Neuro Endocrine Response To Surgical Stress Biology Essay

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Sudden exposure to any type of stress initially produces the sympathetic alarm reaction. The alarm reaction consists of a generalized and profuse sympathetic neural discharge, as well as, an increase in adrenal medullary secretion. If the stressful stimulus persists, the short-lived alarm reaction is followed by a complex neuro-endocrine response which may last hours, days or even weeks. Such a sustained neuro-endocrine response is typically

seen in patients who undergo major abdominal surgery or in patients with multiple fractures or extensive burns. In uncomplicated surgery, the neuro-endocrine response lasts only two to four days. However, in cases with multiple fractures, extensive burns or post-surgical complications, the response may continue for days or weeks.

The changes mentioned above seem to have evolved to aid survival in more primitive environment. Salt and water retention, along with mobilization of glucose, fatty acids and amino acids would be beneficial to and injured animal with no access to food and water. Hence, any possible advantage of stress response in a surgical patient under treatment in modern settings would not be obvious. On the other hand, exaggerated stress response seems to account for the major morbidity in the postoperative period. Nowadays, efforts are being made to attenuate the stress response to trauma and surgery, since it seems impossible or even undesirable to abolish it completely.


Fig.1.1. The fundamental stress response.

The investigations into metabolic effects of surgical stress have been carried out mostly in surgical operations of varying severity, rather than in trauma patients, since the baseline preoperative parameters are available to assess the perioperative and postoperative alterations in metabolic activity. Following a surgical operation (or an extensive trauma), two distinct phases of tissue metabolism can be distinguished:

(1) Catabolic phase lasts 2-4 days after major surgery, but longer in cases with multiple fractures or extensive burns. This is the stage of stress. During this phase, there is increased oxygen consumption, severe protein catabolism leading to loss of lean body mass and negative nitrogen balance, loss of body weight, fluid retention and increased susceptibility to infections.

(2) Anabolic phase follows the catabolic phase. It lasts 4-5 days in uncomplicated surgical operation but longer in patients with prolonged catabolic phase. This phase consists of a slow accumulation of proteins and fat. It is a slow process. Proteins lost in a few days of catabolic phase may be restored over a period of several weeks. Fat stores are replenished over several months.

The Catabolic Phase

This phase is of great interest since its intensity and duration determine the duration of convalescence (the anabolic phase). Over the last few decades, efforts have been made to attenuate or if possible to eliminate the catabolic phase. Some procedures such as regional anesthesia and laparoscopic surgery have been shown to decrease the duration and intensity of the catabolic phase. However, no measure is yet available to totally eliminate this phase. It may not be even prudent to do so. The neuro-endocrine response is a universal a response to all types of stress. Such a response can be eliminated in experimental animals by bilateral adrenalectomy. In such animals, any type of stress such as anesthesia, surgery or hemorrhage is invariably fatal.

The causes of catabolic phase in surgical stress include fear, pain, anaesthesia, surgical trauma (tissue destruction and loss of blood and fluids from the operated site) and post-surgical complications like hemorrhage, hypoxia, shock and infections.


Triggers for Metabolic Response to Surgical Stress







Transient starvation

Tissue trauma: Most important factor : Acts through

Neural pathways

Release of cytokines

Blood loss

Fluid loss

Postoperative complications:

Blood loss

Fluid loss


Mechanism of Neuro-endocrine Response.

The neuro-endocrine in surgical stress is mediated primarily through the hypothalamus resulting in (i) activation of sympatho-adrenal system, and (ii) change in pituitary gland secretion resulting in increased secretion of its target glands. The overall metabolic effect of hormonal changes is increased catabolism, which mobilizes substrates to provide a source of energy. In addition, hypovolemia, if present, sets up its own reflex responses through arterial baroreceptors and volume receptors in order to maintain cardiovascular homeostasis.

Sympatho-adrenal Response: The Alarm Reaction

Fig.1.2. The alarm reaction.

