Corticosteroids – An Overview
12/8/10
EB Notes
OH
PHYSIOLOGY
- hormones
- two types: glucocorticoids (cortisol) and mineralocorticoids (aldosterone)
- both cholersterol based
Glucocorticoids
- cortisol
- produced from zona fasiculata in adrenal cortex
- produced in response to stress: hypoglycaemia, fear, pain, exercise, infection
- also there is circadian variation in cortisol release
- controlled via hypothalamic-pituitary-adrenal axis
- stress -> release of CRH from hypothalamus -> release of ACTH from anterior pituitary -> cortisol released from adrenal cortex
- normal secretion of cortisol = 15-30mg/day -> 5-7mg of prednisone or 20-30mg of hydrocortisone
CNS – behavioural changes
METABOLIC – increased plasma glucose (decreased gluconeogenesis, insulin antagonism, increased in protein catabolism, increased FFA oxidation), potentiate action of GH, catecholamines, glucagons, T3/T4
GASTROINTESTINAL – increased acid and pepsin secretion, decreased prostaglandin synthesis, increased rate of peptic ulceration.
HAEMATOLOGICAL – increased RBC, PLTs, neutrophils, decreased lymphocytes and eosinophils
CARDIOVASCULAR – increased reactivity of peripheral blood vessels to catecholamines
MUSCULO-SKELETAL – increased bone break down -> OP, muscle wasting
Mineralocorticoids
- aldosterone
- produced in the zonaglomerulosa
- daily output: 100-150mcg/day
- secreted in response to; Na+ deficiency -> elevated angiotensin II, elevated plasma K+
RENAL –
1. acts on collecting ducts -> increases production of the Na+/K+ ATPase in the basement membrane, increased Na+ and K+ channels in the apical membrane -> increase in Na+ reabsorption and K+ secretion -> ECF volume expansion.
2. increases excretion of H+ and NH4+
3. increases Cl- reabsorption
OTHER – increased Na+ reabsorption in sweat, salivary and distal colon glands.
ADRENAL INSUFFICIENCY (AI)
- types: primary, secondary and tertiary + acute/chronic
Primary = Addison’s
- destruction of > 90% of adrenal glands
- rare
- causes: autoimmune destruction, haemorrhage, tumour (breast and melanoma), infection (Tb, HIV, meningococcaemia, purpura fulminans) or inflammatory process
- loss of mineralocorticoid and glucocorticoid activity
Secondary
- insufficient production of ACTH
- rare
- mineralocorticoid function intact
- causes: destruction or dysfunction of the pituitary
Tertiary/Iatrogenic/Relative
- suppression of HPA axis over time
- most common
- cause: administration of exogenous glucortiocoids
- mechanism: chronic ACTH suppression -> adrenal atrophy
CONSEQUENCES
Crisis
- concurrent illness, surgery, failure to take medications
- GI: abdominal pain, vomiting and diarrhoea
- CVS: dehydration, hypotension, refractory shock, poor response to inotropes/pressors
- fever
- confusion
Chronic
- GENERAL: weight loss, arthalgia, myalgia
- CNS: fatigue, anorexia, mood change
- CVS: postural hypotension, syncope, salt craving
- SKIN: pigmentation, vitiligo
- ELECTROLYTES: hypoglycaemia, hyponatraemia, hyperkalaemia, increased urea
MANAGEMENT
Diagnosis
- plasma cortisol level < 80mmol/L
- short synacthen test: 250mcg (normal response = cortisol > 525mmol/L)
Treatment
- fluid resuscitation
- reversal of electrolyte abnormalities
- high dose hydrocortisone (100mg IV Q6 hrly)
PERIOPERATIVE STEROID THERAPY
- glucocorticoids introduced into clinical practice in 1949
- soon after there were two deaths from withheld steroids in perioperative period -> “stress doses” in the perioperative period.
