Adrenal insufficiency in Critical illness

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- Section Writer: Dr. Om J Lakhani
- Section Editor: Dr. Om J Lakhani

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Video Lecture:
Q. What are the differences in the HPA axis in Acute vs chronic critically ill patients?
- Acute there is activation of CRH → Increases ACTH→ increases Cortisol
- Chronic → There is suppression of ACTH but cortisol is still high because it is produced by alternate pathways like endotoxins
Q. What about Aldosterone ?
- Acute illness aldosterone is increased
- Chronic illness→ aldosterone reduced
Effects of critical illness on HPA Axis
Q. Describe with a diagram, changes in the HPA axis in critically ill patients.
Q. In terms of absolute values, what are the values of cortisol in normal vs critically ill patients?
- Normal people have cortisol in the range of 5-24 mcg/dl
- In critically ill- they are in the range of 40-50 mcg/dl
Q. What factors produce an increase in cortisol in critically ill patients?
- Activation of CRH due to stress –main
- Reduction of CBG and albumin increases free cortisol
- Reduced GFR → increase half-life of cortisol
- Inflammatory cytokine → increase peripheral conversion of cortisone to cortisol
- Inflammatory cytokines → increase affinity to glucocorticoid receptors
- Reduced breakdown of cortisol by downregulation of enzymes
Q. What happens to CBG in sepsis?
- In critically ill patients, CBG reduces
- Hence free cortisol increases
- Half-life of free cortisol is low
Q. Describe the Negative feedback loop of cortisol in critically ill patients.
- Inflammatory cytokines increase Cortisol → suppress NK-kb transcription → reduce release of inflammatory cytokines
- This is a negative feedback loop
Q. What are the beneficial effects of glucocorticoids in critically ill patients?
- Increase catecholamine
- Increase blood pressure
- Keep cytokines in check
- Produces insulin resistance both hepatic and peripheral which provides more glucose for another purpose of fighting infection and stress
**Acute stress **
Q. Which 2 axes are activated in acute stress?
- HPA axis
- Sympathoadrenal axis
Q. What is the prevalence of adrenal insufficiency in critically ill patients?
- 10-20% in General
- In septic shock- 60%
Q. Is there a component of glucocorticoid resistance also?
- Yes
- Some believe that there is a phenomenon called “Systemic inflammation associated Glucocorticoid resistance”
- This is well-known in COPD patients
- In critical illness- ARDS patients tend to have this
**ASSESSMENT OF ADRENAL RESERVE **
Q. Is cortisol value associated with mortality in critically ill patients?
- It is controversial and results are mixed
- Both low and high cortisol have been associated with high mortality
Q. What should be ideally measured in ICU-free cortisol or total cortisol?
- Free cortisol is ideal
- This is because CBG is reduced in critical illness
- However, assays for free cortisol are not reliable and hence free cortisol is not normally tested in ICU
Q. What is recommended in Williams for assessing adrenal function in critically ill?
- 1. Random Cortisol is done
  - a. <15 ug/dl- Insufficient
  - b. 15-33 ug/dl- Do SST
  - c. If >33 ug/dl- Sufficient
- In SST- Failure of Cortisol to raise by >9 ug/dl- insufficiency present
- These cutoffs are abandoned now, however, they have been used to determine prognosis
Q. Describe the prognosis based on the results of the ACTH stimulation test.
- Good prognosis
  - Baseline cortisol <34
  - Rise of cortisol > 9
  - 26% mortality at 28 days
- Intermediate prognosis
  - Baseline cortisol >34
  - Rise of cortisol >9
  - Or
  - Baseline cortisol <34
  - Rise of cortisol <9
  - Mortality – 62%
- Poor prognosis
  - Baseline cortisol >34 and rise <9
  - Mortality – 82%
Q. Is there any role of low dose ACTH stimulation test?
- Some studies have shown low-dose ACTH stimulation tests to be a better predictor than high-dose
- There are subset of patients with adrenal insufficiency who would be missed by high-dose ACTH stimulation who are diagnosed with low-dose ACTH stimulation
Q. Does the method of cortisol assay create an issue?
- Yes
- Cortisol measured with LC-MS/MS vs immunoassay has a poor correlation in critically ill patients
The Three Situations
Q. What are the three different situations that you have to understand while dealing with potential adrenal insufficiency in critically ill patients?
- 1. Patient with underlying Adrenal insufficiency becoming ill - having either adrenergic crisis or increased requirement of glucocorticoids
- 1. Use of Glucocorticoids in refractory septic shock
- 1. CIRCI- "Critical illness-related corticosteroid insufficiency ” (CIRCI)
Underlying Adrenal insufficiency
See notes on Diagnosis of Adrenal insufficiency, Treatment of Adrenal insufficiency
Q. What are the causes of adrenal insufficiency in critically ill patients?
- Gram-negative and certain gram-positive infection
  - Use of Glucocorticoid use previously and suppression of HPA axis
  - Use of certain drugs
  - HIV infection
  - Adrenal infarct or hemorraghe
  - Pituitary apoplexy / Sheehan’s syndrome / other causes of Panhypopituitarism
Q. Which drugs used in critically ill patients lead to poor cortisol response?
- Etomidate- used for intubation
- Ketoconazole
- Anticonvulsants
- Barbiturates
- Rifampicin
Q. What is Dr. Om J Lakhani's protocol for diagnosis of Adrenal insufficiency?
Q. Recommend preoperative steroid doses in patients with Adrenal insufficiency undergoing surgery?

