97. Rapid Fire Journal Club – MIST 2

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In this episode, we add another article to our Rapid Fire Journal Club. Luke Hedrick and Dave Furfaro discuss the MIST 2 trial published in NEJM in 2011 evaluating enzymatic therapy for complex parapneumonic effusions and empyemas.

 

Article and Reference

We are talking today about the MIST 2 trial evaluating the use of intrapleural tPa and DNase for intrapleural infections.

Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, Bentley A, Kahan BC, Wrightson JM, Davies HE, Hooper CE, Lee YC, Hedley EL, Crosthwaite N, Choo L, Helm EJ, Gleeson FV, Nunn AJ, Davies RJ. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011 Aug 11;365(6):518-26. doi: 10.1056/NEJMoa1012740. PMID: 21830966.

Key Learning Points

  •  
  •  
    • Background:
      • Infections in the pleural space are common and morbid, often requiring surgical intervention. Unfortunately, antibiotics and chest tube drainage often fail. The MIST1 trial (NEJM, 2005) of intrapleural streptokinase showed no benefit. MIST2 studied intrapleural tPA and DNase to ease drainage by breaking down septations and thinning pleural fluid.
    • Study Design (design, primary outcome, participants, etc)
      • Design:
        • Double-blind, double-dummy, 2×2 factorial RCT at 11 UK hospitals from 12/2005 to 11/2008
          • By double dummy, we mean that there was a sham placebo for each of the study drugs
      • Primary Outcome
        • Change in the percent of the hemithorax taken up by effusion on CXR at day 7 compared to day 1
        • Key secondary outcomes:
          • Referral for surgery
          • Hospital LOS
          • All cause 3 month and 12 month mortality
          • AEs
      • Participants
        • Inclusion:
          • Clinical evidence of infection (assessed by recruiting MD; EG, fever, CRP, WBC) and
          • Pleural fluid with any of:
            • Grossly purulent
            • Positive pleural fluid culture or gram stain
            • pH < 7.2
        • Exclusion: aiming to exclude patients with increased bleeding risk or who can’t re-expand the lung after drainage
          • Age < 18
          • Previous intrapleural fibrinolytics, DNase, or both for empyema
          • Allergy to tPA or DNase
          • Coincidental stroke (hemorrhage risk)
          • Major hemorrhage or trauma
          • Major surgery in the last 5 days
          • Previous pneumonectomy on the infected side
          • Pregnancy, lactation
          • Expected survival < 3 months from something other than what caused the pleural problem
        • Summary: Middle-aged, mostly male patients with complicated pleural effusion or empyema occupying 1/3 to 2/5 hemithorax with mostly small-bore CDs for mostly community-acquired infections

Small-bore here meant < 15 Fr

  • Intervention/Limitations
    • N = 210 (193 analyzed) randomized approximately 1:1 to one of the following 4 arms:
      1. tPA/Dnase (10mg and 5mg)
      2. tPA and placebo
      3. DNase and placebo
      4. Double placebo
      • Medications were given BID for 3 days with clamping of the CD for 1 hour after each dose (to keep the drug in the pleural space)
  • Outcomes/Safety
    • Power: with N = 210 (actual analysis = 193), 80% power to detect 1 in 5 more patients with a 50% reduction in pleural opacity on CXR
    • We’ll discuss the outcomes of tPA/DNase in combination because there was a highly significant interaction between the two (P = 0.002) for the primary outcome
    • Efficacy:
      • Primary (pleural effusion size reduction): -29.5% hemithorax vs baseline and -7.9% effusion size vs placebo (P = 0.005)
        • Neither drug worked on their own
      • Secondary:
        • Referral for surgery: 4% vs 16% (OR 0.17, P = 0.03)
        • Hospital LOS (excluding 391d outlier in placebo group): mean 11.8 vs 17 days (P = 0.006)
        • Mortality: no difference
    • Safety:
      • No difference in AE between groups
      • 6 serious events across all groups, mostly related to bleeding (intra-pleural, GI, hemoptysis); other AE were made up of pain with drug administration, transient AMS, rash
  • Takeaway
    • Combination intrapleural enzyme therapy (IET) with tPA and DNase improves drainage of infected pleural fluid, and reduces need for surgery and hospital LOS

Infographic

 

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96. Guidelines Series: GINA Guidelines – Asthma Treatment and Management

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We’re back with our second episode in our guideline initiative, and continuing our review of the Global Initiative for Asthma (GINA) guidelines on asthma. In our first episode of this series, we talked about making the diagnosis of asthma, the importance of appropriate phenotyping, and doing an initial assessment of asthma severity. Today, we’re discussing the initial management of asthma and discussing but pharmacologic and non-pharmacologic treatments. We have a great infographic prepared along with the episode, and a boards-style question for your review.

