Monday, December 19, 2016

Approach to Adrenal Insufficiency

We recently discussed a case of adrenal insufficiency. Here is an overview and some key points about the presentation and work-up for adrenal insufficiency (AI):

Signs and symptoms:  * they are non-specific

History: Nausea, vomiting, anorexia, abdominal pain, presyncope, salt craving (only in primary AI)
Physical Exam: Evidence of volume depletion including tachycardia and hypotension, hyperpigmentation (only in primary AI)
Labs: Normocytic anemia, hyponatremia, hyperkalemia (only in primary AI), hypercalcemia, hypoglycemia

How to diagnose AI:

·         In patients who are unstable, with suspected severe adrenal insufficiency symptoms or adrenal crisis, the JCEM guidelines recommend immediate therapy with IV hydrocortisone at an appropriate stress dose prior to the availability of the results of diagnostic tests
o   There is some practice variation and no universally accepted or evidence-based “stress dose of steroids”
o   Some reasonable doses can include hydrocortisone 100mg IV x1 then hydrocortisone for a total of approximately 200mg IV/day (for example hydrocortisone 50mg IV q6h or hydrocortisone 100 mg IV q8h) x 24 hours then reduce the doses based on clinical picture)
o   If there is a need to give a stress dose of steroids immediately due to clinical instability but there is a plan to still test for AI after by measuring serum cortisol, giving dexamethasone may be a good choice of steroid, as it is not measured in the assays for serum cortisol (hydrocortisone will interfere with the test and is measured in the cortisol radioimmunoassay).  
·         Based on the most recent JCEM guidelines, the recommended test to diagnose adrenal insufficiency is a corticotropin stimulation test (ACTH stim test).
·         If a corticotropin stimulation test cannot be performed, measure morning (8am) serum cortisol
o   If 8 am cortisol <140 140="" nbsp="" nmol="" span="">à adrenal insufficiency
o   If 8 am cortisol 140-500 nmol/L à indeterminate à need further testing (ACTH stim test)
o   If 8 am cortisol >500 nmol/L à essentially rules out AI à in most cases no further testing necessary

Corticotropin stimulation test (ACTH stim test):

How to do it: There are 2 protocols of ACTH Stimulation tests. Both use synthetic ACTH (cosyntropin) to assess the adrenal’s response to ACTH.
Standard high-dose ACTH stimulation test: Give cosyntropin 250 mcg IV and measure serum cortisol at time 0, 30, 60 mins post-injection.
Low-dose ACTH stimulation test: Give cosyntropin 1 mcg IV and measure serum cortisol at time 0 and 30 mins post-injection.

* Can also measure ACTH before giving the cosyntropin to help determine if it is primary or secondary AI
* Do the stimulation test in the morning as cortisol responses are greatest in the morning. If you do it in the evening, you could get a False Positive test in a normal individual.
* Theoretically the low-dose ACTH stim test is a more sensitive test, especially for secondary AI, as it is a more physiological dose of ACTH, but typically high-dose ACTH stim test in the standard test that is done first (it is what is recommended in JCEM guidelines)
*Hold oral contraceptives before ACTH Stim tests, as the increased cortisol-binding globulins with oral contraceptive can affect the results of the test (can lead to underestimation of hypocorticolism)
* If you suspect an adrenal crisis, do not delay glucocorticoid replacement therapy while awaiting the results of ACTH stim test to confirm the diagnosis. You can consider using dexamethasone as the initial steroid of choice as it does not interfere with serum cortisol assays.

How to interpret ACTH Stim test:
Peak serum cortisol >500 nmol/L at any point during ACTH stim test (before or after cosyntropin injection at 30 or 60 mins) à no AI à no further testing necessary
Peak serum cortisol <500 500="" acth="" during="" nbsp="" span="" stim="" test="">à indicates adrenal insufficiency à further testing to determine etiology

Determine etiology:

ACTH Stim test confirms adrenal insufficiency (cortisol remains <500 span="">à measure serum ACTH
ACTH >2-fold the upper limit of the reference range à consistent with Primary AI (including Addison’s disease) à further work up which may include CT adrenal, adrenal antibodies, 17-OH proesterone
ACTH in low/low-normal range à Secondary or tertiary AI à Pituitary MRI, measure other pituitary hormones to rule out panhypopituitarism


Acute management (adrenal crisis): 
ABCs, IV normal saline, electrolyte management, stress-dose steroids (no universally accepted or evidence-based dose, one example is hydrocortisone 100mg IV x1 then hydrocortisone for a total of approximately 200mg IV/day (for example hydrocortisone 50mg IV q6h or hydrocortisone 100 mg IV q8h) x 24 hours then reduce the doses based on clinical picture)

Chronic management:
·         Glucocorticoid replacement: guidelines suggest hydrocortisone (15-25mg) or cortisone acetate (20-35mg) daily in two or three divided oral doses/day, with the highest dose given in the morning
·         Mineralocorticoid replacement: Fludrocortisone (starting dose 50-100 mcg) and no salt intake restriction. Monitor mineralocorticoid replacement based on clinical assessment (salt craving, postural hypotension, electrolytes).
·         Other: medical alert identification, patient education, patient education regarding stress dosing when sick (basics: double or triple dose of oral steroid when sick until recovery (usually 2-3 days); if not tolerating PO intake, need to come to hospital for IV steroids), education and consultation regarding peri-operative management.

