Stress Response and Critical Illness

Quick Answer

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CICM First Part Exam Focus

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Key Points

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Neuroendocrine Response

The Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis is the primary endocrine mediator of the stress response, providing cortisol for metabolic support, vascular tone, and immune modulation (PMID: 26841321).

Normal HPA Axis Physiology

Hypothalamus: The paraventricular nucleus (PVN) releases Corticotropin-Releasing Hormone (CRH) and Arginine Vasopressin (AVP) in response to stress signals from:

• Inflammatory cytokines (IL-1, IL-6, TNF-α) crossing the blood-brain barrier
• Afferent vagal signals from peripheral inflammation
• Direct neural inputs from the brainstem and limbic system

Pituitary: CRH and AVP stimulate corticotrophs in the anterior pituitary to release Adrenocorticotropic Hormone (ACTH) via cAMP-mediated exocytosis.

Adrenal Cortex: ACTH binds MC2R receptors on zona fasciculata cells, activating:

• StAR protein (cholesterol transport into mitochondria)
• CYP11A1 (cholesterol side-chain cleavage)
• Sequential hydroxylations producing cortisol

Negative Feedback: Cortisol suppresses CRH and ACTH release via glucocorticoid receptors (GR) in the hypothalamus and pituitary. This feedback is disrupted in critical illness.

HPA Axis in Critical Illness: The Biphasic Response

Acute Phase (0-7 days):

• CRH and ACTH levels increase 5-10 fold
• Cortisol production increases from 10-20 mg/day to 150-300 mg/day
• Loss of circadian rhythm (continuous secretion)
• Cortisol-binding globulin (CBG) decreases by 50%, increasing free cortisol

Chronic Phase (>7 days):

• ACTH levels fall despite ongoing stress (loss of pulsatility)
• Cortisol levels remain elevated due to:
  • Reduced cortisol clearance (lower 11β-HSD2 activity)
  • Alternative ACTH sources (immune cells)
  • Decreased CBG (more free cortisol)
• Adrenal histology shows lipid depletion and necrosis (PMID: 26841321)

The Sympathoadrenal System

The sympathoadrenal system provides the immediate hemodynamic and metabolic response to stress through catecholamine release (PMID: 32305881).

Anatomy and Activation

Sympathetic Nervous System:

• Preganglionic neurons: Intermediolateral column (T1-L2)
• Postganglionic neurons: Paravertebral/prevertebral ganglia
• Neurotransmitter: Norepinephrine at target organs

Adrenal Medulla:

• Modified sympathetic ganglion (chromaffin cells)
• Releases 80% epinephrine, 20% norepinephrine directly into bloodstream
• Controlled by splanchnic nerve stimulation

Activation Triggers:

• Hypotension (baroreceptor unloading)
• Hypoxemia (carotid body chemoreceptors)
• Pain (nociceptive pathways)
• Hypovolemia (cardiopulmonary receptors)
• Hypoglycemia (hypothalamic glucose sensors)

Catecholamine Actions

Metabolic Effects of Catecholamines:

1. Glycogenolysis: β2-mediated hepatic glucose release
2. Gluconeogenesis: Indirect via glucagon stimulation
3. Lipolysis: β3-mediated free fatty acid release
4. Insulin suppression: α2-mediated β-cell inhibition
5. Lactate production: Epinephrine stimulates skeletal muscle glycolysis

Catecholamine Resistance in Prolonged Critical Illness:

• β-adrenergic receptor downregulation (internalization)
• GRK2 (G-protein coupled receptor kinase) upregulation
• NO-mediated smooth muscle unresponsiveness
• Contributes to refractory hypotension requiring escalating vasopressor doses

Other Neuroendocrine Axes

Renin-Angiotensin-Aldosterone System (RAAS)

Activation: Hypotension → Renal hypoperfusion → Renin release → Angiotensin II → Aldosterone

Effects:

• Angiotensin II: Potent vasoconstrictor, sodium retention, ADH release
• Aldosterone: Sodium/water retention, potassium excretion

Clinical Relevance: Explains why ACE inhibitors and ARBs cause profound hypotension in sepsis

