Hyponatremia due to SIADH requiring Tolvaptan

Today Nicole presented an interesting case with multiple turns which started out with pre-septal cellulitis and evolved into a-fib with RVR complicated by likely pulmonary edema as well as clinical concern foTolvaptanr a septic arthritis of the knee joint with current cultures pending. Amidst his hospital course the patient developed what appeared to be euvolemic hyponatremia with urine/serum osm studies suggest of SIADH. His SIADH was relatively treatment refractory, not responding well to fluid restriction, urea, or hypertonic saline while in the MICU. Ultimately, it did improve with escalating doses of tolvaptan.

Tolvaptan is a vasopressin receptor (ADH) antagonist that selectively targets the V2 receptor which mediates the antidiuretic response. It helps produce a selective water diuresis without affecting sodium or potassium excretion. The original SALT trials supporting its use was published in NEJM in 2006 and this study took hyponatremic patients with either euvolemic or hypervolemic hyponatremia and compared tolvaptan (initial dose 15 mg daily, escalated to 30 mg and then 60 mg based on Na concentrations) versus placebo. It found that the serum sodium concentration was statistically significantly higher at both 4 days and 30 days compared to placebo. However, after discontinuation after 30 days of treatment the hyponatremia recurred back to similar prior values. Major side effects included increased thirst, dry mouth, and increased urination. The patients do benefit by having to adhere to less fluid restriction.
 The attached study is a subsequent analysis of patients enrolled in these SALT trials whose indication was for SIADH. Similarly, patients had a statistically significant increase in sodium at day 4 and day 30, similar side effects. 5.9% of the patients had overly rapid correction of their hyponatremia. Regarding surveys based on symptoms, there was a statistically significant treatment effect favoring tolvaptan for the physical component, and a near-significant trend favoring tolvaptan for the mental status component of the SF-12 Health Survey.
There are limitations to the use of tolvaptan, mainly concerns about a greater than 2.5 fold increase in liver enzymes. For this reason, it should not be used > 30 days and should not be used in patients with liver disease. Other considerations include concerns about rapid overcorrection of sodium. Given the limitation to 30 days, it is best used in severe hyponatremia and when cause of SIADH may be reversible. Tolvaptan can also be cost prohibitive.

Lymphangioleiomyomatosis and metastatic adenocarcinoma of the lung

Today Dr. Govert presented an interesting case of recurrent pneumothorax with CT findings suggestive of bullous emphysema/cystic lung disease. Biopsy ultimately demonstrated lymphangioleiomyomatosis (LAM), shout out to Anmol for the mic drop diagnosis upon entering the room. Ken Lyles would have been proud. Anyways, we briefly discussed the use of sirolimus for LAM. I’ve attached the NEJM RCT comparing sirolimus v placebo in 89 women with LAM. In short, those treated with sirolimus had less decline in FEV1 compared to placebo. They also had lower levels of VEGF-D and improved scores on a quality of life and functional performance survey. During a 12 month observational period of withholding sirolimus (after those randomized to sirolimus were treated), the decline in lung function resumed in the sirolimus group at a similar rate to those in the placebo group.

Nick presented an interesting case of RUL adenocarcinoma of the lung that presented without pulmonary symptoms, but instead with LLQ pain, back pain, anorexia, 25 lb weight loss, and nystagmus/dizziness. Imaging ultimately left adrenal mass and cerebellar mass. We discussed what would likely be first line treatment option, and assuming NGS testing was negative for an actionable mutation (such as EGFR), he would likely be a candidate for chemo + pembrolizumab. In the KEYNOTE-189 phase 3 trial, 616 patients with nonsquamous NSCLC were randomized to pemetrexed + platinum-based chemo plus pembrolizumab or placebo. There was superior OS at 12 months in the pembrolizumab containing arm (69.2% versus 49.4%), and improved PFS (8.8 months v. 4.9 months).

As a fun crossover, I also attached a case report in which a patient with LAM who developed metastatic adenocarcinoma of the lung was successfully treated with nivolumab.

Literature references:

Sirolimus_in_LAM

Pembro+ChemoNSCLC

LAM+NSCLC

Fatigue Morning Report

Fatigue is a common and nonspecific symptom with a broad range of etiologies including acute or chronic medical conditions, psychological conditions, medication related effects, substance use.

