Corticosteroids in Critical Illness and Septic Shock

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 zonaglomerulosa responsible for a mineralocorticoid aldosterone- control by kidney- RAAS system. • Middle cortex zonafasiculata 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 AnesthAnalg- 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.