Steroids in critical illness

Mark Daly Consultant Endocrinologist Exeter

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

LG, 55

 48 yr F, presents with collapse, recent diarrhoeal illness  BP 70/40  39.5 o c  Swollen inflamed wrist  CRP 295, WCC 24, creatinine 295, bicarb 10 

Na+ 107, K+ 6.2

LG, 55

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

LG, 55

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

LG, 55, PMH

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

LG, 55

 Differential diagnosis?

     Primary hypoadrenalism • • Supported by U+Es, 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?

LG, 55

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)

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

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 89:4929, 2004

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 <450 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; 60:584-91

More difficult territory

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)

A review of physiology

 The simple approach:

The simple approach

The complex approach

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

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 Cushing’s 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 factor) – macrophage migratory inhibitory

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?

Evidence for HPA axis failure in critical illness  Published data cover very heterogeneous groups  Many with severe sepsis

Hypoadrenalism in septic shock

Study Patient nos Criteria Relative insufficiency 1 2 3 4 5 6 7 8 9 32 22 21 20 22 59 189 45 68 Inc<250 Inc<200 Peak<500 Inc<200 19 75 24 45 Base<1000+inc<20 0 B<690 55 61 Inc<248 Inc<248 B<500 54 33 32

J Clin Endo Metab 2006,91:3725-45

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 cortisol:DHEAs ratio predicted death  BUT are we simply dealing with severity of illness markers?

Assessing HPA function in critical illness

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:

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

600 500 400 300 200 100 0 CBG-bound Albumin-bound Free

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 350:1629-38

Should we use the SST?

GR, 78 yrs old

 Collapse post-hip replacement, severe headache  BP 80/50  Na+115  Diagnosed SIADH  Fluid-restricted

GR, 78 yrs old

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

GR, 78 yrs old

Clinical conclusion

 SST is not valid in acute onset of secondary hypoadrenalism

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 > 25 g/l, peak <20 mcg/dl (550)= deficiency

The Coolens method

    U2 x K (1 + N) + U[1 + 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 Jan;91(1):105-14 J Steroid Biochem. 1987 Feb;26(2):197-202

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 β-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

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-responders<250 increment Non-responders benefited from corticosteroid 68 of the non-responders had etomidate ? No published response re benefit for non-etomidate, non responders JAMA 288:862-871

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.

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

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)

Corticus – a word of caution

 Clinical trials register:  Study Type: Interventional Study 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 Apr;35(4):1012-8.  Annane is listed as last author and also on trials database

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 2007;41:1456-65

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

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

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

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

Finally…..

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