  • 1/3 of primary care visits are centered around fatigue

 

History

  • First ask what your patient means by fatigue; here are some common responses:
    • Anhedonia, abulia (lack of motivation)
    • difficulty initiating activities
    • subjective sense of weakness
    • difficulty with concentration, memory
    • problems with initiating or sustaining sleep
    • dyspnea on exertion; decreased exercise tolerance
  • UpToDate has a great table with causes of subacute and chronic fatigue: https://www.uptodate.com/contents/image?imageKey=PC%2F116315&topicKey=PC%2F2783&search=fatigue&rank=1~150&source=see_link
  • Other questions to ask in history: 
    • ask how long has the patient has been feeling fatigued
    • ask about functional limitations (e.g. are they able to carry out their tasks at work)
    • ***Ask about what a typical day looks like*** (what time do you wake up, what are you doing during the day)
    • screen for depression with PHQ2 -> if positive -> PHQ9
    • screen for anxiety
    • ask about sleep (what time do you go to bed, what do you do before going to bed, how long does it take to fall asleep, how often do you wake up at night, what time do you wake up?)
    • screen for OSA with STOP-BANG (https://www.mdcalc.com/stop-bang-score-obstructive-sleep-apnea)
    • Screen for drug and alcohol use (e.g. AUDIT-C or Binge drinking screening question)
    • Supplements (e.g. St. John’s wart)

After a careful physical exam (see UpToDate table above for key physical exam findings), here are some initial screening labs to consider:

  • CBC
  • CMP
  • TSH
  • Vitamin D – can use supplementation as a placebo effect
  • Vitamin B12 – B12 deficiency can be caused by metformin and PPI use; consider MMA if B12 in ~300 range, supplement if <200
  • Appropriate cancer screening interventions based upon the patient’s age and sex should be updated as necessary to exclude common occult malignancies as a potential cause for fatigue.

Chronic fatigue syndrome (CFS)

  • High prevalence with depression, trauma, fibromyalgia, POTS
  • Underlying pathophysiology is unclear but may be associated with epigenetic changes caused by trauma; high risk of chronic medical conditions in patients with early childhood trauma
  • Diagnosis of exclusion; diagnostic criteria from Institute of Medicine of the National Academies. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an illness. Report Brief, February 2015:

CFS Diagnosis requires that the patient have the following three symptoms:

  1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than six months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest.
  2. Post-exertional malaise – Worsening of a patient’s symptoms and function after exposure to physical or cognitive stressors that were normally tolerated before disease onset.
  3. Unrefreshing sleep.

At least one of the two following manifestations is also required:

  1. Cognitive impairment – Problems with thinking or executive function exacerbated by exertion, effort, or stress or time pressure.
  2. Orthostatic intolerance – Worsening of symptoms upon assuming and maintaining upright posture. Symptoms are improved, although not necessarily abolished, by lying back down or elevating the feet.

 

Therapies:

  • Counseling: Tell patients that fatigue is rarely one thing. Usually combination of multiple factors – anxiety, sleep, anemia, etc.
  • Counseling on substance use:
    • Focus on the long-term consequences (e.g. “While alcohol may help you sleep at night, over time, use of substances will not get you quality sleep.”)
    • It may take > 1 month off substance until patient notices a difference.
  • Exercise:
    • do not have to go to the gym and work out 1-2 hours in order to get exercise
    • goal is increase physical activity
    • Set a smart goal
    • Ask what is a realistic amount of time you can walk each day? E.g. start 5 min, add 1 min a week, by end of a year, will be working out 60 min
  • A trial of antidepressant drugs should be offered to patients with depressive symptoms:
    • SSRI
      • Fluoxetine – most stimulating; most weight neutral; starting dose 10mg daily
      • Vortioxetine
      • Generally, better to dose SSRIs in the morning to avoid causing insomnia
    • SNRI
      • Venlafaxine – starting dose 37.5 mg daily
      • Duloxetine – starting dose 20 mg daily; better if targeting pain
      • Desvenlafaxine – 50-100 mg; doesn’t have as many drug-drug interactions
      • Milnacipran – FDA approved for fibromyalgia
      • Levomilnacipran
    •  Bupropion
      • Has more stimulating effect
      • Can help with weight loss
      • great for smoker with fatigue
      • SR formulation is cheaper; BID dosing (don’t take 2nd dose at bedtime; better to take at breakfast and before dinner); start at 100 mg daily (150 mg approved for smoking cessation)
      • XL is once a day dosing; has fewest side-effects; doses: 150, 300, 450mg
      • Side-effects:
        • Risk of seizures is relatively low, but still avoid in pt with seizure disorder
        • Avoid in pt with eating disorder
  • CBT may be useful in some patients with idiopathic chronic fatigue. It typically involves a series of one-hour sessions designed to alter beliefs and behaviors that may delay recovery. It is also offered online.
  • Follow-up: Have the patient return to clinic within first 1-2 months to assess progress

