Systemic Response to Injury and Metabolic Support
BASIC SCIENCE QUESTIONS
1. The vagus nerve mediates which of the following in the setting of systemic inflammation?
A. Enhanced gut motility
B. Decreased protein production by the liver
C. Decreased tumor necrosis factor (TNF) production
D. Increased heart rate to increase cardiac output
The vagus nerve exerts several homeostatic influences, including enhancing gut motility, reducing heart rate, and regulating inflammation. Central to this pathway is the understanding of neurally controlled anti-inflammatory pathways of the vagus nerve. Parasympathetic nervous system activity transmits vagus nerve efferent signals primarily through the neurotransmitter acetylcholine. This neurally mediated anti-inflammatory pathway allows for a rapid response to inflammatory stimuli and also for the potential regulation of early proinflammatory mediator release, specifically tumor necrosis factor (TNF). Vagus nerve activity in the presence of systemic inflammation may inhibit cytokine activity and reduce injury from disease processes such as pancreatitis, ischemia and reperfusion, and hemorrhagic shock. This activity is primarily mediated through nicotinic acetylcholine receptors on immune mediator cells such as tissue macrophages. Furthermore, enhanced inflammatory profiles are observed after vagotomy, during stress conditions. (See Schwartz 9th ed., p. 17.)
2. Cytokines are which type of hormone?
B. Amino acid
C. Fatty acid
Cytokines are polypeptide hormones. Humans release hormones in several chemical categories, including polypeptides (e.g., cytokines, glucagon, and insulin), amino acids (e.g., epinephrine, serotonin, and histamine), and fatty acids (e.g., glucocorticoids, prostaglandins, and leukotrienes). There are no carbohydrate hormones. (See Schwartz 9th ed., p. 17.)
3. Which of the following is a function of heat shock proteins?
A. Binding of autologous proteins to improve ligand binding
B. Induction of the white cell oxidative burst
C. Binding to capillary endothelium to prevent fluid extravasation
D. Stabilization of membranes to prevent cell lysis
Heat shock proteins (HSPs) are a group of intracellular proteins that are increasingly expressed during times of stress, such as burn injury, inflammation, and infection. HSPs participate in many physiologic processes, including protein folding and protein targeting. The formation of HSPs requires gene induction by the heat shock transcription factor. HSPs bind both autologous and foreign proteins and thereby function as intracellular chaperones for ligands such as bacterial DNA and endotoxin. HSPs are presumed to protect cells from the deleterious effects of traumatic stress and, when released by damaged cells, alert the immune system of the tissue damage. (See Schwartz 9th ed., p. 20.)
4. Which of the following is an eicosanoid?
A. Tumor necrosis factor (TNF)
B. Arachidonic acid
Thromboxane is an eicosanoid. Arachidonic acid is one of two precursors of the eicosanoids. TNF and IL-10 are cytokines. Eicosanoids are derived primarily by oxidation of the membrane phospholipid arachidonic acid (eicosatetraenoic acid) and are composed of subgroups, including prostaglandins, prostacyclins, hydroxyeicosatetraenoic acids (HETEs), thromboxanes, and leukotrienes. The synthesis of arachidonic acid from phospholipids requires the enzymatic activation of phospholipase A2 (Fig. 2-1). Products of the COX pathway include all of the prostaglandins and thromboxanes. The lipoxygenase pathway generates leukotrienes and HETE…. Eicosanoids are produced primarily through two major pathways: (1) with arachidonic acid (omega-6 fatty acid) as substrate and (2) eicosapentaenoic acid (omega-3 fatty acid) as substrate. (See Schwartz 9th ed., p. 22.)
FIG. 2-1. Schematic diagram of arachidonic acid metabolism. LT = leukotriene; PG = prostaglandin; TXA2 = thromboxane A2.
