Pathologizing Lipid Laden Macrophages (LLMs) in Vaping Associated Lung Injury (VALI)

It's time to weigh in on an ongoing debate being waged in the correspondence pages of the NEJM.  To wit, what is the significance of lipid laden macrophages (LLMs) in VALI?  As we stated, quite clearly, in our original research letter,

"Although the pathophysiological significance of these lipid-laden macrophages and their relation to the cause of this syndrome are not yet known, we posit that they may be a useful marker of this disease.3-5 Further work is needed to characterize the sensitivity and specificity of lipid-laden macrophages for vaping-related lung injury, and at this stage they cannot be used to confirm or exclude this syndrome. However, when vaping-related lung injury is suspected and infectious causes have been excluded, the presence of lipid-laden macrophages in BAL fluid may suggest vaping-related lung injury as a provisional diagnosis."

There, we outlined the two questions about their significance:  1.) any relation to the pathogenesis of the syndrome; and 2.) whether, after characterizing their sensitivity and specificity, they can be used in diagnosis.  I am not a lung biologist, so I will ignore the first question and focus on the second, where I actually do know a thing or two.

We still do not know the sensitivity or specificity of LLMs for VALI, but we can make some wagers based on what we do know.  First, regarding sensitivity.  In our ongoing registry at the University of Utah, we have over 30 patients with "confirmed" VALI (if you dont' have a gold standard, how do you "confirm" anything?), and to date all but one patient had LLMs in excess of 20% on BAL.  For the first several months we bronched everybody.  So, in terms of BAL and LLMs, I'm guessing we have the most extensive and consistent experience.  Our sensitivity therefore is over 95%.  In the Layden et al WI/IL series in NEJM, there were 7 BAL samples and all 7 had "lipid Layden macrophages" (that was a pun).  In another Utah series, Blagev et al reported that 8 of 9 samples tested showed LLMs.  Combining those data (ours are not yet published, but soon will be) we can state the following:  "Given the presence of VALI, the probability of LLM on Oil Red O staining (OROS) is 96%."  You may recognize that as a statement of sensitivity.  It is unusual to not find LLMs on OROS of BAL fluid in cases of VALI, and because of that, their absence makes the case atypical, just as does the absence of THC vaping.  Some may go so far as to say their absence calls into question the diagnosis, and I am among them.  But don't read between the lines.  I did not say that bronchoscopy is indicated to look for them.  I simply said that their absence makes the case atypical and calls it into question.

You Have No Idea of the Predictive Value of Weaning Parameters for Extubation Success, and You Probably Never Will

As Dr. O'brien eloquently described in this post, many people misunderstand the Yang-Tobin (f/Vt) index as being a "weaning parameter" that is predictive of extubation success.  Far from that, it's sensitivity and specificity and resultant ROC curve relate to the ability of f/Vt after one minute of spontaneous ventilation to predict the success of a prolonged (~ one hour) spontaneous breathing trial.  But why would I want to predict the result of a test (the SBT), and introduce error, when I can just do the test and get the result an hour later?  It makes absolutely no sense.  What we want is a parameter that predicts extubation success.  But we don't have that, and we probably will never have that.

In order to determine the sensitivity and specificity of a test for extubation success, we will need to ascertain the outcome in all patients regardless of their performance on the test of interest.  That means we would have to extubate patients that failed the weaning parameter test.  In the original Yang & Tobin article, their cohort consisted of 100 patients.  60(%) of the 100 were said to have passed the weaning test and were extubated, and 40(%) failed and were not extubated.  (There is some over-simplification here based on how Yang & Tobin classified and reported events - its not at all transparent in their article - the data to resolve the issues are not reported and the differences are likely to be small.  Suffice it to say that about 60% of their patients were successfully weaned and the remainder were not.)  Let's try to construct a 2x2 table to determine the sensitivity and specificity of a weaning parameter using a population like theirs.  The top row of the 2x2 table would look something like this, assuming an 85% extubation success rate - that is, of the 60 patients with a positive or "passing" SBT score (based on whatever parameter), all were extubated and the positive predictive value of the test is 85% (the actual rate of reintubation in patients with a passing weaning test is not reported, so this is a guess):

The Respiratory Rosenhan Experiment on Obese Patients

Normally this post would be on Status Iatrogenicus, but the implications for "evidence" and the EBM movement are too important, so it goes here.

For those not inclined to read about the Rosenhan Experiment, a brief history.  In the early 1970s, Dr. Rosenhan a Stanford psychologist, was concerned about the validity of psychiatric diagnoses.  So he and a half dozen confederates faked mental illness and presented themselves to several prominent psychiatric facilities.  Their feigned symptoms were sufficient to have them admitted with psychiatric diagnoses, usually paranoid schizophrenia.  After admission, they behaved normally.  Nonetheless, they had been diagnosed, put on psychotropic medications, and not allowed to leave until they signed documents swearing to continue the medications upon their release.  The damning report of this experiment was published in Science Magazine in 1973 with the title "On Being Sane in Insane Places."

