A. Overview of Pathways
[Figure] "Selected Responses to Stress"

1. Stressors (Table 1, Ref [1])
   1. Physical: Heat (includes fever), cold, irradiation
   2. Oxygen: reactive oxygen species (ROS), hydrogen peroxide, ischemia (hypoxia/anoxia)
   3. Acid-Base Disturbances: alkalosis, acidosis, pH shift
   4. Biologic: infection, autoimmune inflammation, fever
   5. Physiological: emotion, hormonal imbalance (hypothalamic-pituitary-adrenal or HPA axis)
   6. Osmotic: change sin concentration of salt, sugars and other osmolytes
   7. Nutrition: starvation (various nutrients)
   8. Alcohols: ethanol, methanol, butanol, propanol, octanol, ethylene glycol
   9. Metals: cadmium, copper, chromium, zinc, tin, aluminum, mercury, lead, nickel
   10. Mechanical (Trauma): compression, shearing, stretching
   11. Various chemical toxins
   12. Severe dehydration / dessication
2. Effects of Stimuli
   1. Inflammatory Stimuli favor cytokine mediated pathways
   2. Trauma, non-inflammatory stimuli favor sympathetic nervous system pathways
3. Initial Systems Activated
   1. Adrenergic System (Catecholamines)
   2. Cortisol (Direct)
   3. Hypothalamic - autonomics and pituitary activation
   4. The Locus Ceruleus-Norepinephrine (LC/NE) system [3]
4. Adrenergic (Sympathetic) Systems
   1. Mainly catecholamines
   2. Primarily Epinephrine
   3. Norepinephrine from the Locus Ceruleus
   4. Mainly act on ß-adrenergic receptors
5. Direct Cortisol Activation from Adrenals
   1. Likely due to sympathetic stimulation
   2. Cortisol also from activation of hypothalmic-pituitary-adrenal (HPA) axis
6. Insulin-Couterregulatory hormones are stimulated leading to hyperglycemia (no ketosis)
7. Various Pro- and Anti-Inflammatory Cytokines
   1. Inflammatory stimuli (such as infections) can directly stimulate IL-1 and TNFa production
   2. Macrophages appear to play major role here
   3. IL-6 is likely to be the major mediator of stress response pathways in human disease
   4. IL-6 has pro- and anti-inflammatory properties and protects hepatocytes from death [4]
8. Chaperones and Heat-Shock Proteins [1]
   1. Cellular stress leads to protein unfolding
   2. Chaperones are proteins which help other proteins fold properly into a functional state
   3. Chaperones associate with other proteins in the cell to form chaperoning teams
   4. These chaperoning teams can aide cell recovery following stressors
   5. Several major chaperoning teams have been identified in cells
   6. Heat-shock proteins (HSP) are a family of chaperones
   7. HSPs are induced by heat and various other stressors
   8. HSPs are divided into at least six subfamilies based on molecular weight
   9. Chaperone dysfunction has been implicating in aging and disease
9. These pathways form a bridge between the immune and endocrine systems
10. Long term responses to stress, called allostatic load, lead to changes in homeostasis [5]

B. Main Acute Effects of Hormones

1. Elevated Temperature
   1. IL-6 appears to be the major endogenous pyrogen
   2. IL-1 and TNFa both stimulate IL-6 production
2. Acute Phase Reactants (APRs)
   1. IL-6 and other inflammatory mediators induce liver synthesis of APRs
   2. Over 40 APRs have been identified
   3. C-Reactive Protein (CRP) is one of these and is considered surrogate marker for IL-6
   4. Erythrocyte Sedimentation Rate is mainly affected by fibrinogen, another APR
   5. IL-6 stimulates progenitor cells, leading to thrombocytosis and neutrophilia
   6. Thrombocytosis and leukocytosis are both acute inflammatory response markers
3. Hyperglycemia
   1. Very common in stress situations due to "insulin counterregulatory hormones"
   2. Exacerbated in diabetics
   3. Glucagon
   4. Growth Hormone
   5. Cortisol
   6. Catecholamines
   7. Possibly also Prolactin
   8. Hyperglycemia occurrs without ketosis as insulin is present
4. Cardiovascular Effects
   1. Increased heart rate and contractility due to sympathetic drive
   2. Damage to heart may be exacerbated by these adrenergic stimuli
   3. Tissue and cardiac perfusion is often subnormal or suboptimal in ICU patients
   4. Proloned chronic stress can lead to myocardial hypertrophy and increased ischemia
   5. ß-adrenergic activation is prevailing pathway
   6. Alpha-adrenergic vasoconstriction and ischemia is not generally physiologic
5. Catabolic Effects
   1. Stress associated with increased protein turnover
   2. Also associated with negative nitrogen balance
   3. Skeletal muscle function comprised by protein breakdown
   4. Respiratory muscle weakness leads to increased problems and complications
   5. High levels of APR especially TNFa are likely etiologies
   6. Treatment of critically ill adults with recombinant human growth hormone to reverse these catablic effects has lead to 1.9-2.4 fold increased mortality [6]

