Quick rundown of the articles we talked about today in morning report:
ANDROMEDA-SHOCK trial, JAMA 2019: RCT of 424 patients with septic shock randomized to capillary refill vs lactate to target resuscitation efforts. Primary outcome of interest was 28 day mortality. While the difference between the two groups was not statistically significant, the study may have been underpowered. Interestingly, there were lower rates of organ dysfunction at 72 hours with the cap refill guided resuscitation than lactate. So keep doing your cap refill bedside exam!
E-cigarettes vs nicotine-replacement therapy (NRT): Multi-center RCT in the UK that randomized 886 people to e-cigarettes or NRT of their choice for 3 months. Outcome of interest was abstinence from smoking at 6 months and 1 year. They found a significantly higher rate of abstinence in the e-cigarette group than the NRT group. However, while only 9% of the abstinent NRT users were still using NRTs at 1 year, over 80% of the abstinent e-cigarette users were still using e-cigarettes at the end of the study period! Together with the alarmingly high incidence of e-cigarette use amongst adolescents, the results of this study would have to be interpreted cautiously.
EAGLES trial. Lancet. 2016: Multi-center, double-blind, RCT looking at neuropsychiatric effects of varenicline (Chantix), bupropion, or nicotine patch or placebo involving ~4k people without psych history and 4k people with psychiatric history. Study found that Chantix resulted in the highest rates of sustained abstinence across all study arms. In the psychiatric cohort, there were no differences between the treatment groups in terms of rates of psychiatric events. Bottom line: use Chantix whenever you can to help your patients trying to quit smoking!
EXTEND trial. NEJM. 2019: Multi-center, randomized, placebo-controlled trial of 225 patients who presented with ischemic stroke within 4.5-9 hours after onset of symptoms with radiologic evidence of salvageable brain tissue randomized to receive tPA vs conservative management. The primary outcome of interest was functional status at 90 days and was significantly better for the intervention group vs control arm. Caveats are that symptomatic intracranial hemorrhage was six times higher in the intervention group than the control arm. 65% of the patients in the study woke up with neurologic deficits and had an unknown time of onset.
Thyroid hormone replacement for subclinical hypothyroidism (Feller et al. JAMA. 2018): Meta-analysis of 21 RCTs with 2192 patients randomized to hormone replacement or no replacement. The study found no significant difference in qualify of life, thyroid replacement symptoms, fatigure/tiredness, depression, cognition, or SBP after 12 months of therapy. Based on this study, the new guidelines state that in patients with no symptoms of hypothyroidism or non-specific symptoms of hypothyroidism who have fT4 within normal limits and TSH <20, thyroid hormone therapy is strongly recommended against.
Thanks Brandan for presenting an elderly lady who developed sudden onset headache, CN3 palsy, and bitemporal hemianopia. She had a CTH that was unremarkable the day before, and a repeat CT found a large pituitary “mass,” and MRI was concerning for pituitary apoplexy!
This case demonstrates a few important concepts:
Visual Field Pathology (commonly tested!)
A: Optic Nerve pathology or structural pathology leading to complete blindness in one eye, i.e. trauma, optic nerve neuropathy, optic neuritis (i.e. MS)
B: Bitemporal hemianopsia= optic chiasma pathology until proven otherwise.
Physiology: Lacteral rectus, with CN VI innervation, remains intact and not opposed by the medial rectus which is innerved by CN III. Down because the superior oblique (innerved by CN IV) is unopposed by the paralyzed superior rectus, inferior rectus, and inferior oblique
Ischemic (affects somatic fibers over parasympathetic, typically spares the pupils)
Tumors (mass effect so both somatic and parasympathetic fibers are typically affected)
Cavernous sinus thrombosis (don’t miss this!)
Pituitary apoplexy: A Medical Emergency!
Hemorrhage or infarction of the pituitary gland usually involving a pituitary adenoma, and occasionally it may be the first manifestation of a pituitary adenoma.
HTN, surgeries, coagulopathies, certain meds (i.e. VKA, DOACs, antiplatelets)
Sudden onset headache, vomiting, encephalopathy, visual field defect, hemodynamic instability (esp with ACTH defects).
DI is very common in the immediate setting, but as axons in the pituitary die, ADH is released which can lead to SIADH (but only transient until stores of ADH are used up), followed by recovery but it depends on the extent of the damage.
Management: IVF, hydrocortisone (get labs first)
Acute secondary adrenal insufficiency is seen in 2/3 of pts, important cause of mortality.
Acute hypocortisolemia leads to hemodynamic instability
Inc vasopressin release from posterior pit can lead to fluid and lyte disturbances.