5. Omega-3 fatty acids have which of the following effects on the inflammatory response?
A. Increased inflammatory response
B. Decreased inflammatory response
C. Delayed inflammatory response
D. No effect on the inflammatory response
Omega-3 fatty acids have specific anti-inflammatory effects, including inhibition of NF-B activity, TNF release from hepatic Kupffer cells, as well as leukocyte adhesion and migration. The anti-inflammatory effects of omega-3 fatty acids on chronic autoimmune diseases such as rheumatoid arthritis, psoriasis, and lupus have been documented in both animals and humans. In experimental models of sepsis, omega-3 fatty acids inhibit inflammation, ameliorate weight loss, increase small bowel perfusion, and may increase gut barrier protection. In human studies, omega-3 supplementation is associated with decreased production of TNF, interleukin-1β, and interleukin-6 by endotoxin stimulated monocytes. In a study of surgical patients, preoperative supplementation with omega-3 fatty acid was associated with reduced need for mechanical ventilation, decreased hospital length of stay, and decreased mortality with a good safety profile. (See Schwartz 9th ed., p. 22.)
6. Which of the following are known effects of tumor necrosis factor (TNF)?
A. Decreases catabolic response
B. Promotes insulin entry into cells
C. Enhances the expression of eicosanoids
D. Delays activation of the coagulation pathway
Tumor necrosis factor alpha (TNF) is a cytokine that is rapidly mobilized in response to stressors such as injury and infection, and is a potent mediator of the subsequent inflammatory response. TNF is primarily synthesized by macrophages, monocytes, and T cells, which are abundant in peritoneum and splanchnic tissues. Although the circulating half-life of TNF is brief, the activity of TNF elicits many metabolic and immunomodulatory activities. TNF stimulates muscle breakdown and cachexia through increased catabolism, insulin resistance, and redistribution of amino acids to hepatic circulation as fuel substrates. In addition, TNF also mediates coagulation activation, cell migration, and macrophage phagocytosis, and enhances the expression of adhesion molecules, prostaglandin E2, platelet-activating factor, glucocorticoids, and eicosanoids. (See Schwartz 9th ed., p. 24.)
7. Which of the following are adhesion molecules (i.e., cells that mediate leukocyte to endothelial adhesion)?
A. Platelet activating factor
C. Transforming growth factor beta (TGF-β)
D. Tumor necrosis factor (TNF)
There are 4 families of adhesions molecules: selectins, immunoglobulins, Beta (CD18) integrins, and Beta (CD29) integrins. L-selectin is a member of the selectin family of adhesion molecules. Platelet activating factor is a phospholipid which mediates leukocyte function but does not contribute to adhesion. TGF-β is a polypeptide growth factor which is upregulated in some malignant tumors. TNF is a cytokine which is upregulated in inflammatory conditions, but which does not play a role in adhesion of leukocytes to endothelium (Table 2-1). (See Schwartz 9th ed., p. 33.)
TABLE 2-1 Molecules that mediate leukocyte-endothelial adhesion, categorized by family
8. The primary physiologic effect of nitric oxide (NO) is
A. Increased platelet adhesion
B. Increased leukocyte-endothelial adhesion
C. Increased microthrombosis
D. Increased smooth muscle relaxation
Nitric oxide (NO) was initially known as endothelium-derived relaxing factor due to its effect on vascular smooth muscle and has important functions in both physiologic and pathologic control of vascular tone. Normal vascular smooth muscle relaxation is maintained by a constant output of NO and subsequent activation of soluble quanylyl cyclase. NO also can reduce microthrombosis by reducing platelet adhesion and aggregation (Fig. 2-2). NO easily traverses cell membranes and has a short half-life of a few seconds and is oxidized into nitrate and nitrite. NO is constitutively expressed by endothelial cells; however, inducible NO synthase, which is normally not expressed, is upregulated in response to inflammatory stimuli, which increases NO production. Increased NO is detectable in septic shock and in response to TNF, IL-1, IL-2, and hemorrhage. NO mediates hypotension observed during septic shock; however, a clinical trial of a nonselective NOS inhibitor showed increased organ dysfunction and mortality. (See Schwartz 9th ed., p. 33.)