Summarized by Dr. Eric Wei based on a presentation from Dr. Gregory Brown

Dermatology for the Internist

Dermatology for the Internist

Lecture by Dr. Sarah Wolfe. Summarized by Dr. Eric Wei

Epic Tricks

  • General Dermatology Order Sets!
    • Type in “Gen Derm” into the order section and numerous order sets will come up to treat common conditions including acne, atopic dermatitis, urticaria, hidradenitis, psoriasis. This is a great place to start as it highlights first, second, and third line treatment options

The language of dermatology

Primary features:

  • Macule: flat, < 1cm
  • Papule: elevation of any type, < 1 cm
  • Patch: flat, > 1 cm
  • Plaque: elevated, > 1cm
  • Nodule: like plague but dome shaped

Secondary features:

  • Crust
    • Hemorrhagic Crust (aka scab)
    • Yellowing of the crust–> suggests superficial infection with staph/strep
  • Scale
  • Fissure
  • Lichenification
  • Erosion
  • Ulceration

Color

  • Erythematous, white, purple, brown, yellow, black, etc.

Distribution

  • Examples:
    • atopic dermatitis commonly distributed where shoe rubs feet
    • candida likes pannus, chest, moist areas
    • Psoriasis – interdigital and plantar surfaces of the toes; well-demarcated plague with a thick silvery scale

Please see the Stanford 25 website which has an excellent introduction to the language of dermatology with great photos and videos: https://stanfordmedicine25.stanford.edu/the25/dermatology.html

 

Tinea Pedis (Athlete’s Foot) & other Tinea conditions (corporis, cruris, etc.)

  • Clinical Patterns:
    • Interdigital – flaking epidermis between toes
      • Maceration can occur between the toes. Shows up first between the fourth and fifth toes.
    • Moccasin – Forms a rim around the bottom of the foot
    • Vesicobullous – blister forming
  • Treatment
    • First line:
      • Clotrimazole cream BID x 4 weeks (can buy OTC as Lotrimin)
      • Terbinafine Cream (e.g. Lamasil)
  • Things to avoid!
    • Do not treat something that may be fungal with a topical steroid –> this will cause the rash to increase in size. If you are unsure if it is inflammatory or fungal, opt to treat for 4 weeks with OTC anti-fungals and instruct patient to use a topical steroid if this first line therapy is ineffective

 

Onychomycosis

  • Key findings: subungual debris and nail discoloration
  • What tests should be ordered?
    • Fungal culture of subungual debris (textbook answer, although this is not always done clinically)
  • Treatment
    • First line: Oral terbinafine x 3 months
      • After treatment, the nail will take roughly 1 year to “grow out” before it may return to normal.
      • Treatment failure rate: 50%
      • Terbinafine risks: low risk of hepatotoxicity; check baseline LFTs
    • Ciclopirox nail lacquer
      • This is a toenail polish. Must be used daily for 1 year. Treatment success rate is only 11%
    • Second Line
    • Itraconazole
      • Pulse dosing for 3 months: 200mg BID x 7 days during the first week of every month.
      • You must watch out for interactions with other medications: e.g. statins
    • Fluconazole
      • If there is concern for co-infection with mold, it can be useful

 

Tinea versicolor (pityrosporum yeast)

  • May be hypo or hyperpigmented
  • Treatment:
    • Ketoconazole shampoo – 5 days
    • Selenium sulfide (Selsun Blue)

Stasis dermatitis

  • rash that results from 3rd spaced fluid; due to hemosiderin spilled from RBCs
    • Tx: Triamcinolone; avoid skin, face, groin, armpits
  • Compression wraps “unna boot” -> transition to compression stockings (20-30 mmHg)

 

 

Candida

  • Candida will involve scrotum; dermatophytes usually doesn’t involve scrotum.
  • Treatment: clotrimazole, nystatin, ketoconazole (not great for dermatophytes)

Insomnia

Excellent visual recap on insomnia by Dr. Wei. Adapted from a lecture by Dr. Spector