Any signs of hemodynamic instability: Can do 50-100mg hydrocortisone Q6H or continuous infusion 2-4mg/hr
Role of surgical management:
Decision to operate based on whether there is deteriorating level of consciousness, severely reduced visual acuity, or presence of visual field defects.
Otherwise, medical management with corticosteroids, monitoring, re-evaluation is recommended.
Vision outcomes: Conflicting data on medical vs surgical management.
Pituitary function outcomes: No difference b/w surgical vs medical management
Please refer to this paper for a detailed read on pituitary apoplexy!
Thanks to John for presenting the case of a middle-aged woman with metastatic renal cell carcinoma who presented with subacute diffuse weakness and constipation, found to have symptomatic hypercalcemia, treated with IV fluids and zoledronic acid.
A third of patients with malignancy develop hypercalcemia in their disease course. Hypercalcemia of malignancy is associated with very poor prognosis (~50% 30 day mortality).
Constipation plus polyuria is the most specific symptom combination for hypercalcemia
Denosumab is superior to zoledronic acid in treating hypercalcemia of malignancy and is safe to use in renal failure.
One way to quickly determine the etiology of hypercalcemia from your chemistry panel is to look at the chloride to phosphate ratio. A ratio > 33 is highly suggestive of a PTH or PTHrP mediated process.
** Primary hyperPTH is the most common cause of hypercalcemia in the outpatient setting. Malignancy is the most common cause of hypercalcemia in the inpatient setting.
Treatment of hypercalcemia:
No treatment if asymptomatic
Avoid exacerbating factors
If chronic/asymptomatic ⇒ same tx as Ca <12
If acute/symptomatic ⇒ same tx as Ca 14-18
IVF – lots!
Lasix only if concurrent renal/heart failure
Bisphosphonate (zoledronic acid >>pamidronate if malignancy. Denosumab if refractory to ZA or severe renal impairment)
Thanks to Jess for presenting the fascinating case of a middle-aged woman with family history of autoimmune disease who presented with acute onset of fatigue and abdominal pain, found to have vitiligo on exam. Work up revealed hyponatremia due to a secondary adrenal insufficiency, pancytopenia, and panhypopituitarism possibly due to a yet to be diagnosed autoimmune disorder!
Remember that hyponatremia is a problem of water regulation that can be compounded by low solute intake.
Primary adrenal insufficiency is disorder at the level of the adrenal glands and manifests with low sodium and high serum potassium levels.
Secondary adrenal insufficiency is disorder at the level of the pituitary and manifests with low/normal sodium and normal potassium levels (because low cortisol leads to high ADH levels and hyponatremia).
Make sure to do work up to rule out panhypopituitarism. Keep in mind that the most sensitive test for HPA access integrity is LH/FSH.
Tertiary adrenal insufficiency is disorder at the level of the hypothalamus and presents similarly to secondary AI.
Test for adrenal insufficiency with a cort-stim test and/or AM cortisol and ACTH levels.
Remember these three steps to working up hyponatremia:
Is there a sodium problem? check serum osm
Are the kidneys responding appropriately? check urine osm
Is ADH revved up for a hemodynamic reason? check urine Na
Failure of adrenal glands
Causes: Addison’s (most common in the US), infiltrative processes (TB, sarcoid), hemorrhage, toxins
Labs would show ↓Na and ↑potassium (b/c aldosterone is gone)
Failure of pituitary (low ACTH)
Causes: pituitary lesions, surgeries, TBI, drugs
Clinically may present with loss of other anterior pituitary hormones
Labs would show ↓Na (because low cortisol leads to high ADH levels) but normal potassium levels (b/c aldosterone is active)
Failure of hypothalamus (low CRH)
Causes: more commonly iatrogenic (cessation of high dose glucocorticoid therapy without taper) or post surgical interventions.
Inflammation of the pituitary
Four categories based on histologic findings:
Most common form
Seen in late pregnancy and post-partum period
Also associated with CTLA4 inhibitors like ipilimumab
Idiopathic or secondary to GPA, sarcoid, TB
Xanthomatous (most rare)
Headache out of proportion to exam findings
Preferential decrease in ACTH and TSH ⇒ adrenal insufficiency and hypothyroidism
Pituitary size eventually normalizes but pituitary loss of function is often permanent.
Today, we discussed the case of a middle-aged woman with no significant medical history who presented to PCP with a month of nausea, vomiting, weakness, and 30 pound weight loss, found to have severe hypercalcemia likely secondary to a granulomatous disease. Final diagnosis pending biopsy results.
