‫بسم هللا الرحمن الرحيم‬

Faculty of Medicine

Neuro-hormonal response to injury

Presented by: Dr. Rafiq M. Salhab.

General Surgeon
Alahli Hospital, Hebron.
11/09/2022
 Response to injury

 Integrated series of endocrine and metabolic changes to maintain homeostasis

and glucose and oxygen delivery to vital organs and tissues.

 The response is initiated by loss of effective circulatory volume and pain.

 The most important stimulus is the afferent sensory nerve from the injured
area.

 Other stimuli are: hypoxemia, hypercarbia, acidosis, exotoxins, endotoxins,

emotional stress, inflammatory cells and local tissue damage (burns, surgery).
 Response to injury

 Many organs and systems participate in this response: hypothalamus, pituitary

gland, heart , major vessels (carotid sinus), chemoreceptors (carotid bodies),
kidney , adrenals… etc.

 Increased levels of: CRF, ACTH, AVP, Catecholamine, corticosteroids,

glucagon, GH, Aldosterone, cytokines, IL, TNF, eicosanoids, leukotrienes, NO,
endothelins and prostaglandin. Table (1)

 Endocrine (Neuro-hormonal) . Table (2)

 Metabolic
 Immune
 Neuro-hormonal ( Endocrine ) response to injury:

Table(1) Systemic response to injury

Sympathetic nervous system activation

Endocrine stress response

- pituitary hormone secretion

- insulin resistance

Immunological and hematological changes

- cytokines production
- acute phase reaction
- neutrophil leukocytosis
- lymphocyte proliferation

Metabolic response
 Table (2) principal hormonal responses to injury
Endocrine gland hormones Change in secretion

Anterior pituitary ACTH Increases

GH Increases
TSH May increase or decrease
FSH and LH May increase or decrease

Posterior pituitary AVP (ADH) Increases

Adrenal cortex Cortisol Increases

Aldosterone Increases

Pancreas Insulin Often decreases

Glucagon Usually small increases

Thyroid Thyroxin, tri-iodothyronine Decrease

 Neuro-hormonal ( Endocrine ) response to injury:

 Sympathoadrenal response.

 The hypothalamic-pituitary-adrenal axis.

 Local tissue damage mediators: cytokines

Sympathoadrenal response: activated by the hypothalamus.
Catecholamines: Nor-epinephrine and epinephrine.
- Nor-epinephrine is released from sympathetic postganglionic neurons.
- Epinephrine is secreted by the adrenal medulla (local and distant
actions).
 Different types of receptors (α1, α2 , β1, β2 ).
 After injury levels rise immediately and peak within 24-48 hours
(psychological component, fight or flight response to danger or pain)
 Their actions are primarily metabolic and hemodynamic.
- Hyperglycemia: glycogenolysis,↑ glucagon, ↓ insulin.
- Hemodynamic effects: vasoconstriction(α 1), arterial vasodilatation ( β2 ) ,
↑HR, ↑ conductivity, ↑ contractility(β1).
 The effects are dose-dependent:
- Low-dose → β1, β2 .
- High-dose → α1, α2 .
 The hypothalamic-pituitary-adrenal axis: Table (2) figure 1
 Pain and hypovolemia are the primary stimuli . (NA).
 The response is proportional to the magnitude of the volume loss.
 Maximum response is achieved when the volume is decreased by 30-40%.
 Rapid losses are not as well tolerated as slow losses.
Hypothalamus: hypothalamic releasing factors stimulating the pituitary gland.
Anterior pituitary (adeno-hypophysis):
1. ACTH: in response to CRH from hypothalamus.
- stored as a large molecule POMC (pro-opiomelanocortin).
- acts on zona fasciculata of adrenal cortex to produce Cortisol and Aldosterone from
zona glomerulosa.
- Cortisol has negative feedback on ACTH secretion (which is inhibited during
sequential injury, severe hypovolemia and Cushing disease).

Cortisol: has complex activity on carbohydrate , fat and protein.(metabolism)

-proteolysis and gluconeogenesis in the liver.
-inhibition of glucose uptake by cells.
-lipolysis → glucose.
-anti inflammatory activity: Phospholipase A 2 , ↓ cytokines, ↓ neutrophils and macrophages
in inflammation zone.
-inhibits conversion of T4 to T3
Figure 1 Hypothalamic-pituitary-adrenal -axis
Aldosterone:
-Renin-angiotensin system.
-increased resorption of Na and Cl, K excretion.
- ↑ production of AVP.
2. Growth hormone (GH):GHRF
-insulin-like growth factor(IGF-1 and IGF2).Somatomedins (from the liver).
-the main action during stress is to promote protein synthesis.
-lipolysis → hyperglycemia.
-carbohydrates breakdown (glycogenolysis)→ hyperglycemia.
-inhibition of glucose uptake.
3. TSH:
- is decreased during stress because of Cortisol effect ? → decreased T 3 →
decreased metabolic rate and oxygen consumption.
- exogenous steroids suppress T3.
4. FSH and LH
-Their secretion is suppressed after injury: decreased testosterone and estrogen.
-Menstrual dysfunction.
-decreased libido.
5. Prolactin:
The importance of its action following injury is not well known.

 B-Endorphin: endogenous opioid.

