Internal Medicine Journal Club

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Internal Medicine Journal Club
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• Heather Stamat-Valente, DO, MS
• September 20, 2005

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Case 1
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• 78 y/o male admitted with pneumoperitoneum
  remained hypotensive and required vasopressors
  post surgery. Random Total AM Cortisol level
  2.9 mcg/dL and after stimulation test (60 min)
  19.0 mcg/dL
• Repeat random AM Total Cortisol level drawn the
  next day 15.5 mcg/dL

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Case 2
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• 54 y/ male admitted with a perforated duodenal
  ulcer. Patient required 5 different vasopressors
  post surgery. Random Total AM Cortisol level
  7.6 mcg/dL
• Lab normals _at_ IRMC
• Total AM Cortisol 4.3-22.4 mcg/dL

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Measurements of Serum Free Cortisol in Critically
Ill Patients
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• A. Hamrahian, MD, T. Oseni, MD, and B. Arafah, MD
• NEJM 2004, 3501629-1638

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Background
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• The incidence of adrenal insufficiency in sepsis
  and septic shock is approximately 30-70
• Defined as hypotension resistant to volume
  resuscitation and dependent on vasopressors
• In 2002, a study by Annane and colleagues
  demonstrated that steroids improve mortality in
  patients with septic shock and adrenal
  insufficiency

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Background
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• In the study by Annane, adrenal insufficiency was
  defined as an increase in total cortisol
  lt 9 mcg/dL in response to a 250 mcg
  Cosyntropin Stimulation Test
• This formed the basis for current practice of
  treating patients with septic shock and adrenal
  insufficiency with stress dose steroids

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Background
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• Still, there is controversy about the best
  indicator of adrenal insufficiency in critically
  ill patients
• Several criteria have been suggested to define
  adrenal insufficiency such as
• Cosyntropin-stimulated total cortisol lt 18 mcg/dL
• Change in total cortisol lt 9 mcg/dL in response
  to stimulation test
• Total random cortisol level lt 25 mcg/dL

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Background
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• 90 of circulating cortisol is protein bound
• 70 to Corticosteroid-binding protein
• 20 to Albumin
• Changes in binding proteins can alter measured
  serum total cortisol concentrations without
  influencing free cortisol levels
• Free cortisol level is the physiologically
  active form of the hormone

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Background
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• Measured total cortisol levels can be
  misleadingly lower than anticipated and result in
  an incorrect diagnosis of adrenal impairment
• Current standards for defining adrenal
  insufficiency are based on healthy persons who
  have normal concentrations of binding proteins

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Hypotheses
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• Patients with presumable normal adrenal function,
  but decreased cortisol binding proteins, will
  have lower than expected concentrations of serum
  total cortisol, but appropriately elevated
  concentrations of free cortisol levels
• The measurement of free cortisol concentrations
  will identify patients with normal or increased
  adrenal function, who on the basis of low total
  cortisol levels, would otherwise been incorrectly
  diagnosed with adrenal insufficiency

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Methods

• Patient Population and Study Design
• Setting U.S. tertiary care center. IRB approved
  with written informed consent obtained from study
  participants, their legal guardians, or DPOA
• Patients 66 critically ill with various
  illnesses and Acute Physiology, Age, and Chronic
  Health Evaluation (APACHE III) score 15 or higher
• 60 patients from medical, surgical, or cardiac
  ICUs and 6 from general medical wards
• 33 Healthy volunteers and 7 patients with adrenal
  insufficiency secondary to hypopituitarism
• Design Cohort Study

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APACHE III

• Comprised of the sum of three components
• Acute physiology score, a chronic health problems
  score, and an age score
• Scores range from 0 to 299
• Physiology (0 to 252)
• Chronic health evaluation (0 to 23)
• Age (0 to 24)
• Higher values representing a worse prognosis

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Methods

• Exclusion Criteria
• History of hypothalamic-pituitary, adrenal, or
  liver disease
• Glucocorticoid or estrogen intake within the last
  year
• Medication known to influence glucocorticoid
  secretion within the last 6 months
• Pregnancy or breast-feeding

