A Special 50th Digest

February 17, 2024 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue, we cover ARDS Guidelines, Vermont’s new fungal problem, TRAVERSE and fracture risk, and an extended shelf life for Naloxone. Effortlessly absorb important medical news, with our twice monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

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Issue 50

02/17/2024

Appetizers (to whet your appetite) 

Palate Cleanser (aka the melon part of the meal) 

The Main Course

A Digestif or two

Appetizers

Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels. 
-Beth Garbitelli MD, Laura Glick MD, Alyssa Mancini MD

• A Bone to Pick with Testosterone? NEJM recently published a subtrial of TRAVERSE–a double-blind, randomized, placebo-controlled trial evaluating cardiovascular safety of testosterone-replacement therapy in middle-aged/older men with hypogonadism–that examined clinical fracture risk. In this trial, 5204 men with hypogonadism aged 45-80 years were randomly assigned to apply a testosterone or placebo gel daily (with similar rates of osteoporosis medication use in each group).  After 3.2 years of median follow-up, a clinical fracture had occurred in 3.50% of participants in the testosterone group and 2.46% of participants in the placebo group (HR 1.43, 95% CI 1.04 to 1.97), with other fracture endpoints also higher in the testosterone group. Most fractures were associated with trauma (e.g. falls). (AM) 
• Weight loss and cancer risk.  JAMA just published a prospective cohort analysis of > 157,000 health professionals over age 40 (from the Nurses’ Health/Health Professionals Follow-Up Studies) assessing rates of cancer diagnosis in the year following a 2-year period of weight loss, compared to rates of cancer in those without recent weight loss. Over mean follow-up of 28 years, recent weight loss >10% of body weight was associated with an increased rate of cancer during the 12 following months compared to those without recent weight loss (1362 versus 869 cancer cases/100,000 person-years). Cancer diagnoses were more common among participants whose weight loss was classified as unintentional based on recent changes in physical activity and diet. There was a particular association with recent weight loss and cancers of the upper gastrointestinal tract (including cancers of the esophagus, stomach, liver/biliary tract, and pancreas) as well as leukemia. (AM)  
• A longer shelf-life to safe lives. The United States Food and Drug Administration (FDA) recently extended the shelf-life of Narcan (naloxone hydrochloride) 4mg nasal spray from three to four years. The nasal spray used to reverse opioid overdose was first approved in 2015, with a shelf life of two years at that time and an extension to three years in 2020.  In March 2023, the FDA approved the nasal spray for over-the-counter, non-prescription use. This new four-year shelf-life extension applies only to naloxone nasal spray 4mg produced and distributed after January 17, 2024. (LG)
• Eosinophils to guide oral steroids in COPD exacerbations? The STARR2 study, published in The Lancet Respiratory Medicine, was a double-blind, randomized trial in U.K. primary care practices assessing eosinophil-guided steroid prescribing.  Ninety three patients with COPD exacerbations were randomly assigned to blood eosinophil directed treatment (BET)–14 days oral prednisolone (30 mg) if the eosinophil count >2% or placebo if the eosinophil count was <2%– or standard of care treatment (ST), in which all patients received 14 days of oral prednisolone (30 mg). The trial was ultimately converted from a superiority to non-inferiority design after randomization errors were discovered (non-inferiority margin set at an upper 95% CI margin of 1.105).  In a modified intention-to-treat analysis, there were 14 (19%) treatment failures in the BET arm compared to 23 (32%) with standard treatment, a non-significant estimated effect (RR 0.6, 95% CI 0.33-1.04, p=0.07) which met the non-inferiority endpoint. (LG) 
• Mycoses on the move: The rare fungal disease blastomycosis is classically thought to be most common in the Ohio/Mississippi River Valleys and Great Lakes regions, but recent data from the CDC has found a higher-than-expected incidence of blastomycosis in Vermont. Investigators crunched insurance claims data from 2011- 2020 and found an estimated mean annual blastomycosis incidence of 1.8 cases/100,000 persons, which is greater than the mean annual incidences from 1987-2017 in the majority of the 5 states with mandated blastomycosis reporting. Moreover, in 2019, Vermont’s mean incidence rate of blastomycosis topped all 5 mandated reporting states numbers. Why Vermont? Some suspect that regional acidic spodosol soil in Vermont might actually be a suitable habitat for blastomyces species. (BG)

Palate Cleanser

The melon part. To get rid of the taste of those pesky apps.  And to fill your brain with some fun facts.

Sitting at Work – A Dangerous Pastime?  

If sitting is the new smoking, exercise may be the best prevention, according to an article recently published in JAMA by Gao et al. This prospective cohort study followed over 480,000 adults in Taiwan for 20 years and evaluated mortality outcomes associated with prolonged occupational sitting. 

Those who reported predominantly sitting at work had a 16% higher risk of all-cause mortality and 34% increased risk of cardiovascular disease-related mortality, even after adjusting for various factors including sex, age, education, smoking, drinking, and body mass index. They also found that the individuals predominantly sitting at work with <30 minutes per day of leisure-time physical activity would need to increase their daily physical activity by 15-30 minutes daily to reduce their mortality risk to a level similar to that of inactive individuals who do not predominantly sit at work. 

Maybe this is the excuse you needed to get on trend with a standing desk, or at least to stop and smell the roses on a wellness walk during your break! 

– Jennifer DeSalvo MD

The Main Course

Cyrus Askin, MD
Pulmonary & Critical Care Medicine

Updated Guidelines on the Management of Acute Respiratory Distress Syndrome: What do they mean for the bedside clinician in 2024?