- for many years we overcooked these patients with large doses of steroids
- new guidelines:
- those on 5mg or less of prednisone OD -> don’t need supplementation
- minor operation -> normal dose + 25mg hydrocortisone in OT
- moderate operation -> normal dose + 25mg hydrocortisone Q6hourly for 24 hours
- high risk operation -> normal dose + 25mg hydrocortisone Q6 hours for 48-72 hours
Prednisone 1mg =
Hydrocortisone 4mg =
Dexamethasone 0.15mg =
Triamcinolone 0.8mg =
Methylprednisolone 0.8mg =
Betamethasone 0.15mg =
SEVERE SEPSIS + SEPTIC SHOCK
- basis: that patients with severe sepsis has relative adrenal insufficiency
- difficult to diagnose because of the questionable validity of using plasma cortisol and the synacthen test.
- benefit shown in meningitis
- 1970’s + 1980’s – massive doses of steroid (30mg/kg) -> no survival benefit + increase in secondary infections
AnnaneD,SbilleV,CharpentierC,et al:“Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock”.JAMA2002;288:862-871
- RCT in refractory septic shock
- low dose hydrocortisone + fludrocortisone VS placebo
- n = 300
-> non-responders to cosyntrophin test + given steroid -> significant decrease in mortality (P = 0.02)
-> duration of vasopressor therapy shorter
- problems: bad trial design, use of etomidate
SprungCL,AnnaneD,KehD,et al:“CORTICUS Study Group: Hydrocortisone therapy for patients with septic shock.”N Engl J Med2008;358:111-124.
- 2008 – CORTICUS - ANZICS
- MRCT
- low dose hydrocortisone vs placebo
-> no survival benefit
-> shock reversed more quickly
-> more superinfections, hyperglycaemia, hypernatraema
- weakness: patients were less sick than Annane’s study and was underpowered
The COIITSS Study Investigators (2010) “Corticosteroid Treatment and Intensive Insulin Therapy for Septic Shock in Adults: A Randomized Control Trial” JAMA 303 (4):341-348
- septic shock: corticosteroids VS insulin therapy VS both improved outcomes +/- mineralocorticoid
- MRCT
- inclusion criteria: adult, septic shock, MODS, hydrocortisone
- exclusion criteria: no consent, moribund, pregnant, co-enrolement
- primary end points = hospital mortality and 90 day mortality
- secondary end points = 28, 90 and 180 day mortality, ventilator free days, ICU length of stay, hospital length of stay, hypoglycaemia, infectious complications, weakness
- n = 509
- ITT analysis
Intensive Insulin Group
-> double hypoglycaemic rate
-> no increase in mortality
-> no difference in secondary outcomes
-> no difference in synth-ACTH-en responders
-> no difference in fludrocortisone patients
Fludrocoritisone Results
-> no increase in mortality
-> no difference in inotropes
-> excess superinfection rate -> don’t use in septic shock
Criticisms
- did not reach required recruitment levels
- not blinded
- tested multiple variables
SUMMARY
- steroids are not good in low risk patients with sepsis
- most people with refractory shock receive low dose steroids
- those in the middle – the literature is not clear
ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)
- mortality = 40-60%
- pathophysiology: excessive inflammation and vascular permeability with extravasation of plasma and leukocyte infiltration (fibroproliferative stage) -> steroids thought to reduce the extent of theses processes
Meduri study (JAMA)
- cross over trial
-> reduction in lung injury score
-> improved mortality
Meduri study
-> reduction in length of ICU stay
-> reduction in duration of IPPV
SteinbergKP,HudsonLD,GoodmanRB,et al:National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: “Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.”N Engl J Med2006;354:1671-1684.
- n = 180
- MRCT
- methylprednisolone for 14 days with taper VS placebo
-> reduced shock symptoms
-> reduced ventilator days
-> improved pulmonary compliance
-> increased mortality in patient who had had steroids > 14 days
-> increased neuromuscular weakness
-> NO improvement in survival
- outcomes in trials have varied -> two recent systematic reviews have reached opposite conclusions!
Agarwal R, Nath A, Aggarwal AN, Gupta D. “Do glucocorticoids decrease mortality in acute respiratory distress syndrome? A meta- analysis.”Respirology 2007;12:585-90.