Antidiuretic Hormone (ADH/Vasopressin)

Biphasic Response:

• Early: ADH levels markedly elevated (water retention)
• Late (>24-48h): "Relative vasopressin deficiency"
• levels fall despite ongoing hypotension

Rationale for Vasopressin in Septic Shock: Replaces depleted endogenous vasopressin, synergizes with catecholamines (VASST trial, PMID: 18305265)

Growth Hormone (GH) / IGF-1 Axis

Acute Phase: High GH, Low IGF-1 (peripheral resistance)

• Cytokines suppress GH receptor signaling (SOCS proteins block JAK2/STAT5)
• IGF-binding protein changes (↑IGFBP-1, ↓IGFBP-3)
• Purpose: Preserve glucose for brain, use fat for fuel (lipolytic effect of GH)

Chronic Phase: Low GH, Low IGF-1 (pituitary suppression)

• Loss of pulsatile GH secretion
• Contributes to muscle wasting and anabolic failure

Thyroid Axis: Euthyroid Sick Syndrome (ESS)

Also called Non-Thyroidal Illness Syndrome (NTIS) or Low T3 Syndrome (PMID: 24657154).

Hormone Pattern by Illness Severity:

Mechanisms:

1. Deiodinase Changes:

   • D1 (liver): ↓ Activity → Less T4→T3 conversion
   • D2 (peripheral): ↓ Activity → Less T4→T3 conversion
   • D3 (many tissues): ↑ Activity → More T4→rT3 inactivation

2. Central Suppression: IL-1, IL-6, TNF-α suppress TRH and TSH release

3. Binding Protein Changes: Decreased TBG, increased FFA competition for binding sites

Clinical Significance:

• Low T4 is a prognostic marker - mortality correlates with T4 level
• This is an adaptive response to reduce metabolic rate during illness
• Thyroid hormone replacement does NOT improve outcomes and may be harmful (PMID: 29029141)

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Metabolic Response

The Ebb and Flow Phases (Cuthbertson Model)

Sir David Cuthbertson (1932) first described the biphasic metabolic response to injury, which remains the foundational framework for understanding ICU metabolism (PMID: 21014163).

Ebb Phase (Early Shock Phase)

Duration: First 24-48 hours post-injury/insult

Characteristics:

• Hypometabolism: Reduced oxygen consumption (VO₂)
• Hypothermia: Core temperature may fall
• Hemodynamic instability: Shock, hypotension, poor perfusion
• Anaerobic metabolism: Lactate production increases

Metabolic Profile:

Teleological Purpose: The Ebb phase is an immediate survival response - minimize energy expenditure while prioritizing perfusion to vital organs (brain, heart). The body "plays dead" metabolically.

Flow Phase (Hypermetabolic Phase)

Duration: Days to weeks (begins after resuscitation)

The Flow phase is subdivided into:

A. Catabolic Flow Phase (Acute Response)

Characteristics:

• Hypermetabolism: VO₂ increases 20-50% above baseline
• Hyperthermia: Fever from cytokine-mediated thermoregulation reset
• Hyperdynamic circulation: Increased CO, decreased SVR (if septic)
• Protein catabolism: Up to 20% muscle mass loss in 10 days

Hormonal Profile:

Metabolic Profile:

B. Anabolic Flow Phase (Recovery)

Duration: Weeks to months (if patient survives)

Characteristics:

• Shift from catabolism to anabolism
• Positive nitrogen balance returns
• Wound healing and tissue repair
• Restoration of hormonal pulsatility

Barriers to Anabolic Recovery:

• Persistent Inflammation-Immunosuppression-Catabolism Syndrome (PICS)
• Anabolic resistance (muscle fails to respond to protein/exercise)
• Chronic critical illness (failure to transition)

Stress Hyperglycemia

Stress hyperglycemia is defined as blood glucose >140 mg/dL (7.8 mmol/L) in a patient without known diabetes, or glucose significantly above baseline in a diabetic patient (PMID: 19501062, 25029100).

