Monthly Archives: November 2022

Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism

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“Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism” JACC, 2017, Europe

Question: Does thrombolytic therapy for submassive PE impact long-term outcomes?

Study Type:  Long-term follow-up of a multicenter, double-blind, placebo-controlled trial

Study Population: Study focused on a subset of patients from the PEITHO trial (NEJM, 2012). In PEITHO, 1,006 adults with confirmed PE + RV dysfunction (on either TTE or CT) + elevated troponin I or T were randomized to heparin +/- a single weight-based intravenous bolus of tenecteplase.  After a protocol amendment, consent was obtained from a subset of these patients to obtain 2-year survival data and prospectively conduct long-term clinical and echocardiographic follow-up.

Primary Outcome: Death from any cause at 2 years

Results: 709 patients included (70% of entire PEITHO cohort). Compared to patients without 24-month follow-up, patients in the study had a lower mean body weight (81.8 kg vs. 84.4 kg) and less prior VTE (25% vs. 32%). Patients in the follow-up cohort had a mean age of 66.6 and 8.2% had active cancer. Overall, treatment with tenecteplase was not associated with any improvement in long-term outcomes. Notable results (tenecteplase % listed first): death from any cause between randomization and 2-year follow-up (20.3% vs. 18%), persistent clinical symptoms (36% vs. 30%), NYHA class III or IV dyspnea (12% vs. 10.9%), 1 or more echo indicators of pulmonary HTN or RV dysfunction (44.1% vs 36.6%), PASP (31.6 vs. 30.7)

Caveats: Only included a subset of the PEITHO cohort, only 40% of included patients had TTE f/u, up to 33% of patients had missing data for various endpoints, outcomes not stratified by submassive risk (i.e., rising troponin, progressive hypoxemia, etc), duration to determine risk of CTEPH may not be long enough to truly identify people who develop the disease.

Take-home Point: Among patients with submassive PE (defined by the presence of RV dysfunction and elevated troponin), systemic thrombolytics does not appear to improve long-term mortality, functional outcomes, or rates of pulmonary hypertension compared to anticoagulation alone.

Commentary

–       Despite the limitations noted above (I am not sure why assessing long-term outcomes was not a pre-specified aim of the study before it started), this is an important article.

–       The PEITHO study remains the highest quality trial of thrombolytics for submassive PE. In that trial, lytics decreased the risk of a composite endpoint of hemodynamic collapse or death within 7 days (3% with lytics vs. 6% with placebo driven almost entirely by a decrease in hemodynamic collapse) at the cost of an increased risk of bleeding including ICH (2% with lytics vs 0.2% with placebo for ICH). Important also to recognize that the inclusion criteria for PEITHO were VERY liberal – all you needed was a +trop and some evidence of RV dysfunction. Many would argue that a large # of PEITHO pts should never have been given lytics at all.

–       Based on very flawed studies (TOPCOAT, MOPPET), many clinicians give lytics for submassive PE with the goal of improving functional status and decreasing the risk of CTEPH. The results of this article should temper enthusiasm for such a strategy as there was no signal in any of the outcomes assessed that lytics was beneficial.

–       This study does not specifically address catheter-directed therapy nor does it help answer whether lytics are beneficial in particularly high-risk patients (rising troponins, mild hypoxemia, relative hypotension, rising lactate, etc.).

–       In summary, there is potentially (likely?) a role for lytics in a very high-risk group of patients with submassive PE but accumulating evidence suggests that when lytics are given to all patients who meet criteria for submassive PE, they increase rates of bleeding and provide little short or long-term benefit.

Academic Half Day 11/18/2022: Managing Respiratory Failure in the ICU Part 2

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Mechanical Ventilation in Severe Asthma

The effects of ventilatory pattern on hyperinflation, airway pressures, and circulation in mechanical ventilation of patients with severe air-flow obstruction – Am Rev Respir Dis 1987

  • Initial case series mentioned by Dr. Corbridge that described the relationship between minute ventilation, tidal volume, and inspiratory time on pulmonary hyperinflation in states of severe airflow obstruction

Mechanical ventilation for severe asthma – CHEST 2015

  • Helpful review of how to manage the ventilator in severe asthma

Management of life-threatening asthma – CHEST 2022

  • New CHEST review which provides more details on pharmacotherapies

Advanced Topics in ARDS and Ventilator Management

Acute Respiratory Distress Syndrome – Nat Rev Dis Primers 2019

  • Nice review which summarizes a lot of what we know about ARDS pathobiology

Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy – Am J Respir Crit Care Med 2013