1.       Bornstein S et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guildeline. J Clin Endocrinol Metab. 2016;101(2):364-89
2.     Klose M et al. Factors influencing the adrenocorticotropin test: role of contemporary cortisol assays, body composition, and oral contraceptive agents.  J Clin Endocrinol Metab. 2007;92(4):1326. 

Tuesday, November 15, 2016

Group A Steptococcal infection

In morning report, we discussed the case of a man with HIV presenting with sepsis and odynophagia with head and neck lymphadenopathy and symptoms of sinusitis.

We discussed the following learning points:

1.       Head and neck infection: a history of odynophagia, lymphadenopathy and sinusitis is concerning for a head and neck infection. The differential diagnosis would include:
a.       Deep neck space infections such as retropharyngeal abscesses
b.      Peritonsillar abscesses and submandibular space infections (Ludwig’s angina)
c.       Suppurative parotitis
d.      Pharyngitis
e.      Lymphadenitis (including TB lymphadenitis)
f.        Epiglottitis  
g.       Laryngotracheitis
h.      Diphtheria

2.       CD4 count : we discussed that the differential diagnosis will change and be informed by the opportunistic infections that patients with HIV are susceptible to with different CD4 counts:

3.       Meningitis examination: With the history of fever and headache, the question of meningitis comes up. Looking at the JAMA Rational Clinical Examination article on “Does this adult patient have acute meningitis?” from 1999, absence of fever, neck stiffness and altered mental status effectively rules out meningitis. One of the most sensitive maneuvers in the diagnosis of meningitis is jolt accentuation (sensitivity 100%, specificity 54%, positive LR 2.2, negative LR 0); a negative jolt accentuation may essentially exclude meningitis.

In this case, there was no evidence of meningitis on exam (negative jolt accentuation) and swabs and blood cultures were positive for Group A Streptococcus (Sterptococcus pyogenes).  

4.       Group A Streptococcus (GAS) infections:

Types of GAS infection include:
-          Streptococcal tonsillopharyngitis “strep throat”
-          Skin and soft tissue infections
o   Cellulitis
o   Erysipelas
-          Necrotizing fasciitis
-          Myositits
-          Pneumonia
-          Postpartum endometritis
-          Bacteremia associated with toxic shock syndrome

Nonsuppurative Complications of GAS pharyngitis include:
-          Scarlet Fever
-          Rheumatic Fever
-          Glomerulonephritis
-          Toxic Shock Syndrome

Treatment of GAS:
-          GAS is universally sensitive to penicillin and as such penicillin is the first line treatment.
-          Clindamycin is generally used in addition to a beta-lactam in the treatment of invasive GAS has it inhibits protein synthesis, suppressing synthesis of bacterial toxins, and there is evidence that it reduces mortality.
-          For toxic shock syndrome, there is some evidence supporting the adjunctive use of IVIG
-          Don’t forget that early aggressive surgical intervention is key for invasive soft tissue infections, such as necrotizing fasciitis. 

Attia et al. Does this adult patient have acute meningitis? JAMA. 1999;282(2):175-81.
Carapetis et al. Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group A streptococcal infections. Clin Infect Dis. 2014;59(3):358.   
Davies et al. Invasive Group A Streptococcal Infections in Ontario, Canada. NEJM. 1996;335:547-54.

Wessels. Streptococcal Pharyngitis. NEJM. 2011;364:648-55. 

Wednesday, September 28, 2016

Approach to a common presentation - Syncope

In morning report we’ve had several cases that presented with syncope. Here is an approach to syncope:

1.       Get a detailed history. History is key for syncope and to help with the differential diagnosis. Ask if it is witnessed, exactly what happened before (ie. Precipitating factors such as stressors, exertion, positional changes), during (i.e. was the patient sitting/standing/changing position at the time, was there a loss of consciousness, was there a prodrome, was there facial or other injury, etc) and after (i.e. post-ictal confusion points to seizure, etc) including associated symptoms and if this has ever happened before.