Meet Our Co-Hosts

Rupali Sood  grew up in Las Vegas, Nevada and made her way over to Baltimore for medical school at Johns Hopkins. She then completed her internal medicine residency training at Massachusetts General Hospital before returning back to Johns Hopkins, where she is currently a second year pulmonary and critical care medicine fellow alongside Tom. Rupali’s interests include interstitial lung disease, particularly as related to oncologic drugs. And she also loves bedside medical education.

Tom Di Vitantonio  is originally from New Jersey and attended medical school at Rutgers, New Jersey Medical School in Newark. He then completed his internal medicine residency at Weill Cornell, where he also served as a chief resident. He currently is a second year pulmonary and critical care medicine fellow at Johns Hopkins, and he’s passionate about caring for critically ill patients, how we approach the management of pulmonary embolism, and also about medical education of trainees to help them be more confident and patient centered in the care they have going forward.

Key Learning Points

  1. Introduction to Asthma Guidelines
  • The podcast continues a guideline series on asthma, focusing on the Global Initiative for Asthma (GINA) 2024 guidelines.
  • Emphasizes practical applications for clinicians managing asthma in different settings.
  1. Importance of Evidence-Based Asthma Management
  • Asthma treatment must be systematic and personalized, considering recent clinical evidence.
  • Previous reliance on short-acting beta agonists (SABAs) as rescue inhalers has shifted towards inhaled corticosteroid (ICS)-containing therapies.
  • Over-reliance on SABAs is linked to increased exacerbations, airway inflammation, and poor long-term outcomes.
  1. Stepwise Approach to Asthma Management (GINA 2024)
  • The Track 1 approach (preferred) centers around ICS-formoterol as both maintenance and reliever therapy (MART).
  • Track 2 (alternative approach) includes daily ICS or ICS-LABA with a separate SABA as a reliever.

Stepwise Therapy

  • Step 1-2 (Mild asthma): Low-dose ICS-formoterol as needed for symptom relief.
  • Step 3 (Moderate asthma): Low-dose maintenance ICS-formoterol (MART therapy).
  • Step 4 (Persistent symptoms): Medium-dose ICS-formoterol (MART) with additional inhaler adjustments.
  • Step 5 (Severe asthma): Consider biologic therapies, phenotyping, and additional controllers.
  1. MART Therapy as a Game-Changer
  • Maintenance and Reliever Therapy (MART):
    • Uses a single inhaler for both daily maintenance and symptom relief.
    • Reduces overuse of SABAs.
    • Provides real-time up-titration of ICS during exacerbations.
    • Leads to better adherence and control.
  • Supporting Evidence from Trials:
    • SIGMA 1 & 2, Novel Start, Practical (2018-2019): Showed ICS-formoterol reduces exacerbations and steroid exposure compared to SABAs.
    • MANDALA (2022): Showed ICS-SABA improves outcomes over SABA alone, though not a true MART study.
  1. Practical Considerations in Asthma Management
  • Patient adherence is critical—educate on proper inhaler use and symptom monitoring.
  • Insurance and cost barriers may require prescribing alternative inhalers.
  • Review and adjust treatment regularly using the “Assess, Adjust, Review” framework.
  • Avoid high-dose ICS without exploring additional controller therapies like LAMAs, leukotriene receptor antagonists (Montelukast), and azithromycin.
  1. Non-Pharmacologic Interventions
  • Smoking cessation (including vaping/marijuana).
  • Weight management and physical activity.
  • Avoiding triggers (allergens, occupational exposures, pollution).
  • Air purifiers and HEPA filters.
  • Vaccinations (flu, COVID-19) to prevent viral exacerbations.
  • Managing comorbidities (GERD, sleep apnea, anxiety/depression).
  1. Case Discussion & Real-World Application
  • Patient with recurrent asthma symptoms post-viral illness.
  • Started on low-dose ICS-formoterol as needed.
  • Symptoms persisted, leading to maintenance ICS-formoterol (MART therapy).
  • Regular follow-up to monitor and adjust therapy.
  1. Looking Ahead
  • Next episode will focus on biologic therapies for severe asthma.
  • Emphasis on ongoing education, practical application, and patient-centered care.

Infographic

 

Boards Style Question

 

 

 

References

Mauer Y, Taliercio RM. Managing adult asthma: The 2019 GINA guidelines. Cleve Clin J Med. 2020 Aug 31;87(9):569-575. doi: 10.3949/ccjm.87a.19136. PMID: 32868307.

Matera MG, Rinaldi B, Annibale R, De Novellis V, Cazzola M. The pharmacological management of asthma in adults: 2023 update. Expert Opin Pharmacother. 2024 Mar;25(4):383-393. doi: 10.1080/14656566.2024.2332627. Epub 2024 Mar 20. PMID: 38497368.