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Methods

• Baseline serum total and free cortisol,
  cosyntropin-stimulated total and free cortisol,
  and aldosterone concentrations were measured in
  the 66 critically ill patients, 33 healthy
  volunteers, and 7 patients with adrenal
  insufficiency
• APACHE III scores range 15-77 used to determine
  severity of illness underlying disease processes
  were similar
• Patients were divided into two groups based on
  serum albumin concentrations of lt2.5 g/dL (n36)
  or gt2.5 g/dL (n30) Table 1
• Cosyntropin stimulated total cortisol levels
  vary, normal generally gt 18 mcg/dL - this study
  used 18.5 mcg/dL or greater as normal

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Cosyntropin Stimulation Testfor Adrenal
Insufficiency

• Baseline Random Cortisol level
• Cosyntropin 250 mcg Stimulation Test
• Measure 30 and 60 minutes after administration of
  Cosyntropin
• Cosyntropin-Stimulated Total Cortisol lt 18 mcg/dL
• Change in Total Cortisol lt 9 mcg/dL in response
  to stimulation test
• Total Random Cortisol level lt 25 mcg/dL

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Methods

• Statistical Analysis
• Data presented as means and SD
• Kruskal-Wallis ANOVA w/nonparametric data
• Wilcoxon rank sum test for nonparametric data
  comparisons between groups
• Categorical data compared using chi square and
  Fishers exact test
• Bonferronis correction for multiple comparisons
• Regression lines for comparison between groups
• SAS and SPSS

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Results

• The two groups of patients had similar clinical
  characteristics except for serum albumin, total
  protein, corticosteroid-binding globulin, and
  duration of hospitalization Table 1
• Baseline and cosyntropin-stimulated total
  cortisol concentrations were significantly lower
  in the low albumin group

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Results

• However, serum free cortisol concentrations were
  similar in the two groups and were several times
  higher than the values in healthy volunteers
• Fourteen of thirty-six (39) low albumin
  patients had subnormal cosyntropin stimulated
  total cortisol, which is associated with adrenal
  insufficiency Fig. 2 and Tables 2,3

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Results

• However, all 14 patients with subnormal total
  cortisol responses had cosyntropin-stimulated
  free cortisol concentrations higher than controls
  Table 2
• Mineralcorticoid secretion was also measured and
  was normal in both patient groups

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Results

• The base-line and cosyntropin-stimulated serum
  total cortisol concentrations in the 19 patients
  who died were similar to the 47 who survived
• Findings were similar for base-line and
  cosyntropin-stimulated free cortisol as well

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Results

• A comparison of the 18 patients who had sepsis
  with the 48 who had other illnesses showed
  similar concentrations of serum albumin,
  base-line serum total cortisol, base-line serum
  free cortisol, and cosyntropin-stimulated serum
  total and free cortisol

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Results

• The base-line serum total cortisol concentrations
  in healthy volunteers were correlated with
  concentrations of free cortisol and serum
  corticosteroid-binding globulin
• Base-line serum total cortisol concentrations in
  the two patient groups were correlated with serum
  free cortisol levels and albumin concentration
  Fig. 3

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What does all this mean?

• Nearly 40 of the critically ill patients with
  hypoproteinemia had subnormal serum total
  cortisol concentrations even though the adrenal
  function was normal, while serum free cortisol
  concentrations remained elevated
• This implies that serum free cortisol levels may
  be useful to determine who is truly has adrenal
  insufficiency and may prevent the unnecessary use
  of glucocorticoid therapies

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Discussion

• Study Design
• Cohort Study - Advantages
• Ethically safe
• Subjects can be matched
• Can establish timing and directionality of events
• Eligibility criteria and outcome assessments can
  be standardize
• Administratively easier and cheaper than RCT

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Discussion

• Study Design
• Cohort Disadvantages
• Controls may be difficult to identify
• Exposure may be linked to a hidden exposure
• Blinding is difficult
• Randomization not present
• For rare diseases, large sample size, or long
  follow-up necessary

