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

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

Critical Care

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.

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.

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.

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.

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).

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…

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.

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.

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!

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

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.

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.

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.

Other beneficial effects and duration of treatment

Decrease PTSDDecrease incidence AFNecessary for normal gastric and intestinal motility-

possible decrease in bacterial translocation.At least 7 days and taper slowly- unlike asthma,

COPD. Rebound effect.

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.

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 <6hrsContinue for 7days, not abrupt withdrawal.Need more evidence.


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