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Q. What is the volume status in primary vs secondary AI?
- Primary AI- volume deficit
- Secondary AI – Normal/ slightly increased volume status
- Hypotension occurs in both cases
- In primary AI it is Mineralocorticoid deficiency leading to volume depletion which is the cause
- In secondary AI → it is lack of pressor effect and lack of Epinephrine which is the cause
Q. Which is the preferred glucocorticoid in adrenal crisis?
- Hydrocortisone
Q. Is mineralocorticoid required during an acute adrenal crisis?
- Generally no
- This is because the sodium-retaining ability of fludrocortisone takes 2-3 days to appear
- Saline infusion solves the same purpose
- Hence Mineralocorticoid is unnecessary in acute adrenal crisis
Q. Describe the emergent treatment of adrenal crisis.
- 1. Establish intravenous access with a large-gauge needle.
- 1. Draw blood for immediate serum electrolytes and glucose and routine measurement of plasma cortisol and ACTH. Do not wait for lab results.
- 1. Infuse 2 to 3 liters of isotonic saline or 5 percent dextrose in isotonic saline as quickly as possible. Frequent hemodynamic monitoring and measurement of serum electrolytes should be performed to avoid iatrogenic fluid overload.
- 1. Give intravenous hydrocortisone, 100 mg immediately, and every six hours thereafter may be used.
- 1. Use supportive measures as needed.
Q. What is the subsequent management?
- 1. Continue intravenous isotonic saline at a slower rate for the next 24 to 48 hours.
- 1. Search for and treat possible infectious precipitating causes of the adrenal crisis.
- 1. Perform a short ACTH stimulation test to confirm the diagnosis of adrenal insufficiency, if the patient does not have known adrenal insufficiency.
- 1. Determine the type of adrenal insufficiency and its cause if not already known.
- 1. Taper parenteral glucocorticoid over one to three days, if precipitating or complicating illness permits, to oral glucocorticoid maintenance dose.
- 1. Begin mineralocorticoid replacement with fludrocortisone, 0.1 mg by mouth daily, when saline infusion is stopped. (for Primary adrenal insufficiency)
Q. What type of fluid should be avoided during initial resuscitation of an acute adrenal crisis?
- Avoid hypotonic fluids as they can worsen the hyponatremia
Use of Glucorticoids in Refractory septic shock
Q. What is the current definition of Refractory septic shock?
- The current definition of refractory septic shock is characterized by the following key points:
  - Persistently Low Mean Arterial Pressure: Despite volume resuscitation and titrated administration of vasopressors and inotropes, mean arterial pressure remains low in the context of a proven or suspected infection coupled with organ dysfunction
  - High-Dose Vasopressor Therapy: Defined as an inadequate response to high-dose vasopressor therapy, which typically means more than 0.5 mcg/kg/min of norepinephrine or its equivalent
  - Association with High Mortality Rate: Refractory septic shock carries a significantly high mortality rate, emphasizing the critical nature of this condition and the challenge it poses in clinical management.
Q. What was the classical definition used in Clinical trials?
- SBP <90 mm Hg despite 1 hour of adequate fluid and vasopressor administration
Q. Describe the FRENCH trial in this area and what were the results.
- The French trial randomly gave critically ill patients a placebo vs Hydrocortisone 50 mg IV /6 hrly + Fludrocortisone 50 mcg
- They enrolled the patient within 8 hours of septic shock
- Before starting they performed 250 mcg ACTH stimulation and defined patients as
  - Adequate adrenal reserve- raise of cortisol >9 mcg/dl
  - Inadequate adrenal reserve – the rise of cortisol </= 9 mcg/dl
- Results
  - Patients in the intervention group had reduced mortality compared to the placebo overall
  - Patients having adequate adrenal reserve did not have any difference in mortality compared to placebo
  - Patients with inadequate adrenal reserve had more benefits compared to placebo
Q. What is the CORTICUS trial and what were their results?
- The trial was similar but the results were the opposite
- They used hydrocortisone 50 mg IV /6 hrly with no fludrocortisone for 5 days and then tapered
- They also did the ACTH stimulation and cutoff similar to the French trial
- They found no difference in mortality in the hydrocortisone group
Q. What was the difference between the French and CORTICUS trials?
Q. What does meta-analysis show?
- Meta-analysis shows that corticosteroids are more beneficial for patients having severe pressor-dependent septic shock