Arismendi E, Ribo P, García A, Torrego A, Bobolea I, Casas-Saucedo R, Palomino R, Picado C, Muñoz-Cano R, Valero A. Asthma Control According to GINA 2023: Does Changing the Criteria Improve Asthma Control? J Clin Med. 2024 Nov 6;13(22):6646. doi: 10.3390/jcm13226646. PMID: 39597790; PMCID: PMC11594371.

http://ginasthma.org/2023-gina-main-report/

https://www.uptodate.com/contents/an-overview-of-asthma-management-in-children-and-adults

https://onlinelibrary.wiley.com/doi/full/10.1111%2Fresp.14782

Dubin S, Patak P, Jung D. Update on Asthma Management Guidelines. Mo Med. 2024 Sep-Oct;121(5):364-367. PMID: 39421468; PMCID: PMC11482852.

 

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95. Clinical Pearl: Prone Positioning with Elevated Intracranial Pressure

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Today we have a mini-episode / clinical pearl. We previously discussed the PROSEVA trial and the evidence for prone positioning in ARDS. In that trial, patients with elevated intracranial pressure (ICP) were excluded. We are joined now by Dr. Jon Rosenberg, a neuro intensivist, to discuss his how prone positioning can still be employed for patients with neurologic injuries and elevated ICP.

 

Meet Our Guest

Dr. Jon Rosenberg is an assistant professor of neurology and neurosurgery at Westchester Medical Center, New York Medical College. He’s also the associate program director of the Neurocritical Care Fellowship at Westchester Medical Center and a frequent contributor to the Neurocritical Care Society podcast.

 

Key Learning Points

  1. Elevated Intracranial Pressure (ICP) and Proning: A Common Misconception
  • Elevated ICP is often considered a contraindication to proning, but this is more of a relative caution rather than an absolute contraindication.
  • Many neuro ICUs have successfully proned patients with elevated ICP, particularly since the COVID-19 pandemic, when critical care units had to manage both respiratory failure and neurological conditions simultaneously.
  1. Patient Selection for Proning with Elevated ICP
  • Most patients with elevated ICP can still be proned, including those with:
    • Global cerebral edema (e.g., post-anoxic brain injury, liver failure)
    • Focal lesions (e.g., traumatic brain injury, large ischemic strokes, intracerebral hemorrhage)
  • Situations where proning might be more concerning:
    • Severe hemodynamic instability (multi-pressor shock)
    • Morbid obesity (e.g., >300 lbs), where physically flipping the patient is a major challenge
  1. Theoretical Concerns with Proning in Elevated ICP
  • Loss of neurological exam access (sedation + flipped position makes pupil and motor exam difficult)
  • Jugular venous compression (especially if the head is turned to one side)
  • Cerebrospinal fluid (CSF) flow obstruction, depending on the lesion
  • Risk of increased ICP if venous outflow is impaired or head positioning is not optimized
  1. Best Practices for Proning Patients with Elevated ICP
  • Patients with invasive ICP monitors vs. without monitors:
    • If possible, placing an ICP monitor (EVD or parenchymal bolt) before proning provides better guidance.
    • Without a monitor, providers must rely on other practices like maintaining strict MAP goals and sodium targets, and indirect signs of increased ICP.
  • Positioning considerations:
    • Keep the head midline to prevent jugular venous compression.
    • If head positioning is not neutral, place the dominant/internal jugular facing upward to maintain venous drainage.
    • Maintain the head of the bed elevated even while prone (reverse Trendelenburg positioning).
  • Hemodynamic management:
    • Target a higher MAP (e.g., 70–75 mmHg, sometimes 75–80 mmHg) to ensure adequate cerebral perfusion pressure (CPP) if there is no ICP monitor
    • Avoid hypotension, as MAP – ICP = CPP, and low MAP could critically reduce cerebral perfusion.
      • A normal intracranial pressure is 7 – 15 mmHg
      • The recommended CPP is between 60 – 70 mmHg
  • Sedation & Sodium Management:
    • Consider deep sedation (RASS -5) to reduce metabolic demand and intracranial blood volume.
    • Consider keeping sodium >145 mmol/L prophylactically to mitigate brain swelling if no ICP monitor in place
  1. When to Reconsider Proning (i.e. when to supinate)
  • If a patient’s ICP spikes significantly (e.g., from 20 to 60 mmHg) despite medical management (hypertonic saline, sedation, paralysis, etc.).
  • If new signs of neurological deterioration emerge (e.g., changes in pupil exam once patient is repositioned).
  • Hemodynamic instability that is unmanageable in the prone position.
  1. Literature and Future Considerations
  • Small case series have demonstrated success in proning patients with traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage.
  • While more formal research is needed, the neurocritical care community has begun embracing proning for neuro patients, provided that proper precautions are taken.

