Credits - Section Writer: [[Dr. Om J Lakhani]] - Section Editor: [[Dr. Om J Lakhani]] **Join our WhatsApp channel to get regular updates from “Notes in Endocrinology” and “Endocrinology India”:** [**https://whatsapp.com/channel/0029VaFyQnfHbFUz0LVdBO3****h**](https://whatsapp.com/channel/0029VaFyQnfHbFUz0LVdBO3h) Support us: 1. [Support you by Becoming a YouTube member (Click here)](https://www.youtube.com/channel/UC6zQSf7dLDqfQOeM4mNUBTQ/join).  - Premium Membership- Download PDF version of Notes, Get ad free video and more - Consultant Membership- Above plus Download Powerpoint presentation of the notes 2. Support us by purchasing our book - Click here for more details: - [[Volume 1- THE BEST OF NOTES IN ENDOCRINOLOGY BOOK SERIES]] - [[Volume 2- THE BEST OF NOTES IN ENDOCRINOLOGY - DIABETES SPECIAL]] - Video Lecture: - <iframe width="560" height="315" src="https://www.youtube.com/embed/u3MH1K_Y_zE?si=mGBUKXOllTYgYoSG" title="YouTube video player" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen></iframe> - 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 - 2. Use of Glucocorticoids in refractory septic shock - 3. 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? - ![[Pasted image 20240210155704.png]] - Q. Recommend preoperative steroid doses in patients with Adrenal insufficiency undergoing surgery? - -  - 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. - 2. Draw blood for immediate serum electrolytes and glucose and routine measurement of plasma cortisol and ACTH. Do not wait for lab results. - 3. 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. - 4. Give intravenous hydrocortisone, 100 mg immediately, and every six hours thereafter may be used. - 5. 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. - 2. Search for and treat possible infectious precipitating causes of the adrenal crisis. - 3. Perform a short ACTH stimulation test to confirm the diagnosis of adrenal insufficiency, if the patient does not have known adrenal insufficiency. - 4. Determine the type of adrenal insufficiency and its cause if not already known. - 5. Taper parenteral glucocorticoid over one to three days, if precipitating or complicating illness permits, to oral glucocorticoid maintenance dose. - 6. 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: 1. 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.