Pulmonology – Emergency Medicine Literature of Note

BIPAP IPAP: Higher is Better?

The cornerstone of treatment for severe exacerbations of chronic obstructive pulmonary disease remains non-invasive positive pressure ventilation. Typically, this involves bi-level positive pressure settings, preventing alveolar collapse while assisting with inspiration and gas exchange. This works – most of the time. When it doesn’t work – endotracheal intubation.

This trial, the HAPPEN trial, looks at a little bit different approach. If typical BIPAP settings aren’t working, why not just IPAP harder?

In this unblinded, randomized-controlled trial, patients with acute exacerbations of COPD received traditional NIPPV with inspiratory pressures <18 cmH20 or “high-intensity” NIPPV, with airway pressures titrated up to 20-30 cmH20. The equipoise from this trial comes from a body of literature in which this “high-intensity” treatment paradigm has been used to improve respiratory physiology on an intermittent, outpatient basis. Extending these data to the acute setting, these authors aimed to use “high-intensity” NIPPV in an attempt to decrease rates of endotracheal intubation.

As per the authors report, the trial was a “success” – indeed, such a “success” it was stopped early for benefit. Among the ~150 patients in each arm, those randomized to “high-intensity” NIPPV improved their primary outcome of “need for endotracheal intubation” – 4.8% in the “high-intensity” cohort (IPAP settings of ~25 cmH2O) versus 13.7% in the “low-intensity” cohort (IPAP settings of ~18 cmH2O). These observations were durable in both unadjusted and adjusted results, as well as across most pre-specified subgroups.

However, “need for endotracheal intubation” was not the same as “received endotracheal intubation” – “need for endotracheal intubation” was a composite outcome of worsening acidosis, worsening clinical status, or respiratory arrest. In actuality, the number of patients intubated in each group were the same – 3.4% and 3.9% in each group. Crossover from “low-intensity” to “high-intensity” was permitted, however, and may have reduced the number of “low-intensity” patients requiring intubation. However, the unblinded nature of the trial confounds a bit of interpretation of the influence of the crossover event. There were more safety and adverse outcomes associated with the “high-intensity” cohort, with “abdominal distension” and intolerance of NIPPV the most frequent safety excess, and “severe alkalosis” the most frequent “serious adverse event”.

While this seems an interesting and plausible idea for treating COPD, this trial has almost-zero applicability to the emergency department. Patients enrolled in this trial were effectively “subacute” COPD inpatients whose length of illness was a median of 6 days at time of enrollment, had already been on “low-intensity” NIPPV for at least six hours, had near-normal mean pH of 7.31, and mean respiratory rate of 22 at time of randomization. These were, effectively, stable-but-not-fully-improved inpatients at a small risk for further deterioration, not the acute respiratory distress seen in the ED.

This is still an interesting idea, though, and there is likely equipoise to test NIPPV with higher inspiratory pressures in the ED. Tidal volumes, dyspnea scores, and accessory muscle use were all superior at higher IPAP settings, and may confer benefit in the acute setting. That said, I would not implement this practice without sufficient evidence from an ED setting, as the signals of IPAP intolerance may be as problematic in a patient-oriented sense as the perceived physiologic advantages.

“Effect of High-Intensity vs Low-Intensity Noninvasive Positive Pressure
Ventilation on the Need for Endotracheal Intubation in Patients With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease”
https://jamanetwork.com/journals/jama/article-abstract/2823763

Put an End to Routine Chest Tubes

If you’ve watched any television or cinema, you’ve probably seen a violent encounter or two leading to a puncture wound to the chest. The affected party is usually worse for the wear. The suffering is real.

So, if there were a way – if you suffered a pneumothorax – to forgo such an invasion of the thoracic cavity, would you? The U.S. and European guidelines regarding the necessity of such a procedure are not in agreement, and include both chest tube placement and aspiration as options. However, neither explore another option – no intervention. Now, that paradigm may be dramatically altered.

This is a rather simple trial: spontaneous pneumothorax of moderate-to-large (32% or greater, by the Collins method) would be randomized to intervention or conservative management. By intervention, patients would undergo placement of a small-bore chest tube with subsequent observation and discharge or hospital admission as necessary. By conservative, patients were observed in the Emergency Department and discharged unless worsening as defined in the study protocol. The primary outcome was full lung expansion 8 weeks after randomization, with a non-inferiority margin of -9% percentage points.

There were 316 patients randomized, and 25 of the 162 randomized to the conservative management arm underwent an intervention owing to worsening symptoms during initial observation. The remaining cases represented those assessed for outcomes at 8 weeks.

Short story: Success – full expansion in 98.5% with intervention and 94.4% with conservative management.