Bottom Line

  • Proning is not an absolute contraindication for patients with elevated ICP—it can be done safely with proper monitoring, patient selection, and precautions.
  • Having an ICP monitor makes the process more controlled and allows clinicians to adjust treatment in real time.
  • Key considerations: Maintain cerebral perfusion, optimize head positioning, monitor hemodynamics, and have a plan for reversing if ICP becomes unmanageable.

 

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94. The Impact of Reduced NIH Indirect Cost Payments

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On February 7, 2025 it was announced that the National Institutes of Health (NIH) would be capping indirect cost payments for research grants at 15%. This is a massive reduction from the current standard, and will have widespread impacts on research, healthcare delivery, and trainee and young faculty development throughout the United States. We have a special episode today to try to explain what this change really means, the broad impact it will have on the healthcare system and scientific research, and what we as a the healthcare community can / should be doing. Please feel free to reach out to us with any thoughts or questions from the episode.

 Meet Our Guests

Dr. Theodore “Jack” Iwashyna is a Bloomberg Distinguished Professor at Johns Hopkins School of Medicine and the Johns Hopkins Bloomberg School of Public Health. Jack is a critical care physician and focuses on research to understand the broader context of critical illness, and the long term impact on patients’ lives. He is an enormously productive and successful researcher with numerous publications in the field of critical care, and is a pioneer in the field of ICU survivorship. He is a devoted mentor and has received accolades from numerous societies

Dr. Kathryn Hibbert is an Assistant Professor of Medicine at Harvard Medical School and a pulmonary and critical care physician at Massachusetts General Hospital. She is the MICU Director at MGH, as well at the Vice Chair for Critical Care.

Summary of Key Points

  1. Overview of NIH Funding
    • NIH research funding is divided into direct costs (salaries, supplies, specific project expenses) and indirect costs (infrastructure, utilities, administrative support).
    • Indirect costs support shared research resources like lab space, IT infrastructure, and institutional overhead.
  2. Recent Policy Change & Impact
    • A sudden 15% cap on indirect cost reimbursement for NIH grants was announced late on a Friday, catching the academic community off guard.
    • Many universities typically receive 50-60% in indirect cost reimbursements, making this a drastic cut.
    • This change could severely affect research institutions by reducing available funding for shared infrastructure, education, and clinical care.
  3. Broader Ramifications
    • Threat to Medical Research: Loss of funding for essential research infrastructure could slow or halt key medical advancements, such as cancer therapies, CF treatments, and more.
    • Impact on Education & Clinical Care: Reduced research funding could lead to cuts in trainee programs, fewer job opportunities, and diminished support for clinical services, particularly those serving vulnerable populations.
    • Economic Consequences: Academic medical centers are often major employers in states across the U.S. A reduction in funding could lead to job losses and economic downturns in affected regions.
  4. Political and Institutional Response
    • Legal challenges were quickly filed, resulting in a temporary restraining order against the policy change.
    • The administration’s actions were seen as an attack on academic freedom and scientific independence.
    • The impact extends beyond select universities or states. States like Texas, Ohio, Florida, and Iowa stand to lose millions in research funding.
  5. Advice for Early-Career Researchers
    • Continue applying for NIH grants as normal, following institutional guidance.
    • Stay informed about evolving policies.
    • Engage in advocacy—contact representatives, raise awareness, and contribute to public discussions.
  6. Call to Action
    • The speakers urge medical professionals, researchers, and the public to share knowledge about what the impact of these changes would be, and prevent them from becoming permanent.
    • They emphasize the critical role of NIH-funded research in improving healthcare outcomes worldwide and encourage continued engagement in the conversation.

References and Further Reading

https://www.al.com/news/2025/02/katie-britt-vows-to-work-with-rfk-jr-after-nih-funding-cuts-cause-concern-in-alabama.html

https://www.forbes.com/sites/michaeltnietzel/2025/02/10/what-the-nih-cut-to-indirect-cost-payments-could-cost-red-states

https://www.npr.org/2025/02/12/nx-s1-5292359/what-cuts-to-nih-funding-could-mean-for-american-universities

https://www.press.jhu.edu/books/title/53759/transformation-american-health-insurance?srsltid=AfmBOoqvR5-TrqcsIC6ELO3AdZgjFWkIJ9jdlawJpyxJDus1cM–LxLr

https://global.oup.com/academic/product/time-to-heal-9780195181364?cc=us&lang=en&

https://www.africa.upenn.edu/Articles_Gen/Letter_Birmingham.html

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93. Guidelines Series: GINA Guidelines – Asthma Diagnosis and Assessment

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Today we are launching a new Pulm PEEPs initiative! We are going to be reviewing some of the major guidelines that are available in pulmonary and critical care. We are starting by diving into the Global Initiative for Asthma (GINA) guidelines on asthma. The goal of this initiative is to breakdown the guidelines into digestible and helpful discussions, and to talk about key issues that are pointed out by the guideline authors. Our first episode will be the start of the GINA guidelines and we’re discussing the initial diagnosis and evaluation of patients with asthma.