-> current evidence does not support the efficacy of steroids in ARDS
Meduri G, Marik P, Chrousos G, Pastores S, Arlt W, Beishuizen A, et al. Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature.Intensive Care Med 2007
-> prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcome variable and has a distinct survival benefit
What about steroids for ARDS prophylaxis? - increase in ARDS and subsequent mortality (weak trend)
SUMMARY
- exact place of steroids in ARDS is unknown
- further investigation required
MENINGITIS
van de BeekD,de GansJ,McIntyreP,et al:Corticosteroids for acute bacterial meningitis.Cochrane Database Syst Rev2007;1
de GansJ,van de BeekD:European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators: Dexamethasone in adults with bacterial meningitis.N Engl J Med2002;347:1549-1556
- systematic reviews
- dexamethasone with first antibiotics in community acquired bacterial meningitis
-> reduces mortality
-> reduces severe hearing loss
-> reduces neurological sequelae
TBI
RobertsI,YatesD,SandercockP,et al:CRASH trial collaborators: Effect of intravenous corticosteroids on death within 14 days in 10,008 adults with clinically significant head injury (MRC CRASH trial): Randomised placebo-controlled trial.Lancet2004;364:1321-1328.
EdwardsP,ArangoM,BalicaL,et al:CRASH trial collaborators: Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months.Lancet2005;365:1957-1959.
- 48 hours of IV steroids vs placebo
-> increased mortality within 14 days
-> increases mortality @ 6 months
-> increased risk of severe disability
ACUTE SPINAL CORD INJURY
BrackenMB,ShepardMJ,CollinsWF,et al:A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study.N Engl J Med1990;322:1405-1411.
- high dose methylprednisolone within 8 hours in injury
-> evidence supported use
MillerSM:Methylprednisolone in acute spinal cord injury: A tarnished standard.J Neurosurg Anesthesiol2008;20:140-142.
GeorgeER,ScholtenPJ,BuechlerCM:Failure of methylprednisolone to improve the outcome of spinal cord injury.Am Surg1995;61:659-663.
PointillartV,PetitjeanME,WiartL:Pharmacotherapy of spinal cord injury during the acute phase.Spinal Cord2000;38:71-76.
- criticisms of NASCIS: study design flawed, statistical analysis flawed, conflicting evidence
BrackenMB:Steroids for acute spinal cord injury.Cochrane Database Syst Rev2002.CD001046
-> supports use of methylprednisolone
TsutsumiS,UetaT,ShibaK,et al:Effects of the Second National Acute Spinal Cord Injury Study of high-dose methylprednisolone therapy on acute cervical spinal cord injuryresults in spinal injuries center.Spine2006;31:2992-2996.
-> supports use of methylprednisolone
LeypoldBG,FlandersAE,SchwartzED,et al:The impact of methylprednisolone on lesion severity following spinal cord injury.Spine2007;32:373-378.
-> patients who had methylprednisolone had significantly less intramedullary haemorrhage than those who were no treated.
EckJC,NachtigallD,HumphreysSC,et al:Questionnaire survey of spine surgeons on the use of methylprednisolone for acute spinal cord injury.Spine2006;31:E250-253.
- n = 305 spine surgeons
-> 90% would initiate methylprednisolone especially within the 8 hour window
-> reasons given: institutional protocol, medicolegal reasons
-> only 24% used steroids because of a belief in improved outcomes!
Summary
- controversial issue
- methylprednisolone may have role in neurological protection in early spinal cord injury
- a well designed RCT’s is required
SUMMARY OF PROVEN ROLES FOR STEROIDS
Airway
- croup
- decreased post-extubation stridor in those at risk
Breathing
- anaphylaxis
- asthma
- COPD
- PJP pneumonia
Nervous
- bacterial meningitis
- myasthenic crises
- myxoedema coma
- decreases cerebral oedema associated with brain tumour
Endocrine
- Addison’s
- hypercalcaemia
- myxoedema coma
- hypothalamic-pituitary-adrenal insufficiency
- previous steroid use
Other
- purpura fulminans
- fulminant vasculitis
- organ transplantation
- various malignancy (lymphoma)
- anti-emetic
- palliative care
ACCEPTED BUT CONTROVERSIAL USES OF STEROIDS
- severe sepsis with resistant shock
- spinal injury
- early ARDS
CONTRAINDICATIONS TO USE OF STEROIDS
- Cushings disease
- traumatic brain injury
- late ARDS (after 2 weeks)
Jeremy Fernando (2011)