Metabolic Response to Injury

BASIC CONCEPTS IN HOMEOSTASIS

Homeostasis is the state of steady internal, physical, and chemical
conditions maintained by living systems. This is the condition of
optimal functioning for the organism and includes many variables,
such as body temperature and fluid balance, being kept within
certain pre-set limits (homeostatic range).
Resuscitation, surgical intervention and critical care can return the
severely injured patient to a situation in which homeostasis
becomes possible once again
MEDIATORS OF THE METABOLIC RESPONSE TO INJURY
The classical neuroendocrine pathways of the stress response
are bi phasic
Acute phase
consist of Corticotrophinreleasing factor (CRF) released from
the hypothalamus increases adrenocorticotrophic hormone
(ACTH) release from the anterior pituitary. ACTH then acts on
the adrenal to increase the secretion of cortisol.
Hypothalamic activation of the sympathetic nervous system
causes release of adrenalin and also stimulates release of
glucagon. Intravenous infusion of a cocktail of these ‘counter-
regulatory’ hormones (glucagon, glucocorticoids and
catecholamines) reproduces many aspects of the metabolic
response to injury.

Chronic phase associated with hypothalamic suppression

and low serum levels of the respective target organ
hormones. Changes contribute to chronic wasting.
 The innate immune system (principally macrophages)
interacts in a complex manner with the adaptive immune
system (T cells, B cells) in co-generating the metabolic
response to injury
Proinflammatory cytokines including interleukin-1 (IL-1),
tumor necrosis factor
alpha (TNF_), IL-6 and IL-8 are produced within the first 24
hours and act directly on the hypothalamus to cause pyrexia.
Such cytokines also augment the hypothalamic stress
response and act directly on skeletal muscle to induce
proteolysis while inducing acute phase protein production in
the liver. Proinflammatory cytokines also play a complex role
in the development of peripheral insulin resistance.
Within hours of the upregulation of proinflammatory cytokines, endogenous
cytokine antagonists enter the circulation (e.g. interleukin-1 receptor antagonist
(IL- 1Ra) and TNF soluble receptors (TNF-sR-55 and 75)) and act to control the
proinflammatory response.
counter-inflammatory response changes include the development of a
(regulated by IL-4, -5, -9 and -13 and transforming growth factor
beta (TGF_)) which, if accentuated and prolonged in critical
illness, is characterized as the CARS compensatory anti-
inflammatory response syndrome and results in
immunosuppression and an increased susceptibility to
opportunistic (nosocomial) infection
AND
Physiological response to injury ((THE ‘EBB FLOW’
MODEL))
In the natural world, if an animal is injured, it displays a
characteristic response, which includes immobility, anorexia
and catabolism
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.
The ebb phase is characterized by hypovolemia, decreased
basal metabolic rate, reduced cardiac output, hypothermia and
lactic acidosis. The predominant hormones regulating the ebb
phase are catecholamines, cortisol and aldosterone.
Following resuscitation, the ebb phase evolves into a
hypermetabolic flow phase, This phase involves the
mobilization of body energy stores for recovery and
repair, and the subsequent replacement of lost or
damaged tissue. It is characterized by tissue
oedema (from vasodilatation and increased capillary
rate leakage), increased basal metabolic
output, cardiacincreased(hypermetabolism),
increased leukocytosis,body temperature,raised
increased gluconeogenesis. andconsumption oxygen
The flow phase may be subdivided into an initial
catabolic phase, lasting approximately 3–10 days,
followed by an anabolic phase, which may last for
weeks if extensive recovery and repair are required
following serious injury.
During the catabolic phase, the increased production of
counter-regulatory hormones (including catecholamines,
cortisol, insulin and glucagon) and inflammatory cytokines (e.g.
IL-1, IL-6 and TNF_) results in significant fat and protein
mobilization, 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 glycemic control.
Insulin resistance
Following surgery or trauma, postoperative hyperglycemia
develops as a result of increased glucose production combined
with decreased glucose uptake in peripheral tissues. Decreased
glucose uptake is a result of insulin resistance which is
transiently induced within the stressed patient. Suggested
mechanisms for this phenomenon include the action of
proinflammatory cytokines and the decreased responsiveness
of insulin-regulated glucose transporter proteins. The degree of
insulin resistance is proportional to the magnitude of the
injurious process.
Following routine upper abdominal surgery, insulin resistance
may persist for approximately 2 weeks.
Postoperative patients with insulin resistance behave in a
similar manner to
individuals with type II diabetes mellitus. The mainstay of
management of insulin resistance is intravenous insulin
infusion.
THE COMPOUNDTHAT FACTORSAVOIDABLE
TO INJURYRESPONSE
Continuing hemorrhage
During simple hemorrhage, pressor receptors in the carotid
artery and aortic arch, and volume receptors in the wall of the
left atrium, initiate afferent nerve input to the central nervous
system (CNS), resulting in the release of both aldosterone and
antidiuretic hormone (ADH). Pain can also stimulate ADH
release. ADH acts directly on the kidney to cause fluid
retention.
Decreased pulse pressure stimulates the juxtaglomerular
apparatus in the kidney and
directly activates the renin–angiotensin system, which in turn
increases aldosterone release.
Hypothermia
Hypothermia results in increased elaboration of
adrenal steroids and catecholamines. When
compared with normothermic controls, even mild
hypothermia results in a two- to three-fold increase
in postoperative cardiac arrhythmias and increased
catabolism.
Tissue oedema
During systemic inflammation, fluid, plasma proteins,
leukocytes, 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.
Increased capillary leak is mediated by a wide variety of
mediators including
cytokines, prostanoids, bradykinin and nitric oxide.
Vasodilatation implies that intravascular volume
decreases, which induces shock if inadequate
resuscitation is not undertaken.
Systemic inflammation and tissue response
Under-perfusion
The vascular endothelium controls vasomotor tone and
microvascular flow, and regulates trafficking of nutrients and
biologically active molecules. When endothelial activation is
excessive, compromised microcirculation and subsequent cellular
hypoxia contribute to the risk of organ failure. Maintaining
normoglycemia with insulin infusion during critical illness has been
proposed to protect the endothelium and prevent organ failure via
preservation of the microcirculation in vital organs.
Starvation
During starvation, the body is faced with an obligate need to generate
glucose to sustain cerebral energy metabolism (100 g 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 mobilization is mainly dependent on a fall in circulating
insulin levels.
Eventually, accelerated loss of lean tissue (the main
source of amino acids for hepatic gluconeogenesis) 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.
Avoiding unnecessary fasting in the first instance and
early oral/enteral/parenteral nutrition form the platform
for avoiding loss of body mass as a result of the varying
degrees of starvation observed in surgical patients.
Modern guidelines on fasting prior to anesthesia allow
intake of clear fluids up to 2 hours before surgery
.
Immobility
Immobility has long been recognized as a potent stimulus
for inducing muscle wasting. Inactivity impairs the
normal meal-derived amino acid stimulation of protein
synthesis in skeletal muscle. Avoidance of unnecessary
bed rest and active early mobilization are essential
measures to avoid muscle wasting as a consequence of
immobility.