Meet Our Co-Hosts

Rupali Sood  grew up in Las Vegas, Nevada and made her way over to Baltimore for medical school at Johns Hopkins. She then completed her internal medicine residency training at Massachusetts General Hospital before returning back to Johns Hopkins, where she is currently a second year pulmonary and critical care medicine fellow alongside Tom. Rupali’s interests include interstitial lung disease, particularly as related to oncologic drugs. And she also loves bedside medical education.

Tom Di Vitantonio  is originally from New Jersey and attended medical school at Rutgers, New Jersey Medical School in Newark. He then completed his internal medicine residency at Weill Cornell, where he also served as a chief resident. He currently is a second year pulmonary and critical care medicine fellow at Johns Hopkins, and he’s passionate about caring for critically ill patients, how we approach the management of pulmonary embolism, and also about medical education of trainees to help them be more confident and patient centered in the care they have going forward.

Key Learning Points

Understanding Asthma & the GINA Guidelines

  • Asthma is a heterogeneous disease characterized by recurring respiratory symptoms (breathlessness, wheezing, cough, chest tightness) with variable airflow limitation.
  • The 2023 & 2024 Global Initiative for Asthma (GINA) guidelines emphasize phenotyping asthma to improve diagnosis and treatment.
  • Asthma differs from other obstructive lung diseases due to reversible airway obstruction, which can be demonstrated through diagnostic testing.

Diagnosing Asthma

  • Clinical history is crucial, particularly identifying symptom triggers (cold air, exercise, allergens).
  • Spirometry is the standard diagnostic tool, looking for an increase in FEV1 or FVC ≥12% and 200 mL after bronchodilator use.
  • Alternative tests include:
    • Peak expiratory flow monitoring over time.
    • Bronchoprovocation tests (e.g., methacholine challenge) to assess airway hyperresponsiveness.
    • Fractional exhaled nitric oxide (FENO) and blood eosinophils as markers of type 2 inflammation.

Asthma Phenotypes & Precision Medicine

  • Different asthma phenotypes guide personalized treatment approaches:
    • Type 2  inflammation: Characterized by eosinophilic inflammation, high FeNO, good steroid responsiveness, and potential for biologic therapy.
    • Non-Type 2 inflammation: Associated with neutrophilic inflammation, poor steroid responsiveness, and potential benefit from macrolides or bronchodilators.
  • Asthma-COPD overlap requires a distinct treatment approach due to persistent obstruction.

Imaging & Adjunctive Tests

  • Imaging is not routinely needed in asthma but can be useful for:
    • Bronchiectasis (suspected allergic bronchopulmonary aspergillosis – ABPA).
    • Asthma-COPD overlap (CT chest for emphysema).
    • Chronic sinusitis or nasal polyps (CT sinus imaging).

Assessing Asthma Control

  • Asthma is not a one-time diagnosis; continuous reassessment is crucial.
  • Asthma control is assessed at every visit, considering:
    • Symptom frequency
    • Exacerbations
    • Inhaler technique
    • Comorbidities
  • Rule of Twos: Asthma is not well-controlled if:
    • Symptoms occur >2 times per week.
    • Nighttime awakenings >2 times per month.
    • Rescue inhaler use >2 times per week (excluding pre-exercise use).
  • Peak flow meters are valuable for self-monitoring and guiding asthma action plans.

Conclusion

  • Asthma assessment is a continuous process, incorporating history, spirometry, biomarkers, and patient-reported symptoms.
  • Future episodes will cover asthma treatment, including biologics and inhaler therapy.
  • Infographics and questions will accompany this series for further learning.

Infographic

Board Style Questions

References

Mauer Y, Taliercio RM. Managing adult asthma: The 2019 GINA guidelines. Cleve Clin J Med. 2020 Aug 31;87(9):569-575. doi: 10.3949/ccjm.87a.19136. PMID: 32868307.

Matera MG, Rinaldi B, Annibale R, De Novellis V, Cazzola M. The pharmacological management of asthma in adults: 2023 update. Expert Opin Pharmacother. 2024 Mar;25(4):383-393. doi: 10.1080/14656566.2024.2332627. Epub 2024 Mar 20. PMID: 38497368.

