1. Corticosteroids in Critical Illness and Septic Shock Dr. TH De Klerk Critical Care

2. Background  Critical illness and Endocrine insufficiency/failure.  Definition: Any life threatening condition requiring support of vital organ function to prevent imminent death.  Critical illness = Ultimate form of severe physical stress.  Prolonged critical illness- intensive care support dependence >10 days.  Patients survive insults beyond capacity of the natural defense systems. Unlikely that body developed mechanisms to cope with prolonged critical illness. Maladaptive responses.

3. Stress response- Historic perspective  Robert Hooke introduced concept of stress in physics.  Claude Bernard introduced notion of fixed internal milieu and homeostasis- 1878.  Bradford Cannon described fight-and-flight response-1915.  Hans Seyle- General Adaptation Syndrome- Good vs Bad Stress-1936.  Bodies reaction to a change in environment, that requires physical response to maintain internal stability through constancy- Bruce McEwen 2007- concept of allostasis.  Current ICU practice based on idea of maintaining the constancy of internal environment.

4. Stress response  Immediate stress response comprise many orchestrated neuro-endocrine, cellular, immune and bio-energetic adaptations with common response pathways.  Not all people have same response and variations in same individual at different times.  The relationship between physiological variables non-linear but with marked connectivity and that small changes can result in major consequences- dynamic systems (chaos) theory.  Mitochondria act as common pathway and considered the principle cellular stress system in terms of bio-energetic requirements.  Stress response and catabolism not same, but closely linked.

5. Stress response- Phases  Initial phase- aim is to restore physiology and prevent organ dysfunction. Golden hour of treatment.  Established organ failure- strategy to support the intrinsic cellular mechanisms of protection and tolerance- hibernatory approach.  Recovery and repair- normal physiological values progressively reintroduced as therapeutic targets.

6. Cortisol and the Stress Response  Cortisol and adrenalin are the main endocrine regulators of the metabolic response to stress.  Hormone- regulatory substance secreted into and transported by tissue fluids, most commonly blood.  Normally diurnal pattern.  Stress overrides all other regulatory mechanism of cortisol secretion irrespective of time of day or serum cortisol concentration.  Hypercortisolemia proportionate to severity of illness.  Outer cortex zona glomerulosa responsible for a mineralocorticoid aldosterone- control by kidney- RAAS system.  Middle cortex zona fasiculata responsible for glucocorticoids- control central ACTH (pituitary) and CRH (hypothalamus).

7. Cortisol and the Stress Response  Early phase: ACTH and cortisol increased. Adaptive  Late phase: ACTH decreased and cortisol increased. Maladaptive response? Reason?  Endothelin independently increase cortisol production.  ANP and Substance P decrease ACTH secretion.  Normal daily cortisol production 20-30mg.  Increase 10-12X with severe physiological stress.  Therefor 200-300mg hydrocortisone “stress-dose”.  But new evidence…

9. Cortisol in Critical Illness  Main reason for increased cortisol levels- reduced cortisol breakdown.  Decreased expression and activity of cortisol-metabolizing enzymes.  Liver: 5- Alpha and –Beta reductase.  Kidney: 11-Beta dehydrogenase type 2. Cortisol to inactive cortisone.  11-Beta dehydrogenase type 1 liver and adipose tissue cortisone activated to cortisol.  Circulating bile acids during sepsis- cholestasis, suppress expression and activity of cortisol metabolizing enzymes.  Current dose 200-300mg- 3X too high.

10. Adrenal Insufficiency in Critical illness and relation to Sepsis  Primary Adrenal Insufficiency- involve adrenal glands. Primary infection of adrenals: Disseminated TB, HIV, CMV, Histoplasmosis, Cryptococcus. Adrenal hemorrhage- DIC, meningococcus- Waterhouse Friedrichson syndrome. Drug related rifampicin, -azole antifungals, etomidate and phentoin.  Secondary Adrenal Insufficiency- involve pituitary gland. HIV and TB.  Critical illness-related corticosteroid insufficiency (CIRCI)- inadequate for severity of illness.  Difficult to differentiate pre-existing disease and severe illness induced endocrine dysfunction.