Long story: If patients with missing data after 56 days were imputed as treatment failures, because more of those in the conservative management arm were lost to follow-up, these data are potentially fallible.

So, this clearly indicates conservative management is probably the preferred course, recognizing a significant number will require an intervention due to early progression. The risk difference is uncertain – or “fragile” – enough the uncertainty regarding management strategies should be shared with patients, in that there could yet be an undefined disadvantage to conservative management. However, it is probably the case patients who did not undergo a drainage procedure and did not return for follow-up were asymptomatic and functioning well. The available data on long-term follow-up even better reinforces the case for conservative management, as need for additional surgical procedures and 12-month recurrences all favored the conservative arm.

These data do not address whether aspiration as an initial strategy has any value, whether in short-term functional improvement or similar long-term outcomes. Considering how well the conservative management cohort did, however, it may ultimately be challenging to show a specific advantage to adding an aspiration procedure. This may perhaps be addressed by future trials.

“Conservative versus Interventional Treatment for Spontaneous Pneumothorax”

https://www.nejm.org/doi/full/10.1056/NEJMoa1910775

YEARS, But Wells

It’s the Monday after Thanksgiving, so it’s time to turn the brains back on – and notice an oddly robust cultivation of articles worthy of comment dropped just before the holiday. This is the first, the “Pulmonary Embolism Graduated D-Dimer” (PEGeD) study, a rather obtuse name for what is effectively a pretest likelihood-adjusted implementation of D-dimer. This is also, effectively, what was done with the YEARS protocol – so, what’s new?

In this iteration of the concept, the authors use the Wells score, stratifying patients to either low, moderate, or high probability. A few published work-up algorithms describe pathways of care in which low probability leads to PERC, while the higher-risk cohort undergoes D-dimer testing or directly to CTPA to rule out PE. In this algorithm, those with “low” probability still undergo D-dimer testing – but with a cut-off threshold of 1000 ng/mL warranting advanced imaging. The primary outcome was symptomatic, objectively-verified venous thromboembolism, including PE and deep venous thrombosis, at 90 days.

These authors enrolled a cohort of 2,017 patients between 2015 and 2018, with 1,752 in the “low” probability cohort, 218 “moderate”, and 47 “high”. Overall prevalence of PE on initial testing was 7% and advanced imaging was performed on 34%, for an imaging yield of 24%. The general finding of most importance to the practicing clinician is their observation that 1,285 low-risk patients had D-dimer <1000 ng/mL and 40 moderate-risk patients had D-dimer <500 ng/mL and none had VTE detected at 90 day follow-up. Helpfully, these authors even compare their yield directly to the YEARS protocol – and find about 40 fewer patients would have undergone imaging with PEGeD than YEARS, which makes it basically a wash. They also compare their strategy to an age-adjusted D-dimer, which is a bit odd, considering they are not competing strategies, but synergistic.

The idea of pretest-adjusted D-dimer has been around a very long time, dating back to at least 2012. There’s nothing magical about a cut-off of 1000 ng/mL other than Round Numbers, but it is a serendipitously reasonable starting point for this approach. The real elephant in the room, however, is there were only 87 PEs in their low-risk cohort, for a prevalence of 4.9%. This may yet even over-represent the prevalence of PE in community practice in certain settings (read: the United States). Considering the accepted miss rate for PE is considered to be at least 1%, owing to the likelihood of false-positives and harms from anticoagulation, it is likely an even more aggressive cut-off or imaging-elimination strategy should be pursued.

However, I certainly do not want to minimize this work – adding good, prospective data pushing imaging stewardship is of great importance, whatever minor shortcomings might be observed. At the very least, please considering using PEGeD or YEARS as the basis for your imaging algorithm – and add age-adjusted D-dimer on top for even better reductions in unnecessary imaging.

“Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability”
https://www.nejm.org/doi/full/10.1056/NEJMoa1909159

Steroids for Severe Influenza?

There’s a little bit of evidence supporting the use of corticosteroids in both severe sepsis and in severe pneumonia. Severe influenza is both of these things, yet neither. Should we try corticosteroids?

Many have – but, unfortunately, few have rigorously evaluated it. This systematic review found 30 eligible studies, all of which were observational excepting one randomized trial. From this poor-quality data, associations between steroid use and increased mortality and increased hospital-acquired infection were observed. While this hardly excludes a potential benefit to steroids in selected cases of severe influenza, it certainly ought to encourage you to defer use of steroids until high-quality data supports the practice, if ever.

“Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis.”
https://www.ncbi.nlm.nih.gov/pubmed/31743228

ATS + IDSA CAP 2019

As the authors of this document lead off, it has been more than 10 years since the last American Thoracic Society/Infectious Diseases Society of America community-acquired pneumonia guideline – and much has changed. And, reflecting this, Much Has Changed.

