Steroids in ICU Alun Ellis
OVERVIEW
PRIMARY
Physiology of steroid hormones
Steroid production
Commonly used preparations and pharmacology
FELLOWSHIP
Steroid syndromes
Indications for steroids in critical illness
Steroid hormones
Glucocorticoids
Mineralocorticoids
Androgens
Oestrogens
Progestrogens
No storage capability
Biological effects of cortisol
Carbohydrate metabolism Stimulate gluconeogenesis via cell signalingMobilise AA’s from extrahepatic tissues Reduction of glucose utilisation by cells by inhibiting action of glucose
Protein metabolism Diminishes tissue stores of protein and increases liberation of AA’sDecreases protein synthesis (except liver)
Fat metabolism Increases fatty acid breakdown and oxidation in the liver
Water/electrolytes Enhances Na reabsorption and K excretionIncreases renal blood flow and water excretion
Blood Increase RBC and platelet production, reduction of circulating lymphocytes and eosinophils
Cardiovascular system ‘Permissive effect’ on vascular toneInhibit production of prostaglandins which are vasodilatorsReduces permeability of capillaries
GIT Increases acid and pepsin production
Foetus Important in production of foetal surfactant
Steroid types Glucocorticoid
Hydrocortisone
Prednisolone
Methylprednisolone
Dexamethasone
Mineralocorticoid
Fludrocortisone
HYDROCORTISONE
Pharmacokinetics
A Rapid, 96% bioavail.
D High VD, 90% protein bound to CBG
M Half life 60-90 mins, CY3A4
E Glucuronidation
DEXAMETHASONE
Pharmacokinetics
A 70-80% bioavailability
D 70-80% protein bound
M Half life 190 mins
E Glucuronidation
METHYLPREDNISOLONE
Pharmacokinetics
A 80-90% bioavail
D 80% protein bound
M Half-life 1.8-5 hours
E Hydroxylation, 20% in bile, 10% in faeces
SEPTIC SHOCK
Bone 1987
Annane 2002
CORTICUS 2008
Follows the concept of relative adrenal insufficiency
Jurney 1987
Chest, n=70 Prospectively studyGiven 250mcg synacthen
Small amount of patients who are non-responders (unable to increase their cortisol levels in stress -> relative adrenal insufficiency)- these patient have high mortality and may improve with low dose steroid administration- normal response in sepsis: cortisol >500nmol/L (random) or a rise of > 200nmol/L following ACTH administration
Bone 1987
NEJM, n=382 at 19 centres
Randomised to receive 30mg/kg IV methylprednisolone x 4 doses at time of enrolment or not
No difference in 14 day mortality
No effect on reversal of shock, more likely to die from secondary infection
Not a rigorous study…
Annane 2002
JAMA, n=300 RCT, 19 ICUs in France. 3-8 hours of onset of septic shock.50mg QID hydrocortisone and 50mcg fludrocortisone vs. placebo for 7 days‘Non-responders’ identified through use of cosyntropin stimulation test (<9mcg/dL increase in serum cortisol)
Non-responders: reduced 28 day mortality (63 vs 53%, NNT = 10)Responders: No significant difference
Overall steroid therapy reduced duration of vasopressor therapy (7 vs 9 days)
CORTICUS 2008
NEJM, n-499 patients, septic shock within 72 hoursMulticentre RCT, 50mg hydrocortisone QID vs placebo for 5 days with taperingAll patients received a stimulation test, non-resp <9mcg/dL at 60mins
28 day mortality no different between groups (39 vs 36%, p=0.69)No difference in mortality of non-responder subgroup
Reversal of shock quicker (3.3 vs 5.8 days)Those receiving steroids had higher incidence of hyperglycaemic, hypernatraemia, and opportunistic infections
Study was underpowered (had planned to enrol 800 patients)
MEDURI
JAMA n=24Q6H infusions of methylprednisolone 2mg/kg/day tapered down after two weeksIf extubated jumped to day 15RESULTS: Reduced lung injury score, reduced mortality ( 0 vs 63%)Half of placebo group crossed over to steroids
Chest n=72, ARDS within 72 hours of admission1mg/kg/day as IV infusionsSwitched to oral doses once extubated as daily doseRESULTS: Reduced lung injury score after 7 days, reduced days of mechanical ventilation, reduced ICU length of stay, reduced ICU mortality. No hospital LOS/mortality benefit.
LaSRS
NEJM, n=180 with persistent ARDS for 7-28 days (over 7 years!)Methylprednisolone 2mg/kg stat and then 0.5mg/kg Q6H for 14 days, followed by 0.5mg/kg Q12HNo difference in 60 day mortality (29.2 vs 28.6)
Those randomised after 14 days had higher mortality rates with steroids
Improved ventilator-free days and ICU-free days
Higher incidence of myopathy with methylprednisolone
Acute Spinal Injury
NASCIS I-III trials
NASCIS I (1984) – Methyl pred
NASCIS II (1990) – Methylpred and naloxone
NASCIS III (1997) – Methylpred and tirilazad
WHAT TO TAKE HOME
Use steroids early in ARDS
Don’t use in ARDS after 14 days
Steroids may not affect overall mortality but may reverse shock
earlier
Don’t do short synacthen test and a normal cortisol is not necessarily
reassuring
Current recommendations are against using methylprednisolone for
acute spinal injury
THANK YOU