Arismendi E, Ribo P, García A, Torrego A, Bobolea I, Casas-Saucedo R, Palomino R, Picado C, Muñoz-Cano R, Valero A. Asthma Control According to GINA 2023: Does Changing the Criteria Improve Asthma Control? J Clin Med. 2024 Nov 6;13(22):6646. doi: 10.3390/jcm13226646. PMID: 39597790; PMCID: PMC11594371.

http://ginasthma.org/2023-gina-main-report/

2024 GINA Main Report

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92. Journal Club with BMJ Thorax – COPD and Emphysema

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Today is our second episode in our collaborative series with BMJ Thorax. Our mission at Pulm PEEPs is to disseminate and promote pulmonary and critical care education, and we highly value the importance of peer reviewed journals in this endeavor. Each month in BMJ Thorax, a journal club is published looking at high yield and impactful publications in pulmonary medicine. We will be putting out quarterly episodes in association with Thorax to discuss a journal club publication and synthesize four valuable papers. This week’s episode covers four articles related to lung health, COPD, and emphysema.

Meet Our Guests

Chris Turnbull is an Associate Editor for Education at Thorax. He is an Honorary Researcher and Respiratory Medicine Consultant at Oxford University Hospitals. In addition to his role as Associate Editor for Education at BMJ Thorax, he is also a prominent researcher in sleep-related breathing disorders.

 Ewan Mackay is a Respiratory Clinical Research Fellow who has started his PhD in London. His research focus is on chronic cough and in the development of new patient-reported outcome measures as well as respiratory physiology, particularly in relation to exercise and disease.

Journal Club Papers

To submit a journal club article of your own to Thorax, you can contact Chris directly – christopher.turnbull@ouh.nhs.uk


To engage with Thorax, please use the social media channels (Twitter – @ThoraxBMJ; Facebook – Thorax.BMJ) and subscribe on your preferred platform, to get the latest episodes directly on your device each month.

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91. Tylenol Toxicity and Acute Liver Failure

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This week we’re talking about a case as a lens for discussing Tylenol toxicity and Acute Liver Failure. These relatively common critical care presentations are essential knowledge for anyone practicing in the ICU. Listen in for some key discussion both about toxicology and the diagnosis and management of acute livery injury and failure.

 

Meet Our Guests

Kalaila Pais received her MD from Howard University College of Medicine and is currently a second year internal medicine resident at BIDMC. She is interested in pulmonary and critical care, as well as medical education. She also had the idea for this episode and was essential in its writing and production.

Hima Veeramachaneni received her MD from University of Missouri-Kansas City School of Medicine, and her residency at Emory where she was also a Chief Resident at Grady Memorial Hospital. She is a gastroenterologist and completed her GI and transplant hepatology training at Emory. She is also now doing a critical care medicine fellowship year.

 

Case Presentation

Presentation: Patient found down, surrounded by liquor bottles, with coffee-ground emesis, hemodynamic instability, scleral icterus, and metabolic derangements.

Key Lab Findings:

  • Severe transaminitis (AST >10,000, ALT ~3,000).
  • Elevated bilirubin (5.8), lactate (16), and INR (>2).
  • Metabolic acidosis with a pH of 7.04.
  • Tylenol level: 41 (slightly elevated but inconclusive without ingestion timing).

 

Key Learning Points

Infographic:

Acute Liver Injury vs. Acute Liver Failure

  • Acute Liver Injury (ALI): Elevated liver enzymes without encephalopathy or significant synthetic dysfunction.
  • Acute Liver Failure (ALF): Defined by:
    • Presence of encephalopathy.
    • Coagulopathy (elevated INR).
    • Rapid onset (<26 weeks) in patients without pre-existing liver disease.
  • ALF often leads to complications such as cerebral edema, which necessitates aggressive management.

Tylenol Toxicity and Interpretation

  • Pathophysiology:
    • Tylenol overdose overwhelms liver glutathione, leading to accumulation of NAPQI, which causes hepatocyte necrosis.
  • Interpretation of Tylenol Levels:
    • Timing of ingestion is critical to interpreting levels.
    • The Rumack-Matthew Nomogram is used for acute ingestions but requires a known ingestion time.
  • Management:
    • N-acetylcysteine (NAC): Standard of care; acts as a glutathione precursor and mitigates liver damage.
    • Early use is recommended in suspected cases of Tylenol toxicity, even if ingestion timing is unclear.

Critical Management Principles

  • Stabilization: Focus on airway, hemodynamics, and perfusion.
    • Monitor for signs of cerebral edema (e.g., pupillary changes, seizures).
    • In select patients, use hypertonic saline to maintain sodium levels (145–150 mmol/L) to mitigate cerebral edema risks.
  • CRRT and Plasma Exchange:
    • Continuous renal replacement therapy (CRRT) for hyperammonemia and acidosis.
    • Plasma exchange (PLEX) may stabilize cytokine storms and improve survival.
  • Organ-Specific Considerations:
    • Renal failure: Common due to hepatorenal syndrome; requires CRRT.
    • Coagulopathy: Managed with blood products as needed but indicates worsening liver synthetic dysfunction.

