Corticosteroids Overview

PHYSIOLOGY

• hormones
• two types: glucocorticoids (cortisol) and mineralocorticoids (aldosterone)
• both cholesterol based

GLUCLOCORTICOIDS

• cortisol
• 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

Effects

• 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 zona glomerulosa
• daily output: 100-150mcg/day
• secreted in response to; Na+ deficiency -> elevated angiotensin II, elevated plasma K+

Effects

• 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 glucocorticoids
• mechanism: chronic ACTH suppression -> adrenal atrophy

Adrenal 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 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

Diagnosis

• plasma cortisol level < 80mmol/L
• short synacthen test: 250mcg (normal response = cortisol > 525mmol/L)

Management

• 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

Conversion

• 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
• 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.

• 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)

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
• 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!

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
• vasculitidies (e.g. GCA)
• 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

– Cushing disease
– traumatic brain injury
– late ARDS (after 2 weeks)

References and links

LITFL

• CCC – Steroid conversion
• CCC – Corticosteroids Overview
• CCC – Steroids and Septic Shock Literature Summaries
• CCC – Adrenal Insufficiency
• Basic Science – Pharm 101: Corticosteroids

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