FIG. 2-2. Endothelial interaction with smooth muscle cells and with intraluminal platelets. Prostacyclin (prostaglandin I2, or PGI2) is derived from arachidonic acid (AA), and nitric oxide (NO) is derived from L-arginine. The increase in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) results in smooth muscle relaxation and inhibition of platelet thrombus formation. Endothelins (ETs) are derived from “big ET,” and they counter the effects of prostacyclin and NO.
9. Prostacyclin has which of the following effects in systemic inflammation?
A. Inhibition of platelet aggregation
C. Increased adhesion molecules
D. Decreased cardiac output
Prostacyclin is a member of the eicosanoid family and is primarily produced by endothelial cells. Prostacyclin is an effective vasodilator and also inhibits platelet aggregation. During systemic inflammation, endothelial prostacyclin expression is impaired, and thus the endothelium favors a more procoagulant profile. Prostacyclin therapy during sepsis has been shown to reduce the levels of cytokines, growth factors, and adhesion molecules through a cAMP-dependent pathway. In clinical trials, prostacyclin infusion is associated with increased cardiac output, splanchnic blood flow, and oxygen delivery and consumption with no significant decrease in mean arterial pressure. However, further study is required before the widespread use of prostacyclin is recommended. (See Schwartz 9thed., p. 33.)
10. How many calories per day are required to maintain basal metabolism in a healthy adult?
A. 10-15 kcal/kg/day
B. 20-25 kcal/kg/day
C. 30-35 kcal/kg/day
D. 40-45 kcal/kg/day
To maintain basal metabolic needs (i.e., at rest and fasting), a normal healthy adult requires approximately 22 to 25 kcal/kg per day drawn from carbohydrate, lipid, and protein sources. (See Schwartz 9thed., p. 34.)
11. The primary source of calories during acute starvation (5 days fasting) is
B. Muscle (protein)
D. Ketone bodies
In the healthy adult, principal sources of fuel during short-term fasting (5 days) are derived from muscle protein and body fat, with fat being the most abundant source of energy. (See Schwartz 9th ed., p. 34.)
12. Which of the following is the primary fuel source in prolonged starvation?
B. Muscle (protein)
D. Ketone bodies
In prolonged starvation, systemic proteolysis is reduced to approximately 20 g/d and urinary nitrogen excretion stabilizes at 2 to 5 g/d (Fig. 2-3). This reduction in proteolysis reflects the adaptation by vital organs (e.g., myocardium, brain, renal cortex, and skeletal muscle) to using ketone bodies as their principal fuel source. In extended fasting, ketone bodies become an important fuel source for the brain after 2 days and gradually become the principal fuel source by 24 days. (See Schwartz 9th ed., p. 35.)
FIG. 2-3. Fuel utilization in extended starvation. Liver glycogen stores are depleted, and there is adaptive reduction in proteolysis as a source of fuel. The brain uses ketones for fuel. The kidneys become important participants in gluconeogenesis. RBC = red blood cell; WBC = white blood cell. (Adapted with permission from Cahill GF: Starvation in man. N Engl J Med 282:668, 1970. Copyright © Massachusetts Medical Society. All rights reserved.)
13. Which of the following is the primary fuel source after acute injury?
B. Muscle (protein)
D. Ketone bodies
Lipids are not merely nonprotein, noncarbohydrate fuel sources that minimize protein catabolism in the injured patient. Lipid metabolism potentially influences the structural integrity of cell membranes as well as the immune response during systemic inflammation. Adipose stores within the body (triglycerides) are the predominant energy source (50 to 80%) during critical illness and after injury. Fat mobilization (lipolysis) occurs mainly in response to catecholamine stimulus of the hormone-sensitive triglyceride lipase. Other hormonal influences which potentiate lipolysis include adrenocorticotropic hormone (ACTH), catecholamines, thyroid hormone, cortisol, glucagon, growth hormone release, reduction in insulin levels, and increased sympathetic stimulus. (See Schwartz 9th ed., p. 36.)