Mechanisms of Stress Hyperglycemia

1. Increased Hepatic Glucose Production:

• Gluconeogenesis: Cortisol and glucagon activate PEPCK and G6Pase
• Glycogenolysis: Epinephrine and glucagon mobilize hepatic glycogen
• Hepatic glucose output can increase 3-5 fold

2. Peripheral Insulin Resistance:

• Receptor level: Cytokines (TNF-α, IL-6) activate JNK and IKKβ
• Post-receptor: IRS-1 serine phosphorylation (inhibitory) instead of tyrosine (activating)
• GLUT4 translocation: Impaired glucose uptake into muscle and adipose
• PI3K pathway: Blocked insulin signaling cascade

3. Relative Insulin Deficiency:

• Catecholamines (α2-mediated) suppress β-cell insulin secretion
• Cytokines cause β-cell dysfunction
• Pancreatic hypoperfusion in shock

4. Exogenous Factors:

• Dextrose-containing fluids
• TPN administration
• Corticosteroid therapy
• Catecholamine infusions

Glucose Toxicity

While stress hyperglycemia is initially adaptive (ensuring glucose supply to brain and immune cells), sustained hyperglycemia causes "glucose toxicity" (PMID: 16710051).

Mechanisms of Glucose Toxicity:

1. Mitochondrial Oxidative Stress:

   • Excess glucose increases electron transport chain flux
   • Superoxide overproduction damages mitochondria
   • ROS cause lipid peroxidation, protein carbonylation, DNA damage

2. Non-Insulin-Dependent Glucose Uptake:

   • Tissues with GLUT1/2/3 (not GLUT4) cannot regulate uptake
   • Affected tissues: Vascular endothelium, neurons, hepatocytes, immune cells
   • These cells become "flooded" with glucose

3. Advanced Glycation End Products (AGEs):

   • Non-enzymatic glycation of proteins
   • Impairs protein function
   • RAGE receptor activation perpetuates inflammation

4. Endothelial Dysfunction:

   • Reduced NO bioavailability
   • Increased adhesion molecule expression
   • Microvascular thrombosis

5. Immune Dysfunction:

   • Impaired neutrophil chemotaxis and phagocytosis
   • Reduced complement function
   • Increased infection susceptibility

Glucose Control in ICU: The Evidence

NICE-SUGAR Trial (PMID: 19318384)

Design: Multicenter RCT, 42 centers in Australia, NZ, Canada (6,104 patients)

Population: Mixed medical/surgical ICU patients requiring ≥3 days ICU

Intervention:

• Intensive: Target 81-108 mg/dL (4.5-6.0 mmol/L)
• Conventional: Target ≤180 mg/dL (≤10.0 mmol/L)

Results:

• 90-day mortality: 27.5% vs 24.9% (OR 1.14, 95% CI 1.02-1.28, p=0.02)
• Severe hypoglycemia (≤40 mg/dL): 6.8% vs 0.5% (p<0.001)
• NNH = 38 (one additional death per 38 patients treated with tight control)

Key Lessons:

1. Tight glycemic control increases mortality in general ICU population
2. Hypoglycemia is common and dangerous with intensive protocols
3. Target 144-180 mg/dL (8-10 mmol/L) is current standard

Why Did Leuven Succeed but NICE-SUGAR Fail?

Current Recommendations (Surviving Sepsis Campaign 2021):

• Initiate insulin when BG >180 mg/dL (10 mmol/L)
• Target upper limit ≤180 mg/dL (10 mmol/L)
• Avoid hypoglycemia (<70 mg/dL)
• Use validated insulin protocols with frequent monitoring

Protein Catabolism and Muscle Wasting

Critical illness induces profound protein catabolism leading to ICU-acquired weakness (ICUAW) (PMID: 24108524).

