Metabolic Response to Stress in the Neonate Who Has Surgery

After completing this article, readers should be able to: Over the past 4 decades, there have been remarkable improvements in our ability to care for critically ill infants. Progress in surgical and critical care of neonates has led to improved survival rates. Our understanding of the nutritional requirements of infants continues to advance. In contrast to years past, practitioners caring for critically ill infants undergoing surgery today have various nutritional options, including specialized parenteral and enteral formulations. Although our understanding of host defense and nutritional support continues to evolve, the interplay between the immune system and metabolism is being investigated. Hence, we are improving the match between the infant’s energy expenditure and nutritional requirements. Critical to further progress is additional understanding of the metabolic response of a neonate to surgical stress.All living organisms require energy to survive. Fuel sources enter into complex metabolic cascades to form the ultimate energy substrate, adenosine triphosphate (ATP), a fuel needed to drive and maintain all physiologic systems. Under stressful conditions, intrinsic substrate mobilizes to synthesize additional energy substrate. In essence, host substrate is mobilized for the promotion of healing after injury. Cytokines, released in response to injury, drive the catabolic response to stress, but in abundance, as with the systemic inflammatory response syndrome (SIRS), cytokines are detrimental to the organism. The nutritional requirements of a neonate are significantly greater than those of an adult because not only are there requirements for substrate intake to fulfill basic metabolic needs, but there are metabolic needs to maintain rapid and continued growth and development. Furthermore, the metabolic response to stress in a neonate, as may result from major illness or surgery, is markedly different than that of an adult exposed to the same stress. In this review, such differences are highlighted.Our understanding of the importance of nutrition and metabolism to humans has grown considerably over the millennia. Ancient Africans understood the link between food and infection. In fact, early Egyptians used honey to treat wound infections. Hippocrates, in the fifth century B.C., recognized the benefits of sensible diet for good health and commonly based his treatment of illnesses on diet. In the second century A.D., Galen further exhorted the importance of food, believing it to be a critical fuel for the body that is “used up by our heat as oil is by a flame.” Greater refinement in the understanding of nutrition and metabolism followed the Middle Ages. Remarkably, by the late 16th century, Robert Lower recognized that chyle represented the fatty component of an ingested meal, which admixes with blood to deliver nutrients throughout the body. The 19th century saw the breakthrough in the recognition of carbohydrates, protein, and fat as the basic substrates in food for nutrition and metabolism. Justus Von Lieg described the urea cycle and introduced the concept of nitrogen balance. Claude Bernard recognized the importance of pancreatic secretions to digestion and that the liver stored sugars as glycogen and synthesized sugars, as well. Carl Voit, a pupil of Von Lieg, built the first respiratory calorimeter. Subsequently, Muller and DuBois used calorimetry to characterize increased nitrogen excretion associated with fever and due to an increase in metabolic rate. In the 1920s, Sir David Cuthbertson first characterized the resultant increase in metabolic rate and protein catabolism following trauma or injury. This was our first evidence that stress directly affected metabolism.Drs Isidore S. Ravdin and Jonathan E. Rhoads fervently studied the relationship between surgery and metabolism over the next several decades as it became increasingly clear that malnutrition was associated with greater mortality in the surgical patient population. In the 1960s, Dr Rhoades charged Dr Stanley Dudrick with tackling the problems associated with parenteral nutrition. Initially, Dr Dudrick conducted intravenous hyperalimentation experiments in beagle puppies, subsequently applying his observations to six severely malnourished adult patients who had chronic complicated gastrointestinal problems. In all six patients, Dudrick showed positive nitrogen balance with the use of his hyperalimentation solution, thus revolutionizing the approach to caring for patients who are unable to use their alimentary tracts for nutrition. In 1967, Dudrick applied his experience in adults to a 2.5-kg neonate at birth who had near-total small bowel atresia. At 19 days of age, the infant weighed only 1.8 kg due to profound malnutrition. A polyvinyl catheter was inserted via a right external jugular vein cut-down into the superior vena cava and tunneled subcutaneously over the chest wall. After 6 weeks of escalating hyperalimentation, the child gained 1.6 kg. The child survived 22 months, growing to a maximum weight of 8.3 kg before dying. Dudrick soon published his initial set of observations using hyperalimentation