- ↑ concentrations in circulation after injury reflect pituitary hormone secretion.
- associated with hyperglycemia.
- some opioid peptides have the ability to suppress immunologic function.
- analgesic effect.
- their precise action still under investigation.
Posterior pituitary (Neuro-hypophysis):
AVP (ADH):
-is synthesized in the hypothalamus and stored in the Neurohypophysis.
-stimulated by increased plasma osmolality, ACTH, Angiotensin II, Cortisol,
pain and Catecholamines.
-its action:
osmo-regulatory: resorption of solute-free water.
vasoactive: peripheral vasoconstriction (splanchnic bed).
metabolic: hepatic glycogenolysis and gluconeogenesis.

Head injury can cause:

-SIADH
-Diabetes insipidus.
Local tissue damage mediators: cytokines
 Produced de novo locally at site of injury by activated leukocytes, fibroblasts and
endothelial cells as an early response.
 They include Interleukins (IL), Interferons, eicosanoids and endothelial cell
factors.
 Major role in mediating immunity and inflammation.
 Cell-to-cell (paracrine) and distant (hormonal) functions.
 Cytokines that affect immune function are termed lymphokines and include: IL,
TNF (tissue necrosis factor) and the Interferons.
 After major injury the main cytokines released are IL-1, TNF-α and IL-6 and they
promote the synthesis of hepatic acute –phase proteins.
 Regional anaesthesia with local anaesthetic agents inhibits the stress response to
surgery and can produce a beneficial effects on organ function post-operatively.
IL-1:
- ↑ T cell proliferation.
- fever.
- anorexia.
- deceased pain.
- breakdown of skeletal muscle.
- hyperglycemia by suppression of insulin secretion.
TNF (Cachectin):
 Stimulated by complement activation
 Produced by monocytes, macrophages, Kupffer cells, mast cells and
endothelial cells.
 TNF + IL-1: hypotension, tissue necrosis, cell death, release of prostaglandin,
cytotoxic for islet cells.
 TNF + IL-2: eicosanoids and platelet-activating factor. Hypotension in sepsis.
 IL-6:
- ↑ 30-60 min after injury and significant after 2-4 h.
- ↑ is proportional to the degree if insult.
- enhance immune function and hepatic protein synthesis.
- promote the synthesis of hepatic acute –phase proteins.
 Interferon γ: Glycoprotein produced by lymphocytes T.
- activates macrophages to release IL-1 and TNF.
- ↑monocytes IL-2 expression.
- inhibits viral replication.
- inhibits PGE2 reducing the immuno-suppression effect of PGE2 .
Eicosanoids: the fat mediators of shock. Figure 2
 Derived from arachidonic acid in response to hypoxia , ischemia, injury,
fibrinogens, endotoxin, nor-epinephrine, AVP, angiotensin II bradykinin,
serotonin and histamine.
 Prostaglandins, thromboxane and leukotrienes (COX, thomb.synth,LOX)
 Their effects depend on what stimulates their production and what cells
produce them for example:
- Prostacycline (PGI2) produced by vascular endothelial cells: vasodilatation.
- thromboxane A 2 (TxA2) causes vasoconstriction and platelet aggregation.
- leukotrienes including slow-releasing substance of anaphylaxis: they produce
capillary leakage, bronchospasm and vasoconstriction.
 Prostaglandins are the major component of inflammatory response.
 ARDS, pancreatitis and some forms of renal failure (caused by
Eicosanoids ?).
Figure 2
Interaction between the Immune system and the Neuro-endocrine system:

- IL-1 And IL-6 can stimulate secretion of ACTH.

- the Cortisol response to surgery is sufficient to depress IL-6 concentration.

Metabolic response to injury:

 Activation of stress hypermetabolism following surgery, trauma, or sepsis.

 Resistant hyperglycemia to provide energy and substrate for tissue repair and
to activate immune function and the inflammatory response.
 Increased levels of: CRF, ACTH, AVP, Catecholamine, corticosteroids,
glucagon, GH.
 Decreased or normal Insulin level, with peripheral resistance to insulin.
 Hyperglycemia: glycogenolysis, gluconeogenesis, reduced peripheral cell
utilization of glucose.
 Increased use of protein as fuel leading to hypoalbuminemia and decreased
muscle mass.
Metabolic response to injury continue:
Two phases of response:

1. Ebb phase (24-36 hours). Decompensation , ↓O2 consumption, fluid

imbalance and cellular shock.
2. Flow phase (can last days, weeks or months). body adaptation: ↑cellular
activity, ↑ hormonal stimulation, ↑metabolic rate, ↑body temperature, ↑ N
loss in response to stress hormonal and inflammatory mediators.
A.Catabolic: ↑gluconeogenesis, ↑REE, ↑proteolysis, ureagenesis, ↑ urine N loss.
(clinically: tachypnea, fever, tachycardia, lab: leukocytosis, hyperlactatemia,
azotemia and hyperglycemia).
B.Anabolic: weight gain and positive N balance.
Metabolic sequelae of the endocrine response:
increased secretion of catabolic hormones as a survival mechanism using stored
body fuels and retaining salt and water, giving the body a chance to survive
without food until healing and repair had taken place.
 Carbohydrate metabolism:
- increased blood levels of glucose
- increased glycogenolysis.
- increased gluconeogenesis.
- peripheral insulin resistance.
 Protein metabolism:
- skeletal muscle is broken down, amino acids are used as energy and substrate.
- marked weight lost and muscle wasting.
- increased Nitrogen secretion in the urine.
 Fat metabolism:
- lipolysis of TGL to glycerol and fatty acids.
- glycerol is used for gluconeogenesis in the liver.
- fatty acids are converted to ketone bodies or re-esterified in the liver and
muscles.