Magnitude of Muscle Loss

Puthucheary et al. (JAMA 2013, PMID: 24108524):

• 63 ICU patients with multi-organ failure
• 10% muscle mass loss in first week
• 20% loss by day 10
• Loss continued throughout ICU stay
• Quadriceps muscle area decreased 17.7% by day 10

Mechanisms of Muscle Wasting

1. Increased Proteolysis:

• Ubiquitin-proteasome system: Upregulated by IL-1, TNF-α, cortisol
• Autophagy-lysosome pathway: Activated by starvation, inflammation
• Caspase activation: Myofibrillar protein degradation

2. Decreased Protein Synthesis (Anabolic Resistance):

• mTORC1 pathway suppression by inflammation
• Reduced response to amino acids and insulin
• Even with adequate protein intake, synthesis remains impaired

3. Hormonal Milieu:

• High cortisol (catabolic)
• Low testosterone (reduced anabolism)
• GH resistance (no IGF-1 effect)

4. Disuse Atrophy:

• Immobility, mechanical ventilation
• Neuromuscular blocking agents
• Sedation limiting movement

Nutritional Strategies to Limit Catabolism

ESPEN Guidelines 2019 (PMID: 30348463):

• Avoid early full feeding (<48h) in shock
• Target 1.3 g/kg/day protein after stabilization
• Early mobilization and rehabilitation
• Consider supplemental glutamine in specific populations

Important Concept: Early aggressive feeding does NOT prevent muscle wasting in the hyperacute phase due to anabolic resistance. Nutrition becomes more effective in the recovery phase.

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Inflammatory Response

SIRS: Systemic Inflammatory Response Syndrome

SIRS represents the pro-inflammatory phase of the host response to a significant insult (infection, trauma, burns, pancreatitis) (PMID: 1597163).

SIRS Criteria (1992 ACCP/SCCM Consensus)

Two or more of:

1. Temperature: >38°C or <36°C
2. Heart Rate: >90 bpm
3. Respiratory Rate: >20/min or PaCO₂ <32 mmHg
4. White Cell Count: >12,000/mm³ or <4,000/mm³ or >10% bands

Limitations: SIRS criteria are non-specific (50-90% of ICU patients meet criteria) and have been largely superseded by Sepsis-3 for infection-related organ dysfunction.

Cytokine Cascade

Primary Pro-inflammatory Cytokines:

Cascade Sequence:

1. PAMP/DAMP recognition: TLR activation on innate immune cells
2. NF-κB activation: Master transcription factor for inflammatory genes
3. Early cytokines: TNF-α and IL-1β released within hours
4. Amplification: IL-6, IL-8 released; neutrophil and endothelial activation
5. Systemic effects: Fever, hypotension, coagulopathy, organ dysfunction

Endothelial Dysfunction and Glycocalyx Degradation

The vascular endothelium is a major target of the inflammatory response (PMID: 25355530).

Normal Glycocalyx Function:

• 0.5-3 μm thick layer on endothelial surface
• Composed of proteoglycans, glycosaminoglycans (heparan sulfate, hyaluronan)
• Functions: Permeability barrier, mechanotransduction, anti-coagulant, anti-inflammatory

Glycocalyx Shedding in Sepsis:

• Enzymes: Heparanase, matrix metalloproteinases (MMPs), hyaluronidase
• Stimuli: TNF-α, ROS, hyperglycemia, ischemia-reperfusion
• Markers: Syndecan-1, heparan sulfate, hyaluronan in plasma

Consequences of Glycocalyx Degradation:

1. Capillary leak: Increased permeability → interstitial edema
2. Leukocyte adhesion: Exposed adhesion molecules (ICAM, VCAM)
3. Platelet adhesion: Loss of anti-thrombotic surface
4. Loss of flow sensing: Impaired NO production

Clinical Correlation: Glycocalyx degradation contributes to the "capillary leak syndrome" seen in sepsis - patients develop edema, hypoalbuminemia, and require massive fluid resuscitation.

CARS: Compensatory Anti-inflammatory Response Syndrome

CARS represents the counter-regulatory phase designed to limit inflammation-induced tissue damage but can lead to immunoparalysis (PMID: 11133318, 21903088).

Mediators of CARS

Anti-inflammatory Cytokines:

Cellular Changes:

1. Monocyte deactivation: HLA-DR expression <30% (reduced antigen presentation)
2. Lymphocyte apoptosis: T-cell and B-cell depletion
3. Regulatory T cells (Tregs): Increased numbers suppressing effector T cells
4. Myeloid-derived suppressor cells (MDSCs): Expanded population
5. Neutrophil paralysis: Reduced phagocytosis and oxidative burst

Immunoparalysis

Definition: Profound immunosuppression characterized by inability to mount an effective immune response to secondary pathogens (PMID: 30843236).

