Case Based Presentations Metabolic/Endocrine

1. Case Based PresentationsMetabolic/Endocrine Neil Mclean October 2, 2008

2. Case #1 • 45 year male presents to the emergency department with complaints of a persistent headache and muscle weakness. He also states he feels like his muscles are cramping up on him. While at the triage he develops palpitations. • His vitals are taken and are • 105 225/130 16 100% 37.2

3. He is moved into the ED and you are called approx 1 hour later because of “refractory hypertenstion” You see that they have not been able to control his blood pressure with the use of IV Labetolol/hydralazine and SL captopril. You send some blood work and his sodium is 157 and his potassium is 2.1 You astutely consider Conn’s syndrome in your differential and embark to prove your case.

4. Functional Adrenal Anatomy

5. Functional Adrenal Anatomy

7. Conn Syndrome • Discovered by JW Conn in 1955 • Primary Hyperaldosteronism • Unilateral aldosterone producing adenoma 60% • aka Conn syndrome • Idiopathic hyperaldosteronism • Bilateral adrenal hyperplasia

8. Epidemiology Twice as common in women ~0.5-1.2% of pts with hypertension

9. Clinical Presentation • Hypertension • Usually refractory • Hypokalemia • Hypernatremia • Metabolic Alkalosis

10. Conn Syndrome • Investigations • The best screening is upright plasma aldosterone to plasma renin activity ratio • stop meds for 2 weeks as most can affect the levels of aldosterone or renin. • Alpha-blockers and sympatholytic agents can be used to control BP

11. aldosterone–to–renin ratio • renin activity ratio of >30 or plasma aldosterone concentration of greater than 0.5 nmol/L (18ng/dL) is suggestive of primary aldosteronism • sensitivity of 91%, positive predictive value of 69% and a negative predictive value of 98% • Test inaccurate if on ARB, ACEi

13. Investigations • Another test is oral sodium loading for 3 days and 24-hour urine collections of aldosterone • urine sodium must be >200 meq to document adequate sodium loading • urinary aldosterone of >14 μg is suggestive of hyperaldosteronism • 2 l of isotonic saline is infused over 4 h to suppress aldosterone production and plasma aldosterone level >10 ng/dl is diagnostic

14. Imaging • CT imaging should be performed to assess for aldosterone-producing adenoma • Radionuclide scanning with 131 iodocholesterol (NP-59 cholesterol) • performed over 2 to 5 days and has 72% accuracy

15. Investigations • Differential adrenal venous sampling is quite useful in detecting unilateral disease • Complications include adrenal infarction, technical limitation, and failure to cannulate the adrenal vein 25% of the time

16. Treatment • Andenomas • A success rate for surgery is around 70-80% and HTN may require treatment for 3 months postop • Spironolactone used preop diminishes postop hypoaldosteronism and hypokalemia • Most can be done by MIS

17. Treatment • All other conditions, treatment is medical. • Spironolactone at doses from 25 to 400 mg per day have been used succesfully • BP may take about 2 months to normalize • Other antihypertensive agents may to be used concomitantly

18. CASE #2 66 year old Female presents with 2 day history of urinary symptoms. This am, husband noticed that she was difficult to rouse and called EHS. Pt arrived and is obutunded. Temp 39.4 BP 75/45 HR 123 RR 24 SAO2 99% on 10L mask

19. ICU called to assess and urine dip comes back +++Leuks and Nitrites PMHx: Hypothyroid, HTN After a quick evaluation, this patient is obviously septic and needs to be intubated

20. Medications for induction Begin fluid bolus, phenylephrine on standby Midazolam (fast-acting sedative), 2 mg in this case Con: vasodilator, thus can worsen vasodilatory shock Pro: amnestic properties, see below Ketamine 1-2 mg/kg Fentanyl (analgesia, suppression of innate respiratory drive) Rocuronium for paralysis if needed (rapid sequence) Fewer metabolic caveats (K) than sux, but longer-acting if airway control proves impossible

21. Ketamine Pro: Hemodynamically stable (may increase cardiac output) Fast-acting, short duration ? Bronchodilator Con: Increased ICP in hypertensive patients, or those with existing intracranial hypertension Reemergence phenomenon Hallucinations (K-hole) Varying availability (such as in Surrey)

23. Etomidate Also hemodynamically stable, fast-acting, short duration of action Main controversy is adrenal suppression In the adrenal gland, it inhibits C-11 Hydroxylase, which metabolizes deoxycorticosterone to corticosterone (which goes on to aldosterone), and 11-doxycortisol to cortisol. First noted in the early 80s. Does this translate into adverse clinical effects, in setting of modern management of septic shock?