to provide full support of the nutritional needs of neonates who have gastrointestinal tract anomalies, showing, among other results, a marked improvement in survival. Thus began the parenteral nutrition era.The basic food sources of energy are carbohydrates, lipids, and protein, which are broken down into glucose, fatty acids, and amino acids. Metabolic utilization of such basic substrates varies in anabolic and catabolic conditions. Under anabolic conditions, glycogen storage, protein synthesis, and lipogenesis occur in the body. Because the need to synthesize glucose and ketones under catabolic conditions is paramount, all glycogen, protein, and fat are broken down to fulfill this demand. Glucose utilization depends on the relative oxygen availability for its metabolism. Under aerobic conditions, a single molecule of glucose enters the Kreb’s cycle and, via glycolysis and oxidative phosphorylation, nets the synthesis of 36 molecules of ATP. Under anaerobic conditions, there is a net production of two molecules of ATP from one molecule of glucose. In terms of calories, 1 g of carbohydrate yields approximately 4 kcal of energy. Under catabolic conditions, the carbon skeletons of nearly all amino acids may enter the gluconeogenesis pathway in the form of pyruvate, a key intermediate in glucose synthesis. Oxidation of fatty acids yields molecules of acetyl-coenzyme A, which then enter the tricarboxy acid cycle. If the tricarboxy acid cycle is saturated, oxidation produces ketones. Glucose is the preferred substrate of the brain, the renal medulla, and erythrocytes. During starvation, both glucose and ketones are used as the primary substrate of the brain.Infants have limited capacity to metabolize glucose compared with adults. Poor glucose metabolism is exacerbated in preterm or low-birthweight infants. Experiments show that glucose intake is the primary determinant of total body carbohydrate and fat metabolism. The maximal oxidative capacity for glucose in infants undergoing surgery is equivalent to the energy expenditure of the infant (18 g/kg per day). Glucose intake in excess of 18 g/kg per day leads to net fat synthesis and cessation of fat oxidation. Significant consequences of this include hypercarbia, tachypnea, hypertriglyceridemia, and fatty liver deposition. Net fat oxidation remains minimal regardless of fat intake in the setting of excessive glucose intake in the infant having surgery. Hence, care must be taken not to exceed the infant’s capacity to metabolize glucose.Positive nitrogen balance in infants is critical for the maintenance of adequate growth and development. Neonates require approximately 2.5 to 4.0 g protein per kilogram bodyweight per day, including essential amino acids. Requirements can be higher with protein-wasting conditions such as the infant who has a proximal jejunostomy. Protein metabolism is dependent not only on protein intake but also on total energy intake. Nonprotein caloric intake in the form of fat or carbohydrate minimizes protein oxidation and, thus, can support positive nitrogen balance.Much of what is known regarding the surgical stress response is defined in the adult population; little is known in the pediatric age group, and more specifically, the neonatal population. Nevertheless, lessons learned from the adult population are important in attempts to assess and manage the metabolic consequences of surgical stress in the neonate. In adults, sepsis, surgery, or trauma initiates a hypometabolic “ebb” phase followed by a prolonged hypermetabolic “flow” phase. In essence, the magnitude of surgical stress is defined by the severity of injury or inflammation/infection associated with a particular condition. During the hypermetabolic phase, mobilization and utilization of substrates from existing tissues is increased for the purpose of meeting the metabolic needs of vital organs, promoting tissue repair, and supporting activation of the immune system. Commonly, this is in the setting of starvation, ischemia, and acidosis, all of which exacerbate the generalized catabolic state. Such a metabolic response to surgical stress has evolved to enhance survival.During the hypermetabolic phase in surgically stressed adults, there is a redistribution of protein accompanied by acute nitrogen loss. Total body protein is a combination of skeletal muscle and visceral organ protein. During pronounced surgical stress, protein from the skeletal muscle compartment shifts to the visceral organ compartment. Skeletal muscle mass plays a key role in the patient’s ability to withstand prolonged catabolic state because it represents 30% to 50% of the total protein mass. During the hypermetabolic phase, stressed individuals have increased urinary nitrogen excretion that relates directly to the extent of injury and mobilization of substrate. Nitrogen is excreted primarily in the form of urea.The resting energy expenditure is greatest in the neonate; hence, the caloric requirements of neonates and infants are also greater than those of older children, adolescents, and adults (Table 1). Following sepsis, surgery, or trauma, adults undergo a hypometabolic “ebb” phase, which persists for up to 24 hours, followed