The "Stress Response" to critical illness

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This is an adaptive response to massive physiological stress, designed to mobilise the body stores of metabolic substrates and to increase their availablility to the tissues.

This chapter is an attempt to bring together information about the various adaptive and maladaptive ways in which the human organism attempts to cope with a massive physiological insult. These insults come in many forms, and for each a different response is warranted; however, there are features which are common to most instances of severe acute illness, and these can be describe by the unifying term "stress reponse".

Some of the specific endocrine changes which occur as a part of the stress response are discussed in their own dedicated chapters. Others have yet to merit their own article.

• Sick euthyroid syndrome
• Relative adrenal insufficiency of critical illness
• Stress-induced hyperglycaemia

• Increased cortisol secretion and peripheral sensitivity

Increased levels of Human Growth Hormone

In critical illness, there is a cytokine-induced acute alteration in the response to growth hormone. Specifically, the following changes are observed:

• First, a decrease in the levels of GH-binding protein

• Also, a decrease in the expression of peripheral GH receptors
• Thus, a loss of peripheral sensitivity to growth hormone
• This leads to a feedback-driven increase in the secretion of growth hormone.
  • The presence of excess GH opposes the effects of insulin at the liver and peripheral tissues, and encourages lipolysis.
  • GH does this by uncoupling insulin-stimulated PI 3-kinase from its downstream signals. Insulin will bind to its receptor, but the downstream second-messenger effects are inhibited, and there is no increase in transmembrane glucose transport.
• At the same time, levels of insulin-like growth factor (IGF-1) and its binding protein (IGFBP-1) decrease. This is thought to be due to the loss of "pulsatility" in GH secretion (its concentration normally waxes and wanes cyclically over the course of the day). The liver normally secretes IGF-1 and IGFBP-1 in response to GH pulses, but with the decrease in the expression of peripheral (and thus also hepatic) GH receptors, the liver remains indifferent to rising GH levels.
  • The decrease in IGF-1 and IGFBP-1 result in decreased anabolic ("somatotropic") peripheral effects of GH. These hormones normally catalyse skeletal muscle hypertrophy and protect myocytes from protein catabolism.

For visual learners, this interaction can be expressed as a needlessly complex diagram:

The net total of GH activity is therefore two-sided. More GH is released, but a part of its effects is blocked completely. Thus, you get the GH-driven increase in insulin resistance and an increase in lipolysis, but the anabolic effects never manifest because the secretion of IGF-1 is inhibited.

Decreased anabolic stimulus

Theoretically, this enhanced secretion of growth hormone is supposed to enhance the response of an organism to severe illness. The anti-insulin and lipolytic effects of growth hormone free up the metabolic fuel substrates for use by the immune system and the struggling organs, while the decreased IGF-I activity puts brakes on energy-expensive anabolic activities.

However, in the long term, this relative hyposomatotropism results in inappropriately poor anabolic activity, when you need it most (eg. when you are weaning from the ventilator). This contributes to the pathogenesis of the wasting syndrome in critical illness. In the absence of normal growth hormone activity, muscle wasting is difficult to arrest even with optimal protein supplementation, and muscular strength rehabilitation is hampered by slow muscle growth.

"Sick Euthyroid" syndrome of critical illness

The clinical manifestations and pathophysiology of the "sick euthyroid" syndrome are discussed in detail elsewhere. It is a disorder of decreased T3 levels along with the presence of abnormally large amount of rT3 which is biologically inactive and thus acts as a competitive antagonist of T3. The overall thyroid dysfunction is thus amplified, and the pituitary gland responds to this with complete indifference, without any increase in TSH production.

In summary, there are a few key features. The appearance of cytokines (especially TNF-α) changes the expression of peripheral deiodinase enzymes, favouring the conversion of T4 into the uselessly inactive rT3, rather than proper T3. Increasing levels of the apostate rT3 molecule are a characteristic feature of this disorder.

As a response to lower levels of free T3, the TSH transiently increases, but may be normal in critical illness because the beleaguered pituitary gland cannot produce a normal hormonal response in the context of wildly deranged physiology, crashing organ system function and whatnot.

Decreased reproductive hormone secretion

When suffering from catastrophic organ system failure, the last thing you tend to think about is sex. This analogy extends to the molecular endocrine level. Acute physiological stress results in a sudden decrease of testosterone production, driven by a decrease of LH release, and this low level is sustained as a critical illness becomes chronic. This may well contribute to the muscle wasting of critical illness. As time goes on, chronically low LH levels can give rise to clinically relevant hypogonadism.

Additionally, prolactin levels decrease acutely in critical illness, which fits in well with the hypothesis that the stress response is all about energy conservation. The organism of the primate mother at the dawn of time would have been better served (in evolutionary terms) by focusing her metabolic substrates on healing her broken leg, rather than lactating uselessly.

Increased cortisol levels

In critical illness, there is an appropriate increase in cortisol levels, which is a normal response to physiological stress.

The net effect of this cortisol release takes many forms.

In summary:

• Increase in the acute provision of energy:
  • Increased release of blood glucose
  • Decreased utilisation of glucose by insulin-sensitive tissues
  • Decreased protein synthesis
  • Mobilisation of fat reserves into free fatty acids
• Improved hemodynamic status
  • Increased vascular sensitivity to catecholamines
  • Increased fluid and sodium retention (aldosterone effects)
• Downregulation of immune response
  • Anti-inflammatory effects at the level of endothelium

This increase in the efects of cortisol is not mediated solely by increased corticosteroid synthesis. There also seems to be an increase in cortsiol receptor sensitivity. At the same time, the levels of cortisol-binding protein are decreased, thereby increasing the free fraction of cortisol.

Relative adrenal insufficiency

There is critical illness, and then there is critical illness. The latter is entirely a product of civilisation. Think of an example. Never before in the prehistory of man has human physiology ever been challanged by multi-organ sysem failure in the setting of bone marrow transplant, with dialysis, ECMO, vasopressors, chemotherapy agents and mechanical ventilation. The normal stress responses which evolved in an environment of "nature red in tooth and claw" are totally unprepared for the physiological stress of modern intensive care.

This thought process has led to the theory that in this environment of unnaturally increased physiological stress, the normal stress response is inadequate. This "relative adrenal insufficiency" is a concept which deserves a prolonged rambling digression, for which this chapter has no space (the digression has been parked in the chapter on the  relative adrenal insufficiency of critical illness)

In summary, it is a situation when the adrenocortical stress response to critical illness is inadequate in magnitude to match the severity of the illness.