutritional support may over- or underestimate caloric requirements throughout the course of illness and healing. Oversupplementation of calories, particularly in the form of carbohydrates, can lead to carbon dioxide retention and respiratory muscle fatigue. Oversupplementation of carbohydrates in human patients has been thought to contribute to impaired ability to wean from mechanical ventilation [29]. If, however, the patient's REE is measured at a time-point at which the patient is hypometabolic, nutritional support may underestimate the patient's changing caloric needs and may actually contribute to malnutrition. The most recent recommendations by veterinary nutritionists describe feeding veterinary patients at least 50% and no more than 100% of their calculated REE, in anticipation that the patient's actual energy needs will change over the course of disease and recovery [30]. In general, the formula: [(30 x Body weight in kg) + 70] = Kcal/day is used to calculate a patient's resting energy expenditure for nutritional support purposes.

The Hypothalamic-Pituitary-Thyroid Axis

The hypothalamic-pituitary-thyroid axis plays an important role in numerous cellular functions during states of health, including cellular oxygen consumption, basal energy metabolism, growth and development, regulation of cardiovascular indices, and regulation of carbohydrate and lipid metabolism [31]. During health, the hypothalamus secretes thyrotropin-releasing hormone (TRH) into the median eminence of the pituitary. The pituitary gland, in turn, releases thyroid-stimulating hormone (TSH), which stimulates the thyroid glands to produce and secrete the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Triiodothyronine is the active form of thyroid hormone. Approximately 10 to 20% of T3 in circulation is released directly from the thyroid glands, and 80 to 90% is a result of conversion of T4 to T3 by enzymatic activity in the peripheral tissues. Both T4 and T3 feed back to the hypothalamus and pituitary gland to suppress further thyroid stimulation.

Down-regulation of the thyroid axis has been documented in a variety of systemic illnesses and injury in veterinary patients, including hyperadrenocorticism, pneumonia, sepsis, diabetes mellitus, renal and hepatic disease, and neoplasia [32-33]. During periods of stress and healing, down-regulation of thyroid hormone metabolism may be a teleological adaptive mechanism by which energy expenditure and protein loss decrease in order to allow healing to occur. During non-stressed starvation, T3 levels decline within 3 days of decreased nutrient intake [34]. Glucocorticoid release during stress is a primary mediator of inducing euthyroid sick syndrome in human and nonhuman animals. Euthyroid sick syndrome is characterized by impaired release of thyrotropin-releasing hormone from the hypothalamus, decreased pituitary responsiveness to TRH, decreased TSH release from the pituitary gland, and decreased level of thyroid-binding proteins in circulation. Complicating factors include decreased conversion of T4 to T3 owing to impaired monoiodinase enzyme activity, and decreased affinity of T3 for peripheral receptors. Euthyroid sick syndrome can be distinguished from true hypothyroidism by the presence of normal to low endogenous TSH in the presence of low T4. In true hypothyroidism, the lack of negative feedback of T4 to the pituitary gland results in elevated eTSH levels in the presence of low T4. Supplementation of thyroid hormone in euthyroid sick syndrome is ineffective at increasing patient survival.

In dogs, euthyroid sick syndrome has been documented in both acute [2] and chronic illnesses [35-38]. In one study, 67% of dogs admitted to a veterinary critical care unit displayed derangements of the thyroid axis, including decreased T3 and T4 concentrations [2]. Similarly, an increase in euthyroid sick syndrome was observed in surgical patients in the postoperative period compared with the same animals preoperatively [32]. In humans, severely decreased thyroid hormone function has been associated with an increase in morbidity and mortality [1,39]. Improvement of clinical condition was associated with similar improvements in thyroid axis function.

Nutritional Support and Glutamine

Nutritional support in surgical patients should be proactive, and ideally should aim to meet the patient's ongoing needs and prevent endogenous protein catabolism [40]. In every patient, a daily nutritional assessment should be considered. Is the patient able to eat? Is vomiting or diarrhea present that can increase nutrient loss or prevent nutrient absorption? Is there excessive loss of protein in the urine or from wound exudates? Is the animal third spacing fluid and protein? Based on the answers to these questions, the route and amount of nutritional support can be decided. In all cases, enteral nutrition is preferred, whenever possible. If enteral nutrition is impossible, parenteral nutrition should be implemented. Both enteral and parenteral nutritional support should provide not only a source of protein, carbohydrate, and lipids, but should also provide other nutrients that can become depleted during the course of illness. As a general rule, protein should compose 30 to 45% of a cat's diet and 15 to 30% of a dog's diet on an as fed dry matter basis [41]. Carbohydrates should be less than 50% of a cat's diet and approximately 50% of a dog's diet on an as fed dry matter basis[41]. Fat should constitute 10 to 30% of a cat's and 10 to 20% of a dog's diet on an as fed dry matter basis[41]. Enteral products formulated specifically for use in critically ill patients are available (Clinicare, Abbott Animal Health, North Chicago, IL; Maximum Calorie, The Iams Company, Dayton, OH; A/D, Hill's Pet Nutrition, Topeka, Kansas) and are an excellent source of calories, protein, and fat in ratios that are highly digestible for veterinary patients with critical illness or in the post-surgical period. A complete review of parenteral nutrition is located elsewhere in this text.

Glutamine

Glutamine is a nonessential amino acid that is required for numerous physiologic processes throughout the body, including normal enterocytes function, nucleic acid and protein synthesis, renal ammoniagenesis, carbohydrate metabolism and gluconeogenesis, and cellular immune function. Although glutamine is abundant in host tissues, demand quickly exceeds the body's synthetic capacity during states of illness, and the nutrient becomes "conditionally essential" in critically ill and surgical patients. Glutamine depletion has been associated with negative nitrogen balance, enterocyte atrophy, suppressed cellular immune function, and increased risk of bacterial translocation and sepsis. Glutamine supplementation in human enteral and parenteral formulations has been shown to increase muscle protein synthesis, peripheral leukocyte numbers, and overall nitrogen balance [42]. Although limited studies have been performed in veterinary patients, stable glutamine dipeptides are available in commercial enteral nutrition formulations (Clinicare, Abbott Animal Health, North Chicago, IL) and may help promote gastrointestinal health during the pre- and post-surgical periods.

Omega-3 Fatty Acids

The ratio of omega-3 to omega-6 polyunsaturated fatty acids has been implicated in playing a role in inflammatory conditions both in human and veterinary patients [43]. Omega-3 fatty acids are derived from alpha-linolenic acid, and omega-6 fatty acids are derived from linoleic acid. Both fatty acids are essential nutrients in cats and dogs. Breakdown of omega-3 and omega-6 fatty acids by cyclooxygenase and lipooxygenase ultimately results in the production of mediators of inflammation, namely, eicosanoids, prostaglandins, leukotrienes, and thromboxanes[43]. In general, proinflammatory mediators are the breakdown products of omega-6 fatty acids, whereas breakdown of omega-3 fatty acids, namely, eicosapentaenoic acid, produces anti-inflammatory mediators [43]. Fish oil supplementation, a potent source of omega-3 polyunsaturated fatty acids, may be beneficial in decreasing proinflammatory conditions in some species.