C. Thyroid Changes

1. Believed to be attempt to decreased metabolic activity in sickness
2. "Euthyroid-Sick Syndrome" [7]
   [Figure] "Euthyroid Sick Syndrome"
   1. T4 low
   2. T3 low (impaired peripheral conversion)
   3. Reverse T3 (rT3) low
   4. TSH normal or slightly low (as chronicity of illness increases)
   5. Treatment with thyroxine replacement is ineffective
3. Hypothyroidism
   1. Pericardial effusion
   2. Impaired ventilatory responses to hypercapnia and hypoxia
   3. Loss of lateral 3RD of eyebrows
   4. Proximal Myopathy (increased serum CK)
   5. Measure TSH level to determine if hypothyroid
   6. TSH will elevated in hypothyroid, decreased or normal in most sick euthyroid patients
   7. Coarse hairy periorbital edema, loss of axillary hair, hypotension, hypothermia

D. Adrenal Axis [7]

1. Failed cortisol stress response can lead to circulatory collapse (shock)
2. The following conditions of adrenal insufficiency can underly early shock:
   1. Addison's Disease
   2. Hyperpigmentation
   3. Especially skin folds and gums
      1. Due to increased MSH (melanocyte stimulating hormone) production
      2. Also from Zidovudine (AZT)
   4. Autoimmune disease - vitiligo
   5. Hypopituitarism - very fine wrinkling, especially in face
   6. Adrenal Suppression - prior glucocorticoid use, meningococcemia, sepsis, any acute illness
   7. Mixed primary/secondary adrenal insufficiency common in severely ill patients
3. Waterhouse-Friedrichson Syndrome (Adrenal Hemorrhage)
   1. Meningococcemia
   2. Purpura
   3. Fever
   4. Adrenal Destruction
4. Normal stress response usually causes cortisol levels to increase leading to:
   1. Hyperglycemia
   2. Precipitation of DKA or Hyperosmolar state in diabetics only
   3. Gastric stress ulcerations, GI bleeding (failure to heal gastric ulcers/erosions)
   4. Sodium Retention and maintenance of vascular tone
5. Assessment of Cortisol Response [7]
   1. ~25% of patients with sepsis will have adrenal hyporesponsiveness
   2. In severely ill patients, cortisol levels >34µg/dL should be found
   3. If serum cortisol <15µg/dL in severely ill patients, hypoadrenalism likely
   4. For levels 15-34µg/dL, recommend corticotropin (ACTH) stimulation test
   5. ACTH infusion 250µg iv bolus and determine blood cortisol levels 1-2 hours later
   6. If cortisol increase after ACTH <9µg/dL, then hypoadrenalism likely
   7. Patients with persistent hypotension may be treated with hydrocortisone
6. Glucocorticoids in Severe Illness [8]
   1. Recommendations for use based relative hypoadrenalism in critically ill patients
   2. Normal persons increase hypothalamic-pituitary-adrenal action in response to stress
   3. Patients with occult adrenal insufficiency may decompensate in stressful situations
   4. All patients with history of glucocorticoid use need high dose replacement therapy
   5. All patients with history of adrenal insufficiency will need replacement therapy also
7. Stress Dose Steroids [7]
   1. Hydrocortisone 50mg IV q6-8 hours recommended for adrenal insufficiency
   2. Must include both glucocorticoid and mineralocorticoid activity

E. Syndrome of Inappropriate ADH (SIADH)

1. Syndrome of inappropriate secretion of anti-diuretic hormone (vasopressin)
2. Urinary Osm >500 mOSM due to effects of ADH
3. May occur even in presence of hyponatremia
4. Often accompanied by increase in resorbed sodium due to aldosterone (Urine Na+ <20mM)
5. IL-6 appears to directly stimulate ADH secretion

F. Hypocalcemia

1. Most common ICU Serum Abnormality is hypocalcemia
2. Level of ionized calcium is of critical concern
3. Hypocalcemia usually due to secondary hypoparathyroidism
4. Serum free fatty acid increase in sick patients leads to increased Ca2+ binding to proteins
5. Hypocalcemia may lead to insensitivity to calcium blocking therapies
6. Blood products containing citrate will chelate calcium (replace calcium with blood)
7. Other common electrolyte disorders: low sodium, low magnesium
8. Cell calcium may be further depleted during cell death
9. Abnormal ectopic calcification may also occur