This is the immediate response to all types of stress. That is why it was called the alarm reaction by Selye. It is a component of what he called General Adaptation syndrome. The generalized increase in sympathetic neural discharge is accompanied by increased adrenal medullary secretion (adrenal medulla is supplied by preganglionic sympathetic fibres). The release of adrenal medullary catecholamines occurs within seconds or minutes. The stage can be easily recognized by the cardio-vascular effects such as tachycardia and hypertension.

In some types of stress, such as hypoglycemia, severe exercise, hemorrhage, and exposure to severe cold stress, the sympatho-adrenal response is often sufficient to provide appropriate metabolic and cardiovascular responses to maintain homeostasis till the stressogenic stimulus disappears. In other cases, where the stress persists and sympatho-adrenal response is inadequate for the degree of stress, a complex neuro-endocrine response supervenes. The most characteristic feature of this phase is hypothalamus-mediated increase in ACTH and cortisol secretions. However, endocrine response is widespread in involves a large number of hormones( Fig. 1.3). The catabolic phase corresponds to the maintenance phase of GAS by Salye. It results from further efforts of the body to maintain homeostasis in the face of persistent stress. If severe and persistent, stress may lead to detrimental metabolic and immunological consequences; that may be fatal (the exhaustion phase of GAS).

Fig.1.3. The neuro-endocrine response to surgical stress.

1. Adreno-corticotropic Hormone (ACTH) and Cortisol

The hypothalamic-mediated increased secretion of ACTH from the anterior pituitary leads to prompt increase in plasma cortisol secretion. Plasma levels of both the hormone are found to increase within minutes of the start of surgery. In the preoperative, perioperative and postoperative periods, a number of triggers may act independently or in combination to increase the secretion of ACTH and cortisol. The metabolic effects of high plasma concentrations of cortisol are listed below:

1. Hyperglycemia by (i) inducing synthesis of hepatic enzymes involved in

neoglucogenesis, and

(ii) Decreasing peripheral (skeletal muscle) glucose


2. Increased plasma free fatty acids (FFA) levels by activating the enzyme hormone-sensitive lipase in the adipose tissue.

3. Enhanced protein catabolism, particularly in the skeletal muscle, leading to negative nitrogen balance.

4. Immunosuppression by decreasing the number of circulating T- and B-lymphocytes.

5. Salt and water retention in the kidneys.

6. Anti-inflammatory action. In high concentrations, cortisol interferes with the synthesis of mediators of inflammatory response, particularly prostaglandins. Thus, various aspects of inflammatory response such as accumulation of neutrophils and macrophages are inhibited.


Whereas the role of enhanced cortisol secretion during stress is well-known, the increased secretion of ACTH seems to have a role in addition to that of increasing the adrenal cortical secretion. During exposure to stress, the plasma ACTH levels are far above those required for maximal cortisol secretion by the adrenal cortex. In this connection, it is pertinent to mention that ACTH is derived from the larger protein molecule, proopiomelanocortin (POMC), which undergoes post-translational splitting to yield ACTH, β-endorphin and certain other polypeptide fragments. β-endorphin is a potent endogenous opioid analgesic.

2. Adrenal Medullary Catecholamines

Adrenal medullary epinephrine and norepinephrine play a key role in the metabolic response to anesthesia and surgery. Their secretion begins to increase during induction of anesthetic agent and continues 2-3 days postoperatively. Medullary catecholamines make notable contribution to hypermetabolic state observed during the catabolic phase of surgical stress.

The metabolic actions of catecholamines, particularly epinephrine are listed below:

Hyperglycemia. Both the catecholamines produce hyperglycemia through a number of mechanisms:

Glycogenolysis in the liver and skeletal muscle.

Inhibition of insulin secretion.

Increased glucagon secretion.

Increased plasma FFA levels.

Calorigenic action. Catecholamines increase metabolic rate of the body by increasing chemical thermogenesis.

Activation of rennin-angiotensin system.

The cardiovascular effects of catecholamines help in the maintenance of homeostasis in the face of blood and other body fluid losses during surgery.