Psychiatric hospitals were blindsided, having been caught unawares and humiliated.  They challenged Rosenhan to "do it again", but the second time they would be vigilant about these disimulations.  Send us some more fakes, they said.  On the second experiment, they determined that 40 some patients were confederates.  But Rosenhan had the upper RosenHand - he had send no confederates.  Sensitivity, if it can be called that, suffered to specificity on round two.

Previously I have complained about patients who are intubated but needn't have been (see here, and here.)  Oftentimes, after the fact, it is difficult to determine whether the intubation was necessary, especially with alleged upper airway compromise, and with obese patients.  With the latter, roentgenograms of the chest are difficult to interpret because of "fatelectasis" or atelectasis in obese persons,  "flatelectasis" due to recumbency, fluid loading after paralysis and intubation, all which may require high PEEP to counteract.  If you were not present prior to intubation, it is very difficult to determine if respiratory distress preceded the intubation, or if "won't breathe" was mistaken for "can't breathe".  The differentiation between those two entities is "critical".

A man in his late 40s was sent to us recently for "acute respiratory failure" on the ventilator receiving 100% FiO2 and PEEP of 16.  EMS responded to a call to his 18-wheeler that he could not breathe.  His SpO2 was in the 50% range and he was admitted to a local hospital.  There were basilar opacities, and oxygen was administered.   He weighed near 500#.  The opacities were said to represent pneumonia and he was given antibiotics.  Not long after admission, in the middle of the night, he could not be aroused, an ABG was obtained, and his PaCO2 was 90-something with a pH of 7.10 or thereabouts.  This was interpreted to represent acute hypercapneic respiratory failure, on top of his "acute hypoxemic respiratory failure" and an hour-long intubation ensued.  Afterwards he was sent to us on the aforementioned high ventilator settings.

Trial of Extubation: An Informed Empiricist’s Approach to Ventilator Weaning

“The only way of discovering the limits of the possible is to venture a little way past them into the impossible.”    –Clark’s Second Law

In the first blog post, Dr. Manthous invited Drs. Ely, Brochard, and Esteban to respond to a simple vignette about a patient undergoing weaning from mechanical ventilation.  Each responded with his own variation of a cogent, evidence based, and well-referenced/supported approach.  I trained with experts of similar ilk using the same developing evidence base, but my current approach has evolved to be something of a different animal altogether.  It could best be described as a “trial of extubation”.  This approach recently allowed me to successfully extubate a patient 15 minutes into a trial of spontaneous breathing, not following commands, on CPAP 5, PS 5, FiO2 0.5 with the vital parameters in the image accompanying this post (respiratory rate 38, tidal volume 350, heart rate 129, SpO2 88%, temperature 100.8).  I think that any account of the “best” approach to extubation should offer an explanation as to how I can routinely extubate patients similar to this one, who would fail most or all of the conventional prediction tests, with a very high success rate.

A large part of the problem lies in shortcomings of the data upon which conventional prediction tests rely.  For example, in the landmark Yang and Tobin report and many reports that followed, sensitivity and specificity were calculated considering physicians’ “failure to extubate” a patient as equivalent to an “extubation failure”.  This conflation of two very different endpoints makes estimates of sensitivity and specificity unreliable.  Unless every patient with a prediction test is extubated, the sensitivity of a test for successful extubation is going to be an overestimate, as suggested by Epstein in 1995.   Furthermore, all studies have exclusion criteria for entry, with the implicit assumption that excluded patients would not be extubatable with the same effect of increasing the apparent sensitivity of the tests.

Even if we had reliable estimates of sensitivity and specificity of prediction tests, the utility calculus has traditionally been skewed towards favoring specificity for extubation success, largely on the basis of a single 20-year old observational study suggesting that patients who fail extubation have a higher odds of mortality.  I do not doubt that if patients are allowed to “flail” after it becomes clear that they will not sustain unassisted ventilation, untoward outcomes are likely.  However, in my experience and estimation, this concern can be obviated by bedside vigilance by nurses and physicians in the several hours immediately following extubation (with the caveat that a highly skilled airway manager is present or available to reintubate if necessary).  Furthermore, this period of observation provides invaluable information about the cause of failure in the event failure ensues.  There need be no further guesswork about whether the patient can protect her airway, clear her secretions, maintain her saturations, or handle the work of breathing.  With the tube removed, what would otherwise be a prediction about these abilities becomes an observation, a datapoint that can be applied directly to the management plan for any subsequent attempt at extubation should she fail – that is, the true weak link in the system can be pinpointed after extubation.