The first step in working up hypercalcemia is correcting for albumin. Keep in mind that patients with hypoalbuminemia may have a falsely low serum calcium level. Conversely, patients with multiple myeloma who have a high paraprotein serum concentration may have a falsely elevated total serum calcium level. When in doubt, check an ionized serum calcium to confirm true hypercalcemia.
Think of hypercalcemia in two broad categories of PTH dependent disorders and PTH independent disorders (see below).
25-OH vitamin D has a long half life and is the best laboratory test to determine adequate nutritional intake of vitamin D. In contrast, 1,25OH vitamin D has a short half life.
Remember that bone is the largest reservoir of calcium in the body.
Remember to confirm true hypercalcemia by correcting for albumin and/or measuring ionized calcium for people with conditions such as multiple myeloma who may have a falsely elevated total serum calcium due to increased paraprotein binding.
Check out this super awesome previous post on hypercalcemia on our blog for more details. Here is the simplified diagnostic algorithm we went over today:
No treatment if asymptomatic
Avoid exacerbating factors
If chronic/asymptomatic ⇒ same treatment as Ca <12
If acute/symptomatic ⇒ same treatment as Ca 14-18
IVF – LOTS!
Lasix only if the patient has concurrent renal/heart failure
Zoledronic acid >> pamidronate for patients with malignancy
Do not use in patients with Cr >4.5
Denosumab (RANKL) if refractory to zoledronic acid or in patients with severe renal impairment
Same treatment as Ca 14-18 PLUS
Treatment options: (table adapted from UpToDate)
* Only used in patients with renal insufficiency or heart failure, judicious use of loop diuretics may be required to prevent fluid overload during saline hydration.
Vitamin D metabolism
Remember the following simplified pathway of vitamin D metabolism
25-OH vitamin D has a long half-life and the best laboratory test to perform to determine adequacy of nutritional intake
In work up of hypercalcemia, it is also important to check 1,25-dihydroxyvitamin D levels. Why?
Remember that 1-alpha hydroxylase is an enzyme in the kidney that converts 25-OH vitamin D into its metabolically active form ⇒ 1,25-dihydroxyvitamin D
It turns out that in certain granulomatous diseases and lymphoma, activated monocytes in affected tissues start to express 1-alpha hydroxylase as well, resulting in overproduction of 1,25-dihydroxyvitamin D.
So, in work up of hypercalcemia that is PTH-independent, if you notice elevated 1,25-dihydroxyvitamin D with normal 25-OH vitamin D levels, suspect granulomatous disease or lymphoma causing exogenous 1,25-dihydroxyvitamin D production.
Thanks to Austin for presenting the case of an elderly woman with h/o psychiatric disorder who presented with acute/subacute onset of AMS, severe hypothermia, sinus bradycardia, and hypotension with work up revealing hypothyroidism suspicious for myxedema coma!
Exam findings for hypothermiachange depending on severity of hypothermia (see below).
It is crucial to measure core body temperature for accuracy especially when you are rewarming the patient (esophageal is the best, rectal/bladder are ok prior to rewarming but can remain low in spite of increasing core body temp so do not rely on these metrics alone)
Think of etiologies of hypothermia broadly within the categories of increased loss or decreased heat generation.
The most common causes of hypothermia are sepsis, exposure, and hypoglycemia.
The hallmarks of myxedema coma are AMS, hypothermia, and a precipitating event (i.e. infection, exposure, meds, etc.)
Myxedema coma is a medical emergency with a high mortality rate. So consult endocrine early when you are suspecting it.
Always treat myxedema coma with levothyroxine AND steroids until you have ruled out a concurrent adrenal insufficiency.
↑ HR, ↑ RR, ↑ BP, hyperventilation
Body’s attempt to preserve heat. When peripheral vasoconstriction occurs to keep blood closer to vital organs, BP rises. Kidneys see this rise in BP and act to correct it by dumping fluid! (Oh kidneys…)
Humidified inspired air
Confusion, slurred speech
↓ HR, hypoventilation
Can also start to notice other cardiac manifestations such as prolonged QTc, QRS, osborn (J) waves, ST elevations/depressions.
↓ renal blood flow
Passive, external (see above) PLUS
Forced heated air
Warm water immersion
Warm humidified air (42°C)
Warm IV fluids (42°C)
Body cavity lavage (in trauma patients only)
Edema (due to poor renal blood flow) of extremities and lung
↓ HR, ↓ BP (due to drop in cardiac output), hypoventilation, ventricular arrhythmias
Cardiac manifestations more common as with moderate hypothermia
mechanism is poorly understood but thought to be due to paralysis of the nerves regular vascular muscle tone leading to vasodilation and sensation of a heat flush which results in the patient wanting to take their clothes off.