A few interesting tidbits:

Do not obtain blood cultures in the outpatient setting, and blood cultures are recommended as inpatients only for severe CAP and when MRSA and P. aeruginosa are being covered. This, of course, is likely moot given our current triage of potential sepsis.
Basic outpatient CAP should be amoxicillin, doxycycline, or macrolide (based on local resistance) monotherapy. Add in comorbidities, and combination therapy or monotherapy with a respiratory fluoroquinolone is indicated.
Procalcitonin is not reliable to augment clinical judgment when CAP is suspected.
The Pneumonia Severity Index is the preferred decision instrument to augment clinical judgement regarding hospitalization.
Inpatient antibiotics are universally ß-lactam plus macrolide, or monotherapy with a respiratory fluoroquinolone. Empiric MRSA and P. aeruginosa coverage is suggested only if prior infection, not in those with risk factors alone.
No routine empiric anerobic coverage for suspected aspiration pneumonia.
No routine steroids for CAP, even severe.
Various recommendations regarding nfluenza and suspicion of CAP – treat with both antiviral and antibiotic therapy.
No follow-up chest x-ray documenting resolution of infiltrates is necessary in the outpatient setting if the patient is clinically improved.

Details, doses, and rationale within – many caveats, conditional recommendations, and need for additional research.

“Diagnosis and Treatment of Adults with Community-acquired Pneumonia: An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America”
https://www.atsjournals.org/doi/10.1164/rccm.201908-1581ST

CRP for COPD

If you follow this blog, you’ve probably read various critiques of the use of procalcitonin to guide antibiotic prescribing. Procalcitonin, a non-specific inflammatory marker, provides a small amount of informational value regarding the underlying etiology of infection, but my underlying criticism of its envisioned use is:

The baseline rate of antibiotic prescribing is so poor, and the likelihood of poor outcomes so low, a safe reduction in prescribing is guaranteed.
It provides about the same area-under-the-curve for predicting bacterial etiologies as C-reactive protein.
The pro-procalcitonin studies and contributions are effectively covered in the fingerprints of the manufacturers of the assay.

So, then, replace the above complaints with – well, mostly just the top one, because here we are with CRP doing the same things for which procalcitonin is advertised, and the apparent conflict-of-interest is turned down a few notches.

In this study, 86 primary care clinics in England and Wales randomized patients with a diagnosis of COPD and a clinical diagnosis of an acute exacerbation to use of point-of-care CRP testing versus usual care. Similar to those studies seen with procalcitonin, prescribers were provided guidance with respect to various CRP levels and recommendations for either prescribing, possible prescribing, or do not prescribe. The primary outcome and secondary outcomes were associated with receipt of any antibiotics, quality of life, and adverse health outcomes.

Over the course of two years, 649 patients were randomized to the two arms, with a handful of each failing to properly undergo initial study procedures. The prescribing rate at the index visit in the “usual care” group: 69.7%. The prescribing rate with CRP: 47.7%. A winner is CRP!

Except that 76% of patients had CRP less than the threshold at which antibiotics were recommended. Another 12% were in the “antibiotics maybe” group. Thus, nearly 90% of the entire cohort were suspected of having no or limited benefit to antibiotics – so, of course any safety margin to deprescribing would be satisfied. And, considering the baseline rate of prescribing was 70%, again, there is basically no possible way a stewardship intervention could fail.

The editorial accompanying this article is darkly amusing, stating “the findings from this study are compelling enough to support CRP testing as an adjunctive measure to guide antibiotic use in patients with acute exacerbations of COPD”. However, it also goes on to note these data hardly identify “which patients (if any) truly benefit from antibiotic therapy”(emphasis mine). Some trials testing 100% antibiotic prescribing vs. zero prescribing (e.g., placebo) have found minimal, or no, benefit. As with procalcitonin, our problem is a pervasive culture of over-prescribing, and ultimate answer is the same for CRP: we don’t need to introduce a marginally informative test into this low-stakes patient population, we simply need to snap out of our collective insanity.

“C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations”
https://www.nejm.org/doi/10.1056/NEJMoa1803185

Antibiotics & Hospitalization for Asthma

Reactive airway disease and asthma exacerbations. The mainstays of treatment are beta-agonist bronchodilators, systemic corticosteroids, and other adjunctive therapies as indicated. Conspicuously absent from treatment guidelines is any role for antibiotics – but that’s not stopping folks from using them.

In this retrospective data on inpatient hospitalizations comprised of 19,811 patients with acute asthma, 8,788 (44%) received antibiotics within the first two days of hospitalization. Patients receiving early antibiotics were mildly more ill than those who did not, and in their unadjusted analysis “treatment failure” was more common and length-of-stay was longer, as were antibiotic-associated adverse effects. The authors then performed a more evenly-matched propensity score analysis, featuring comparing 6,833 patients in each cohort – and find roughly the same associations, again favoring those who were not treated with antibiotics.