Q. What was the APROCCHHS trial?
- In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo
Q. Is corticosteroid beneficial in patients with less severe septic shock?
- No
Q. How is glucocorticoid administered in eligible patients?
- Hydrocortisone – 50 mg IV /6 hrly (200 mg/day)
  An infusion of 10mg/hr can be given, which shows less glucose variability, however, mortality benefits are not known on infusion as most trials done on bolus
Q. Is fludrocortisone required?
- The COIITSS study found no difference in hydrocortisone alone vs H + fludrocortisone
- Hence fludrocortisone is not recommended
- High dose Hydrocortisone has good mineralocorticoid activity
Q. How long to give?
- This is not clearly defined
- Generally given for 5-7 days
- not stop abruptly – worsen hemodynamics – taper gradually
Q. When to taper and when not to taper glucocorticoids for these patients?
- To taper- when steroids used for >7 days → reduced to 50% doses → when hydrocortisone dose is <50 mg/day- can consider adding mineralocorticoid
- When steroid use <7 days- no need to taper
Q. What is the current consensus about the use of Glucocorticoids in refractory septic shock?
- Key Points of Consensus
  - Potential Benefit: There is evidence suggesting that low-dose, short-course glucocorticoids (specifically hydrocortisone) may offer benefits in refractory septic shock, including:
    - Faster resolution of shock
    - Reduction in the need for vasopressors
    - Potential improvement in survival rates
  - Not a first-line Therapy: Glucocorticoids are not recommended as a first-line treatment for septic shock. They are primarily used in refractory cases.
  - Dosing and Duration: Current recommendations favor low-dose hydrocortisone (often 200mg per day) for a short duration (typically up to 7 days).
  - Potential Risks: Glucocorticoid use comes with potential risks, including:
    - Increased risk of infections
    - Hyperglycemia (high blood sugar)
    - Gastrointestinal bleeding
CIRCI
Q. Who coined the term CIRCI?
- Marik et al
Q. Give the concept of absolute vs relative adrenal insufficiency in critically ill patients.
- Absolute adrenal insufficiency – true adrenal insufficiency which is rare and seen in <3%
- Most cases we see in ICU are relative adrenal insufficiency also known as “Critical illness-related corticosteroid insufficiency ” (CIRCI)
- This is the amount of cortisol required considering the critical illness condition is not sufficient
Q. What is the correct term for relative Adrenal insufficiency in Critically ill patients?
- It should be called “Critical illness-related corticosteroid insufficiency ” (CIRCI)
- Terms absolute and relative adrenal insufficiency are avoided
Q. What are the diagnostic criteria for CIRCI?
- It is controversial
- However, a consensus guideline by ‘The American college of Critical Care Medicine’ defines it as follows:
  - Baseline cortisol <10 mg/dl and/or
  - Rise in cortisol </= 9 mcg/dl after high dose ACTH stimulation test
Q. What values of cortisol rule out Adrenal insufficiency?
- Baseline >34 mcg/dl
- Elevation of cortisol >9 mcg/dl over a baseline value
  The above rules out AI in critically ill patients
Q. What are the conditions in which you should suspect CIRCI?
- Hypotension
- Unresponsiveness to catecholamine infusions
- Ventilator dependence
- Abdominal or flank pain
- High fever with negative cultures and unresponsive to antibiotic therapy
- Unexplained mental changes (i.e., apathy or depression)
- Electrolyte abnormalities (hypoglycemia, hyponatremia, hyperkalemia)
- Neutropenia, eosinophilia
- Nausea, vomiting
Q. Give the summary of guidelines from the Surgical Critical Care Net.
Q. Summarize the diagnostic criteria for CIRCI with a diagram
Q. How is ACTH stimulation done in this condition?
- Baseline cortisol
- 250 mcg ACTH is given IM
- after 60 minutes cortisol is repeated
Q. What is the glucocorticoid dose recommendation for this condition?
- Téblick et al recommend a lower dose in this setting of 60 mg /24 hours
Q. What is the difference between CIRCI versus other situations in critical illness requiring glucocorticoids?
- According to Téblick, CIRCI is more of a subacute to the chronic situation arising from a longer duration of critical illness

Reference:

Téblick A, Gunst J, Van den Berghe G. Critical Illness-induced Corticosteroid Insufficiency: What It Is Not and What It Could Be. J Clin Endocrinol Metab. 2022 Jun 16;107(7):2057-2064. doi: 10.1210/clinem/dgac201. PMID: 35358303; PMCID: PMC9202732.

Q. Recommend preoperative steroid doses in patients with Adrenal insufficiency undergoing surgery?