Metabolic Response to Trauma.pptx

overview on metabolic response

1. Presented by: Dr. Neha Umakant Chodankar II MDS Department of OMFS Metabolic Response to Trauma

2. Contents Introduction Detection of Cellular Injury Physiologic response to trauma CNS Regulation Of Inflammation In Response To Injury --- Neuro- endocrine response Mediators of Inflammation Cell Mediated Inflammation Metabolic Changes after Trauma Metabolism In Surgical Patients Metabolism during Starvation Modulation of response Nutrition as Therapy Conclusion

3. Introduction Injury produces profound systemic effects. Hormones, the autonomic nervous system, and cytokines all produce a series of responses that are designed to help defend the body against the insult of trauma and promote healing. Classically , these responses have been described as the stress response , a term coined by the Scottish chemist Cuthbertson in 1932.

4. The cascade of interactions and host responses in a severely traumatized patient follow a recognizable pattern, but the depth and duration of these changes are variable, and usually depend on the extent of the injury and the presence of ongoing stimulation. Each results in marked variations in the metabolic response, and this variability persists during the later chronic and recovery phases of the original injury. The body’s initial response to insult (the acute phase) is directed at maintaining adequate substrate delivery to the vital organs, in particular oxygen and energy.

5. Detection of Cellular Injury Mediated by members of damage associated molecular pattern family Systemic inflammatory response that limit damage and restore homeostasis: 1. Acute proinflammatory response - Innate immune system recognize ligands 2. Anti- inflammatory response - Modulate proinflammatory phase and return homeostasis

6. Physiologic response to trauma The metabolic response to trauma in humans has been defined in 3 phases: 1) Ebb phase or decreased metabolic rate in early shock phase, 2) Flow phase or catabolic phase, 3) Anabolic phase or recovery

7. Ebb phase D evelops within the first hours after injury (24-48 hours ). It is characterized by reconstruction of body’s normal tissue perfusion and efforts to protect homeostasis. In this phase, there is a decrease in total body energy and urinary nitrogen excretion. An early increase is detected in endocrine hormones such as catecholamines and cortisol.

8. As a result of this long lasting response, the adipose tissue, skin and other tissues are destructed . Flow phase Defined as an ‘all or nothing’ reaction High substrate flow should to target systems is essential. Although this response is necessary for survival in the short term, if it persists over a long period of time or if the response is severe it leads to the onset of body damage (2-7. days).

9. The flow phase is an early period catabolism that provides compensating response to the initial trauma and volume replacement, except most minor injuries. In this phase, the metabolic response is directly related to the supply of energy and protein substrates in order to protect tissue, damage repair and critical organ functions. The increased body oxygen consumption and metabolic rate are among these responses.

10. Late anabolic phase: The late anabolic phase is the final phase of the recovery period, and is characterized by gradual restoration of body protein and fat stores and normalization of positive nitrogen balance after the metabolic response to trauma is stopped. It may take a few weeks to several months after serious injury .

11. Phase Duration Role Physiological Response Hormonal response Ebb 24-48hrs Conserve Blood volume and energy Repair BMR Temperature CO2 Hypovolemia Lactic Acidosis Catecholamines Cortisol Aldosterone Flow Catabolic 3-10 days Mobilisation of energy stores- Recovery and Repair BMR Temperature CO2 O2 consumption Cytokines Increased Insulin Glucagon Cortisol Insulin resistance Anabolic 10-60 days Replacement of lost tissue Positive Nitrogen balance Growth hormone IGF

12. Ebb phase Flow phase Hypometabolic state Hypermetabolic state Decreased energy expenditure Increased energy expenditure Cold clammy extremities Warm extremities Cardiac output below normal Cardiac output increased Core temp low Core temp elevated Normal glucose production , elevated levels Increased glucose production, normal or slightly elevated Insulin conc low Low or elevated Catecholamines elevated High normal or elevated Glucagon elevated Elevated Mediated by central nervous system Mediated by central nervous system and cytokines

13. CNS Regulation Of Inflammation In Response To Injury DAMPs and inflammatory molecules convey stimulatory signals to CNS via multiple routes . Inflammatory stimuli interact with receptors on brain to generate proinflammatory mediators ( cytokines, chemokines , adhesion molecules, proteins of complement system, and immune receptors). Inflammation can also signal the brain via afferent fibres ( vagus nerve).