  • Important study which found that < 50% of autopsy specimens from patients who met Berlin Criteria for ARDS had diffuse alveolar damage on pathology. Pneumonia was the most common alternative finding

New Insights into Clinical and Mechanistic Heterogeneity of the Acute Respiratory Distress Syndrome: Summary of the Aspen Lung Conference 2021 – Am J Respir Cell Mol Bio 2022

  • Summary of discussions from Aspen Lung Conference. Provides a nice review of ARDS phenotyping including hypo and hyperinflammatory  phenotypes and implications for clinical trial design

The “baby lung” became an adult – Intensive Care Med 2016

  • Easy to ready summary of “baby lung” concept in ARDS

Driving pressure and survival in the acute respiratory distress syndrome – N Engl J Med 2015

  • Re-analysis of ARDS clinical trials which found that driving pressure was strongly associated with survival and that interventions which lowered delta P were associated with improved outcomes

Fifty Years of Research in ARDS. Spontaneous Breathing during Mechanical Ventilation. Risks, Mechanisms, and Management – Am J Respir Crit Care Med 2017 

  • Nice summary of potential risks and benefits of spontaneous breathing during ARDS. Discusses transpulmonary pressure and pendelluft

Setting PEEP in ARDS

Fifty Years of Research in ARDS. Setting Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome – Am J Respir Crit Care Med 2017

  • Part of 50 years of research in ARDS series (worth reading entire series). Review several approaches to setting PEEP including driving pressure, PV curves, and esophageal pressure monitoring

Liberation from Mechanical ventilation

Summary of ACCP/ATS Liberation from IMV guidelines on this blog 

Two foundational vent liberation trials to know:

A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group – N Engl J Med 1995

  • Landmark weaning trial which found T-piece was superior to weaning by pressure support or IMV

Comparison of three methods of gradual withdrawal from ventilator support during weaning from mechanical ventilation – Am J Respir Crit Care Med 1994

  • Using the specific weaning protocols in the trial, a progressive reduction in pressure support was superior to weaning by T-piece or SIMV

Journal Club

Early Active Mobilization during Mechanical Ventilation in the ICU – N Engl J Med 2022

  • In mechanically ventilated patients, an intervention to achieve the highest possible level of mobilization that was deemed safe during daily therapy did not improve outcomes and was associated with more adverse events compared to usual care

Anaglesia and Sedation in the ICU

2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU,

 

 

 

Quantifying unintended exposure to high tidal volumes from breath-stacking dyssynchrony in ARDS: the BREATHE criteria,

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“Quantifying unintended exposure to high tidal volumes from breath-stacking dyssynchrony in ARDS: the BREATHE criteria,” Intensive Care Medicine, 2016, USA

Note: I am focusing on only one aspect of this paper, see the comments section for more details

Question: Using novel diagnostic criteria, how often does breath-stacking dyssynchrony (BSD) occur in pts with ARDS?

Study Type: Prospective observational study at 2 US hospitals

Study Population: Adult pts with ARDS placed on mechanical ventilation within the previous 24 hours were eligible provided they were ventilated in the assist-control mode. Exclusion criteria included chronic mechanical ventilation, neuromuscular disease compromising spontaneous ventilation, and impending withdrawal of full supportive care

Study Groups: Airflow and pressure were continuously recorded for 72 hours, coded by an analog-digital converter, and read directly into an analysis program. The flow-time waveform was integrated to calculate cumulative tidal volume change over consecutive machine inspiratory cycles. BSD was identified using the BREATHE criteria (consecutive inspiratory cycles + expiratory times <1 sec + expiratory volume between inspiratory cycles at least 2mL/kg PBW less than first inspiratory cycle volume + •120% set inspiratory time {for pressure-targeted breaths} + BSD TV •2mL/Kg PBW above intended TV) (essentially saying the pt inspires twice before fully exhaling the first breath). Medication administration and ventilator management were directed by the ICU team who were blinded to study analysis.