25. Etomidate This effect has been shown to be both dose-dependent and duration-dependent, with a single dose inhibiting adrenal function for up to 24 hours. A crucial period for resuscitation in septic shock. No good RCT data Does etomidate have a bad rap?

26. Etomdiate Systematic review by Jackson, et al. Chest 2005 Mar; 127 (3):1031-8 Given known side effects, caution should be used in septic shock patients (? Concomittant steroids) 1 small RCT (10 etomidate @ 0.3 mg/kg, 8 midazolam 0.05-0.1 mg/kg), with outcome cosyntropin stim test result. Acad Emerg Med. 2001 Jan;8(1):1-7.

27. Etomidate Statistically significantly different at 4 hours (normal in all controls and 30% of intervention group), but all still within lab reference range of normal. No difference at 12 or 24 hrs. No clinical outcomes measured Consecutive patients, not necessarily septic shock

28. Observational data Ray, McKeown. Critical Care 2007, 11:R56 (doi:10.1186/cc5916 159 pts in a single ICU (Scotland); found that patients who were induced with etomidate (septic shock) required less vasopressor support, and had no increased requirement for steroids, nor was clinical outcome affected. Etomidate + steroids had higher mortality (p=0.12)

29. Retrospective Corticus Etomidate treated patients had lower basal cortisol levels Etomidate use was associated with increased mortality, especially in non steriod group

30. What about just giving steroids…? This is a complex issue, as Dr. Mountain will elucidate… CIRCI vs primary adrenal insufficiency as a direct result of etomidate. Should prophylactic steroids be given to any patient induced with etomidate? Data suggest not (Ray study), but there is no large RCT data either way.

31. The patient is successfully intubated and brought to the unit. She is initially volume resuscitated with 5 L of crystalloid and requires 45 mcg/kg/min of Levophed to keep her MAP barely above 60. She is started on appropriate antibiotics. On exam she is cold peripherally and has minimal urine output. Your rock star medical student, says that “she appears to be in refractory shock do you think her adrenal function is impaired?”

32. What is the incidence of relative adrenal insufficiency in sepsis?

33. Depends on your definition of relative adrenal insufficiency – no real consensus exists. Currently accepted definition is based on a study by Annane et al. (2006, Am J Respir Crit Care Med). In two cohorts of septic patients, (N=61 and N=40), the incidence of relative adrenal insufficiency was 60%, as defined by the single dose metapyrone stimulation test.

34. Metapyrone stim test works by blocking the last step of cortisol synthesis, so the immediate precursor (11-B-deoxycortisol) accumulates in serum. Accepted reference standard for relative adrenal insufficiency is an increment of < 7 mcg/dL after overnight test.

35. In the patients that were adrenally insufficient via the metapyrone stim test, base-line cortisol (< 10 mcg/dl), delta cortisol (< 9 mcg/dl), and free cortisol (< 2 mcg/dl) had a positive likelihood ratio equal to infinity, 8.46(95% confidence interval, 1.19–60.25), and 9.50 (95% confidenceinterval, 1.05–9.54), respectively. The bestpredictors of normal adrenalresponsewere cosyntropin-stimulatedcortisol of 44 mcg/dl or greater and delta cortisol of 16.8 mcg/dl orgreater.

36. Why does it occur? (Discuss WF syndrome as part of your answer).

37. Normal stress response Increase in cortisol production by a factor of up to 6 (proportional to degree of stress). Loss of diurnal variation. Increase in production of CRH and ACTH, and loss of negative feedback from cortisol. HPA axis is stimulated by circulating cytokines.