14. 1.Hypothalamic- pituitary- adrenal (HPA ) axis Release glucocorticoids 2. Sympathetic nervous system Release catecholamines An early response of the neuroendocrine system - upregulation of the sympatho -adrenal axis, Neuro-endocrine response

15. This causes inhibition of glucose uptake by tissue, which stimulates glucagon secretion. Sympathetic activity promotes lipolysis within adipose tissue, which begins to provide an energy source for gluconeogenesis. Gluconeogenesis in the liver is stimulated by glucagon .

16. Endocrine Stress Response Hormone Time Effect Catecholamines Stress dependent immediate and continues for 24-48hrs Hyperglycemia Raises metabolic rate Mobilize fatty acids Haemodynamic stability ADH Immediate to 1 week Promotes reabsorption of water Peripheral vasoconstrictor Renin- Angiotensin Vasoconstrictor Release of Aldosterone (conserves Na and eliminates K) Insulin First few hours: decreased secretion Later anabolic: increased release of insulin Glycolysis Glycogenesis Lipogenesis Proinflammatory activity Growth hormone Anabolic phase Protein synthesis Ketogenesis

17. Endocrine Stress Response Hormone Time Effect Catecholamines Stress dependent immediate and continues for 24-48hrs Hyperglycemia Raises metabolic rate Mobilize fatty acids Haemodynamic stability ADH Immediate to 1 week Promotes reabsorption of water Peripheral vasoconstrictor Renin- Angiotensin Vasoconstrictor Release of Aldosterone (conserves Na and eliminates K) Insulin 2 phases First few hours: decreased secretion Later anabolic: increased release of insulin with peripheral insulin resistance Glycolysis Glycogenesis Lipogenesis Proinflammatory activity Growth hormone Anabolic phase Protein synthesis Ketogenesis

18. Endocrine Stress Response Hormone Time Effect Catecholamines Stress dependent immediate and continues for 24-48hrs Hyperglycemia Raises metabolic rate Mobilize fatty acids Haemodynamic stability ADH Immediate to 1 week Promotes reabsorption of water Peripheral vasoconstrictor Renin- Angiotensin Vasoconstrictor Release of Aldosterone (conserves Na and eliminates K) Insulin First few hours: decreased secretion Later anabolic: increased release of insulin Glycolysis Glycogenesis Lipogenesis Proinflammatory activity Growth hormone Anabolic phase Protein synthesis Ketogenesis

19. Histamine Short acting endogenous amine Mediators of Inflammation H1 – bronchoconstriction, increases intestinal motility and myocardial contractility H2 – inhibits histamine release H1/H2 – hypotension, decreased venous return/peripheral blood pooling, increased capillary permeability, myocardial failure .

20. Serotonin It is monoamine neurotransmitter ( 5-hydroxytryptamine ) derived from tryptophan It is a potent vasoconstrictor Released by platelets Present in intestinal chromaffin cells & platelets Other effects include bronchoconstriction, platelet aggregation Unclear role in inflammation

21. Kallikrein-Kinin System Bradykinins are potent vasodilators that are stimulated by hypoxic and ischemic injury, Hemorrhage , sepsis, tissue injury

22. Acute Phase Proteins Nonspecific markers produced by hepatocytes in r esponse to injury, infection, inflammation Induced by IL-6

23. Cytokines Protein mediators, collectively called cytokines, are produced at the site of injury by diverse circulating immune cells - Monocytes , lymphocytes, macrophages, and other cells. The most important cytokines in trauma are tumor necrosis factor (TNF), the interleukins (IL-1 , IL-2, IL-6, and IL-8), the interferons, and various growth factors such as granulocyte-macrophage colony stimulating factor (GM-CSF), and platelet-derived growth factors (PDGFs).

