to injury & trauma

Dr. Hiwa Omer Ahmed Assistant Professor in Surgery

The host response to injury—surgical, traumatic, or infectious—is characterized by various endocrine, metabolic, and immunologic alterations.


The classic response to injury comprises multiple axes. These hormone response pathways are activated by ► (1) mediators released by the injured tissue, ► (2) neural and nociceptive input originating from the site of injury, or ► (3) baroreceptor stimulation from intravascular volume depletion.

. Thehormones

released in response to these activating stimuli may be divided into those primarily under hypothalamopituitary control and those primarily under autonomic nervous system control

Hormones Under Anterior Pituitary Regulation

Pain, fear, anxiety, or emotional arousal generate neural signals to the paraventricular nucleus of the hypothalamus, stimulating the synthesis of corticotropin-releasing hormone (CRH),

In the nonstressed healthy human
ACTH is synthesized, stored, and released by the anterior pituitary upon CRH stimulation. ACTH is a 39–amino acid peptide

being, ACTH release is regulated by circadian signals; the greatest elevation of ACTH occurs late at night and lasts until just before sunrise.

In trauma
► Most

injury is characterized by elevations in CRH and ACTH that are proportional to the severity of injury

► Cortisol

is the major glucocorticoid in human beings and is essential for survival after significant physiological stress.

In trauma

. Cortisol levels in response toinjury are not under the influence of normal diurnal variations and can remain persistently elevated, depending on the type of systemic stress. Burn patients have demonstrated elevated circulating cortisol levels for up to 4 weeks, and soft-tissue injury and hemorrhage may sustain elevated cortisol levels for up to a week

Thyrotropin-Releasing Hormone and Thyroid Stimulating Hormone
Thyrotropin-releasing hormone (TRH) serves as the primary stimulant for the synthesis, storage, and release of thyroid-stimulating hormone (TSH) in the anterior pituitary. TSH in turn stimulates thyroxine (T4) production

In trauma
► Although

T3 levels are frequently decreased after injury, there is no compensatory rise in TSH release. After major injury, reduced available T3 and circulating TSH levels are observed and peripheral conversion of T4 to T3 is impaired. concentrations remain relatively constant. ► In severely injured orcritically ill patients, a reduced free T4 concentration has been predictive ofhigh mortality

Growth Hormones
► Hypothalamic

growth hormone releasing hormone (GHRH) travels through the hypothalamic-hypophyseal portal circulation to the anterior pituitary and stimulates the release of growth hormone (GH) in a pulsatile fashion mostly during the sleeping hours.

In trauma
► There

is a rise in circulating GH levels after injury,The role of GH during stress is to promote protein synthesis whileenhancing the mobilization of fat stores. Fat mobilization occurs by directstimulation in conjunction with potentiation of adrenergic lipolytic effects on adipose stores. In the liver, hepatic ketogenesis also is promoted by GH. GH inhibits insulin release and decreases glucose oxidation, leading to elevated glucose levels

► Somatostatin

is a 14–amino acid polypeptide produced by various cell types, including gastric antrum cells and pancreatic islet D cells

► The

roleof somatostatin in the response to injury is unclear, but it may regulate excessive nutrient absorption and the activities of GH and IGF during convalescence from injury

Gonadotrophins and Sex Hormones
► Luteinizing-hormone

releasing hormone (LHRH) or gonadotropinreleasing hormone (GnRH) is released from the hypothalamus and stimulates folliclestimulating hormone (FSH) and luteinizing hormone (LH) release from the anterior pituitary.

In trauma
► The

most relevant clinical correlation is seen after injury, stress, or severe illness, when LH and FSH release is suppressed. The reduction in LH and FSH consequently reduces estrogen and androgen secretion. ► Estrogens inhibit cell-mediated immunity, natural killer cell activity, andneutrophil function, but are stimulatory for antibodymediated immunity ► . Androgens appear to be predominantly immunosuppressive.

► The

hypothalamus suppresses prolactin secretion from the anterior pituitary by the activities of LHRH/GnRH and dopamine

In trauma

Elevated prolactin levels after injury have been reported in adults, whereas reduced levels are noted in children. ► Like growth hormone, prolactin has immunostimulatory properties

Endogenous Opioids & in trauma
► Elevated

endogenous opioids are measurable after major operations or insults to the patient ► Endorphins also influence the immune system by increasing natural killer cell cytotoxicity and T cell blastogenesis. Interleukin-1 activates

Hormones Under Posterior Pituitary Regulation
► Arginine

Vasopressin ► Vasopressin or arginine vasopressin (AVP) (or antidiuretic hormone, ADH) is synthesized in the anterior hypothalamus and transported by axoplasmic flow to the posterior pituitary for storage.

In truma
► Elevated

AVP secretion is another characteristic of trauma, hemorrhage, open-heart surgery, and other major operations. This elevated level typically persists for 1 week after the insult. ► This effect in the splanchnic circulation may cause the trauma-induced ischemia/reperfusion phenomenon that precedes gut barrier impairment.

► Oxytocin

and AVP are the only known hormones secreted by the posterior pituitary

► but

the role of oxytocin in the injury response is unknown

3. Hormones of the Autonomic System
► Catecholamines

Catecholamines exert significant influence in the physiologic response to stress and injury.