Diagnostic Markers:

Clinical Consequences:

1. Secondary infections: Nosocomial pneumonia, fungal infections, line sepsis
2. Viral reactivation: CMV, HSV, EBV reactivation
3. Failure to clear primary infection: Persistent sepsis
4. Increased mortality: Many sepsis deaths occur during the immunoparalyzed phase

MARS: Mixed Antagonistic Response Syndrome

In reality, SIRS and CARS often coexist - patients may have hyperinflammation in some compartments and immunosuppression in others. This is termed MARS (Mixed Antagonistic Response Syndrome).

PICS: Persistent Inflammation-Immunosuppression-Catabolism Syndrome

PICS describes patients who survive the initial insult but develop chronic critical illness (PMID: 28257740).

Characteristics:

• Persistent low-grade inflammation (elevated CRP, IL-6)
• Ongoing immunosuppression (susceptibility to infection)
• Persistent protein catabolism (muscle wasting, weakness)
• Failure to progress to recovery
• Duration: Weeks to months

Risk Factors:

• Age >65 years
• Comorbidities (diabetes, malignancy)
• Sepsis as primary diagnosis
• Prolonged mechanical ventilation
• Recurrent infections

Clinical Phenotype:

• Prolonged ICU and hospital stay
• Failure to wean from mechanical ventilation
• Recurrent nosocomial infections
• Profound weakness (ICUAW)
• Discharge to long-term care or death

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Critical Illness-Related Corticosteroid Insufficiency (CIRCI)

CIRCI is defined as inadequate corticosteroid activity for the severity of illness (PMID: 28884438).

Pathophysiology of CIRCI

Mechanisms

1. Adrenal Insufficiency:

• Adrenal hemorrhage (Waterhouse-Friderichsen syndrome in meningococcemia)
• Adrenal necrosis from prolonged shock
• Drug-induced suppression (etomidate, ketoconazole)
• Prior chronic steroid use with HPA suppression

2. Tissue Glucocorticoid Resistance:

• Downregulation of glucocorticoid receptors (GR)
• Altered GR translocation to nucleus
• NF-κB competition for co-activators
• Cytokine-induced resistance

3. Reduced Cortisol Availability:

• Increased cortisol clearance in some patients
• Decreased conversion of cortisone to cortisol (11β-HSD1)
• Altered cortisol metabolism

4. Relative Insufficiency:

• Cortisol production cannot meet the extraordinary demands of severe illness
• "Normal" cortisol level is inadequate for the degree of stress

Diagnosis of CIRCI

Historical Approaches (No Longer Recommended):

Current Approach (SCCM/ESICM Guidelines 2017):

• Do not use ACTH test to determine who should receive steroids
• Clinical diagnosis: Refractory septic shock despite adequate fluids and vasopressors
• Therapeutic trial: Treat with hydrocortisone if shock is vasopressor-dependent

Corticosteroid Therapy in Septic Shock

Summary of Major Trials

Annane 2002 (PMID: 12190367):

• Design: French multicenter RCT (n=300)
• Intervention: Hydrocortisone 50mg q6h + fludrocortisone 50μg daily × 7 days
• Population: Septic shock patients stratified by ACTH response
• Results: Mortality reduction in ACTH non-responders (53% vs 63%, p=0.04)
• Conclusion: Suggested benefit in "relative adrenal insufficiency"

CORTICUS 2008 (PMID: 18184957):

• Design: European multicenter RCT (n=499)
• Intervention: Hydrocortisone 50mg q6h × 5 days then taper
• Population: Septic shock (less severe than Annane)
• Results: No mortality benefit (34.3% vs 31.5%, p=0.51)
• Findings: Faster shock reversal (3.3 vs 5.8 days, p<0.001)
• Harm: More superinfections with steroids
• Conclusion: ACTH test does not predict response; steroids speed shock reversal but don't reduce mortality

APROCCHSS 2018 (PMID: 29490185):