38. Normal stress response (cont’d) Levels of corticosteroid binding globulin decrease, leading to increase in free fraction. Also, binding globulin cleaved by enzymes at sites of inflammation. Inflammatory cytokines also increase affinity of glucocorticoid receptors for cortisol.

39. Impaired stress response CRH and ACTH response can be impaired by head injury, central nervous sytem depression, or pituitary infarct, exogenous steroids. Adrenal cortical synthesis can be impaired by multiple mechanisms (eg): Etomidate Antifungals. Steroids, progesterone (decreased production) Rifampin, phenytoin (incr. Hepatic metabolism)

40. Impaired stress response Inflammatory cytokines during sepsis can induce systemic or tissue-specific steroid resistance. “Relative” insufficiency can simply indicate elevated cortisol levels that are nevertheless insufficient to control the inflammatory response.

41. Adrenal hemorrhage Acute adrenal insufficiency may occur as a result of bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis. Adrenal hemorrhage has been associated with meningococcemia (Waterhouse-Friderichsen syndrome) , but Pseudomonas aeruginosa was the most common pathogen in one report of 51 children dying of sepsis and bilateral adrenal hemorrhage. Waterhouse-Friderichsen syndrome has also been reported with sepsis from Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Haemophilus influenzae, and Staphylococcus aureus.

42. Adrenal hemorrhage Symptoms and Signs hypotension or shock (>90 percent of patients); abdominal, back, flank, or lower chest pain (86 percent); fever (66 percent); anorexia, nausea, or vomiting (47 percent); confusion or disorientation (42 percent); and abdominal rigidity or rebound (22 percent) Risk factors anticoagulant drug or heparin therapy or coagulopathy, thromboembolic disease, hypercoagulable states such as antiphospholipid syndrome, physical trauma, the postoperative state, sepsis, and any cause of severe stress

43. Adrenal hemorrhage Pathogenesis Unclear. Increased adrenal blood flow stimulated by ACTH secreted in response to stress may play a contributory role Anticoagulation therapy is implicated in about one-third of patients, but adrenal hemorrhage occurs very rarely in patients who are anticoagulated; when it does, it is usually within the first 2 to 12 days of therapy. A case-control study (23 patients with bilateral massive adrenal hemorrhage and 92 control patients) reported that thrombocytopenia, heparin use, and sepsis were the variables that were most strongly and independently associated with adrenal hemorrhage risk

45. How can you assess adrenal dysfunction in sepsis, and is it a useful test?

46. High dose ACTH stim test: baseline serum cortisol drawn and then 250 mcg of synthetic ACTH (cosyntropin) administered intravenously. Serum cortisol levels drawn 30 and 60 minutes later. In a prospective inception cohort study, a high-dose ACTH stimulation test was performed on 189 patients with septic shock and the results correlated with 28-day mortality

47. Outcomes of septic shock associated with baseline cortisol level and adrenal responsiveness to 250 mcg injection of cosyntropin Data from: Annane, D, Sebille, V, Troche, G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000; 283:1038.

48. Corticus - 477 patients with severe sepsis or septic shock underwent high-dose ACTH testing . Nonsurvivors had a higher baseline cortisol level (30 versus 24 mcg/dL) and a smaller cortisol increase (6 versus 11 mcg/dL) than survivors. Patients with either a baseline cortisol level <15 mcg/dL or a cortisol increase ≤9 mcg/dL had a higher mortality, longer duration of shock, or shorter survival time. High-dose (ACTH) stimulation appears to separate patients with septic shock into different prognostic groups.

49. However, while identification of poor response to ACTH stim test can split groups prognostically, it is controversial whether it predicts response to steroid therapy. Annane study suggests that among patients with inadequate adrenal reserve, hydrocortisone administration decreased 28-day mortality (53 versus 63 percent), ICU mortality (58 versus 70 percent), and hospital mortality (61 versus 72 percent), as well as more vasopressor withdrawal (57 versus 40 percent)

50. However, Corticus found no change in mortality in steroid vs. non-steroid group, regardless of response to stim test, and shorter duration of shock in steroid group regardless of response to stim testing. Opinion based recommendation: ‘Classification of adrenal reserve as adequate or inadequate fails to identify patients who are more likely to benefit from glucocorticoid therapy’.