14. Sepsis increases metabolic needs by approximately what percentage?
Sepsis increases metabolic needs to approximately 150-160% of resting energy expenditure, or 50% above normal. The magnitude of metabolic expenditure appears to be directly proportional to the severity of insult, with thermal injuries and severe infections having the highest energy demands (Fig. 2-4). The increase in energy expenditure is mediated in part by sympathetic activation and catecholamine release, which has been replicated by the administration of catecholamines to healthy human subjects. (See Schwartz 9th ed., p. 36, and Table 2-2.)
FIG. 2-4. Influence of injury severity on resting metabolism (resting energy expenditure, or REE). The shaded area indicates normal REE. (Adapted with permission from Long CL et al: Metabolic response to injury and illness: Estimation of energy and protein needs from indirect calorimetry and nitrogen balance. JPEN J Parenter Enteral Nutr 3:452, 1979.)
TABLE 2-2 Caloric adjustments above basal energy expenditure (BEE) in hypermetabolic conditions
15. What is the most abundant amino acid in the human body?
Glutamine is the most abundant amino acid in the human body, comprising nearly two thirds of the free intracellular amino acid pool. Of this, 75% is found within the skeletal muscles. In healthy individuals, glutamine is considered a nonessential amino acid, because it is synthesized within the skeletal muscles and the lungs. Glutamine is a necessary substrate for nucleotide synthesis in most dividing cells and hence provides a major fuel source for enterocytes. It also serves as an important fuel source for immunocytes such as lymphocytes and macrophages, and is a precursor for glutathione, a major intracellular antioxidant. (See Schwartz 9th ed., p. 46.)
1. A patient presents to the emergency room with a temperature of 39° C, a heart rate of 115, and a respiratory rate of 25. There are no localizing symptoms and the work-up does not reveal any specific source for the fever. Which of the following best describes this patient’s condition?
D. Septic shock
This patient meets the criteria for SIRS. Because there is no identifiable source for the condition, the criteria for infection and sepsis have not been met. Septic shock is sepsis with cardiovascular collapse (Table 2-3). (See Schwartz 9th ed., p. 16.)
TABLE 2-3 Clinical spectrum of infection and systemic inflammatory response syndrome (SIRS)
2. Cortisol is elevated in response to severe injury. How long can this response persist in a patient with a significant burn?
A. 2 days
B. 1 week
C. 1 month
D. 3 months
Cortisol is a glucocorticoid steroid hormone released by the adrenal cortex in response to ACTH. Cortisol release is increased during times of stress and may be chronically elevated in certain disease processes. For example, burn-injured patients may exhibit elevated levels for 4 weeks. (See Schwartz 9th ed., p. 18.)
3. Which of the following can be used to mitigate cortisol effects on wound healing?
A. Vitamin A
B. Vitamin B1
C. Vitamin C
D. Vitamin E
Wound healing also is impaired, because cortisol reduces transforming growth factor beta (TGF-β) and insulin-like growth factor I (IGF-I) in the wound. This effect can be partially ameliorated by the administration of vitamin A. (See Schwartz 9th ed., p. 18.)
4. Which of the following is found in patients with adrenal insufficiency?
Laboratory findings in adrenal insufficiency include hypoglycemia from decreased gluconeogenesis, hyponatremia from impaired renal tubular sodium resorption, and hyperkalemia from diminished kaliuresis. Calcium levels are not typically affected by adrenal insufficiency. (See Schwartz 9th ed., p. 19.)
