HOMEOSTASIS
Concepts of Homeostasis
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? Claude Bernard:? Stability of the "milieu int?rieur" is the primary condition for freedom and independence of
existence.
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? i.e. body systems act to maintain internal constancy.
? Walter Cannon:
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? Term "Homeostasis".? 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.
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? Responses to injury are beneficial to the host and al ow healing/survival.
Concepts of Homeostasis......
? Classical homeostatic control system:
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? Signal detector
? Processor
? Effector
? Negative feedback loop
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? Open loop system:
? Also referred to as non-feedback system
? Type of continuous control system in which the output has no influence or effect on the control
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action of the input signal.
? Only with medical/surgical resolution of the primary abnormality results in classical homeostasis.
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Concepts of Homeostasis......? Elective surgical practice:
? Reduce the need for a homeostatic response by minimizing the primary insult
? e.g. minimal access surgery and `stress-free' perioperative care.
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? Emergency surgery:
? Presence of tissue trauma/ sepsis/ hypovolaemia often compounds the primary problem.
? It requires:
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? To augment artificial y homeostatic responses (e.g. resuscitation)
? And to close the `open' loop by intervening to resolve the primary insult (e.g. surgical treatment of major abdominal sepsis)
? And provide organ support (critical care)
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? While the patient comes back to a situation in which homeostasis can achieve a return to normality.
Graded Nature of the Injury Response
? Response to injury:
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? More severe the injury- Greater the response.? Applies to Physiological/ Metabolic/ Immunological changes.
? Following elective surgery of intermediate severity-
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? Changes may be a transient and modest.? Mild rise in temp./ heart rate/ respiratory rate/ energy expenditure and white cel count.
? Following major trauma/sepsis-
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? Changes are accentuated.? Resulting in SIRS/ hyper metabolism/ marked catabolism/ shock and even multiple organ dysfunction (MODS).
? Genetic variability plays a key role in determining the intensity of the inflammatory response.
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Graded Nature of the Injury Response....Response to injury:
Hypermetabolism and increased nitrogen excretion are closely related to the magnitude of the initial injury and show a gradedresponse.
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Graded Nature of the Injury Response....? Immunological sequelae of major injury:
? Evolve from a Pro-inflammatory State
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? Driven primarily by the innate immune system (macrophages, neutrophils, dendritic cel s).
? Finally- Compensatory Anti-Inflammatory Response Syndrome (CARS)
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? Characterized by suppressed immunity- diminished resistance to infection.? Patients who develop infective complications-
? CARS leads to ongoing systemic inflammation/ acute phase response and continued
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catabolism.
Mediators of the Metabolic Response to
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Injury? `Classical Neuroendocrine
Pathways' of the stress
response consist of:
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? Afferent nociceptive neurons
? Spinal cord
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? Thalamus? Hypothalamus
? and pituitary
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Mediators of the Metabolic Response toInjury.....
? Corticotrophin- Releasing Factor (CRF)- released from the hypothalamus
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? Increases ACTH release- from the anterior pituitary.? ACTH acts on the adrenals- increase the secretion of cortisol.
? Hypothalamic activation of the Sympathetic Nervous System-
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? Release of Adrenaline and Glucagon.? Intravenous infusion of a cocktail of these `counter-regulatory' hormones (glucagon,
glucocorticoids and catecholamine)-
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? Results in many aspects of the metabolic response.
Mediators of the Metabolic Response to
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Injury....? Other mediators:
? Alterations in insulin release and sensitivity.
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? Hypersecretion of prolactin and growth hormone (GH) in the presence of low circulatoryinsulin-like growth factor-1 (IGF-1).
? Inactivation of peripheral thyroid hormones and gonadal function.
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Neuroendocrine response to injury/criticalil ness
? Neuroendocrine response to severe injury/critical il ness is biphasic:
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? Acute phase:? Actively secreting pituitary and elevated counter-regulatory hormones (cortisol, glucagon,
adrenaline).
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? Changes are thought to be beneficial for short term survival.
? Chronic phase:
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? Hypothalamic suppression and low serum levels of the respective target organ hormones.? Changes contribute to chronic wasting.
Immunological changes to injury/critical
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il ness
? Innate immune system (principally macrophages) interacts in a complex manner with the
adaptive immune system (T cells, B cells):
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? Also affects the metabolic response to injury.
? Pro-inflammatory cytokines (IL-1/ TNF/ IL-6 and IL-8):
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? Produced within the first 24 hours of injury.? Act directly on the Hypothalamus-
? Cause pyrexia.
? Augment the hypothalamic stress response.
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? Act directly on skeletal muscle- induce proteolysis.
? Act on liver- Induce acute phase protein production.
? A complex role in the development of peripheral insulin resistance.
Immunological changes to injury/critical
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il ness.....
? Endogenous Cytokine Antagonists enter the circulation:
? Within hours of the Upregulation of Pro-inflammatory Cytokines.
