Steroids in critical illness

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Steroids in critical illness

• Mark Daly
• Consultant Endocrinologist
• Exeter

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This talk

• A challenging case
• HPA axis insufficiency in traumatic brain injury
• Diagnosing corticosteroid deficiency in the
  critical ill patient
• Different approaches
• Controversies
• Understanding the pathophysiology
• Towards a sensible consensus
• Role of corticosteroid use in the ITU setting
• Concept of relative adrenal insufficiency
• Failure of response to conventional vasopressor
  interventions
• Conclusions

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LG, 55

• 48 yr F, presents with collapse, recent
  diarrhoeal illness
• BP 70/40
• 39.5 oc
• Swollen inflamed wrist
• CRP 295, WCC 24, creatinine 295, bicarb 10
• Na 107, K 6.2

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LG, 55

• Admitted to ITU
• Baseline serum taken
• Put on steroids
• Endocrinology consult requested

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LG, 55

• Random cortisol 2
• No ACTH
• LH 55, FSH 72
• PRL 450, TSH 2.9, FT4 18

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LG, 55, PMH

• Thyroid eye disease
• Treated thyrotoxicosis
• Recent uncontrolled hypertension
• Manic depression
• Anti-phospholipid syndrome

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LG, 55

• Differential diagnosis?
• Primary hypoadrenalism
• Supported by UEs, but other explanations
• But recently hypertensive so NOT slow onset
• Secondary hypoadrenalism
• Why such striking preservation of other pituitary
  hormones?
• ?false cortisol result
• ?severe electrolyte loss
• Acute total hypoadrenalism?

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LG, 55
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LG, 55

• Clinical diagnosis of bilateral acute adrenal
  infarction confirmed by CT
• Exacerbation of mania caused by higher dose
  steroids
• Subsequent hyponatraemia caused by excessive
  water drinking (due to mania) then Addisonian
  crisis (omitting steroids)

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HPA axis insufficiency in traumatic brain injury

• TBI leading cause of death and disability in
  young adults
• Autopsies have shown up to pituitary gland
  necrosis in one-third of patients

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HPA axis insufficiency in traumatic brain injury

• Beaumont Hospital Dublin
• 102 neuro-surgical survivors
• Broad-spectrum of AP testing, limited by risk of
  ITT
• 28.4 had at least one AP hormone deficiency
• 10 were ACTH deficient
• Thus
• Clear evidence of pituitary dysfunction as a
  result of acute injury persisting long-term
• BUT
• Is this an acute phenomenon?
• J Clin Endo Metab 894929, 2004

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HPA axis insufficiency in acute traumatic brain
injury

• 50 patients with severe or moderate brain injury
  31 matched controls, median 12 days post injury
• Glucagon stimulation test
• Peak cortisol lt450 in 16
• (80 had gonadotrophin deficiency with low sex
  steroids)
• No reference to free cortisol or albumin levels
• Thus in acute phase of brain injury there is
  evidence of pituitary dysfunction
• Clin Endo (Oxf) 2004 60584-91

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More difficult territory
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Diagnosing adrenal/pituitary insufficiency in
critically ill patients

• Sometimes it feels like late-onset hypogonadism!
• Why?
• Because someone is trying to diagnose a disease
  without a clear pathogenesis and borderline
  results (and equally borderline treatment
  responses)

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A review of physiology

• The simple approach

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The simple approach
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The complex approach
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The clinical approach in sickness and in health

• Autonomic nervous system modulates CRH release by
  hypothalamus
• CRH stimulates ACTH release from anterior
  pituitary
• ACTH stimulates cortisol synthesis (plus
  aldosterone and DHEA)
• Feedback of cortisol to ACTH and CRH

• Vasopressin stimulates ACTH secretion in the
  presence of CRH

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The clinical approach in sickness and in health

• IL-1, IL-6, MIF and TNF-alpha promote high
  corticosteroid levels
• IL-6 receptors seen on pituitary corticotrophs
  and adrenal cortical cells
• Effect in addition to classical pathway
  activation
• Impaired clearance of steroid (esp renal/hepatic
  disease

• Steroid in excess of Cushings AND less
  suppressible
• (best seen in neuro-surgical patients where 24mg
  dexamethasone does not suppress endogenous
  production)
• BUT individual variation in response to stress
• (MIF macrophage migratory inhibitory factor)

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So

• Strong, unsuppressible cortisol secretion in
  stress suggests this is an adaptive response
• So inadequate response suggests failure and
  indication for high-dose steroids?
• AND resistance to gluco-corticoid action may be
  present despite a strong response?

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Evidence for HPA axis failure in critical illness

• Published data cover very heterogeneous groups
• Many with severe sepsis

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Hypoadrenalism in septic shock
J Clin Endo Metab 2006,913725-45
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Hypoadrenalism in septic shock

• Conclusions from small studies - small
  increments more likely to die (but sample of 13 v
  6)
• BUT higher baseline values more likely to die in
  larger studies
• Higher cortisolDHEAs ratio predicted death
• BUT are we simply dealing with severity of
  illness markers?

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Assessing HPA function in critical illness
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Problems of assessing HPA function in acute
illness

• Total versus free cortisol
• Transcortin low capacity, high affinity
• Transcortin may fall in acute illness
• Thus total but not necessarily free cortisol may
  fall
• Can use calculated correction factor, serum
  cortisol divided by the transcortin
  concentrations
• BUT

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Problems of assessing HPA function in acute
illness

• Total versus free cortisol
• Transcortin low capacity, high affinity
• Albumin high capacity, low affinity
• At higher concentrations more will be albumin
  bound (when transcortin is saturated)
• Thus when albumin falls in the stressed
  individual, the effect on total cortisol is
  disproportionate

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Is this a significant effect?