24. TNF influences cellular attraction as part of the local inflammatory response, leukocyte migration, and systemic hypotension . It also promotes muscle catabolism, free fatty acid release, and hepatic synthesis of acute-phase reactants.

25. I nterleukins are polypeptides released from lymphocytes; each is numbered according to the amino acid sequence that elicits its action. Circulating free receptors are known for IL-1 and IL-6. IL-1 can be detected in the circulation within a few hours after injury More profound systemic effects include fever and changes in protein metabolism.

26. Cell Mediated Inflammation

27. PMNLs Catecholamines and glucocorticoids marginalize peripheral PMNs and recruit them from the bone marrow. Capillary endothelial integrity is disrupted, leading to the formation of edema, defects in oxygen delivery, hypoxic cellular injury, and other adverse consequences for cellular homeostasis.

28. Metabolic Changes after Trauma Oxygen and energy requirements are increased in proportion to the severity of the trauma. It is believed that 40% of the total body energy consumption is used for ion pumps and transport process.

29. Lipid Metabolism: Free fatty acids are primary sources of energy after trauma. Triglycerides provide 50-80% of the energy consumed after trauma and critical illness.

30. If the patient is given glucose in a dose more than he can oxidize this will lead to more hepatic steatosis. This phenomenon is more frequent in septic, diabetic, and obese patients. Hepatic ketogenesis is stimulated less in situations where starvation is together with an illness as compared to starvation alone due to high insulin levels. In this way, glucose is used as an energy source in the peripheral injured tissues.

31. The activity of lipoprotein lipase is reduced in fat and muscle by the action of increased proinflammatory cytokines (TNF) in trauma and sepsis. During the ebb phase, plasma fatty acid and glycerol levels increase by lipolysis. Lipolysis continues in the flow phase and the increased free fatty acids inhibit glycolysis. Fatty acid synthesis is inhibited with the effects of increase in glucagon and intracellular fatty acids. However, inhibition is not enough in cases of severe trauma, hemorrhagic shock and sepsis.

32. The rate of ketogenesis following trauma is inversely proportional to injury severity. Ketogenesis is reduced in major trauma, shock and sepsis due to an increase in insulin and increased use of free fatty acids. In minor trauma, ketogenesis is increased but this increase will not reach the level of starvation ketosis.

33. Protein And Amino Acid Metabolism In metabolic response to trauma systemic proteolysis begins especially by the action of glucocorticoids, the catabolism is increased and excretion of urinary nitrogen rise upto 30 g/day.

34. This translates to an average of 1.5% daily loss in body mass. According to this calculation, a traumatized individual with no oral nutrition is going to lose 15% of his body mass in 10 days . Therefore , amino acids cannot be accepted as long-term fuel reserves, and excess amounts of protein losses are incompatible with life. By gluconeogenesis after posttraumatic protein catabolism, amino acids are provided for the synthesis of acute phase proteins, albumin, fibrinogen, glycoproteins, complement factors and similar molecules.

35. Elective surgery and minor trauma lead to a decrease in protein synthesis and mild level protein degradation. Severe trauma, burns and sepsis progress with increased protein catabolism. Increase in urinary nitrogen levels and negative nitrogen balance can be detected at an early stage after injury peaking at day 7. Protein catabolism may continue upto 3 to 7 weeks Protein catabolism is carried out by degradation of skeletal muscle. The increase in protein metabolism is followed by the increase in flow phase and parallels to changes in oxygen uptake and heart rate.

36. Muscle catabolism can be reduced by nutritional support during flow phase. Protein synthesis can be stimulated, but complete suppression of muscle catabolism is not possible. Net muscle protein recovery can be obtained during the anabolic period of the disease only with enough exercise and nutritional support.