G. Critical Illness [13,14]

1. Hyperglycemia often present in acutely ill patients
2. Counterregulatory hormones play major role: norepinephrine, glucocorticoids, others
3. Various medications (above) and parenteral nutrition contribute
4. Hyperglycemia is more detrimental to most acutely ill patients than hypoglycemia
5. Therefore, hyperglycemia should be treated aggressively
6. Close monitoring of plasma glucose is required, goal is average glucose 100mg/dL
7. Insulin with glucose infusions are recommended to maintain 80-110mg/dL plasma glucose
8. Clear morbidity (but not mortality) benefit of tight glucose control in medical ICU [13]
9. Intensive glucose control during cardiac surgery is not beneficial [15]
10. Intensive glucose / insulin therapy after surgery reduced morbidity and mortality [16]

H. Stress Ulcer (GI) Prophylaxis

1. Use of H-2 Blockers, Sucralfate (Carafate®), or PPI is fairly routine in ICU's
   1. Proton pump inhibitors (PPI) are the most effective at reducing gastric acid production
   2. Most studies have shown that upper GI bleeding is decreased with use of these agents
2. H-2 Blockers or PPI, which increase gastric pH, may increase bacterial levels in stomach
   1. Aspiration pneumonia may slightly worse with on H-2 blockers (not sucralfate)
   2. However, these agents reduce the risk of GI bleeding
3. Patients with coagulopathy, venilated, previous ulcers / bleeds should receive prophylaxis:
   1. Coagulopathy and respiratory failure are independent predictors of risk for bleeding
   2. Coagulopathy defined as platelets <50K, or increased PT and/or PTT
   3. Respirator treatment >48 hours is definite risk factor for bleeding
4. Other patients with burns, surgery, etc. should probably also be treated
5. Sucralfate versus Ranitidine (Zantac®, H2 Blocker) Prophylaxis [9]
   1. ICU mechanically ventilated patients
   2. Sucralfate (3.8%) verusus ranitidine (1.7%) of patients developed clinically significant GI bleeding
   3. No differences in pneumonias, mortality, duration of stay in ICU
6. Overall, there appears to be a benefit to routine ulcer prophylaxis in ICU setting [10]
   1. Inclusion of non-English papers and unpublished research shows strong benefit
   2. General prophylaxis with H-2 blockers reduces incidence of GI bleeding ~50%
   3. Sucralfate is associated with reduced overall ICU mortality versus H-2 blockers
   4. Slight increase in risk of pneumonia with H-2 blockers, but not sucralfate
7. Strongly recommend that all ICU patients receive stress ulcer prophylaxis [11]
   1. All patients in ICU (>2-3 days) should receive at least sucralfate
   2. H-2 blocker or preferably PPI should be considered stongly in higher risk patients
   3. High risk includes mechanical ventilation

I. Chronic Effects of Stress [2,5]

1. Effects on Body Weight Regulation
   1. Chronic inflammation often associated with weight loss and frank cachexia
   2. TNFa appears to be main mediator of cachexia
   3. Androgen suppression may also contribute
   4. Cortisol is a catabolic steroid and can lead to loss of muscle mass
   5. Most stress inducers also stimulate leptin production [12]
   6. Thalidomide and other TNFa blockers may improve condition
   7. Pharmacologic doses of growth hormone may also reduce weight loss from inflammation
2. Stress Induced Osteoporosis
   1. Osteoclast Stimulation by IL-6 and other cytokines
   2. Glucocorticoid overproduction in stress exacerbates osteopenia
   3. Elderly with severe stress are more susceptible due to reduced sex hormone levels
   4. Unclear whether usual measures can prevent stress induced osteoporosis
3. Stress Induced Amenorrhea: [3]
   1. The stress systems affect the following female hormones:
   2. CRH, ß-endorphin and cortisol each inhibits GnRH secretion
   3. Cortisol also inhibits LH secretion
   4. Cortisol inhibits synthesis of estrogen and progesterone
   5. Cortisol inhibits estradiol actions
   6. Norepinephrine (NE) stimulates GnRH secretion
   7. Estradiol stimulates CRH synthesis and potentiates norepinephrine actions
4. Cardiovascular Effects
   1. Initially, catechol stimulation and IL-6 can lead to myocardial hypertrophy
   2. Hypertrophic myocardium is increasingly susceptible to ischemic damage
   3. Some inflammatory chemokines and cytokines may cause myocardial cell death
   4. This can lead to dilated cardiomyopathies
   5. Chronic inflammation may also lead to cardiac fibrosis and restrictive cardiomyopathy
   6. Chronic cortisol elevations can exacerbate skeletal and cardiac myopathies
5. Neuronal Damage
   1. Chronic stress may lead to increases in excitatory (mainly glutamate) levels in brain
   2. Eventual neuronal cell death may ensue

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