by a prolonged hypermetabolic “flow” phase. In contrast, newborns undergoing surgery experience a transient hypermetabolic phase involving increased energy expenditure associated with increased heart rate and respiratory rate. However, this response is short-lived, with return of energy expenditure to baseline within 12 to 24 hours. Energy expenditure remains at baseline in the first 5 to 7 days. Interestingly, infants undergoing major surgery more than 48 hours after birth experience a greater increase in energy expenditure immediately after surgery compared with those undergoing surgery within the first 24 hours of birth. One explanation for this difference is the presence of endogenous opioids in the newborn that blunt the response to nociceptive stimuli. A similar return to baseline in energy expenditure occurs in older infants. Of note, resting energy expenditure does not rise significantly in critically ill infants who have SIRS, sepsis, or septic shock, which is in stark contrast to adults.SIRS is the result of an exaggerated inflammatory response to a stressor. In general, patients who have SIRS present with fever, tachycardia, tachypnea, hypotension, and hyperglycemia; pediatric criteria are defined in Table 2. Decreased systemic vascular resistance, decreased oxygen extraction, increased heart rate, increased minute ventilation, and increased gluconeogenesis and fat oxidation characterize the hypermetabolic state. Conditions that initiate SIRS include infection, trauma, hemorrhage, burn injury, ischemia reperfusion, and pancreatitis.There is ample evidence that infection or tissue injury can lead to upregulation of adhesion molecules, which results in recruitment and activation of inflammatory cells at the site of injury or infection. Activated inflammatory cells elaborate various soluble mediators that amplify the inflammatory cascade and ultimately lead to more tissue injury and protein catabolism at remote sites (FigureF1). Normally, inflammation is a highly regulated physiologic process that is designed to restore homeostasis. The beneficial effects of inflammation include the production of acute-phase proteins, clearance of endotoxin, increased bacterial killing, and an anti-inflammatory response. A traumatic insult or infection leads to the release of proinflammatory mediators during the first 48 hours. The proinflammatory process later is counterbalanced by the release of counter-regulatory, anti-inflammatory cytokines that attenuate the proinflammatory response. It is the dynamic equilibrium between these two processes that leads to disease resolution. However, an overexuberant or uncontrolled proinflammatory response can lead to SIRS and associated multiorgan dysfunction (Table 3). Multiorgan dysfunction syndrome occurs in approximately one fifth of all pediatric patients who have SIRS, with a mortality rate of nearly 40%. Similarly, excessive production of anti-inflammatory cytokines can result in a state of immunodepression that can predispose the host to systemic infections and result in multiorgan dysfunction, a state known as the counter-regulatory anti-inflammatory response syndrome. Recently, a new sepsis categorization called the PIRO (predisposition, infection, host response, organ dysfunction) model was introduced to describe sepsis syndrome. The following section describes the cytokine cascade in general and a select set of cytokines that govern the inflammatory response.Considerable interest surrounds the role of cytokines as mediators of the stress response. Cytokines represent a heterogeneous group of short-lived polypeptides and glycoproteins, ranging in molecular weight from 8 to 30 kD, that are essential mediators of immunity and inflammation. They are secreted by a variety of inflammatory cells in response to antigenic or inflammatory stimuli. Cytokines function primarily in an autocrine or paracrine fashion rather than through endocrine mechanisms, although systemic plasma concentrations commonly are measured and reported. However, there is no direct correlation between plasma cytokine values and local tissue events. This observation may be due to many cytokines having soluble receptors that bind their active ligand, thereby neutralizing their biologic activity. In addition, the pleiotropic nature of cytokines makes it difficult to implicate a specific cytokine in local phenomenon because other cytokines may have similar effects. Cytokines serve as intercellular messengers by binding high-affinity surface receptors on specific cells to regulate cell growth, differentiation, and phenotypic behavior. They may amplify or downregulate the inflammatory response by inducing production of other pro- or anti-inflammatory molecules. In addition to cytokine-mediated inflammatory regulation, recent evidence suggests the existence of another set of specific proteins that suppress cytokine signal transduction: suppressors of cytokine signaling (SOCS). SOCS belong to a family of proteins that negatively regulate cytokine signal transduction.Tumor necrosis factor-alpha (TNF-alpha) is both a proximal and a central mediator of acute inflammation. 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