As usual, the limitations are the retrospective nature of a data-dredging exercise such as this, and potential for unmeasured confounders. I wouldn’t make much of the association between no-antibiotics and decreased length-of-stay, as it’s reasonable to expect confounding from selection bias at play for those receiving antibiotics and those who do not. Regardless, antibiotics were frequently used – and rather than wait for proof they are unhelpful, it seems more prudent to wait for proof they are.

There’s also been a fair bit of talk about the so-called anti-inflammatory effect of macrolides, specifically azithromycin. These represented about half the antibiotics used in these patients, and, obviously, there weren’t any further hypothesis-generating signals of benefit along that line of physiologic plausibility.

“Association of Antibiotic Treatment With Outcomes in Patients Hospitalized for an Asthma Exacerbation Treated With Systemic Corticosteroids”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2721036

To COPD, or Not to COPD

This is yet another typically Canadian study, which is to say it’s Ian G. Stiell, et al, producing yet another high-quality risk-stratification profile for Emergency Department patients.

In this week’s episode, we find our heroes prospectively validating the Ottawa COPD Risk Scale (OCRS), a set of 10 criteria identifying COPD patients in the ED at highest-risk for short-term serious outcomes. Short-term serious outcomes, by their definition, was the occurrence of death, admission to a monitored unit, intubation, non-invasive ventilation, myocardial infarction, or hospital re-admission. Their target population was effectively patients with COPD who weren’t otherwise obviously ill, with a set of exclusion criteria for those who clearly necessitated admission on the index visit.

Within their 10 items, there are 16 points available to assign, and the expected risk of short-term outcomes ranged from 2.2% at a score of 0, up to 91.4% at a score of 10. Their validation, however, demonstrated potentially important differing results – with nearly two-fold greater risks for short-term poor outcomes in the lowest (and most common) strata. Then, at the high-end, there simply weren’t enough patients with scores >4 to come to any reliable consensus regarding the accuracy of the risk stratification. In fact, of the 65 patients with scores >4, the overall incidence of serious outcome was only 23% – while the expected risk from their derivation scale would probably be upwards of 40 or 50%. Their explanation: these higher-risk patients were all hospitalized at the index visit, thereby decreasing their expected rate of short-term serious outcome. This may, in fact, be true, but it is rather a hypothesis rather than a well-supported conclusion.

The other question, even assuming this tool is valid, is “what now?” The authors emphasize these data and risk levels are not necessarily prescriptive, but rather give the clinician an objective tool to supplement their decision-making. Will incorporating this tool this improve care delivery and outcomes? Unfortunately, it is impossible to tell. These authors have done the “easy” research, a data collection and number-crunching exercise. Determining its effect on clinical care is another, much harder step – and fraught with limitations due to generalizability from one practice setting to another. I would be wary of incorporating this into your clinical care until better data is available regarding its effect on patient-oriented and resource utilization outcomes – unless you’re ready to prospectively study it!

“Clinical validation of a risk scale for serious outcomes among patients with chronic obstructive pulmonary disease managed in the emergency department”

http://www.cmaj.ca/content/190/48/E1406

TACO Time!

One of the best acronyms in medicine: TACO. Of no solace to those afflicted by it, transfusion-related circulatory overload is one of the least-explicitly recognized complications of blood product transfusion. The consent for blood products typically focuses on the rare transmissibility of viruses and occurrence of autoimmune reactions, yet TACO is far more frequent.

This report from an ongoing transfusion surveillance study catalogued 20,845 patients receiving transfusions of 128,263 blood components. The incidence of TACO was one case per 100 transfused patients. Then, these authors identified 200 patients suffering TACO, and compared their baseline characteristics to 405 patients receiving similar transfusion intensity, but who did not develop TACO. Clinically relevant risk factors for developing TACO identified in their analysis were, essentially:

Congestive heart failure
End-stage or acute renal disease
End-stage liver disease
Need for emergency surgery

… or, basically, the population for whom a propensity for circulatory overload would be expected. It appears, generally speaking, clinicians were aware of the increased risks in these specific patients, as a greater percentage received diuretic treatment prior to transfusion as well. 30-day mortality in those suffering TACO was approximately 20%, roughly double that of those matched controls.

More good reasons to adhere to as many restrictive transfusion guidelines as feasible.

“Contemporary Risk Factors and Outcomes of Transfusion-Associated Circulatory Overload”

https://www.ncbi.nlm.nih.gov/pubmed/29300236

Category: Pulmonology