Ask questions that pertain to the differential diagnosis
Cause of syncope
Reflex syncope “vaso-vagal”
Increase in vagal tone
Can be associated with cough, deglutition, defecation, micturition and situational stress
Orthostatic hypotension
Associated with “pre-syncope” prodrome
Could be associated with positional changes
Associated with hypovolemia, diuretic use, vasodilator use, deconditioning, and autonomic neuropathy (such as related to Parkinson’s, diabetes and alcohol).
Cardiovascular – Arrhythmia
Either bradycardic or tachycardic arrhythmia
Often not associated with a prodrome
May have rapid loss of consciousness resulting in facial trauma
Cardiovascular – Structural
Could be related to:
Valves (aortic stenosis, mitral stenosis, etc)
Outflow obstruction: hypertrophic cardiomyopathy
Vascular: Pulmonary embolism
Pericardial: tamponade
Non-syncope causes of transient loss of consciousness
TIA, vertebrobasilar insufficiency

2.       Do a complete physical exam:
a.       Including orthostatic vitals (remember orthostatic vitals are positive if there are symptoms with standing, or there is a change of ↑30/↓20/↓10 in HR/SBP/DBP – you only need to meet one of the criteria for there to be significant changes on orthostatic vitals)
3.       Risk stratify your patient: One tool is the San Francisco Syncope Rule that defines high-risk criteria for patients with syncope which includes:
a.       History of CHF
b.      Hematocrit <30 30="" o:p="">
c.       Abnormal ECG
d.      Shortness of Breath symptoms
e.      Systolic BP <90 at="" mmhg="" o:p="" triage="">
4.       Use guidelines to guide your work up:
a.       Such as the 2006 AHA/ACFF Scientific Statement on the Evaluation of Syncope (Figure 1):

1.       AHA/ACCF Scientific Statement on the evaluation of syncope. Circulation. 2006;113(2):316-27.

Tuesday, September 13, 2016

Malignancy and Microangiopathic Hemolytic Anemia

Recently there was a morning report during which we discussed anemia in a patient with cancer.

We discussed that when there is a decrease in one of the cell counts, the first step is to look at the rest of the cell counts and to determine if there is a decrease in more than one cell count. This is important as it determines the differential diagnosis.

Isolated decrease in red blood cells (hemoglobin)
Isolated decrease in platelets
Isolated decrease in white blood cell count
Decrease in hemoglobin and platelets
Anemia and thrombocytopenia – Need to think about microangiopathic hemolytic anemia  
Decrease in red blood cells (hemoglobin), platelets and white blood cell count

In this case, the hemoglobin and platelets had decreased from previous values.

As such, we are dealing with anemia and thrombocytopenia. This is important diagnostic information. There are a variety of disorders associated with anemia and thrombocytopenia including:
-          - Aplastic anemia
-          - Hypersplenism
-          - Marrow involvement with malignancy
-          - Autoimmune red blood cell and platelet destruction
-          - Folate or vitamin B12 deficiency
-          - Microangiopathic hemolytic anemia

Microangiopathic hemolytic anemia

  Microangiopathic hemolytic anemia is important to think about and rule out as it is a serious condition. The first step to assess for microangiopathic hemolytic anemia is to get a blood smear (also called blood film).

What are we looking for? Fragments! (aka schistocytes)

If there are fragments, it is consistent with a microangiopathic hemolytic anemia. Fragments are broken apart red blood cells; the red blood cells are broken apart in the intravascular system when there is damage and clot formation in blood vessels that the red blood cells get trapped in and ripped apart. There could also be other indicators of hemolysis including: elevated LDH, elevated indirect bilirubin, and decreased haptoglobin. It is not an immune related cause of hemolysis so the DAT (direct antiglobulin test) should be negative.

Differential Diagnosis of Microangiopathic Hemolytic Anemia (MAHA) and thrombocytopenia

Clinical Presentation
Disseminated intravascular coagulation
Thrombi formation within blood vessels, mechanical damage to red blood cells, thrombocytopenia, consumption of clotting factors
Obstetrical complications
Intravascular hemolysis (i.e. transfusion reaction, malaria)
Bleeding and thrombosis
Organ dysfunction
Thrombotic thrombocytopenic purpura (TTP)
ADAMTS13 deficiency, causing large multimers of von Willebrand factor
Mental status changes
Renal failure
Hemolytic uremic syndrome (HUS)
Shiga toxin-mediated thrombotic microangiopathy
Enteric infection with a Shiga toxin-secreting strain of Escherichia coli or Shigella dysenteriae
Renal failure
More common in children
Pregnancy related: HELLP syndrome, eclampsia  
Unclear – may be related to preeclampsia and abnormal placental function
Obstetrical complication
Elevated liver enzymes
Low platelets
RUQ pain, N+V
Headache, visual changes
Hypertensive Emergency
Unclear – endothelial injury à fibrin strand formation à trapping and shearing of RBCs and plts
Severe hypertension
Severe hypertension
+/- renal dysfunction

