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
• Develops 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
ogradual restoration of body protein and fat stores and
onormalization 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.

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. 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

20. 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

21. 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.

22. 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

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

24. Acute Phase Proteins
• Nonspecific markers produced by hepatocytes in response to injury,
infection, inflammation
• Induced by IL-6

25. 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
otumor necrosis factor (TNF),
othe interleukins (IL-1, IL-2, IL-6, and IL-8),
othe interferons, and
ovarious growth factors such as granulocyte-macrophage colony stimulating
factor (GM-CSF), and
oplatelet-derived growth factors (PDGFs).

26. • 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.

27. • Interleukins 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.

28. Cell Mediated Inflammation

30. 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.

31. 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.

32. 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.

33. • 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.

34. • 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.

35. • 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.

36. 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.

37. • 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.

38. • 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.

39. • 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.

40. 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.

41. • 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.

42. • 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.

43. • 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.

44. 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.

45. • Amino acids, free fatty acids and glucose is released into the bloodstream
from various tissues in stress response. Fat 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.

46. • 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.

47. Metabolism In Surgical Patients
• Adequate nutrition of patients who lost weight and will undergo surgical
procedures is critical.
• Patients 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

48. • 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.

49. 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)

50. • 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)

51. 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 160g FFA and glycerol)
• Stimulated by reduced insulin and increased glucagon and catecholamines

52. 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.

53. • 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.

54. • 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.

55. • 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.

56. 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
oa reduction of the number of enteric organisms that may be responsible for
bacterial translocation.
ostimulation of the enterocyte brush border and gut associated lymphoid
tissue that is an important protective mechanism against the proliferation
of the offending organisms.

57. • 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.

59. 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.

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