Prognosis and Transplant Considerations

  • King’s College Criteria: Guides transplant listing for ALF patients.
    • Factors: Encephalopathy severity, INR, lactate, bilirubin trends.
  • Ethical considerations for liver transplant in patients with substance use or overdose:
    • Emphasis on assessing social support and addressing psychiatric needs.
    • Efforts are made to ensure equitable access to transplant when warranted.

Takeaways for Clinical Practice

  1. Broad Differential Diagnosis: Keep a wide perspective for acute liver presentations, considering toxins, infections, and systemic conditions.
  2. Early Use of NAC: Err on the side of initiating NAC when Tylenol toxicity is suspected.
  3. CNS Focus in ALF: Monitor and manage cerebral edema aggressively.
  4. CRRT & PLEX: Advanced liver support techniques are critical in select cases.
  5. Interdisciplinary Collaboration: Psychiatrists, neurocritical care, and hepatologists play pivotal roles in management.

 

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90. Rapid Fire Journal Club: ANDROMEDA-SHOCK

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We are excited to be back with a Rapid Fire Journal Club. Today’s episode is hosted by PulmPEEPs Associate Editor, Luke Hedrick, and will delve into the ANDROMEDA-SHOCK trial published in JAMA in 2019.

Meet our Guests

Jose Meade Aguilar is a second year Internal Medicine resident at Boston University Medical Campus (BUMC).

Article and Reference

Today the discussion highlights the ANDROMEDA-SHOCK trial (JAMA, 2019) which evaluated whether resuscitation guided by capillary refill time (CRT) is superior to lactate-guided resuscitation in reducing mortality in patients with septic shock.

Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegría L, Teboul JL, Cecconi M, Ferri G, Jibaja M, Pairumani R, Fernández P, Barahona D, Granda-Luna V, Cavalcanti AB, Bakker J; The ANDROMEDA SHOCK Investigators and the Latin America Intensive Care Network (LIVEN); Hernández G, Ospina-Tascón G, Petri Damiani L, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegría L, Teboul JL, Cecconi M, Cecconi M, Ferri G, Jibaja M, Pairumani R, Fernández P, Barahona D, Cavalcanti AB, Bakker J, Hernández G, Alegría L, Ferri G, Rodriguez N, Holger P, Soto N, Pozo M, Bakker J, Cook D, Vincent JL, Rhodes A, Kavanagh BP, Dellinger P, Rietdijk W, Carpio D, Pavéz N, Henriquez E, Bravo S, Valenzuela ED, Vera M, Dreyse J, Oviedo V, Cid MA, Larroulet M, Petruska E, Sarabia C, Gallardo D, Sanchez JE, González H, Arancibia JM, Muñoz A, Ramirez G, Aravena F, Aquevedo A, Zambrano F, Bozinovic M, Valle F, Ramirez M, Rossel V, Muñoz P, Ceballos C, Esveile C, Carmona C, Candia E, Mendoza D, Sanchez A, Ponce D, Ponce D, Lastra J, Nahuelpán B, Fasce F, Luengo C, Medel N, Cortés C, Campassi L, Rubatto P, Horna N, Furche M, Pendino JC, Bettini L, Lovesio C, González MC, Rodruguez J, Canales H, Caminos F, Galletti C, Minoldo E, Aramburu MJ, Olmos D, Nin N, Tenzi J, Quiroga C, Lacuesta P, Gaudín A, Pais R, Silvestre A, Olivera G, Rieppi G, Berrutti D, Ochoa M, Cobos P, Vintimilla F, Ramirez V, Tobar M, García F, Picoita F, Remache N, Granda V, Paredes F, Barzallo E, Garcés P, Guerrero F, Salazar S, Torres G, Tana C, Calahorrano J, Solis F, Torres P, Herrera L, Ornes A, Peréz V, Delgado G, López A, Espinosa E, Moreira J, Salcedo B, Villacres I, Suing J, Lopez M, Gomez L, Toctaquiza G, Cadena Zapata M, Orazabal MA, Pardo Espejo R, Jimenez J, Calderón A, Paredes G, Barberán JL, Moya T, Atehortua H, Sabogal R, Ortiz G, Lara A, Sanchez F, Hernán Portilla A, Dávila H, Mora JA, Calderón LE, Alvarez I, Escobar E, Bejarano A, Bustamante LA, Aldana JL. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019 Feb 19;321(7):654-664. doi: 10.1001/jama.2019.0071. PMID: 30772908; PMCID: PMC6439620.