Any of the above (passive external, active external, active internal) and/or
Etiologies of hypothermia:
Items in red above are the most common causes of hypothermia.
Less reliable since labs have to be warmed prior to processing
ABG is often inaccurate
Coagulopathy may be masked
Hyperkalemia due to rewarming
Complications of rewarming:
Hypotension due to peripheral vasodilation
Ileus and urinary retention
Core temperature after-drop (a condition in which cold peripheral blood gets shunted to the core and results in further decline in temperature. You can avoid this by active internal rewarming like warmed IV fluids)
Yonglu presented a middle age man with no medical history presenting with syncope. In the preceding months, he has been having non-specific fatigue, decreased exercise tolerance, dizziness, and diaphoresis. He was found to be hypoglycemic after this syncopal episode, and in the hospital his labs were consistent with hyperinsulinism when he was in a hypoglycemic state. CT revealed diffuse liver masses concerning for HCC, as well as a lesion on his left iliac crest appearing to be an osteosarcoma. He was also found to have a pancreatic mass as well…
Three malignant processes? Octreotide scan revealed increased uptake at these regions, and biopsy of the liver revealed a diagnosis of a neuroendocrine tumor!
When we think about hypoglycemia, its pattern can actually give us a clue.
Fasting: Most common
Post-prandial: non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), post-bariatric surgery hyperinsulinemic hypoglycemia
Both: Insulin autoantibody, insulinoma
Rare, not enough data
Small cohort: median age 48 years, 77% men
MEN Type 1: Younger presentation, 20s
Pancreatic islet cell origin
Generally benign, single vs multiple
Rare to be malignant (10%)
Pattern: fasting hypoglycemia mainly but can be both
May have some sympathoadrenal sx i.e. palpitations, diaphoresis (seen in this patient), tremulousness
Likes to spread to liver, rarely can have bony mets (~13%)
Whipple’s Triad: Presence of all three demonstrates “true” hypoglycemia
Symptoms of hypoglycemia
Low plasma glucose at time of symptoms
Relief of symptoms when glucose is back to normal
Evidence of inappropriately high serum insulin during episode of hypoglycemia
72 hour fasting plasma glucose test: Supervised fast in order to bring on hypoglycemia in order to evaluate etiology. If pt has underlying hyperinsulinism, 95-99% of the time they will be hypoglycemia within 48 hours of fasting.
Blood test is drawn when pt has sx of hypoglycemia
Test: Glucose, insulin, proinsulin, and c-peptide level.
Normal: suppression of endogenous insulin
Abnormal: Inappropriately elevated insulin, pro-insulin, and c-peptide in setting of hypoglycemia.
Octreotide scan: Increased uptake seen in tumors of neuroendocrine etiology, more sensitive than US, CT, or MRI for detection of somatostatin receptor positive tumors
Evidence of hyperinsulinism
High insulin level
Chromogranin A: used to help diagnose carcinoid tumors (NET of the digestive tract and lungs). Nowadays carcinoid is generally used to refer to well differentiated NETs originating in the lungs. GI tract tumors are now termed NET.
Localized lesion: Surgical resection is curative
Octreotide: Inhibits growth hormone secretion, can switch to Q-monthly formulation
Diazoxide: Diminishes insulin secretion, side effects include hirsutism and edema
Radiation therapy: Data also limited in utility but can be consider if evidence of bony mets (which is also rare for NET)
Minority of NET, namely high-grade, well differentiated with Ki67 index > 20%, are rare and there is no consensus on how to treat these patients. These patients generally respond poorly to platinum/etoposide based regimens used to treat most NETs.
Other options: Temozolomide, Sunitinib (RTK inhibitor), Everolimus (mTOR inhibitor)
Helpful table for hypoglycemia work up.
Beta-hydroxybutyrate (BHB) is by product of alternate metabolism (more specifically ketone bodies) in a fasting state, so it can be elevated in setting of prolonged fasting (not just DKA).
Also thanks to Arathi for pointing out that insulin has a negative feedback on this process, hence in a hyperinsulinemic state (despite concurrent hypoglycemia), beta hydroxybutyrate would be very low!
Insulinomas can appear like hypoglycemia secondary to oral glycemic agents, but the key is the oral glycemic agent screen would be positive in the latter case!
IGF-omas can cause s/sx hypoglycemia due to similarity with insulin. Expect IGF2 levels to be elevated in such cases and elevated BHB.
Please refer to this helpful review article if you want to know more about NETs!
Also please refer to this paper for a case report on AFP-producing pancreatic NET (AFP elevated in this patient!)