The specificity-heavy utility calculus, as I have opined before, will fail patients if I am correct that an expeditious reintubation is not harmful, but each additional day spent on the ventilator confers incremental harm.  Why don’t I think reintubations are harmful?  Because when my patients fail, I am diligent about rapid recognition, I reintubate without observing complications, and often I can extubate successfully the next day, as I did a few months ago in a patient with severe ARDS.  She had marginal performance (i.e., she failed all prediction tests) and was extubated, failed, was reintubated, then successfully extubated the next day.  (I admit that it was psychologically agonizing to extubate her the next day.  They say that a cat that walks across a hot stove will never do so again.  It also will not walk on a cold stove again.  This psychology deserves a post of its own.)

When I tweeted the image attached to this post announcing that the patient (and many like her) had been successfully extubated, there was less incredulity than I expected, but an astute follower asked – “Well, then, how do you decide whom and when to extubate?”  I admit that I do not have an algorithmic answer to this question.  Experts in opposing camps of decision psychology such as Kahneman and his adherents in the heuristics and biases camp and Gary Klein, Gird Gigerenzer and others in the expert intuition camp could have a heyday here, and perhaps some investigation is in order.  I can summarize by saying that it has been an evolution over the past 10 or so years.  I use everything I learned from the conventional, physiologic, algorithmic, protocolized, data-driven, evidence-based approach to evaluate a patient.  But I have gravitated to being more sensitive, to capture those patients that the predictors say should fail, and I give them a chance – a “trial of extubation.”  If they fail, I reintubate quickly.  I pay careful attention to respiratory parameters, mental status, and especially neuromuscular weakness, but I integrate this information into my mental map of the natural history of the disease and the specific patient’s position along that course to judge whether they have even a reasonable modicum of a chance of success.  If they do, I “bite the bullet and pull it.”

I do not eschew data, I love data.  But I am quick to recognize their limitations.  Data are generated for many reasons and have different values to different people with different prerogatives.  From the clinician’s and the patient’s perspective, the data are valuable if they reduce the burden of illness.  I worry that the current data and the protocols predicated on them are failing to capture many patients who are able to breathe spontaneously but are not being given the chance.  Hard core evidence based medicine proponents and investigators need not worry though, because I have outlined a testable hypothesis:  that a “trial of extubation” in the face of uncertainty is superior to the use of prediction tests and protocols.  The difficult part will be determining the inclusion and exclusion criteria, and no matter what compromise is made uncertainty will remain, reminding us that science is an iterative, evolving enterprise, with conclusions that are always tentative.

Much Ado About Nothing? The Relevance of New Sepsis Definitions for Clinical Care Versus Research

What's in a name?  That which we call a rose, by any other name would smell as sweet. - Shakespeare, Romeo and Juliet Act II Scene II

The Society of Critical Care Medicine is meeting this week, JAMA devoted an entire issue to sepsis and critical illness, and my twitter feed is ablaze with news of release of a new consensus definition of sepsis.  Much laudable work has been done to get to this point, even as the work is already generating controversy (Is this a "first world" definition that will be forced upon second and third world countries where it may have less external validity?  Why were no women on the panel?).  Making the definition of sepsis more reliable, from a sensitivity and specificity standpoint (more accurate) is a step forward for the sepsis research enterprise, for it will allow improved targeting of inclusion criteria for trials of therapies for sepsis, and better external validity when those therapies are later applied in a population that resembles those enrolled.  But what impact will/should the new definition have on clinical care?  Are the-times-they-are-a-changing?

Diagnosis, a fundamental goal of clinical medicine is important for several reasons, chief among them:

1. To identify the underlying cause of symptoms and signs so that treatments specific to that illness can be administered
2. To provide information on prognosis, natural history, course, etc for patients with or without treatment
3. To reassure the physician and patients that there is an understanding of what is going on; information itself has value even if it is not actionable

Thus redefining sepsis (or even defining it in the first place) is valuable if it allows us to institute treatments that would not otherwise be instituted, or provides prognostic or other information that is valuable to patients.  Does it do either of those two things?

Dear SIRS: Your Septic System Stinks

I perused with interest the April 2nd JAMA article on the temporal improvement in severe sepsis outcomes in Australia and New Zealand (ANZ) by Kaukonen et al this week.  Epidemiological studies like this remind me why I'm so fond of reading reports of RCTs:  because they're so much easier to think about.  Epidemiological studies have so many variables, measured and unmeasured, and so much confounding you have to consider. I spent at least five hours poring over the ANZ report, and then comparing it to the recent NEJM article about improved diabetes complications between 1990 and 2010, which is similar, but a bit more convincing (perhaps the reason it's in the NEJM).

I was delighted that the authors of the ANZ study twice referenced our delta inflation article and that the editorialists agree with the letter I wrote to AJRCCM last year advocating composite morbidity outcomes in trials of critical illness.  These issues dovetail - we have a consistent track record of failure to demonstrate mortality improvements in critical care, while we turn a blind eye to other outcomes which may be more tractable and which are often of paramount concern to patients.