Primary Outcome: BSD as measured by the BREATHE criteria

Results: 33 pts were enrolled. Notable pt characteristics: mean age (57), shock (91%), pneumonia (83%), duration of MV prior to enrollment (16 hrs), death before discharge or day 28 (27%). Vent characteristics: VC+ (volume-targeted pressure control) (79%), VC (typical volume-cycled ventilation with a set flow rate) (21%), set TV (6 mL/kg PBW), RR (25), PEEP (10), FiO2 (50%), P/F (107). 1,841 hrs were recorded and 2,166,076 breaths were analyzed (80% without neuromuscular blockage). Observed BSD frequency was 27 (7-59) breaths/hr, peak hourly BSD frequency was 170 (55-394) breaths/hr. BSD frequency was sustained for more than 60 breaths/hr during 18% (1-37) of hrs recorded without NMB. TV during BSD was 11.3 (9.7-13.3) mL/kg PBW. Peak airway pressure minimally increased with BSD.

Caveats: Small sample size, 743 hours not recorded or included for various reasons, does not establish any connection between BSD and outcomes including ventilator-induced lung injury.

Take-home Point: Among pts with ARDS ventilated in assist-control mode, breath-stacking dyssynchrony occurs and exposes pts to potentially injurious tidal volume.

Commentary

  • The BREATHE criteria are fine, but for residents easier to just remember that BSD is “inspiratory flow triggered before complete expiration” (i.e., the pt is triggering a 2nd breath before fully exhaling the first).

  • I have purposely ignored one of the main aspects of this study: comparing the BREATHE criteria to other methods of measuring BSD. Unless you are really into reading about ventilator dyssynchrony, this part of the paper is less interesting than the more basic message that BSD occurs (sometimes quite often) in AC modes.

  • This paper is a nice reminder that when you are setting a tidal volume in either VC or VC+, this does not guarantee that this is the volume your pt will receive before exhaling. You may think your pt is receiving “lung-protective ventilation,” but frequent episodes of BSD may cause your pt to receive very large TVs (in the above study, an average Vt of 11 mL/kg PBW). These results highlight the importance of looking at ventilator waveforms in your pts and frequently evaluating synchrony.

  • Whether decreasing BSD improves outcomes remains to be seen. This is one of the proposed mechanisms by which early neuromuscular blockade may improve outcomes in ARDS but more studies are needed to prove this connection.

 

Grand Rounds: COLDSTER trial

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Thanks to Scott for summarizing this trial today! COLDSTER

Cold Weather Health Risks: A Detailed Guide | Everyday Health

In patients who had COVID 3-8 weeks ago, who have dyspnea or hypoxia and >20% abnormalities on CT, do high vs low dose steroids help and is one dose better than the other?

290 patients -> 160 excluded (82 too mild lung abnormalities)

130 randomized 1:1 -> high dose (40 x1 w then 30mg x1w then 20mgx2w then 10mg x2w) vs low dose (10mg x6w) treatment

Baseline tests, 2, 4 weeks in telephone checkin for adherence, adverse effects, final 6 week checkin – lost 4 in one arm and 5 in another arm

57yo, only 32% female, 73% had at least one comorbidity, all had required hospitalization for acute COVID, 98% having WHO severe disease, 43% received mech vent, 91% had organizing pneumonia patterns on CT

Scored images by lobe and averaged and primary outcome was >90% radiological improvement and they also had numerous subgroups.

There were low rates of ‘complete radiological response’ in both groups 25%-19%. Both groups had improvements in FVC, 6MWT, symptom scores, and overall CT scores.

Both groups had adverse effects including hyperglycemia (though only 30%), hypertension (23-21%), cushinoid habitus (20%). No deaths in either groups, 3 infections in high dose and 1 in low dose group, all treated.

It seems that in these post-acute COVID patients, low steroid dose with 10mg prednisolone performs similarly to high dose steroids to improve symptoms and imaging.

Limitations include the small size and lack of blinding. There haven’t yet been a placebo trial either, so that could be a next step. Also, was this done too soon, as patients may still have been recovering from the original infection? Multi-center would be nice as well, and blinding where able (for example, reviewers of the CT).

Thanks, Dr. Laurenzo!

ILD Roundup 11/11/22

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It’s been a few weeks since our most recent ILD roundup – we’re glad to be back! This weeks ILD conference was chock full of pearls as usual.

1. First, we discussed the implications of leukocyte telomere length (LTL) testing on decision to use immunomodulatory therapy. Recall that PANTHER-IPF showed evidence of harm in patients with IPF receiving prednisone, azathioprine and n-acetylcysteine (NAC).

 

Could LTL serve as a biomarker to predict patients at risk of harm from use of immunomodulatory therapy in IPF?   