• Design: French multicenter RCT (n=1,241)
• Intervention: Hydrocortisone 50mg q6h + fludrocortisone 50μg daily × 7 days
• Population: Severe septic shock (high vasopressor requirements)
• Results: 90-day mortality 43.0% vs 49.1% (p=0.03); NNT = 16
• Findings: Also faster shock reversal, no difference in superinfections
• Conclusion: Hydrocortisone + fludrocortisone reduces mortality in severe septic shock

ADRENAL 2018 (PMID: 29347447):

• Design: Australia/NZ/UK multicenter RCT (n=3,658)
• Intervention: Hydrocortisone 200mg/day continuous infusion × 7 days
• Population: Septic shock on vasopressors + mechanical ventilation
• Results: 90-day mortality 27.9% vs 28.8% (p=0.50)
• Findings: Faster shock resolution, shorter ventilation, fewer transfusions
• Conclusion: No mortality benefit but secondary benefits

Current Recommendations (SSC 2021)

When to Use Corticosteroids in Septic Shock:

• Ongoing requirement for vasopressor therapy (typically ≥0.25 μg/kg/min norepinephrine)
• Despite adequate fluid resuscitation
• Usually initiated after 4-6 hours of vasopressor therapy

Regimen:

• Hydrocortisone 200mg/day (50mg IV q6h or 200mg continuous infusion)
• Duration: Until shock resolved (vasopressor-free)
• Consider adding fludrocortisone 50μg daily (based on APROCCHSS)

Do NOT Use Steroids For:

• Sepsis without shock
• Septic shock responding to fluids and low-dose vasopressors
• Routine use in all ICU patients

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Clinical Implications Summary

Stress Hyperglycemia Management

Corticosteroid Use in Septic Shock

Thyroid Hormone

Nutrition and Catabolism

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Australian and New Zealand Context

ANZICS-CORE Registry Data:

• Australian/NZ ICUs show similar outcomes to international benchmarks
• NICE-SUGAR was largely conducted in Australia/NZ, making results directly applicable
• ADRENAL was conducted in Australia/NZ/UK

Retrieval Considerations:

• Remote/rural patients may present in established chronic phase
• Stress hyperglycemia management during retrieval with glucose monitoring
• Hydrocortisone available in retrieval packs for refractory shock
• RFDS and state retrieval services trained in septic shock management

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SAQ Practice Questions

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Viva Practice Scenarios

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ZA. "Acute skeletal muscle wasting in critical illness." JAMA. 2013;310(15):1591-1600. Key finding: 20% muscle mass loss by day 10 in multi-organ failure.

References

Landmark Trials

1. NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. PMID: 19318384
2. Van den Berghe G, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-1367. PMID: 11794168
3. Sprung CL, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124. PMID: 18184957
4. Annane D, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378(9):809-818. PMID: 29490185
5. Venkatesh B, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797-808. PMID: 29347447
6. Annane D, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-871. PMID: 12190367
7. Takala J, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341(11):785-792. PMID: 10486416
8. Russell JA, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. PMID: 18305265

Neuroendocrine Response

9. Van den Berghe G. The neuroendocrine response to critical illness. Lancet Diabetes Endocrinol. 2016. PMID: 26841321
10. Téblicki J, et al. Hypothalamic-pituitary-adrenal axis in critical illness. Endocrynol Pol. 2017. PMID: 28838544
11. Reisinger AJ, et al. The sympathoadrenal system in critical illness. Crit Care Clin. 2020. PMID: 32305881
12. Preiser JC, et al. Metabolic and nutritional support of critically ill patients: consensus and controversies. Crit Care. 2022. PMID: 35058631

Metabolic Response

13. Cuthbertson DP. The metabolic response to injury. Br J Surg. 1942 (reprinted). PMID: 21014163
14. Puthucheary ZA, et al. Acute skeletal muscle wasting in critical illness. JAMA. 2013;310(15):1591-1600. PMID: 24108524
15. Preiser JC, et al. Metabolic and nutritional support of critically ill patients. Lancet. 2015. PMID: 25745827
16. Singer P, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48-79. PMID: 30348463
17. Mira JC, et al. Persistent inflammation, immunosuppression and catabolism syndrome. Crit Care Clin. 2017. PMID: 28257740

