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
Jeremy Fernando (2011)
Mineralocorticoids
-
aldosterone
produced in the zona glomerulosa
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
Jeremy Fernando (2011)
-
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)
Jeremy Fernando (2011)
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
Annane D, Sbille V, Charpentier C, et al: “Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in patients with septic
shock”. JAMA 2002; 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
Sprung CL, Annane D, Keh D, et al: “CORTICUS Study Group: Hydrocortisone therapy for
patients with septic shock.” N Engl J Med 2008; 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
Jeremy Fernando (2011)
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
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-> reduction in duration of IPPV
Steinberg KP, Hudson LD, Goodman RB, 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
Med 2006; 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 Beek D, de Gans J, McIntyre P, et al: Corticosteroids for acute bacterial
meningitis. Cochrane Database Syst Rev 2007; 1
de Gans J, van de Beek D: European Dexamethasone in Adulthood Bacterial Meningitis Study
Investigators: Dexamethasone in adults with bacterial meningitis. N Engl J
Med 2002; 347:1549-1556
- systematic reviews
Jeremy Fernando (2011)
- dexamethasone with first antibiotics in community acquired bacterial meningitis
-> reduces mortality
-> reduces severe hearing loss
-> reduces neurological sequelae
TBI
Roberts I, Yates D, Sandercock P, 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. Lancet 2004; 364:1321-1328.
Edwards P, Arango M, Balica L, et al: CRASH trial collaborators: Final results of MRC CRASH,
a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injuryoutcomes at 6 months. Lancet 2005; 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
Bracken MB, Shepard MJ, Collins WF, 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 Med 1990; 322:1405-1411.
- high dose methylprednisolone within 8 hours in injury
-> evidence supported use
Miller SM: Methylprednisolone in acute spinal cord injury: A tarnished standard. J Neurosurg
Anesthesiol 2008; 20:140-142.
George ER, Scholten PJ, Buechler CM: Failure of methylprednisolone to improve the outcome
of spinal cord injury. Am Surg 1995; 61:659-663.
Pointillart V, Petitjean ME, Wiart L: Pharmacotherapy of spinal cord injury during the acute
phase. Spinal Cord 2000; 38:71-76.
-> criticisms of NASCIS: study design flawed, statistical analysis flawed, conflicting evidence
Bracken MB: Steroids for acute spinal cord injury. Cochrane Database Syst
Rev 2002.CD001046
-> supports use of methylprednisolone
Tsutsumi S, Ueta T, Shiba K, et al: Effects of the Second National Acute Spinal Cord Injury
Study of high-dose methylprednisolone therapy on acute cervical spinal cord injury results in
spinal injuries center. Spine 2006; 31:2992-2996.
-> supports use of methylprednisolone
Jeremy Fernando (2011)
Leypold BG, Flanders AE, Schwartz ED, et al: The impact of methylprednisolone on lesion
severity following spinal cord injury. Spine 2007; 32:373-378.
-> patients who had methylprednisolone had significantly less intramedullary haemorrhage
than those who were no treated.
Eck JC, Nachtigall D, Humphreys SC, et al: Questionnaire survey of spine surgeons on the use
of methylprednisolone for acute spinal cord injury. Spine 2006; 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
Jeremy Fernando (2011)
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)