- two types: glucocorticoids (cortisol) and mineralocorticoids (aldosterone)
- both cholesterol based
- produced from zona fasiculata in adrenal cortex
- produced in response to stress: hypoglycaemia, fear, pain, exercise, infection
- 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
- 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)
- primary, secondary and tertiary + acute/chronic
Primary = Addison’s
- destruction of > 90% of adrenal glands
- causes: autoimmune destruction, haemorrhage, tumour (breast and melanoma), infection (Tb, HIV, meningococcaemia, purpura fulminans) or inflammatory process
- loss of mineralocorticoid and glucocorticoid activity
- insufficient production of ACTH
- mineralocorticoid function intact
- causes: destruction or dysfunction of the pituitary
- suppression of HPA axis over time
- most common
- cause: administration of exogenous glucocorticoids
- mechanism: chronic ACTH suppression -> adrenal atrophy
- concurrent illness, surgery, failure to take medications
- GI: abdominal pain, vomiting and diarrhoea
- CVS: dehydration, hypotension, refractory shock, poor response to inotropes/pressors
Chronic adrenal insufficiency
- GENERAL: weight loss, arthralgia, myalgia
- CNS: fatigue, anorexia, mood change
- CVS: postural hypotension, syncope, salt craving
- SKIN: pigmentation, vitiligo
- ELECTROLYTES: hypoglycaemia, hyponatraemia, hyperkalaemia, increased urea
- plasma cortisol level < 80mmol/L
- short synacthen test: 250mcg (normal response = cortisol > 525mmol/L)
- 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
- see Corticosteroids in Refractory Shock
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 these 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
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
- 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.
- urrent 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)
- exact place of steroids in ARDS is unknown
- further investigation required
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
- dexamethasone with first antibiotics in community acquired bacterial meningitis
-> reduces mortality
-> reduces severe hearing loss
-> reduces neurological sequelae
TRAUMATIC BRAIN INJURY
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 injury-outcomes 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
-> 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, but written by the lead investigator of NASCIS
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.
- NASCCIS II supports use of methylprednisolone
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!
- 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
- decreased post-extubation stridor in those at risk
- PJP pneumonia
- bacterial meningitis
- myasthenic crises
- myxoedema coma
- decreases cerebral oedema associated with brain tumour
- myxoedema coma
- hypothalamic-pituitary-adrenal insufficiency
- previous steroid use
- purpura fulminans
- vasculitidies (e.g. GCA)
- organ transplantation
- various malignancy (lymphoma)
- palliative care
ACCEPTED BUT CONTROVERSIAL USES OF STEROIDS
– severe sepsis with resistant shock
– spinal injury
– early ARDS
CONTRAINDICATIONS TO USE OF STEROIDS
– Cushing disease
– traumatic brain injury
– late ARDS (after 2 weeks)