Homeostasis, the internal milieu of the human body

Homeostasis, the internal milieu of the human body

1. Homeostasis & Response to Injury

2. ‘Homeostasis’ refers to the maintenance of constant internal environment of the body ( homeo = same; stasis= standing) The coordinated physiological process which maintains most of the steady states of the organism; i.e. complex homeostatic responses involving the brain, nerves, heart, lungs, kidneys and spleen work to maintain body constancy We live in a perfectly organized and controlled internal environment, which is called ‘milieu interieur’

3. In essence, the concept evolved that the constancy of the ‘milieu intérieur ’ allowed for the independence of organisms, that complex homeostatic responses sought to maintain this constancy, and that within this range of responses were the elements of healing and repair. But these ideas pertained only to normal physiology and mild/moderate injury In the modern era, such concepts do not account for disease evolution following major injury/sepsis Such patients exemplify less of the classical homeostatic control system and more of the ‘open loop’ system, whereby only with medical/surgical resolution of the primary abnormality is a return to classical homeostasis possible.

4. Resuscitation, surgical intervention and critical care can return the severely injured patient to a situation in which homeostasis becomes possible once again

5. RESPONSE TO INJURY The response to injury is graded: the more severe the injury, the greater the response This concept not only applies to physiological/metabolic changes but also to immunological changes/sequelae

6. Following surgery of intermediate severity, there may be a transient and modest rise in temperature, heart rate, respiratory rate, energy expenditure and peripheral white cell count Following major trauma/sepsis, these changes are accentuated, resulting in a systemic inflammatory response syndrome (SIRS), hypermetabolism, marked catabolism, shock and even multiple organ dysfunction (MODS). The metabolic response is not only graded, but it also evolves with time. In particular, the immunological

7. Response Components Physiological Metabolic Clinical Laboratory Increased Cardiac Output Hypermetabolism Fever Leucocytosis / Leucopenia Increased Ventilation Accelerated Gluconeogenesis Tachycardia Hyperglycemia Increased Membrane Transport Enhanced Protein breakdown Tachypnea Elevated CRP / Altered acute phase reactants Weight loss Increased Fat Oxidation Presence of wound or inflammation Hepatic / Renal dysfunction Wound Healing Anorexia

8. MEDIATORS OF THE METABOLIC RESPONSE TO INJURY Neuro-endocrine (Hormonal) Metabolic and Cytokine axes

9. Neuro-endocrine response The Neuro-endocrine response to severe injury/critical illness is biphasic Acute phase characterized by an actively secreting pituitary & elevated counter regulatory hormones (cortisol, glucagon, adrenaline) Changes are thought to be beneficial for short-term survival. Chronic phase associated with hypothalamic suppression & low serum levels of the respected target organ hormones. Changes contribute to chronic wasting

10. The constellation of Neuro-endocrine changes following injury acts to Provide essential substrates for survival Postpone anabolism Optimize host defense These changes may be helpful in the short term, but may be harmful in the long term, especially to the severely injured patient who would otherwise not have survived without medical intervention

11. Physiological response The natural response to injury includes Immobility Anorexia Catabolism

12. Metabolic response to injury in humans is divided into “ebb “ and “flow” phases

13. The ebb phase begins at the time of injury and lasts for approximately 24–48 hours. It may be attenuated by proper resuscitation, but not completely abolished.

14. Ebb phase is characterized by Hypovolemia Decreased Basal Metabolic Rate Reduced Cardiac Output Hypothermia Lactic Acidosis Decreased Insulin Hyperglycemia Gluconeogenesis Increased substrate consumption Hepatic Acute phase response Immune activation

15. The predominant hormones regulating the ebb phase are Catecholamines Cortisol Aldosterone The main physiological role of the ebb phase is to conserve both circulating volume and energy stores for recovery and repair.

16. Following resuscitation, the ebb phase evolves into a hypermetabolic flow phase, which corresponds to SIRS. This phase involves the mobilization of body energy stores for recovery and repair, and the subsequent replacement of lost or damaged tissue.

17. It is characterized by Tissue oedema (from vasodilatation and increased capillary leakage) Increased basal metabolic rate (hypermetabolism) Increased cardiac output Raised body temperature Leukocytosis Increased oxygen consumption Increased gluconeogenesis

18. The flow phase may be subdivided into Catabolic phase, lasting approximately 3–10 days Anabolic phase, which may last for weeks During the catabolic phase, the increased production of counter-regulatory hormones and inflammatory cytokines results in significant fat and protein mobilisation , leading to significant weight loss and increased urinary nitrogen excretion. The increased production of insulin at this time is associated with significant insulin resistance and, therefore, injured patients often exhibit poor glycaemic control.

19. The combination of pronounced or prolonged catabolism in association with insulin resistance places patients within this phase at increased risk of complications. Obviously, the development of complications will further aggravate the neuroendocrine and inflammatory stress responses, thus creating a vicious catabolic cycle.