5. Overfeeding (RQ >1.0) in a critically ill patient can result in
B. Increased risk of infection
D. Increased risk of DVT
Excess glucose from overfeeding, as reflected by RQs >1.0, can result in conditions such as glucosuria, thermogenesis, and conversion to fat (lipogenesis). Excessive glucose administration results in elevated carbon dioxide production, which may be deleterious in patients with suboptimal pulmonary function, as well as hyperglycemia, which may contribute to infectious risk and immune suppression…. Overfeeding may contribute to clinical deterioration via increased oxygen consumption, increased carbon dioxide production and prolonged need for ventilatory support, fatty liver, suppression of leukocyte function, hyperglycemia, and increased risk of infection. (See Schwartz 9th ed., p. 38.)
6. Which of the following is the initial enteral formula for the majority of surgical patients?
A. Low-residue isotonic formula
B. Elemental formula
C. Calorie dense formula
D. High protein formula
Most low-residue isotonic formulas provide a caloric density of 1.0 kcal/mL, and approximately 1500 to 1800 mL are required to meet daily requirements. These low-osmolarity compositions provide baseline carbohydrates, protein, electrolytes, water, fat, and fat soluble vitamins (some do not have vitamin K) and typically have a nonprotein-calorie:nitrogen ratio of 150:1. These contain no fiber bulk and therefore leave minimum residue. These solutions usually are considered to be the standard or first-line formulas for stable patients with an intact gastrointestinal tract. (See Schwartz 9th ed., p. 42.)
7. Which nutrient is proportionally increased in “pulmonary failure” enteral formula?
In pulmonary-failure formulas, fat content is usually increased to 50% of the total calories, with a corresponding reduction in carbohydrate content. The goal is to reduce carbon dioxide production and alleviate ventilation burden for failing lungs. (See Schwartz 9th ed., p. 43.)
8. Which vitamin is not present in commercially prepared intravenous vitamin preparations and, therefore, must be supplemented in a patient receiving TPN?
A. Vitamin A
B. Vitamin D
C. Vitamin E
D. Vitamin K
Intravenous vitamin preparations also should be added to parenteral formulas. Vitamin deficiencies are rare occurrences if such preparations are used. In addition, because vitamin K is not part of any commercially prepared vitamin solution, it should be supplemented on a weekly basis. (See Schwartz 9th ed., p. 45.)
9. New onset of glucose intolerance in a TPN dependent patient can be due to
A. Zinc deficiency
B. Copper deficiency
C. Chromium deficiency
D. Manganese deficiency
The most frequent presentation of trace mineral deficiencies is the eczematoid rash developing both diffusely and at intertriginous areas in zinc deficient patients. Other rare trace mineral deficiencies include a microcytic anemia associated with copper deficiency, and glucose intolerance presumably related to chromium deficiency. The latter complications are seldom seen except in patients receiving parenteral nutrition for extended periods. The daily administration of commercially available trace mineral supplements will obviate most such problems. Manganese deficiency is extremely rare and poorly described but may be associated with poor wound healing. (See Schwartz 9th ed., p. 45.)
10. Which of the following is a potential physiologic effect of anabolism (positive nitrogen balance)?
B. Metabolic acidosis
Glycosuria can result from hypokalemia. Since potassium is the most abundant intracellular anion, anabolism requires a large shift of potassium into the new cells, leading to serum hypokalemia.
Potassium is essential to achieve positive nitrogen balance and replace depleted intracellular stores. In addition, a significant shift of potassium ion from the extracellular to the intracellular space may take place because of the large glucose infusion, with resultant hypokalemia, metabolic alkalosis, and poor glucose utilization. In some cases as much as 240 mEq of potassium ion daily may be required. Hypokalemia may cause glycosuria, which would be treated with potassium, not insulin. Thus, before giving insulin, the serum potassium level must be checked to avoid exacerbating the hypokalemia. Magnesium tends to follow potassium—in this setting hypomagnesemia would be expected, not hypermagnesemia. Serum calcium levels should not be significantly affected by anabolism. (See Schwartz 9th ed., p. 46.)