11. Clinical presentation of Adrenal Insufficiency  Classic symptoms not elicit in comatose/ intubated patients.  Hyponatremia and hyperkalemia rare.  Patient with refractory shock or unexplained hypoglycaemia.  Two hemodynamic pictures: hyperdynamic shock with vasodilatation, mycocardial depression with hypovolaemia. Ie. Can mimic any type of shock!!  High index of suspicion- risk factors!

12. Risk factors CIRCI  Disease severity  Persistent/complicated septic shock  Low platelets  Renal replacement therapy- dialysis  Liver cirrhosis >50%  Men  Age> 65Yrs  Burns  Low cholesterol, low HDL levels.  Low BMI <18

13. Diagnosis of adrenal insufficiency  Early morning cortisol and ACTH- diurnal response.  Insulin- induced hypoglemia test- dangerous.  Low and high dose ACTH stimulation test.  Random level cortisol. Total vs free cortisol.  Plasma levels poorly correlate with tissue cortisol levels.  Immunoassays vs liquid chromatography- tandem mass spectrometry.  Random >1200nmol/L- unlikely, <275nmol/L-Annane et al. Need 700nmol/L for maximal vasopressor response.  ACTH-stimulation 250ug >275nmol/L increase adequate response- Annane et al.  Surviving Sepsis Guidelines 2012 suggest giving hydrocortisone if poor response to fluids and initial vasopressor, within 6hrs onset of septic shock.

14. Evidence for Corticosteroids  Schumer et al. 1976, Veterans Administrative Systemic Sepsis Cooperative Study Group 1987, Bone et al- 1987. High-dose corticosteroids.  Scneider et al-1991- physiological and not pharmacological doses in septic shock.  Large RCT’s French trial- Annane- mortality benefit. CORTICUS- no mortality benefit. < 8hrs onset septic shock in French trial.  Most recent meta-analysis Feb 2014 Anesth Analg- decrease need for vasopressors at 7 and 28 days, not reduce mortality. Methylprednisolone vs hydrocortisone, high vs low quality RCT’s.  Timing, dose, route and duration.  Goal- physiologic replacement vs. anti-inflammatory effect.

15. Mechanisms Cortisol in Shock  Increased synthesis B-receptors, reverse receptor dysfunction and increased second messenger response.  Increase angiotensinogen production- increase AT2.  Decrease prostaglandin E2 and Kallikrein synthesis- vasodilators.  Decreased expression of inducible nitric oxide synthase in vascular endothelium and myocardium.  Protects endothelial glycocalyx against ischemia- and TNF alpha-induced disruption. Mast cell stabilization. Protect intercellular junctions of endothelium.  Decrease endothelial activation of coagulation and inflammatory cell migration.

16. Other beneficial effects and duration of treatment  Decrease PTSD  Decrease incidence AF  Necessary for normal gastric and intestinal motility- possible decrease in bacterial translocation.  At least 7 days and taper slowly- unlike asthma, COPD. Rebound effect.

17. Risks  Immune suppression- dose related.  Hyperglycaemia.  Critical illness myopathy and Critical illness polyneuropathy- Cochrane Analysis 2014 Jan- no effect on its own on incidence.  Delirium and long term neurocognitive dysfunction.  PUD and pancreatitis.

19. Summary  All ICU patients at risk, increase with severity of illness.  Especially prolonged ICU stay (>10 days) maladaptive endocrine responses.  Testing HPA-axis not really helpful.  Current dose 200-300mg may be too high- aim for 100mg per day.  Definite hemodynamic benefits.  Early in septic shock <6hrs  Continue for 7days, not abrupt withdrawal.  Need more evidence.