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

Nervous

  • bacterial meningitis
  • myasthenic crises
  • myxoedema coma
  • decreases cerebral oedema associated with brain tumour

Endocrine

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)


CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health, a Clinical Adjunct Associate Professor at Monash University, and the Chair of the Australian and New Zealand Intensive Care Society (ANZICS) Education Committee. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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