3. Insulin and Glucagon

These hormones are important regulators of blood glucose level. Insulin lowers blood glucose level, whereas glucagon secretion results in hyperglycemia. Their secretion from the islets of Langerhans usually varies in a reciprocal manner. Sympathetic discharge and circulating catecholamines suppress insulin release and promote glucagon secretion.


This hormone has strong anabolic actions on carbohydrate, protein and fat metabolism. Liver, skeletal muscle and adipose tissue are the chief target organs for insulin. The metabolic effects of insulin are listed below.

A. Liver:

Increased glycolysis.

Increased glycogen synthesis.

Increased protein synthesis.

Increased fatty acid synthesis.

Decreased gluconeogenesis.

Decreased glucose output

Decreased ketogenesis.

Skeletal Muscle

Increased glucose utilization.

Increased glycogen synthesis

Increased amino acid uptake.

Increased protein synthesis

Increased K+ uptake.

Decreased protein catabolism.

C. Adipose Tissue

Increased glucose uptake.

Increased fatty acid synthesis.

Increased triglyceride deposition.

Activation of lipoprotein lipase.

Inhibition of hormone-sensitive lipase.

Increased K+ uptake.

Impaired insulin secretion is an important feature of surgical stress. Sympatho-adrenal discharge increases at the start of surgical stress and continues well into postoperative period. Inhibition of insulin secretion can be explained by the direct effects of sympathetic neural discharge and circulating catecholamines on the β-cells of the islets. During the postoperative period, a reciprocal relationship between a rise in plasma catecholamines levels and a decrease in plasma insulin levels can be demonstrated.

Stress is also associated with a severe, yet reversible, form of insulin resistance. In the perioperative period, the degree of hyperglycemia is often out of proportion to the decreased plasma insulin levels. The insulin-resistance, at least partly, results from increased levels of counter-regulatory hormones such as cortisol, catecholamines and growth hormone. However, marked insulin resistance can develop after elective surgery even without concomitant elevations in the plasma levels of counter-regulatory hormones. The degree of insulin resistance developing after surgery is proportional to the surgical trauma and may persists for 2-3 weeks after uncomplicated abdominal surgery The main sites for insulin resistance seem to be extrahepatic tissues, probably skeletal muscle, where preliminary data suggest that the inhibition of glucose transporting system is involved.


Liver is chief target organ for glucagon. This hormone promotes hepatic production of glucose by: (i) Breakdown of glycogen to glucose (glycogenolysis) and (ii). Synthesis of glucose from amino acids (neoglucogenesis). Plasma glucagon levels increase transiently after major surgery, but this is not the major contributory factor in the production of hyperglycemia during surgical stress.

4. Growth Hormone

Besides the well-known action of growth promotion in childhood, growth hormone has many metabolic actions that operate even in adults. These metabolic effects are listed below:

Stimulation of protein synthesis.

Inhibition of protein break down.

Increased lioplysis in the adipose tissue.

Decreased glucose utilization in the peripheral tissues.

Growth hormone produces its growth promotion and metabolic effects by promoting the synthesis of polypeptide called insulin-like growth factor-1(IGF-1) in the liver. However, not all actions of GH can be attributed to IGF-1. IGF-1 has insulin-like activity, anti-lipolytic activity, protein synthesis and epiphysial growth. Growth hormone actions include decreased insulin sensitivity, lipolysis, protein synthesis and epiphysial growth.

A GH-resistant state is observed during surgical stress. Stress response is characterized by an elevation of growth hormone secretion that is neither accompanied by the corresponding increment in IGF-I nor reflected in nitrogen balance (which remains negative). Thus, whereas anabolic effects of GH are suppressed, the anti-insulin and lipolytic action are permitted to occur.

A 2- to 16- fold increase in plasma growth hormone levels have been observed in perioperative and postoperative period. Much higher plasma levels have been recorded in patients with immediate post-surgical complications. It has been suggested that the rapid postoperative onset of raised GH concentration in plasma may be used as a marker for postoperative complications.