If you practice medicine in 2024, you’re likely familiar with Acute Respiratory Distress Syndrome (ARDS).  The diagnosis and management of ARDS, traditionally characterized by bilateral infiltrates on imaging and acute hypoxemia not due to heart failure, has been the topic of many studies and guidelines.  With ARDS heavily featured in the COVID19 pandemic, we have an update to the 2017 guidelines, written by Dr. Nidia Qadir et al.

Breaking it Down

You may remember the “5 Ps of ARDS management” from our 2020 Curbsiders episode (lung Protective ventilation, optimal PEEP, Prune (keep the lungs dry), Prone positioning, and Paralyze). The 2024 American Thoracic Society Guidelines focus on an overlapping–but slightly different–set of Ps, making management recommendations (see Figure 1 for a visual summary!) based on a systematic review.   

1. “Prednisone” – Should Patients with ARDS Receive Systemic Corticosteroids?

Taking trial data and the availability/low cost of steroids into account, the guideline authors conditionally recommend the use of corticosteroids for ARDS (moderate certainty of evidence). Steroids are used in the critically ill to modulate dysregulated immune responses and for refractory shock in sepsis and other shock states. Several trials have assessed their use in ARDS to decrease pulmonary inflammation, including the 2020 DEXA-ARDS and 2021 RECOVERY trials–with clinical and mortality benefits found in both, leading to the above recommendation. The authors don’t specify a dosing regimen, as ARDS encompasses a range of disease physiologies with different dosing demonstrating benefit in different diseases (e.g. severe community acquired pneumonia or Pneumocystis jirovecii pneumonia). The authors also note that steroid initiation after two weeks of illness may be associated with harm.  

2. “Peripheral Oxygenation”– Should Patients with ARDS Receive Extracorporeal Membrane Oxygenation?

The authors provide a conditional recommendation for the use of VV-ECMO in certain patients with severe ARDS (low certainty of evidence).  Venovenous ECMO (VV-ECMO) can provide pulmonary support (i.e. deliver oxygen and remove carbon dioxide) to patients with severe ARDS whose lungs aren’t able to perform gas exchange. This is a resource intensive and costly intervention performed only at specialized centers. Pooled analysis from two randomized trials, CESAR & EOLIA, suggests a probable decrease in ventilator-free days, pressor-free days, dialysis-free days, and mortality with VV-ECMO.  However, trial limitations included lack of ventilation standardization in the control arm and changes to proning practices over time.  Ultimately the authors recommend consideration of ECMO in select patients most likely to benefit (acknowledging challenges to patient selection and implications for health equity), reminding readers that this should be performed at a high-volume, ECMO-dedicated center.

3. “Paralyze” – Should Patients with ARDS Receive Neuromuscular Blockade?

The authors conditionally recommend neuromuscular blockade in early severe ARDS (low certainty of evidence).  This follows the 2010 ACURASYS trial demonstrating an “adjusted 90-day survival” benefit in patients with severe ARDS treated with neuromuscular blockade (i.e. paralytics), which can theoretically prevent self-injurious breathing patterns and/or ventilatory desynchrony. Subsequently, the 2019 ROSE trial saw no mortality benefit, with concerns raised about paralytics worsening ICU-delirium, weakness, and sarcopenia. Ultimately, the authors made this conditional recommendation based on pooled data from 7 RCTs demonstrating a possible mortality reduction and an increase in ventilator-free days–while also acknowledging ongoing uncertainty around muscle atrophy risks and whether the same benefit can be achieved with deep sedation alone. 

4. “PEEP?” – Should Patients with ARDS Receive Higher (compared to lower) PEEP, with or without LRMs (lung recruitment maneuvers)?

The authors recommend a high-PEEP strategy–without lung recruitment maneuvers–in patients with moderate-to-severe ARDS (conditional recommendation, low-moderate certainty). They recommend against prolonged lung-recruitment maneuvers (LRMs) in that same population (strong recommendation, moderate certainty).  Higher PEEP (positive end-expiratory pressure) improves oxygenation and atelectasis in ventilated patients by “stenting” open smaller airways & alveoli, with overdistention and hemodynamic instability if PEEP is too high. Lung recruitment maneuvers (LRMs) typically include very high levels of PEEP for short durations to overcome atelectatic, consolidated regions of lung.  Two meta-analyses found lower mortality with higher PEEP–albeit using many different PEEP strategies–but with some possible harm from long LRMs.  

What Does it Mean?

Despite the many cases of ARDS that we have collectively seen, the data to support specific interventions is limited, with the guidelines making primarily conditional recommendations, based on low-to-moderate certainty of evidence. While acknowledging gaps in the evidence base, the authors of the 2024 guidelines ultimately present ARDS management recommendations that are practical and supported by the evidence to date.  And while practice may change, these guidelines provide an excellent basic strategy–with nuanced recommendations for more contentious topics–to serve as a guide for those of us managing ARDS in 2024. 

If you want to learn even more, keep an eye out for more ARDS content coming in the next few months to Critical Care Time, a new podcast by Dr. Cyrus Askin and Dr. Nick Mark! 

Read The Guidelines HERE!

Digestifs

Before you go….
we’ve got a few nibbles!

Consolidate your learning with a Quiz!  

This week on The Curbsiders: Episode #426, Breast Cancer for the PCP with Dr. Sandhya Pruthi, is full of high-yield clinical pearls for the primary care doc. From mammogram and pre-biopsy counseling to the latest in treatment of DCIS (And…what is DCIS?), to the risk of late recurrence in breast cancer, we highly recommend this one. 

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Until next time, keep that brain hole digesting! 

The Curbsiders Digest

Issue 50

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Disclosures:

Cyrus Askin, Beth Garbitelli,, Jennifer DeSalvo,  Alyssa Mancini, and Nora Taranto report no disclosures.

Kate Grant reports no disclosures.

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