Win Of the Week! DOM Happy Hour



Thanks to the IM Residency Council, the OHSU Department of Medicine is introducing a new monthly happy hour for residents, faculty, administration, and families to relax and unwind after work.

Stay tuned for future dates!

Next week, we resume our regularly scheduled conference and report schedule.

Weekly Evidence Updates 7.9.18

Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study (Annals of Internal Medicine 7/2018)

Studies investigating the adverse effects of oral hormone replacement therapy (HRT) have been circulating in the literature for many years, with mixed results. The Nurses Health Study (JAMA 1994) concluded that oral contraceptive use was safe, with no evidence of increased mortality amongst 166,755 predominantly pre-menopausal women aged 30-55 years. Conversely, the Women's Health Initiative (WHI study) RCT investigating hormone replacement therapy in post-menopausal found an increased risk of predominantly cardiovascular events (HR 1.22 1.09-1.36), however there was a slight increase in risk of CVA, PE, and invasive malignancies. Further analysis (Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials. JAMA. 2013;310(13):1353–1368. doi:10.1001/jama.2013.278040) noted the complex nature of HRT in post-menopausal women, with lower adverse events in younger women, and increased risk in older women. However, the role of hormones amongst the transgender population has yet to be assessed. The authors of the study published above performed a prospective cohort observing the rate of adverse cardiovascular events occurring in transgender patients using cross-sex hormones compared to cis-gender male and female controls. The Authors found in approximately 4 years of follow-up the transfeminine cohort had an increased risk of VTE, ischemic stroke, and MI compared to cis-gender women (HR 2.0,1.9, and 1.8 respectively). Transfeminine patients also had a higher risk of VTE compared to cisgender men (HR 1.9).

Take home: Cross-sex hormone therapy in transfeminine patients appears to be associated with increased risk of VTE, ischemic stroke, and MI compared to a cisgender control groups. Further studies will be necessary to ascertain the true overall risk associated with these therapies and identify high risk groups to aid in counseling and therapy recommendations.

Find the article here

Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial (The Lancet 7/2018)

The role of sodium bicarbonate in correction of acidosis amongst critically ill patients has been an enticing theory that has been debated for some time. Specifically, acidosis has been associated with decreased vasopressor response, vasodilation, and myocardial depression as described in this article. The Authors above performed a randomized controlled trial assessing the role of sodium bicarbonate in patients admitted with severe acidosis (pH < 7.2) and either a SOFA score≥4 or lactic acid level > 2mmol/L. Patients receiving bicarbonate therapy were maintained on a continuous infusion to maintain a pH > 7.30. The patient population had a high 28-day mortality rate (46% control vs 55% in the sodium bicarb group). The primary outcome of 28-day mortality or single organ failure did not demonstrate a significant difference between groups (p= 0.07). However, when stratified for Acute Kidney Injury Network (AKIN) scores of 2-3, there was a significant difference seen in 28-day mortality, and organ failure at day 7 (p= 0.046, and p=0.014 respectively). Sodium bicarbonate therapy lead to an increase in renal replacement therapy free days, a longer time form enrollment until renal replacement therapy, and a decreased overall use of renal replacement therapy during the patient’s ICU stay. There were no significant differences seen in secondary outcomes other than an increase in vasopressor free days in patients with AKIN 2-3 (1 day vs. 18 days, p=0.022), however this did not translate to the survivors.

Take Home: Sodium bicarbonate therapy with a goal pH of 7.3 did not decrease 28-day mortality amongst the overall patient population (and is hard to achieve! Only 60% of patients in the bicarbonate group reached this goal pH) . Amongst patients with AKIN scores of 2-3, sodium bicarbonate use was associated with decreased mortality. Sodium bicarbonate therapy was associated with more ICU vasopressor free days, and delayed initiation of renal replacement therapy.