Thyroid Hormones

Thyroid hormones are the chief regulator of metabolic rate of the body. At normal plasma concentrations, thyroid hormones have an anabolic activity. However, at high plasma concentrations, they produce protein catabolism. The thyroid gland secretes mostly thyroxin (T4) and a small amount of triiodothyronine (T 3). In the tissues, T 4 is converted to T 3, a derivative many times more potent than T 4, before it can exert its metabolic activity. Normally, approximately 40 % of T 4 is converted T3 and the rest is converted to an inert derivative called reverse T3(R T3).

Surgical stress is a severe hypermetabolic and protein catabolic state. Therefore it may be assumed that thyroid secretions are increased during surgical stress. Actually, plasma T4 levels are unaffected, T3 levels decrease and R T3 levels increase during surgical stress. The increased RT3/ T3 ratio may be due to concurrent increase in plasma cortisol. The significance of decreased plasma T3 levels, if any, is not clear.

Antidiuretic Hormone (vasopressin)

Antidiuretic hormone (ADH) is secreted by the posterior pituitary gland. The two chief stimuli increasing the secretion of the hormone are:

increased plasma osmolality e.g. dehydration and

(ii) decreased extracellular fluid volume e.g. dehydration, hemorrhage. Some other factors known to increase ADH secretion include pain, exercise, stress, and nicotine.

The actions of ADH are listed below:

Antidiuresis: ADH causes retention of water in the collecting ducts of the kidneys resulting in the production of smaller volume of concentrated urine. This action is apparent even at low plasma levels of the hormone (1-10 pg/ml).

Blood pressure increase: Vasopressin (ADH) produces contraction of the smooth muscle of the blood vessels leading to an increase in arterial blood pressure. This action occurs at high plasma level of the hormone (100 pg/ml)

Elevated secretion of ADH is one of the characteristic features of surgical stress. The elevated ADH levels persist for about a week after the operation. Anesthesia itself causes a sharp increase in plasma ADH level, though subsequently blood loss, perioperative and postoperative pain, postoperative nausea and vomiting are some of the factors predisposing a surgical patient to secrete an excess of ADH. Increased ADH secretion after a major surgical operation may help to compensate for blood and fluid loss during surgery. However, surgery is one of the important causes for the development of syndrome of inappropriate ADH release (SIADH).

In SIADH, there is continual release of ADH that is independent of plasma osmolality. The patient is unable to excrete dilute urine, and ingested fluids are retained. Dilutional hyponatremia develops. The amount of ADH re-leased and the elevation of urinary osmolality thus produced is considered to be inappropriate in relation to the level of plasma osmolality or serum sodium concentration. Thus, the hallmark of SIADH is dilutional hyponatremia in the presence of urinary osmolality greater than plasma osmolality and continued urinary excretion of sodium. SIADH puts the patient at risk of water intoxication and severe hyponatremia, even on administration of moderate water load.


Aldosterone is a mineralocorticoid secreted by the zona glomeruloza of the adrenal cortex. Its produces salt and water retention in the collecting ducts of the kidney. Due to sodium-potassium exchange in the epithelial cells of the collecting ducts, there is enhanced urinary potassium loss as well.

Regulation of Secretion

1. Renin-angiotensin mechanism is the most important regulator of aldosterone secretion. The afferent arterioles of the kidney contain juxta-glomerular cells. These cells contain stores of renin a proteolytic enzyme. Juxta-glomerular cells act as baroreceptors and release rennin in response to a fall in afferent arteriolar perfusion pressure. Thus any decrease in intravascular volume due to hemorrhage or dehydration results in increased rennin section into blood. Increased sympathetic discharge due to any stress, including surgical stress also increases rennin release. Renin converts circulating plasma protein angiotensinogen to angiotensin I. An endothelial converting enzyme converts angiotensin I to an Angiotensin II. Angiotensin II acts on the zona glomerulosa cells of adrenal cortex resulting in increased secretion of aldosterone (Fig . 1.4 ).

Fig.1.4. The renin angiotensin system

2. An increase in plasma K+ level also produces increases aldosterone secretion by a direct action on the zona glomerulosa cells.