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Discussion

• Study Limitations
• Study had 18 patients with sepsis, not with
  septic shock or multi-organ dysfunction. All
  references to prior studies and the benefit seen
  with corticosteroids was with septic shock
• The technique for measuring free cortisol levels
  is not widely available, is difficult, and
  expensive
• No standard levels of free cortisol have been
  reported, so the definition of abnormal is not
  known

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Discussion

• This study raises some interesting questions
• What is the true incidence of adrenal
  insufficiency in the critically ill?
• If we have not been treating true adrenal
  insufficiency (using total vs. free levels of
  cortisol) then how do we get a response?
• The study by Annane et al. published in JAMA 2002
  sets the gold standard for using change in total
  cortisol to discriminate responders from
  non-responders
• Do free cortisol concentrations make a
  difference?

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CORTICUS

• Corticosteroid Therapy of Septic Shock
• 800 patient multi-national, prospective,
  double-blind, randomized, placebo controlled
  trial
• The use of low dose steroids to improve 28-day
  mortality in septic shock patients whose cortisol
  levels did not increase gt 9mcg/dL in response to
  cosyntropin stimulation
• Total and free cortisol levels will be compared

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Are the results of this diagnostic study valid?

• Was there an independent, blind comparison with a
  reference (gold) standard of diagnosis?
• Was the diagnostic test evaluated in an
  appropriate spectrum of patients (like those in
  whom it would be used in practice)?
• Was the reference standard applied regardless of
  the test result?

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Can you apply this valid, important evidence
about a diagnostic test in caring for your
patient?

• Is the diagnostic test available, affordable,
  accurate, and precise in this setting?
• Can you generate a clinically sensible estimate
  of your patients pre-test probability?
• Will the resulting post-test probabilities affect
  your management and help your patient?
• Would the consequences of the test help your
  patient?

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Summary

• This study indicates that severe hypoproteinemia
  results in lower than expected concentrations of
  serum total cortisol in 39 of critically ill
  patients
• However, serum free cortisol concentrations are
  consistently elevated suggesting a substantial
  increase in glucocorticoid secretion
• Caution should be used interpreting base-line and
  cosyntropin stimulated serum total cortisol
  values in critically ill patients with
  hypoproteinemia

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Conclusion

• Until serum free cortisol levels become widely
  available, the use of serum total cortisol
  concentration is recommended by the authors of
  this study
• 
  
• Clinical judgment must be exercised in deciding
  whether to administer glucocorticoids to
  critically ill patients

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Conclusion

• Case 1
• Pt. given Solu-Cortef and midodrine off
  vasopresors within 12 hours after first dose
• 2.9-?19 mcg/dL
• 15.5 mcg/dL
• Case 2
• Pt. given Solu-Cortef and off all vasopressor
  therapy within 30 hours after first dose
• 7.6 mcg/dL

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References

• Dubey A, Boujoukos A Free cortisol levels should
  not be used to determine adrenal responsiveness.
  http//ccforum.com/content/9/1/E2 2004.
• Beishuizen A, Thijs LG, Vermes I.Patterns of
  corticosteroid-binding globulin and free cortisol
  index during septic shock and multitrauma.
  Intensive Care Med 2001271584-91.
• leRoux CW, Chapman GA, Kong WM, Dhillo WS, Jones
  J, Alaghband-Zadeh J. Free cortisol index is e
  than serum total cortisol in determining
  hypothalamic-pituitary-adrenal status in patients
  undergoing surgery. J Clin Endocrinol Metab
  2003882045-8.
• Annane D, Sebille V, Charpentier C, Bollaert PE,
  Francois B, Korach JM, Capellier G, Cohen Y,
  Azoulay E, Troche G, Chaumet-Riffaut P,
  Bellissant E Effect of treatment with low doses
  of hydrocortisone and fludrocortisone on
  mortality in patients with septic shock. JAMA
  2002,288862-871.