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

Neurohormonal axis

Adrenal anatomy

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

Potency

The amount of drug required to produce the desired/measured biological effect

log[dose]

dru

g e

ffect

– a

nti

-in

iflam

mato

ryDEXAMETHASONE

HYDROCORTISONE

1mg 25mg

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

STEROID TRIALS IN ICU

SEPTIC SHOCKARDS

ACUTE SPINAL CORD INJURY

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)

ARDS

MEDURI 1998 & 2007 – Early ARDS (<7 days)

LaSRS 2006 – Late ARDS(>7 days)

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

45%

63%

42%

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