3. ACTH is chiefly concerned with release of cortisol from the zona fasciculata of adrenal cortex. Increased ACTH secretion produces a mild and transient increase in aldosterone secretion.

Increase in plasma aldosterone secretion starts just when the patient is being anesthetized and continues during surgery and postoperative period. The level gradually falls over a period of seven to ten days. Significant inverse correlation between plasma renin activity and circulating plasma volume can be observed. However, the increased sympatho- adrenal discharge during the alarm reaction and during perioperative period may increase aldosterone secretion even in the absence of hypovolemia or hypotension.

9. Sex hormones

A decrease in the plasma levels of testosterone and estrogens has been reported during the postoperative period.

10. Cytokines

Experimental and clinical studies have brought evidence that surgical trauma markedly affects the immune system, including both the specific and the non-specific immune responses.

The immune system of the body may be considered as two integrated systems that communicate with each other. Granulocytes, macrophages, and natural killer (NK) and dendritic cells are constituents of the innate immune system, the first line of defense against antigens such as bacteria, viruses, and some types of circulating tumor cells. The acquired immunogical response comprises of cellular and humoral immunity mediated by the T- and B-lymphocytes. The innate and acquired immune systems are closely interlinked.

Cytokines are non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells that act as intercellular mediators. Cytokines whose amino acid sequence is known are called interleukins (IL).Cytokines, may act on the cells producing them in autocrine fashion or other cells both in close proximity (paracrine action), or cells at a distance from the producing cell (endocrine action).

During surgical stress, in contrast to other hormones discussed earlier, the production of cytokines is initiated by tissue trauma rather than by catecholamines or ACTH-cortisol secretion. The release of IL-6 can be particularly linked to the severity of injury inflicted.

Cytokine Release in Major Surgical Trauma

(A) There is an early hyperinflammatory response, which is characterized by (i) release of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF), interleukin (IL)-1, and IL-6, which results in acute phase response and (ii) neutrophil activation and microvascular adherence, as well as (iii) uncontrolled polymorphonuclear (PMN) and macrophage oxidative burst.

Acute phase response collectively refers to a constellation of physiological changes that are initiated immediately subsequent to pathogen infection or tissue trauma. These changes include a shift in liver metabolism such that synthesis of normal carrier proteins is inhibited, whereas production of positive acute-phase proteins is initiated. Other changes associated with acute phase activation are

(i) Fever

(ii) Granulocytosis

(iii) Production of 'acute phase proteins' (APPs) in the liver such as C-reactive protein, fibrinogen and alpha-2 macroglobulin.

(iv) Decrease in plasma concentrations of transport proteins : albumin, transferrin, alpha-2 macroglobulin.

The function of most APPs has not been totally elucidated. The APPs are regarded as having general functions in opsonization and trapping of micro-organisms and their products, in activating complement, in binding cellular remnants like nuclear fractions, in neutralizing enzymes, scavenging free hemoglobin and radicals, and in modulating the host's immune response.

Measurement of acute-phase proteins, especially C-reactive protein, is a useful marker of inflammation. It correlates with the erythrocyte sedimentation rate (ESR).

(B)Anti-inflammatory response

The massive and continuous IL-6 release induces an acute phase response, but, more importantly, also accounts for the up-regulation of major anti-inflammatory mediators, such as prostaglandin (PG) E2, IL-10 and transforming growth factor (TGF)-ß. This results in surgical, trauma-induced, immunosuppression, as indicated by (i) monocyte deactivation, and

(ii) a shift of the Th1/Th2 ratio towards a Th2-dominated cytokine pattern

Table. 1.1. Cytokines: types, sources and major actions.


1. Hypermetabolism

Increased body metabolism is one of the characteristic features of surgical stress. Most dramatic increase in metabolic rate is seen in burn injuries when metabolic rate increases by approximately 50 %. Even in uncomplicated abdominal surgery, a 10% increase in metabolism is usual. The increased metabolism can be correlated with increased adrenal catecholamine discharge. There is no increase in the secretion of thyroid hormones. In fact, plasma T3 levels are lower than normal.