Blood work in different causes of Microangiopathic Hemolytic Anemia (MAHA) and thrombocytopenia

Blood film
Disseminated intravascular coagulation (DIC)
Schistocytes (often 0.5-1%)

High d-dimer
Low fibrinogen
Thrombotic thrombocytopenic purpura (TTP)
Normal d-dimer
Normal fibrinogen
+/- renal insufficiency
Abnormally low ADAMTS13 activity   
Hemolytic uremic syndrome (HUS)

Normal d-dimer
Normal fibrinogen
AKI/Renal failure
HELLP syndrome

Elevated liver enzymes

For further reading: George J and Nester C. Syndromes of Thrombotic Microangiopathy. NEJM. 2014;371(7):654-66. 

Friday, August 26, 2016

Anaphylaxis Management

Today at noon rounds we discussed anaphylaxis. Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Here are some clinical pearls on anaphylaxis.

1.       Have anaphylaxis on your differential diagnosis for an acutely sick patient. If you don’t think about it you may miss it!
2.       Anaphylaxis can mimic other conditions and present differently, which is why it is important to think about it (Internal thought bubble: “Could this acutely sick patient have anaphylaxis?”)

Signs/symptoms of anaphylaxis can include:

-          Symptoms/signs occur rapidly (minutes to hours) after exposure to a known or likely allergen
-          Skin and mucosal symptoms and signs (ie. hives, pruritus, flushing, swollen lips, swollen tongue, angioedema) *This is an important clue to look for as it is present in up to 90% of anaphylactic episodes
-          Respiratory compromise (i.e. nasal congestion, laryngeal itching and “tightness” in the throat, hoarseness, stridor, dyspnea, wheeze, bronchospasm, hypoxemia)
-          Cardiovascular compromise (could also present with hypotension syncope, incontinence, dizziness, tachycardia)
-          Gastrointestinal (i.e. crampy abdominal pain, nausea, vomiting, diarrhea)

Priorities for the management of anaphylaxis:

1.       ABCs (airway, breathing, circulation) CALL FOR HELP!
o   Airway: early intubation is often indicated and one needs to be alert for signs of airway compromise. Call for help from an airway expert (respiratory therapy and anesthesia) early!
o   Breathing: Supplemental oxygen
o   Circulation: IV fluids (normal saline bolus)
o   IV access (two large bore IV catheters) and monitors (cardiac monitors, continuous oxygen saturation monitoring and frequent blood pressure monitoring)
2.       Epinephrine
o   Prompt recognition of anaphylaxis and administration of epinephrine is key!
o   Studies have shown failure or delay in administration of epinephrine may increase the risk of death1
o   The first choice is Epinephrine IM (intramuscular) 1:1000 concentration (1 mg/mL): give epinephrine 0.3-0.5 mg intramuscularly in mid-outer thigh, maximum 3 doses
o   If intramuscular epinephrine is not available quickly, give epinephrine IV. Epinephrine IV (intravascular) 1:10,000 concentration (0.1 mg/mL): give epinephrine 0.1 mg IV slowly over 1-3 minutes. Note that the concentration of epinephrine that is given intravascularly and is often on code carts is different than the concentration of epinephrine that is given intramuscularly. This can cause dosing errors and cardiovascular complications due to overdosing. The 10mL prefilled syringes of epinephrine used in cardiac arrest on the code carts are 1mg of epinephrine in a 10mL prefilled syringe. Therefore, to give 0.1mg for anaphylaxis, you only give 1/10th (1mL) of the prefilled syringe that is given in the ACLS algorithms!  Usually a response is observed after a single dose, giving you time to prepare an epinephrine infusion. If there is an inadequate response to the first dose, a second dose can be given.
o   If there is an inadequate response to initial IM or IV epinephrine, you can start a continuous epinephrine infusion, beginning with epinephrine IV infusion 0.1 mcg/kg/minute
o   If on a beta-blocker and no response to epinephrine, you can give glucagon 1-5mg IV over 5 minutes then an infusion at 5-15 mcg/min  

3.       Removal of inciting antigen (i.e. stop infusion of a suspect medication)
4.       Adjuncts:
o   Glucocorticoids: Methylprednisolone (Solumedrol) 125 mg IV
o   Ventolin PRN
o   Anti-histamines:
                                                               i.      Diphenhydramine (Benadryl) 50 mg IV
                                                             ii.      Ranitidine 50 mg IV

1.       Dhami S et al. Management of anaphylaxis: a systematic review. Allergy. 2014;69(2):168-75.