• 66 critically ill patients
• 7-10 fold increase in free cortisol conc
• AND
• 40 of the hypoproteinaemic patients failed SST
  if total cortisol was used as the marker c/w free
  cortisol
• NEJM 3501629-38

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Should we use the SST?
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GR, 78 yrs old

• Collapse post-hip replacement, severe headache
• BP 80/50
• Na115
• Diagnosed SIADH
• Fluid-restricted

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GR, 78 yrs old

• Further collapse
• Endo SpR reviewed
• Random cortisol 125
• SST rise to 490
• Given steroids
• Developed 3rd nerve palsy

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GR, 78 yrs old
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Clinical conclusion

• SST is not valid in acute onset of secondary
  hypoadrenalism

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Returning to more common critical illness

• Several studies have advocated RISE or increment
  in cortisol as key factor
• Then used as justification for steroid use
• Returning to complication of CBG/albumin levels,
  one proposal
• Interpret in context of albumin
• If albumin gt 25 g/l, peak lt20 mcg/dl (550)
  deficiency

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The Coolens method

• U2 x K (1 N) U1 N K(G T) T 0,
• where T is cortisol, G is CBG, U is unbound
  cortisol,
• K is the affinity of CBG for cortisol at 37 C
• N albumin bound free cortisol ratio
• The value of N would be expected to change with
  altered concentrations of plasma albumin
• Countered by investigating the distribution of
  cortisol (600 nmol/l) in varying concentrations
  of purified human serum albumin solutions using
  equilibrium dialysis.
• Use experimentally derived values of N to further
  calculate free cortisol, thus compensating for
  variations in plasma albumin.
• J Clin Endocrinol Metab. 2006 Jan91(1)105-14
• J Steroid Biochem. 1987 Feb26(2)197-202

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Medication a complicating factor

• Potential effects on binding but also synthesis
• Etomidate is a imidazole used as an anaesthetic
  to facilitate intubation
• Causes reversible inhibition of 11 ß-hydroxylase
• Associated with impaired HPA axis function even
  after single injection
• This has confounded some of the larger studies
• Either should be abandoned or given with steroid
  cover

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Relative adrenal insufficiency

• Patients without risk factors for adrenal
  dysfunction
• critical illness related corticosteroid
  insufficiency (CIRCI). ( inappropriate steroid
  activity given a patient's severity of illness)
• Serum cortisol levels FELT to be inadequate
• 299 patients with septic shock
• Non-responderslt250 increment
• Non-responders benefited from corticosteroid
• 68 of the non-responders had etomidate
• ? No published response re benefit for
  non-etomidate, non-responders
• JAMA 288862-871

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Glucocorticoid therapy during acute illness

• CORTICUS study
• (Corticosteroid Therapy of Septic Shock)
• Multicentre, international, double-blind RCT.
• primary end point was 28-day all-cause mortality
  in "nonresponders" (defined as a change of 9
  mcg/dL in cortisol after a 250-mcg SST
• Secondary end points mortality, organ failure
  resolution, and safety.

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CORTICUS study

• Powered on 800 patients to detect a 10
  difference in mortality.
• 500 participants
• 50 mg of hydrocortisone every 6 hours for 5 days
  with a tapering dose over the next 6 days v
  placebo

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CORTICUS study results

• no differences in these baseline characteristics
  / severity of illness
• For no outcome end point was there a difference
  with use of corticosteroids.
• All-cause mortality was similar (34
  corticosteroids vs 31 placebo).
• Mortality rates also did not vary based on
  responder status.
• nonresponders tended to have higher mortality
  overall.
• Rates of superinfection were higher in those
  given corticosteroids (34 vs 27, P .099).
• The frequency of hospital-acquired new sepsis was
  also higher in those randomized to steroids.
• Hyperglycemia was also more common on study day 1
  in persons treated with corticosteroids.
• (report of American Chest meeting)

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Corticus a word of caution

• Clinical trials register
• Study Type InterventionalStudy
  Design Treatment, Randomized, Double-Blind,
  Placebo Control, Parallel Assignment,
  Safety/Efficacy Study
• BUT
• Adrenal function in sepsis the retrospective
  Corticus cohort study
• Crit Care Med. 2007 Apr35(4)1012-8.
• Annane is listed as last author and also on
  trials database

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A last resort?

• The decision to administer steroids in in sepsis
  cannot be based on markers of adrenal function,
  rather treatment should be considered in septic
  patients with vasopressor refractory hypotension
• Ann Pharmacother 2007411456-65

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Conclusions

• Management of hypoadrenalism in critically ill
  patients with identified aetiology is
  straightforward
• There remains a clear role for considering the
  individual patient and using clinical acumen

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Conclusions

• Total cortisol levels may be misleading in
  critical illness
• Due to alterations in CBG and albumin levels
• This can be corrected for either by testing free
  cortisol OR the Coolens method

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Conclusions

• Drugs previously commonly used in anaesthesia
  impair cortisol synthesis and genuinely
  compromise adrenal function
• Other drugs can affect CBG levels and total
  cortisol measurements

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Conclusions

• The evidence for blanket use of moderate high
  dose steroids in critical illness has NOT been
  made
• Some use pragmatic approach i.e. if all else
  fails

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Finally..

• Thus use clinical acumen and consider the
  aetiology
• Interpret function in the light of altered
  physiology
• Be aware of limitations of interventional studies