Consequent to the complex neuro-endocrine response discussed above, hyperglycemia is commonly observed in the perioperative period. Hyperglycemia results from increased glycogenolysis and gluconeogenesis coupled with development of insulin resistance in the peripheral tissues (skeletal muscle). Marked insulin resistance is present after routine surgical procedures, even in the absence of sepsis or other complications, and may persist up to 20 days thereafter. The degree of increase in the blood glucose level is usually influenced both by patient characteristics (such as pre-existing diabetes) as well as type of surgical procedure (being more common during highly stressful operations such as cardiac surgery). The surgeon usually becomes complacent to hyperglycemia since it is seen so regularly, and it is not easily related to a recognizable adverse perioperative event.

Although plasma glucose abnormalities in hospitalized patients have traditionally been explained by the release of mediators of stress, and hence perioperative hyperglycemia has not been treated aggressively, mainly because it has been considered harmless. However, a growing body of evidence has shown that underlying defects in glucose metabolism may also be an important contributor to the rise in plasma glucose level.

The clinical significance of what most would consider relatively minor increase in perioperative glucose levels is likely to be underestimated. Strong evidence exists to indicate that hyperglycemia alone, with or without diabetes, contributes to morbidity and mortality in surgical patients. Hyperglycemia might be linked to adverse outcome through direct or indirect mechanisms. Short and transient periods of hyperglycemia have been shown to result in abnormalities in each step of granulocyte-phagocytic function i.e. granulocyte adherence, diapedesis, chemotaxis, phagocytosis, and bacterial killing. This impairment in immune function has been associated with an increased risk for wound nosocomial infection. Acute hyperglycemia also results glycosuria associated with osmotic diuresis, electrolyte depletion and dehydration which further potentiate poor wound healing and increased the risk of infections.

Patients with diabetes mellitus have impaired ability to secrete insulin as a compensatory response to insulin resistance. Hence such patients have even greater derangement in glucose metabolism when compared to nondiabetic patients. Patients with a mean blood glucose levels greater than 200 mg/dL within 36 hours following cardiac surgery are more likely to develop infectious complications than their counterparts who maintain better glycemic control.

Besides the surgical patients, hyperglycemia is highly prevalent in the intensive care unit. Numerous studies have demonstrated the association between hyperglycemia and adverse outcomes, independent of pre-existing diabetes. Intervention trials of insulin therapy are limited but, in general, they demonstrate that glucose lowering significantly improves outcomes.

3. Lipolysis

The pattern of endocrine secretions (increased catecholamines, G.H., cortisol secretion and development of insulin resistance) favor greater breakdown of stored fat in to free fatty acids (FFA). Although, lipolysis is substantially increased, the plasma FFA level remains within the normal range. These observations demonstrate, in the face of decreased glucose utilization, there is massive FFA utilization as an energy substrate, especially in the skeletal muscle.

4. Protein catabolism

Protein catabolism is the most important effect of the catabolic phase of surgical stress. It results in anemia, hypoproteinemia, and loss of lean body mass (mainly muscle proteins). An average person loses 400 gm of wet lean tissue every day of the catabolic phase. Increased protein catabolism is reflected in increased urinary losses of nitrogen and potassium.

More than half a century has passed since Cuthbertson observed that bone fractures cause a large increase in urinary nitrogen excretion, thereby establishing negative nitrogen balance as a metabolic hallmark of trauma. Cumulative urinary nitrogen excretion, a traditional measure to quantify oxidative protein losses, has been shown to range between 40 and 80 g after uncomplicated abdominal procedures. Patients suffering from multiple injuries and septic shock lose more than 200 g of nitrogen. Nitrogen losses after severe burns can exceed 300 g. The clinical importance of this catabolic pattern can be appreciated more readily when one remembers that 1 g of nitrogen is the equivalent of 30 g of hydrated lean tissue. The loss of lean muscle mass is of utmost clinical relevance as the length of time for return of normal daily routine after discharge from the hospital is determined by the extent of loss muscle mass during hospitalization. Because protein represents both structural and functional body components, erosion of lean tissue may also lead to devastating consequences such as delayed wound healing, compromised immune function, and diminished muscle strength resulting in prolonged convalescence and increased morbidity.