Find the article here

Weekly Evidence Updates 7.2.18

Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function (JAMA 7/2018)

Metformin has long been associated with a risk of lactic acidosis, leading to cautious prescribing practices. This has led to curtailed use in individuals with decreased renal function (ie. CKD or patients with CHF). Most of this concern arose from a cousin of metformin, phenphormin- which was removed from the US market in 1978. More recent data has shown significant benefit to metformin use amongst these patient populations, ultimately leading to changes in FDA guidelines surrounding metformin prescribing (Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al. Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Ann Intern Med. 2017;166:191–200. doi: 10.7326/M16-1901). Due to these changes, the Authors of the above article aimed to evaluate metformin use in 75,000 patients with varying stages of CKD. Patients with ESRD or an eGFR < 15 mL/min were excluded. The primary outcome was hospitalization for acidosis other than DKA. Metformin use was associated with a risk of acidosis (HR 2.01) at an eGFR < 30 mL/min. Acidosis was also more common amongst patients with CKD either on or off metformin- an important point the authors mention as a potential confounder in prior studies. Interestingly, sulfonylurea had a similar association with acidosis overall compared to metformin.

Take Home: Metformin use appears safe down to an eGFR of 30 mL/min. It should not be initiated at an eGFR below 45 mL/min. This trial confirmed current FDA labeling which recommends against metformin use with an eGFR < 30 mL/min. New prescribing guidelines focus on the eGFR, and no longer consider a creatinine > 1.5 in men or 1.4 in women as contraindications to metformin use.

Click here for the full article

Aldosterone Antagonist Therapy and Mortality in Patients With ST-Segment Elevation Myocardial Infarction Without Heart Failure (JAMA 7/2018)

The mineralocorticoid receptor antagonists (MRA), specifically the aldosterone antagonists eplerenone and spironolactone have been cornerstones of therapy for congestive heart failure since the publishing of the RALES trial (NEJM, 1999) that demonstrated a decreased mortality in patients with NYHA class III-IV HF and an EF < 35%. Since then, further studies have looked at the role of MRA therapy in the ACS setting. Specifically, the EPHESUS trial (NEJM,2003) showed a reduction in morbidity and mortality in patients post-ACS for patients with an EF < 40% and clinical heart failure, or diabetes. The authors of this meta-analysis of 10 studies (4,147 patients) evaluated the role of MRA therapy in STEMI patients with an LVEF > 40% and without clinical heart failure. Most patients included received MRA therapy within 24 hours post-STEMI, and had a follow up period of 6-12 months. The authors found MRA therapy reduced mortality (OR 0.62 (0.42-0.91)) compared to controls. MRA therapy was also associated with a small but significant increase in LVEF (mean difference 1.58%, p=0.03, I2=99). There was no reported difference in the rate of recurrent MI, CHF, or ventricular arrhythmias. Adverse effects included elevated potassium levels.

Take home: Aldosterone Antagonists may improve mortality in patients following STEMI who do not have an LVEF < 40% or clinical heart failure. Ongoing RCT’s are currently being conducted further assess the role of Aldosterone antagonists in post-STEMI care.

Click here for the full article


wotw interns.PNG

After a long and grueling fun-filled orientation process, the 2018-2019 Internal Medicine intern class has acclimated to Portland via the time-honored traditions of visiting Ikea a bunch of times, getting lost in the Gorge, and enjoying a BBQ thrown in their honor by the outgoing IM Intern class!

They start in the hospitals this Sunday, July 1. They're going to be GREAT and EVERYONE is going to be nice to them.

Please help us welcome the new interns to OHSU. We are excited to work with you!

Tuberculous Meningoencephalitis!

This week, we heard about a fascinating case of tuberculous meningoencephalitis from Dr. Bruce Kaufmann.

On presentation, his patient described a subacute, progressive headache, with nonfocal neurologic changes, and neck stiffness which was immediately concerning for a CNS infectious process. She underwent urgent workup including imaging and a lumbar puncture, and was started on empiric antibiotics.