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89. Idiopathic Pulmonary Fibrosis Treatment: RFJC – INPULSIS

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Our episode today is diving into a broader initiative to discuss the management of interstitial lung disease. In this episode we will be talking about the treatment of Idiopathic Pulmonary Fibrosis through the lens of a journal club discussion of the NEJM 2014 INPULSIS trial. Today’s episode is hosted by Pulm PEEPs Associate Editor Luke Hedrick.

Meet Our Guests

Robert Wharton is a recurring guest on Pulm PEEPs as a part of our Rapid Fire Journal Club Series. He completed his internal medicine residency at Mt. Sinai in New York City, and is currently a first year pulmonary and critical care fellow at Johns Hopkins.

Dr. Nicole Ng is an Assistant Profess of Medicine at Mount Sinai Hospital, and is the Associate Director of the Interstitial Lung Disease Program for the Mount Sinai National Jewish Health Respiratory Institute.

Article and Reference

Today the discussion of IPF treatment centers around the 2014 NEJM publication of the INPULSIS trials investigating the efficacy of Nintedanib for the treatment of IPF.

Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2071-82. doi: 10.1056/NEJMoa1402584. Epub 2014 May 18. Erratum in: N Engl J Med. 2015 Aug 20;373(8):782. doi: 10.1056/NEJMx150012. PMID: 24836310.

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Summary of Key Discussion Points

Background and Challenges in ILD Treatment: Interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF), had historically poor treatment outcomes, with numerous therapies showing either no benefit or even harm. Prior to 2014, effective treatments were extremely limited, and lung transplantation was the primary management option.

INPULSIS I and II Trials: These 2014 trials examined nintedanib, an antifibrotic drug initially tested for cancer, in patients with moderate IPF. The studies were well-structured, involving strict criteria to ensure accurate diagnoses and excluding younger patients or those with more advanced disease.

Nintedanib’s Mechanism and Design of the Trials: Nintedanib acts by blocking multiple tyrosine kinases that mediate fibrotic growth factors. Patients were monitored over a year, with primary endpoints focusing on forced vital capacity (FVC) decline—a common surrogate measure for disease progression in ILD trials due to its correlation with survival.

Outcomes: Both trials showed that nintedanib significantly reduced the rate of FVC decline compared to placebo, suggesting that it slowed disease progression. Secondary endpoints included reduced acute exacerbations (significant only in one trial) and minor improvements in quality of life, though these weren’t statistically or clinically significant.

Adverse Effects: Nintedanib’s side effects included gastrointestinal issues (diarrhea, nausea, vomiting) and, less commonly, liver enzyme elevations and cardiovascular events. While post-marketing data suggested some improvements in tolerability, clinicians still monitor for these side effects closely.

Application in Clinical Practice: The trials support nintedanib as an option for slowing IPF progression, though no cure or disease reversal is achieved. Clinicians weigh the choice between nintedanib and pirfenidone (another antifibrotic) based on each drug’s side effect profile and individual patient needs.

Future Directions: The trials paved the way for further research into multi-therapy approaches for ILD, targeting multiple disease pathways, similar to strategies in asthma or COPD. Upcoming therapies and trials aim to provide more targeted and effective options for IPF and other ILDs.

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88. Fellows’ Case Files: NYU

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We are joined today by two amazing educators from NYU for our latest Fellows’ Case Files Episode. Listen today as we go through a great case with some fantastic teaching points highlighted throughout the episode.

Meet Our Guests

Dr. Jeremy Grossman completed his Medicine-Pediatrics residency at Stony Brook Medicine where he was also a Chief Resident. He is currently a second-year PCCM fellow at NYU.

Dr. Shari Brosnahan is an Assistant Professor of Medicine and one of the Assistant Program Directors for the NYU Langone’s Division of Pulmonary, Critical Care, and Sleep Medicine. Her clinical and research interests are focused on pulmonary embolism and thrombosis in critically ill patients.

Case Presentation

An 80-year-old male presents with shortness of breath. At home, his oxygen saturation was 82% on room air, improving only to 86% on 4L nasal cannula. Over the past month, he has experienced worsening symptoms, including a dry cough, fatigue, and difficulty speaking or ambulating due to shortness of breath at rest. He denies recent fever, sputum production, chest pain, or lower extremity swelling and presents to the ED for further evaluation.

Key Learning Points

1.In any patient with a history of malignancy and hypoxia, clinicians should keep pulmonary tumor emboli (PTE) on the differential as early intervention may alter outcomes.

2.PTE contributes to hypoxia via mechanisms of mechanical obstruction of pulmonary arteries leading to shunting, VQ Mismatch, and in some cases pulmonary hypertension due to increased PVR.

3.A wedged aspirate can be used to diagnose PTE ante-mortem

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