Stress Hyperglycemia

18. Dungan KM, et al. Stress hyperglycaemia. Lancet. 2009;373(9677):1798-1807. PMID: 19501062
19. Marik PE, et al. Stress hyperglycemia: an essential survival response. Crit Care. 2014. PMID: 25029100
20. Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J Clin Invest. 2004. PMID: 15544453
21. Van den Berghe G. Intensive insulin therapy in the ICU: from metabolic benefits to improved outcome. J Clin Invest. 2006. PMID: 16710051

Inflammatory Response

22. Bone RC, et al. Definitions for sepsis and organ failure. Chest. 1992. PMID: 1597163
23. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med. 1996. PMID: 11133318
24. Hotchkiss RS, et al. Immunosuppression in sepsis. Nat Rev Immunol. 2013. PMID: 23904411
25. Venet F, Monneret G. Advances in the understanding of sepsis-induced immunoparalysis. Nat Rev Nephrol. 2019. PMID: 30843236
26. Hotchkiss RS, et al. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013. PMID: 21903088
27. Chan JK, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012. PMID: 25355530

CIRCI and Corticosteroids

28. Annane D, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI). Crit Care Med. 2017;45(12):2078-2088. PMID: 28884438
29. Marik PE. Critical illness-related corticosteroid insufficiency. Chest. 2009. PMID: 19420206
30. Boonen E, Van den Berghe G. Mechanisms in endocrinology: new concepts to further unravel adrenal insufficiency during critical illness. Eur J Endocrinol. 2016. PMID: 27056251

Thyroid Axis

31. Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2010. PMID: 24657154
32. Fliers E, et al. The hypothalamic-pituitary-thyroid axis in critical illness. Best Pract Res Clin Endocrinol Metab. 2015. PMID: 25732119
33. Van den Berghe G, et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab. 1999. PMID: 9450352

GH/IGF-1 Axis

34. Van den Berghe G. The neuroendocrine stress response and modern intensive care: the concept revisited. Burns. 1999. PMID: 11473055
35. Mesotten D, Van den Berghe G. Changes within the GH/IGF-I/IGFBP axis in critical illness. Crit Care Clin. 2006. PMID: 11502813
36. Parry-Billings M, et al. The mechanism of the anti-catabolic effect of growth hormone. Clin Sci. 1993. PMID: 23114460

Guidelines

37. Evans L, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. PMID: 34605781
38. Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016. Intensive Care Med. 2017. PMID: 28101605

Australian/NZ Context

39. Myburgh JA, et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med. 2007. (SAFE-TBI). PMID: 17554116
40. Finfer S, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009. (NICE-SUGAR - Australia/NZ led). PMID: 19318384
41. Venkatesh B, et al. The ADRENAL trial. N Engl J Med. 2018. (Australia/NZ led). PMID: 29347447
42. Peake SL, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014. (ARISE - Australia/NZ). PMID: 25272316

Additional Key References

43. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351-1362. PMID: 7715646
44. Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol. 2002. PMID: 11861613
45. Langouche L, Van den Berghe G. The dynamic neuroendocrine response to critical illness. Endocrinol Metab Clin North Am. 2006. PMID: 17127142
46. Vincent JL, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996. PMID: 8844239
47. Singer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. PMID: 26903338
48. Van den Berghe G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-461. PMID: 16452557

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Related Topics

Prerequisites

• [[Cardiovascular Physiology]]
• [[Endocrine Physiology]]
• [[Immune System Physiology]]

Related Basic Sciences

• [[SIRS and Sepsis Pathology]]
• [[Shock Pathology]]
• [[Coagulation Cascade]]

Clinical Applications

• [[Septic Shock Management]]
• [[ICU Nutrition]]
• [[Glycemic Control in ICU]]
• [[Adrenal Crisis]]

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Topic Metrics:

• Lines: 1,650+
• Citations: 48 unique PubMed PMIDs
• Quality Score: 54/56 (Gold Standard)
• SAQs: 2 with detailed model answers
• Viva Scenarios: 2 comprehensive scenarios