We reviewed our classic lumbar puncture workup to differentiate between bacterial, viral, and fungal/TB etiologies:

This chart can be a little overwhelming sometimes, especially when comparing bacterial and fungal/TB etiologies. In general, the major differences are the presence of lymphocytes (vs. neutrophils) and the less dramatic elevation of protein and less dramatic drop in glucose. I like to think of the bacterial organisms as consuming glucose and generating protein waste product. Finally, extremely high protein levels are also consistent with meningeal carcinomatosis!

In the case of Bruce’s patient, nucleic acid testing sent from the initial lumbar puncture quickly returned consistent with tuberculosis! She was started on appropriate antibiotics, and follow up imaging demonstrated persisting multifocal tuberculomas, however, and a prolonged course of antibiotics has been initiated.

Meningeal Tuberculosis is a rare phenomenon in the United States, with recent data suggesting only 100 cases in the US yearly. It comprises 1% of total TB cases, and 5-15% of extrapulmonary TB. What was puzzling in this case was the apparent lack of risk factors (known immunosuppression, exposure history) in an otherwise healthy, young woman who had emigrated from Vietnam several decades prior to presentation. Bruce’s learning point focused on high-quality evidence supporting a short-term mortality benefit of adjunctive corticosteroids in addition to appropriate antibiotics.

Weekly Evidence Updates 6.25.18

Combined analysis of Asthma Safety Trials of Long-Acting 2- Agonists (NEJM 6/2018)

Controversy has surrounded whether or not long acting beta agonist (LABA) medications are safe in patients with asthma, with some trials showing increased mortality with their use, and others demonstrating that they are safe to use when combined with an inhaled corticosteroid (ICS). The study presented above is the result of a pooled, prospective analysis of a randomized controlled trial assessing the non-inferiority of LABA+ICS vs ICS alone. The authors looked at asthma related intubation and death as a primary outcome. Secondary outcomes included serious asthma related events (which added in hospitalizations), and asthma exacerbations. The authors found no difference in the rate of serious asthma related events, but fewer asthma exacerbations with the LABA+ICS combination. This data arrives on the heels of 2 other recently published studies looking at the use of budesonide/formoterol as both maintenance and reliever therapy (SMART therapy: Single Maintenance And Reliever Therapy) for patients with mild asthma (O’byrne, Paul M., et al. "Inhaled combined budesonide–formoterol as needed in mild asthma." New England Journal of Medicine 378.20 (2018): 1865-1876.). It is worth noting that industry was heavily involved in the above study as this safety trial was mandated by the FDA.

Article Link

Take home: LABA+ICS appears safe for use in patients with asthma (current guidelines already use for moderate persistent asthma and more severe asthmatics). Their use may be worthwhile in patients with mild persistent asthma as single agent reliever therapy. Their use as a first line maintenance therapy with overall less corticosteroid exposure compared to ICS maintenance has yet to be studied.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock (APROCCHSS Trial) (NEJM 3/2018)

Steroids have been used in septic shock for some time. Some trials demonstrated a mortality benefit (ie. Annane D, Sébille V, Charpentier C, et al. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock. JAMA. 2002), while others have not demonstrated this such as the ADRENAL (nejm 2018), HYPRESS (JAMA 2016), and CORTICUS (nejm 2008). The effects of steroids in shock are not entirely clear, but are thought to augment vascular tone in response to vasopressors. The APROCCHSS trial randomized patients to hydrocortisone+fludrocortisone (50 mg Q 6 hours and 50 mcq QD, respectively) vs. drotrecogin alfa (aPC- now off the market), a combination of all three drugs, or placebo. These were given for 7 days in patients with evidence of indisputable or probable septic shock (documented infection+SOFA score 3-4 in at least 2 organ systems for at least 6 hours, and vasopressors for ≥ 6 hours). The Authors found that the combination of hydrocortisone plus fludrocortisone reduced all cause mortality at day 90, at discharge from the ICU or hospital, and at day 180. Mortality overall was high (43% in treatment arm, and 49% in control arm at day 90), speaking to the high mortality seen in septic shock. Significant adverse events were not seen, other than more hyperglycemia in the steroid group.