The principal underlying defect appears to be an accelerated rate of proteolysis and amino acid oxidation along with an insufficient increase in protein synthesis. Endogenous amino acid oxidation from the muscle after abdominal surgery has been shown to increase by 90%, while whole body protein synthesis increases by 10% only. The magnitude of this alteration is substantial considering the fact that muscle tissue represents approximately 45% of body weight.

The biochemical factors initiating, regulating and sustaining the catabolic response to surgery have not been fully identified. Much of the observed catabolic profile can be explained by specific hormonal alterations known as the neuro-endocrine stress response. Surgical stress results in increased secretion of several pituitary hormones and activation of the sympathetic nervous system, resulting in elevations in the plasma levels of cortisol, and catecholamines. Moreover, there is marked impairment of tissue insulin sensitivity.

And additional factor promoting the loss of lean body mass is the prolonged bed rest necessitated for recovery from a major surgical operation. In the absence of the stimulation afforded by physical activity, metabolic homeostasis is compromised, and a rapid deterioration in functional capacity can occur. In one recent study, it was demonstrated that 28-day bed rest in otherwise healthy young volunteers resulted in approximately 0.5 kg loss of lean leg mass. Amino acid kinetics revealed a significant decrease in protein synthesis. Compared with bed rest alone, exogenous administration of cortisol coupled with prolonged inactivity substantially increased loss of muscle protein due to a reduction in muscle protein synthesis as well as increased protein catabolism.

5. Salt and Water Retention

In 1959, Francis Moore coined the terms 'sodium retention phase' to describe the changes which accompany the catabolic phase of injury and 'the sodium diuresis phase' to describe the return of the normal ability to excrete sodium chloride and water, signaling the recovery and convalescence. These observations emphasize how the pathophysiology of the response to injury increases the vulnerability of surgical patients to errors in fluid and electrolyte administration, and the importance of prescribing fluids with a clear understanding of this response. A UK study in 1997 showed that postoperative patients were frequently in positive fluid balance of 7 litres or more, with a positive sodium load of 700 mmol in the first few postoperative days.

Although avoidance of perioperative hypovolaemia remains an essential requirement and preoperative intravascular optimization improves outcome, excessive fluid infusion leading to sodium, chloride and water overload is now becoming recognized as a major cause of postoperative morbidity and mortality.

A number of hormonal changes, an essential component of the catabolic phase, lead to salt and water retention. Hypotension and hypovolemia are potent stimuli for increased secretion of antidiuretic hormone, renin and angiotensin II, but their plasma concentrations have been found to increase even in absence of any such stimulus during surgery. In fact, plasma renin activity increases just when the patient is being anesthetesized and continues during surgery and seven to ten days postoperatively. Due to surgical manipulations maximum plasma renin activity up to twenty folds of the normal value have been recorded.

ADH levels are universally elevated post-operatively when compared with pre-operative values. However, inappropriate ADH secretion (SIADH), a disorder characterized by ADH release in spite of the inhibitory influence of hypoosmolality( hyponatremia) is a serious complication. Surgical stress is one of the causes SIADH. The diagnosis of SIADH is suggested upon presentation with typical symptoms of weight gain, weakness, lethargy and mental confusion which ultimately progress to convulsions.

Post -operative hyponatraemia is a common clinical problem occurring in 1% of patients, with symptomatic hyponatraemia (SIADH) occurring in 20% of these patients. SIADH is more frequently seen in patients undergoing major surgeries such as on the heart or spine. However, occasionally it may occur during relatively minor abdominal surgeries. Post -operative patients develop hyponatraemia due to a combination of non-osmotic stimuli for ADH release, such as subclinical volume depletion, pain, nausea, stress, edema-forming conditions and administration of hypotonic fluids.