► Both

of the major catecholamines, norepinephrine and epinephrine, are increased in plasma after injury, with average elevations of three to four times above baseline immediately after injury, reaching their peak in 24 to 48 h before returning to baseline levels

► The

mineralocorticoid aldosterone is synthesized, stored, and released in the adrenal zona glomerulosa. Its release may be induced by angiotensin II, hyperkalemia, and the pituitary hormone known as aldosterone stimulating factor (ASF),.

In trauma
► but

ACTH is the most potent stimulus for aldosterone release in the injured patient ► The major function of aldosterone is to maintain intravascular volume by conserving sodium and eliminating potassium and hydrogen ions. . After injury, ACTH stimulates a brief burst of aldosterone release. Angiotensin II induces a protracted aldosterone release that persists well after ACTH returns to baseline.

► Renin

is synthesized and stored primarily within the renal juxtaglomerular apparatus near the afferent arteriole. The juxtaglomerular apparatuscomprises the juxtaglomerular neurogenic receptor, the juxtaglomerularcell, and the macula densa. Renin initially exists in an inactive form as prorenin. The activation of renin and its release is mediated by ACTH, AVP,glucagon, prostaglandins, potassium, magnesium, and calcium.

In trauma
► their

secreation increased in injury ► The renin-angiotensin system participates in the response to injury by maintaining volume homeostasis

► The

netresult of impaired insulin production and function after injury is stress-induced hyperglycemia, which is in keeping with the general catabolic state. ► . In the injured patient, a biphasic pattern of insulin release is observed. The first phase occurs within a few hours after injuryand is manifested as a relative suppression of insulin release, reflecting the influence of catecholamines and sympathetic stimulation. The later phase ischaracterized by a return to normal or excessive insulin production but with persistent hyperglycemia, demonstrating a

► The

release of glucagon after injury is initially decreased, but returns to normal 12 h later. By 24 h, glucagon levels are supranormal and can persist for up to 3 days.


Even after the normalization of macroendocrine hormone function after the primary injury, the persistence of systemic inflammation, the progression of organ dysfunction, and even late mortality indicate the presence of other potent mediators influencing the injury response.

These mediators usually are small proteins or lipids that are synthesized and secreted by immunocytes. These micromolecules, collectively referred to as cytokines, are indispensable in tissue healing and in the immune response generated against microbial invasions. Asmounting evidence suggests, the activities of these cytokine mediators are integrally related to classic hormone function and metabolic responses to injury

Cytokine-Mediated Response

Cytokines exert their influence by binding to specific cell receptors and activating intracellular signaling pathways leading to modulation of gene transcription. By this mechanism, cytokines influence immune cell production, differentiation, proliferation, and survival

Tumor Necrosis Factoralpha ► The release of TNF-a in response to

acute injury is rapid and shortlived.Experiments simulating an acute inflammatory response by means of endotoxin challenge in human subjects have demonstrated a monophasitumor necrosis factor (TNF) appearance curve, peaking at approximately 90 min and followed by a return to undetectable levels within 4 h . Even with a half-life of 15 to 18 min, the brief appearance of TNF caninduce marked metabolic and hemodynamic changes and activate

► TNF-a

also induces the biosynthesis and release of interleukin-1 (IL-1) from macrophages and endothelial cells.

In truma
► Among

its effects, IL-1 induces the classic inflammatory febrile response to injury by stimulating local prostaglandin activity in the anterior hypothalamus. Associated with the hypothalamic activity is the induction of anorexia by an IL-1 effect on the satiety center

► Although

necessary as an inflammatory mediator in promoting T lymphocyte proliferation, immunoglobulin production, and gut barrier integrity, IL-2 has not been readily detectable in the circulation during acute injury. Similar to IL-1, its short half-life of less than 10 min adds to the difficulty in detecting it after injury



The description of human biochemical responses to injury and the classification of such responses into an ebb and flow phase by Cuthbertson and others provides a useful model by which the metabolic response to injury may be characterized

Ebb & flow phase

Ebb & flow

Except with the most minor injury, the flow phase is ushered in by compensatory mechanisms resulting from volume repletion and cessation of initial injury conditions. The metabolic response associated with the flow phase serves to direct energy and protein substrates so as to preserve critical organ function and repair damaged tissues.

Energy balance
► These

changes can reflect the degree of underlying injury ► Injury of any magnitude beyond the most trivial is associated with an increase in energy expenditure and increases in oxygen consumption that vary directly with the severity of injury

Fat metabolism

Free fatty acids are a principal source of energy after injury. Lipolysis is enhanced by the immediate elevations in ACTH, cortisol, catecholamines, glucagon, and growth hormone levels, reduction in insulin level, and increased sympathetic nervous system activity

Carbohydrate Metabolism
► Systemic

glucose intolerance is well documented in injured patients. By contrast, basal insulin levels are elevated by several times during the early flow phase, indicating a state of relative insulin resistance. ► Increases in plasma glucose levels are proportional to the severity of injury and to some extent are correlated with surviva

Protein and Amino Acid Metabolism
► The

intake of protein for a healthy young adult is approximately 80 to 120 g, or 13 to 20 g of nitrogen per day. Daily fecal and urinary excretion of nitrogen is 2 to 3 g and 13 to 20 g, respectively. After injury, daily nitrogen excretion in the urine increases to 30 to 50 g as urea nitrogen

► The

magnitude of nitrogen loss also is related to the age, sex, and physical condition of the patient. Young healthy males lose more protein in response to an injury than do women or the elderly, presumably because they have a higher lean body mass than the latter two patient subsets.

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