37. Carbohydrate Metabolism Administration of glucose to surgical patients during fasting aims to reduce proteolysis and to prevent the loss of muscle mass . Daily infusion of 50 g of glucose increases fat oxidation and suppresses ketogenesis . In case of excessive glucose administration excessive carbon dioxide production will occur, resulting in adverse effects in patients with suboptimal pulmonary function. Administration of glucose during fasting reduces protein breakdown for gluconeogenesis, but this reduction is not sufficient to meet the requirements in trauma and sepsis.

38. Other hormonal and proinflammatory factors are effective in protein degradation under stress conditions, and muscle breakdown is inevitable. Administering insulin in increased stress decreases protein breakdown in muscle tissue. This effect has been found to occur by increasing muscle protein synthesis and by preventing protein degradation in hepatocytes . One of the most important body responses to traumatic stimulation during critical illness is providing sufficient substrate to organs and cells where mitochondrial respiration is not possible.

39. Glucose can be used in hypoxic tissue and inflammatory cells with this feature. Glucose is also important in recovering wounds The severity of injury and tissue damage after trauma parallels hyperglycemia. In the early period of Ebb phase, glycogen stores, primarily hepatic, are used only for a period of 12-24 hours . In the late phase of trauma, the flow phase, amino acids, lactate, pyruvate and glycerol is used for renal and hepatic gluconeogenesis.

40. Increased endogenous glucose synthesis occurs in critical illness. This situation cannot be completely inhibited by exogenous glucose and insulin administration. Gluconeogenesis is an essential process that is driven by stress hormones and cytokines. The first metabolic change after trauma is gluconeogenesis . The lactate metabolism capacity is normally 150 grams, and increases to large amounts under stress. Glucose is synthesized from alanine in a similar manner. In this way, the nitrogen that is formed during amino acid metabolism is introduced to blood stream, and glucose production in the liver is ensured.

41. Physiological Effects Of Insulin And Insulin Resistance In Stress The decrease in the normal anabolic effect of insulin, i.e. the development of insulin resistance, is the main source of a series of reactions in response to injury and the consequent metabolic state. Insulin controls protein metabolism Insulin also controls fat metabolism The specific signaling pathways in insulin sensitive cells are activated to provide anabolic reactions such as glycogen storage, protein synthesis in muscle, or as to block lipolysis in fat cells.

42. Amino acids, free fatty acids and glucose is released into the bloodstream from various tissues in stress response. F at is consumed in the body rather than glucose . It has been reported that by infusing sufficient amount of insulin to keep glucose within normal range, the remaining metabolism is normalized.

43. From a clinical point of view, insulin infusion sufficient enough to normalize glucose levels can be used as the final aim to achieve these reactions and can be used to achieve glucose control. Tight glycemic control will improve the outcomes of critically ill patients following major trauma.

44. Metabolism In Surgical Patients Adequate nutrition of patients who lost weight and will undergo surgical procedures is critical. P atients generally die not due to their present diseases, but because of secondary complications due to malnutrition. In starvation, glucagon and epinephrine stimulate glycogenolysis through the cAMP pathway, while cortisol and glucagon stimulate gluconeogenesis. Factors Affecting Surgical Response ----Age, Nutrition and diet, Anesthesia and Operative stress

45. Postoperatively, the utilization of glucose is reduced due to insulin resistance, with an increase in triglyceride and free fatty acid break down due to an increase in catecholamine secretion. The increase in the use of lipid does not affect glucose management. However, the relative insulin resistance can be reduced by preoperative glucose loading. The degree of hyperglycemia significantly affects postoperative outcome and morbidity.

46. Metabolism During Fasting Comparable to changes seen in acute injury Average human requires 25-40 kcal/kg/day of carbs, protein, fat Normal adult body contains 300-400g carbs (glycogen) – 75-100g hepatic, 200-250g muscle (not available systemically due to deficiency of G6P)

47. Following the first 24 hours of fasting, liver and kidney glycogen stores will be depleted, and the glucose demand of tissues is provided by protein degradation and gluconeogenesis. For the first 5 days of fasting, there is upto 75 g/day of protein degradation. After the fifth day, the stress hormone response decreases and protein degradation levels decrease down to 15-20 g/day Metabolism of Simple Starvation Lactate is not sufficient for glucose demands Protein must be degraded (75 g/d) for hepatic gluconeogenesis Proteolysis occurs from decreased insulin and increased cortisol Elevated urinary nitrogen (7 -> 30 g/d)