Prosthetic Valves and Infective Endocarditis

Prosthetic Valves

-mechanical valve if pts are younger than 50
           -will need lifelong warfarin anticoagulation (see below). Using direct thrombin inhibitors and factor Xa inhibitors is not rec d/t risk of valve thrombosis.
-bioprosthetic valves if older than 70.  (If they’re somewhere between 50 and 70, then it becomes a discussion)
-bioprosthetic valves usually last ~15 years so we tend not to use those in younger patients as they’ll need a replacement
-after getting a valve, pts will undergo a TTE to document baseline performance. If they have a bioprosthesis, they will need to get a yearly TTE beginning 10 years after surgery
Mechanical valve INR goals (used to be a range, but is now a single number to minimize time pts spend at the low end of the range):
-Aortic (if no risk for VTE) — 2.5
-Mitral, older gen mech aortic valve (ball in cage), or aortic valve with risk factors for VTE — 3.0
-Antiplatelet therapy with low dose ASA is recommended for those with a mechanical prosthesis and for pts with a bioprosthesis.
Infective Endocarditis
RF: implanted devices, advanced age, DM, immunosuppression, IVDU, congenital heart disease, cardiac transplant with valvulopathy
DX by Duke criteria (two major, one major plus three minor, or five minor criteria)
Blood cultures are positive in 90% of IE cases and serologic testing is req in culture negative IE.
We classify prosthetic valve endocarditis based on time from surgery:
-Early (<60d) associated with hospital-acquired microbes like staph aureus
-Intermediate (60-365d) most commonly coag negative staph
-Late (>365d) microbes typically resemble those of native valve endocarditis
Workup:
-BCX (before abx)
-TTE
-then TEE if not TTE not diagnostic, intracardiac device leads are present, or abscess is suspected (Andrew astutely pointed out that new 1st deg AV block may be indicative of an abscess!)
Management:
-ABX (can narrow once you have micro data back) – duration variable
-Early surgery (during hospitalization + before completion of abx) if
-symptomatic HF and valvular dysfunction
-left sided IE c/b fungal infections or high resistant organisms
-complications like annular or aortic abscess, penetrating lesions, or significant heart block
-persistent bacteremia or fevers >5-7d despite appropriate abx therapy
-also considered if pt has recurrent emboli and large (>10mm) left sided vegetation
PPX:
PPX recommended before dental procedures in special populations as below. Usually amoxicillin in the outpatient setting.
-hx of endocarditis
-cardiac transplant with valve regurgitation d/t structurally abnormal valve
-prosthetic valves
-other prosthetic material used for valve repairs (annuloplasty rings or chords)
-congenital heart disease
Author: Juliette Logan, MD

Peut-Hegler Anomaly and MDS

In Intern Report this week, we discussed Peut-Helger Anomaly. One of the key features of this is decreased lobulation as seen in the bilobed nucleus below connected by a thin strand.

This is in contrast to neutrophils with increased lobulation (or hypersegmentation, ie greater than five lobes) suggesting a megaloblastic process or (rarely!) iron deficiency anemia.

We also distinguished between easily confused MDS and MPNs. MDS leads to dysplastic cells. MPNs cause proliferation of cell lines, but these cell are often normal appearing.

Myelodysplastic syndromes are processes with ineffective hematopoiesis leading to dysplastic, hypercellular bone marrow and peripheral blood cytopenias
-most often idiopathic but can be secondary to chemotherapy, radiation, benzene
-make sure to rule out deficiencies (Vit b12, folate, copper), etoh consumption, meds, HIV
-PBS: dysplastic cells!
        -these cells don’t function well which is why these pts have an increased risk of infection and bleeding
-DX: BMBX
-Prognosis: variable depending on bone marrow blasts, degree of cytopenias, and cytogenetics
-Older patients who are asymptomatic and have mild features, can be monitored
-Allogeneic hematopoietic stem cell transplantation is the only potentially curative option–this is often too toxic for most older adults. Usually only done in young patients at high risk for AML conversion
        -treatment goals are to treat symptomatic cytopenias and reduce the risk of progression to AML
                 -high risk of AML conversion–>can give hypomethylating agents (azacytidine and decitabine)
                 -low risk (-5q abnormality)–>can give lenalidomide if transfusion dependent
Author: Juliette Logan, MD
Sources: MKSAP 18, Uptodate.com