This question was asked in a recent post-hoc analysis1 of the PANTHER-IPF2 and unpublished ACE-IPF study. The authors found that short LTL (<10%ile) was associated with an increased risk of the composite outcome of death, lung transplantation or FVC decline in those exposed to prednisone/azathioprine/NAC (HR 2.84; 1.02-7.87, p=0.04). This association was not found in either cohort when patients with LTL >10%ile were examined.  

The authors propose that this may be related to unmasking of an immune dysfunction phenotype in patients with short LTL through immunosuppression. When the same criteria were applied to an unrelated cohort of patients participating in a longitudinal observational study at UTSW, there was actually a significant improvement in the prednisone/azathioprine/mycophenolate group with LTL >10%ile.   

Kaplan-Meier curve – UTSW cohort

 

2. Our next patient was a woman in her 70s with GERD and chronic joint pain. with CT imaging after mechanical fall concerning for ILD. Has developed progressive DOE over past year, with steroid responsiveness. The overall CT pattern was most consistent with fibrotic NSIP, but perilobular opacities were also noted. A differential consideration of organizing pneumonia3 was discussed. 

 

What is a perilobular opacity?  

A perilobular opacity refers to polygonal opacity around interlobular septa and with sparing of the secondary pulmonary lobule. As Dr. Agrawal brought up to the group, this tends to have more diffuse distribution than a a “reversed halo/atoll sign” which is a focal finding.   

“Reverse halo”, or “Atoll” sign in organizing pneumonia

 

Perilobular opacity in association with bronchial wall thickening and bronchial dilation in organizing pneumonia

 

 

What are the radiographic features most consistent with organizing pneumonia, and what are their primary differential considerations?  

 

3. A final case we discussed was a former tobacco user in his 70s, with RA on MTX, Humira and prednisone, former asbestos exposure, who presented to VA clinic with progressive DOE over past 6-12 mo. A transbronchial biopsy performed in 2021 with negative cytology for malignancy but otherwise non-diagnostic. CT with showed significant asbestos related pleural disease. Reticulation was seen mostly in association with pleural plaques. Despite the diagnosis of seropositive RA, our multi-disciplinary consensus was asbestos-related pulmonary fibrosis. The question of anti-fibrotic treatment was raised.  

 

What is the evidence for antifibrotic therapy in asbestos-related pulmonary fibrosis?  

Remember, the INBUILD4 trial showed evidence of benefit (lower annual rate of FVC decline) for antifibrotics in non-IPF fibrosing ILDs. Did they include asbestos-related fibrosis? Hard to say! Looking at the supplementary information (see Table below), 81/663 patients fell into category of “other ILDs” which did include exposure-related ILDs among others, but didn’t specifically mention asbestosis.  

 

The RELIEF5 study was a phase II placebo controlled RCT that looked at use of antifibrotic agents for non-IPF ILDs (fibrosing NSIP, CHP, and asbestos related pulmonary fibrosis). Patients enrolled had experienced disease progression despite conventional therapy. Of note, only 5 of 127 patients included with asbestos-related pulmonary fibrosis. They followed patients for 48 weeks and reported a significantly lower rate of decline in FVC as a % of predicted value.   

The annual rate of decline in FVC (-36.6 vs –114.4, p=0.21) did not meet statistical significance. Why is this relevant? A quick refresher6 on the endpoints for the IPF anti-fibrotic trials:  

 

Sources:

  

 

Morning report 11/14/22

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Elderly man with history of coronary disease and heart failure presenting with respiratory failure and moderate large bilateral effusions. On lifelong DAPT.

1) Will thoracentesis help?

Dyspnea from altered respiratory mechanics (pushing down on diaphragm and against chest wall) and impaired gas exchange, hypoxemia through pulmonary shunt v/q mismatch, and thoracentesis often doesn’t have immediate effect on gas exchange.

Small study – shows improves respiratory mechanics and oxygenation.

2) What should we do about AC?

Old guidelines from 2010 recommend against, practice patterns are all over the place.  Papers with small numbers all had pretty low bleeding outcomes, especially in the hands of an experienced provider with ultrasound use.

More recently, Patel et al reported 451/8951 thoracentesis done on NOAC/antiplatelets, and there were ZERO bleeding complications. Done by IP.

Interestingly, draining one side led to less fluid on the other wise. Suspected to be Buffalo chest – plero-pleural communication – refers to life-threatening condition in which a simultaneous bilateral pneumothorax occurs due to this communication. Can be seen post-op thoracic surgery too.

Thanks for the case, Dr. Rowe!

Timothy Rowe, MD, Pulmonary and Critical Care