48. Metabolism of Prolonged Starvation Proteolysis is reduced to 20g/d and urinary nitrogen excretion stabilizes to 2-5g/d Organs (myocardium, brain, renal cortex, skeletal muscle) adapt to ketone bodies in 2-24 days Kidneys utilize glutamine and glutamate in gluconeogenesis Adipose stores provide up to 40% calories ( approx 160 g FFA and glycerol) Stimulated by reduced insulin and increased glucagon and catecholamines

49. Modulation of Response Researchers have tested novel therapeutic strategies and options aimed at selectively inhibiting the undesirable actions of cytokines while allowing the appropriate responses to be expressed . Some effects of cytokines on target tissue have been successfully blocked by the use of anticytokine antibodies and specific cytokine receptor antagonists . Pharmacologic manipulation of the end-organ response to stress is also accomplished with some drug classes that act on specific mediators of the response.

50. Control of hyperglycemia in critically ill surgical patients has been shown in a large, prospective, randomized trial to decrease morbidity and mortality. Intensive insulin therapy (IIT) requires maintenance of blood glucose levels below 110 mg/ dL . Subsequent analysis found that increased mortality from hypoglycemic events negates the benefits of IIT in clinical practice. Trauma patients , however, were a subset found to having benefited the most from IIT. Further investigation is necessary to determine safe and effective mechanisms for glycemic control in trauma patients.

51. Hydrocortisone therapy : In trauma patients there is some evidence that hydrocortisone therapy attenuates the stress response. Further research is needed to establish practical therapeutic strategies, particularly in traumatic brain injury , in which high-dose steroids have been associated with an increase in mortality. Human activated protein C ( drotrecogin alfa [activated ]) was one of the first approved recombinant agents targeting the procoagulant and generalized inflammatory response that occurs during sepsis.

52. Pharmacologic manipulation of the response to traumatic injury has been met with limited success. Research continues to attempt to identify agents that protect the patient from the deleterious effects of the host response . Knowing which patient may benefit from a particular medication may be a function of that individual’s unique DNA . Current studies have identified specific genetic polymorphisms that are predictors of adverse outcomes in severe trauma and sepsis. Future investigation may help develop individually tailored treatments.

53. Nutrition as Therapy The advantages of enteral nutrition over parenteral nutrition have been clearly demonstrated, and the gastrointestinal tract should be used whenever possible . The traditional preference is to feed patients by the enteral route for reasons that include a reduction of the number of enteric organisms that may be responsible for bacterial translocation. s timulation of the enterocyte brush border and gut associated lymphoid tissue that is an important protective mechanism against the proliferation of the offending organisms.

54. The route of feeding may also have an impact on the production of cytokines after injury; thus, use of the enteral route may confer an additional advantage . Considerable attention has focused on nutrients that attenuate the metabolic response to injury. Nutrients that appear to enhance the immune system include arginine, glutamine, and nucleic acids. The immune system may be enhanced by altering the relative amounts of omega-6 versus omega-3 unsaturated fatty acids . Other nutrients may act as oxidants, preventing damage by free radicals, such as the common antioxidants vitamins A, C, E, and the trace element selenium.

55. Conclusion Injury produces a series of physiologic changes mediated by local and systemic agents and systemic effects. The metabolic response aims to promote substrate delivery to the injured organs and promote healing . An understanding of the metabolic response allows the clinician to support the patient through the physiologic changes associated with the stress response caused by injury. Future research offers the promise of directly tailoring treatment and modulating the metabolic response to minimize the impact of major trauma.

56. References Oral and Maxillofacial Trauma 4 th edition Fonseca Schwartz’s Principles of Surgery 11 th edition Turgay Şimşek et al Response to trauma and metabolic changes: posttraumatic metabolism Ulusal Cer Derg 2014; 30: 153-9