Article Link

Take Home: For patients with septic shock who have been on vasopressor therapy for at least 6 hours, addition of hydrocortisone and fludrocortisone improves overall mortality at 90 days and hospital discharge.

irAEs-ing (I'm raising) Awareness: Immune checkpoint inhibitors

Yesterday Tara shared with us a great case of an older male with acute hypoxic respiratory failure and diffuse pulmonary ground glass opacities and consolidations, not improving with diuresis and treatment for presumed pneumonia, ultimately felt to have pneumonitis secondary to his ongoing treatment with Pembrolizumab for metastatic bladder cancer.

First things first—what is pemrolizumab? Pemrolizumab lives within the word of immunotherapies for cancer and specifically is a check point inhibitor. Fun fact: it has been credited with the successful treatment of Jimmy Carter’s melanoma.

Immunotherapies are a distinct class of cancer treatement, different from traditional chemotherapy, radition and surgery. The main types of immunotherapy include:

  • Monoclonal antibodies: alemtuzumab, trastuzumab
  • Cancer vaccinations: prevention (HPV, HBV) and treatment (sipuleucel-T for prostate CA)
  • Immune checkpoint inhibitors: pembrolizumab, ipilimumab, nivolumab, atezolizumab

Our story involves the immune checkpoint inhibitors (ICPI). These drugs work by “taking the breaks off the immune system” and thus allowing the body to better attack the cancer. While this can be helpful for fighting cancer cells, you can imagine that when things go awry it can cause trouble. When this happens it is called an immune related adverse event (irAEs).

The jist is that when these drugs block the normal “cop” of the immune system (the guy that normally slows it down/shuts it down) your immune system is free to go on a field trip around your body and do what it pleases. And, as we all know, a by product of the immune system's presence is inflammation. In simpler terms, inflammation causes “itises”. So, side effects of these medications are consistent with overactive immune systems and thus inflammation of just about any organ in your body: encephalitis, uveitis, arthritis, pneumonitis, myocarditis, nephritis. The most common systems impacted are GI :(colitis, enteritis, hepatitis) SKIN: dermatitis, vitiligo—nuts! Not an “itis”), and ENDOCRINE (thyroiditis, adrenalitis, pituitaritis- not a real word).

Original cartoon representation below:


Tara’s patient had pneumonitis with consistent imaging showing ground glass opacities and consolidations on XR and CT scan. Note: there is no pathonogmonic findings on lung imaging and pulmonary manifestations of ICPI-induced pneumonitis can present as: DAD, organizing inflammatory pneumonia, sarcoid-life pulmonary granulomatosis, COP…

While cough and dyspnea can be present in up to 40% of patients undergoing ICPI therapy, pneumonitis is only present in 2-4% and can be fatal in 0.2%.

As you might expect, the treatment for ICPI-induced pneumonitis (or really any "itis") is shut down the inflammation through immunosuppression. In other words, steroids and then stronger immunosuppresants, if refractory.

Below is a great algorithm for ICPI-induced pneumonitis specifically from the Annals of Oncology. This wonderful article provides the management guidelines for just about all of the ICPI-related toxicities. You can find it here.

Annals Onc Algorithm.png

ICPI and their side effects are becoming increasingly common. As such, this ICPI FAQ from the NEJM is a wonderful resource to help answer many of the practical questions that arise from patients and providers alike about how ICPIs work, why they can cause trouble, and if irAEs are encountered, what that means for current and future treatment of their cancers.


Take home points:

  • If your patient has or had cancer, always know what treatment they received or are receiving- it often is relevant to their presenting symptom(s)
  • Immunotherapy for cancer and specifically immune check point inhibitors are being used and their side effects can be thought of as all the “itises”. Have a HIGH index of suspicion for their side effects when a patient presents with an inflammatory picture
  • Don’t overthink the treatment- suppress the problem, start steroids/immunosuppression