Signs and symptoms of SIADH are primarily related to the dysfunction of the central nervous system and correlate with severity and rapidity of development of hyponatremia. Anorexia, nausea, and malaise are the earliest findings, followed by headache, irritability, confusion, muscle cramps, weakness, obtundation, seizures, and coma. These occur as osmotic fluid shifts result in cerebral edema and increased intracranial pressure. Whereas most patients with serum sodium concentration above 125 mEq/L are asymptomatic, those with lower levels typically have symptoms, especially in the setting of a rapid decrease. When sodium concentration drops below 105 mEq/L, life-threatening complications are likely to occur.

6. Immunosuppression

There are widespread and significant surgery-induced alterations in an array of immune functions, including NK cell activity, lymphocyte cell numbers and proliferation, and cytokine secretion by immune cells. NK cell activity is suppressed within hours of surgery and lasts for days. Several studies have shown by direct comparison that a more invasive surgery is associated with a greater magnitude of NK suppression. Individuals undergoing major surgery for cancer are at greatest risk for a profound and long-lasting reduction in NK cell activity.

Because macrophages and NK cells are among the first response immune cells, their communications with other immune cells via cytokine production is highly important in assessing the immune consequences of surgery, with particular implications for post-surgical infection. In addition to evidence of a primary suppressive factor from surgery on NK cells, local factors released from damaged tissue, such as prostaglandins, are well-known contributors to inflammation and hence, inflammatory cytokine production. Tumor necrosis factor, IL-1, and IL-6 are key inflammatory cytokines that have been associated with surgery-induced decrements in immune functions.

Suppression of cellular immunity is another important host responses to surgical stress. Post-surgical immunosuppression may predispose the patient to septic complications. Moreover, surgical immunosuppression may allow the metastatic spread of malignant cells. Immune effector cells are intimately involved in the patient's response to cancer. The increased immunosuppression after open surgery could potentially inhibit immune effector cell tumor surveillance as well as inhibit scavenging of any residual or micrometastatic disease or of tumor cells shed at the time of the operation.

Can and should post-surgical catabolic response be abolished?

As discussed in detail above, surgical injury is followed by profound changes in endocrine metabolic function and various host defense mechanisms leading to catabolism and immunosuppression etc. These physiologic changes are supposed to be involved in the pathogenesis of postoperative morbidity. Therefore, efforts are being made to evolve techniques to attenuate, the catabolic phase.

Epidural analgesia

Effective afferent neural blockade with continuous epidural local

anesthetic techniques inhibits a major part of the endocrine

metabolic response, leading to improved protein economy but

without detrimental effects on inflammatory or immunologic

responses. Epidural analgesia, at present, is the most effective measure to attenuate the surgical stress responses ( Ch. )

Opioids and NSAIDS

In contrast, pain treatment with other modalities such as

nonsteroidal antiinflammatory drugs = (NSAIDs) and opioids has

only a small inhibitory effect on endocrine metabolic responses.

Minimally invasive surgery

This is another well established measure which attenuates the endocrine metabolic responses and reduces the inflammatory response and immune suppression

Anabolic therapy

An aggressive nutritional approach can sustain the hypermetabolic response to some extent. But, often, it is insufficient by itself, making anabolic agents that abrogate catabolism of structural protein a necessary linchpin of effective therapy. It has been suggested that anabolic therapy can be safely integrated into the management of severe injury and critical illness and should result in improvement in outcome.


The potential to modulate the activity of the immune system by interventions with specific nutrients is termed immunonutrition. Altered supply of nutrients is used to modify inflammatory or immune responses. Administration of "Immune nutrient cocktails" (Table 1.2 ) have been advocated specially to improve the survival of septic patients during the intensive care period.


Table 1.2 Immune Nutrient Cocktail

(i)Amino acids



(ii) Ω-3 fatty acids

(iii) Nucleic Acids

(iv) Anabolic hormones


Insulin-like growth factor-1 (IGF-1)


Anabolic steroids

Human growth hormone