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? e.g. interleukin-1 receptor antagonist [IL-1Ra] and TNF-soluble receptors [TNF-sR-55 and 75].? Act to control the pro-inflammatory response.
? A complex adaptive changes includes:
? Development of a Th2-type counter-inflammatory response.
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? Regulated by IL-4, -5, -9 and -13 and transforming growth factor beta [TGF].
? If accentuated and prolonged in critical illness- characterized as the CARS.
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? Results in immunosuppression- increased susceptibility to nosocomial infection.Immunological changes to injury/critical
il ness....
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? Duration and magnitude of acute inflammation as wel as the return tohomeostasis are influenced by-
? Specialized proresolving mediators (SPM)- include essential fatty acid-derived
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lipoxins, resolvins, protectins and maresins.
? Uptake and clearance- of apoptotic polymorphonuclear neutrophils and microbial
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particles? Reduce- proinflammatory cytokines and lipid mediators
? Enhance the removal of cel ular debris.
Immunological changes to injury/critical
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il ness.....
? Systemic inflammatory response syndrome following major injury:
? Is driven initially by proinflammatory cytokines (e.g. IL-1, IL-6 and TNF).
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? Is fol owed rapidly by increased plasma levels of cytokine antagonists andsoluble receptors (e.g. IL-1Ra, TNF-sR).
? If prolonged or excessive may evolve into a counterinflammatory response
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syndrome.
The `Ebb and Flow ' model of metabolic
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response? Natural physiological response to injury includes:
? Immobility/rest
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? Anorexia? Catabolism
? Sir David Cuthbertson divided the metabolic response to injury:
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? Into `ebb' and `flow' phases
Ebb phase
? Begins at the time of injury and lasts for approximately 24?48 hours.
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? Characterized by-? hypovolemia/ decreased BMR/ reduced cardiac output/ hypothermia and lactic acidosis.
? Predominant hormones regulating the ebb phase- catecholamines/ cortisol/ aldosterone.
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? Magnitude of response depends on:
? Degree of blood loss.
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? Stimulation of somatic afferent nerves at the site of injury.? Main physiological role of the ebb phase:
? Conserve both circulating volume and energy stores for recovery and repair.
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Flow phase
? Following resuscitation, ebb phase evolves into a hypermetabolic flow phase.
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? This phase involves:? Mobilization of body energy stores- for recovery and repair
? and subsequent replacement of lost or damaged tissue.
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? Characterized by:
? Tissue edema (from vasodilatation and increased capil ary leakage)
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? Increased basal metabolic rate (hyper metabolism)/ Increased cardiac output? Raised body temperature/Leukocytosis
? Increased oxygen consumption
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? And increased gluconeogenesis.
Flow phase.......
? Flow phase may be subdivided into:
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? Catabolic phase? lasting approximately 3?10 days.
? Increased production of counter-regulatory hormones (catecholamines, cortisol, insulin and glucagon) and
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inflammatory cytokines(e.g. IL-1, IL-6 and TNF).
? Significant fat and protein mobilization- significant weight loss and increased urinary nitrogen excretion.
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? Increased production of insulin- associated with significant insulin resistance and poor glycemic control.? Increased risk of complications- further aggravate the neuroendocrine and inflammatory stress responses and creates
a vicious catabolic cycle.
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? Anabolic phase
? may last for weeks if extensive recovery and repair are required fol owing serious injury.
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Key Catabolic Elements of the Flow Phase? During the response to injury, not al tissues are catabolic.
? Essence of coordinated response is-
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? Reprioritise limited resources away from peripheral tissues towards key viscera and wound.
Key Catabolic Elements of the Flow Phase
? Hypermetabolism:
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? Caused by an acceleration of energy-dependent metabolic cycles.
? limited in modern practice on account of elements of routine critical care.
? Skeletal muscle wasting:
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? Provides amino acids for the metabolic support of central organs/tissues.
? Mediated at a molecular level- by activation of the ubiquitin?proteasome pathway.
? Can result in-
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? Immobility? Contribute to hypostatic pneumonia
? If prolonged and excessive- leads to death
Key Catabolic Elements of the Flow Phase
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? Hepatic acute phase response:
? Represents a reprioritisation of body protein metabolism towards the liver and is characterised by:
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? Positive reactants (e.g. CRP): plasma concentration? Negative reactants (e.g. albumin): plasma concentration
? Insulin resistance
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? Fol owing surgery or trauma- hyperglycemia develops as a result of? Increased glucose production
? Combined with decreased glucose uptake in peripheral tissues.
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? Decreased glucose uptake is a result of insulin resistance which is transiently induced.CHANGES IN BODY COMPOSITION FOLLOWING
INJURY
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? Catabolism:? Decrease in fat mass and
skeletal muscle mass
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? Body weight may
paradoxical y increase
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? Expansion of extracellularfluid space
Avoidable factors that compound the
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response to injury
? Continuing haemorrhage
? Hypothermia
? Tissue oedema
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? Tissue underperfusion? Starvation
? Immobility