20. Key catabolic elements of flow phase Hypermetabolism Alterations in skeletal muscle protein Alterations in Liver protein Insulin resistance

21. Hypermetabolism Majority of trauma patients demonstrate energy expenditure approximately 15 - 25% above predicted healthy resting values Factors which increases this metabolism are Central thermo-dysregulation Increased sympathetic activity Increased protein turnover Wound circulation abnormalities etc

22. Hyper metabolism following injury is Mainly caused by an acceleration of futile metabolic cycles Limited in modern practice on account of elements of routine critical care.

23. Skeletal muscle wasting Provides amino acids for protein synthesis in central organ/tissues Is mediated at a molecular level mainly by activation of the ubiquitin-protease pathway Can result in immobility & contribute to hypostatic pneumonia & death if prolonged and excessive

24. Hepatic acute phase response The Hepatic acute phase response represents a reprioritization of body protein metabolism towards the liver & is characterized by: Positive reactants (CRP) : plasma concentration increases Negative reactants (albumin) : plasma concentration decreases

25. Insulin resistance The degree of insulin resistance is directly proportional to magnitude of the injurious process. Following routine upper abdominal surgery, insulin resistance may persist for approx. 2 weeks Postop patients with insulin resistance behave in a similar manner to individuals with type 2 diabetes The mainstay of treatment is IV insulin Intensive insulin infusions are better over conservative approach

26. CHANGES IN BODY COMPOSITION FOLLOWING INJURY

27. Main labile energy reserve in the body is fat Main labile protein reserve in the body is skeletal muscle While fat mass can be reduced without major detriment to function, loss of protein mass results not only in skeletal muscle wasting, but also depletion of visceral protein mass

28. With lean issue, each 1 g of nitrogen is contained within 6.25 g of protein, which is contained in approximately 36 g of wet weight tissue. Thus the loss of 1 g of nitrogen in urine is equivalent to the breakdown of 36 g of wet weight lean tissue. Protein turnover in the whole body is of the order of 150-200 g per day.

29. A normal human ingests 70-100 g of protein per day, which is metabolized and excreted in urine as ammonia and urea(14 g N/day) During total starvation, urinary loss of nitrogen is rapidly attenuated by a series of adaptive changes Loss of body weight follows a similar course, thus accounting for the survival of hunger strikers for a period of 50-60 days

30. Following major injury, and particularly in the presence of ongoing septic complications , this adaptive change fails to occur, and there is a state of auto cannibalism , resulting in continuing urinary nitrogen losses of 10-20 g/day(500 g lean tissue/day) As with total starvation, once loss of body protein mass has reached 30-40 % of the total, survival is unlikely

31. In critically ill patients with resuscitation, <24 hrs – Body weight increases due to extracellular water expansion by 6-10 litres . This can be overcome by careful intra operative management of fluid balance 1-10 days – Total body protein will diminish by 15% and body weight will reach negative balance as the expansion of extra cellular space resolves This can be overcome by blocking Neuro endocrine response with epidural analgesia and early enteral feeds

32. Avoidable factors that compound the response to injury Continuing haemorrhage Hypothermia Tissue edema Tissue under perfusion Starvation Immobility

33. Volume loss : Careful limitation of intra operative administration of colloids and crystalloids so that there is no net weight gain Hypothermia : RCT have shown that normothermia by an upper body forced air heating cover reduces wound infection, cardiac complications and bleeding and transfusion requirements Tissue edema : During systemic inflammation, fluid, plasma proteins, leucocytes, macrophages and electrolytes leave the vascular space and accumulate in the tissues. This can diminish the alveolar diffusion of oxygen and may lead to reduced renal function

34. Systemic inflammation and tissue under perfusion The vascular endothelium controls vasomotor tone and micro vascular flow and regulates trafficking of nutrients and biologically active molecules. Administration of activated protein C to critically ill patients has been shown to reduce organ failure and death and is thought to act, in part, via preservation of the micro circulation in vital organs Maintaining the normoglycemia with insulin infusion during critical illness has been proposed to protect the endothelium, probably in part, via inhibition of excessive iNOS - induced NO release , and thereby contribute to the prevention of organ failure and death

35. Starvation During starvation, the body is faced with an obligate need to generate glucose to sustain cerebral energy metabolism(100g of glucose per day) This is achieved in the first 24 hours by mobilizing glycogen stores and thereafter by hepatic gluconeogenesis from amino acids, glycerol and lactate. The energy metabolism of other tissues is sustained by mobilizing fat from adipose tissue Such fat metabolization is mainly dependent on a fall in circulating insulin levels.

36. Eventually , accelerated loss of lean tissue is reduced as a result of the liver converting free fatty acids into ketone bodies, which can serve as a substitute for glucose for cerebral energy metabolism. Provision of 2 liters of IV 5% D as iv fluids for surgical patients who are fasted provides 100g of glucose per day and has a significant protein sparing effect. Modern guidelines on fasting prior to anesthesia allow intake of clear fluids upto 2 hours before surgery. Administration of carbohydrate drink at this time reduces perioperative anxiety and thirst and decreases post operative insulin resistance

37. Immobility : Has been recognized as a potent stimulus for inducing muscle wasting. Early mobilization is an essential measure to avoid muscle wasting

38. Prospective Approach To Prevent Unnecessary Aspects Of The Surgical Stress Response Minimal access techniques Blockade of afferent painful stimuli (epidural anesthesia) Minimal periods of starvation Early mobilization

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