The following rant focuses on sepsis research, but these principles are universal. I apologize for the agitated nature of this post, but I just can’t hold it in any longer. If I read one more correlational study which tries to imply causation, I might just explode. In order to prevent burnout, I’m going to journal these thoughts instead. So, hang on to your hats, because things are going to get a bit heated.
Repeated observational studies in sepsis are fake news
Time-to-intervention studies are the most obvious offenders.
On the display floor, an exhibitor promised to reduce "door to speculum time." Just take me now, lord.
— Joe Lex (@JoeLex5) October 15, 2013
Three years ago, I wrote a post about the fallacy of time-to-intervention studies. The gist was as follows. Many studies attempt to retrospectively correlate outcomes with the time delay to therapy (e.g. door-to-needle time, door-to-antibiotic time, and my personal favorite, door-to-furosemide time). Numerous confounders tend to produce positive correlations, for example:
- Prompt treatment may correlate with better care overall (e.g. treatment at higher-quality centers, during daytime hours, in the absence of overcrowding).
- Rapid treatment may be a surrogate marker for patients who were previously healthy and present in a straightforward fashion, facilitating easy triage and diagnosis.
We’ve been hoodwinked by time-to-intervention studies before. One example is the notorious four-hour antibiotic rule in pneumonia. A few time-to-intervention studies suggested that early antibiotics for pneumonia improved outcomes. Guidelines and government regulators mandated that antibiotics must be given within four hours. Eventually it became clear that this mandate promoted misdiagnosis and clostridium difficile, causing it to be rescinded.
Time-to-intervention studies are seductive, because they make our pet interventions appear highly effective. We want to believe these studies. They are exciting. If we could just give everybody in the waiting room of the emergency department two liters of fluid and a dose of cefepime, they would all do great! Yahoo!
When I wrote that blog in 2014, I thought that it was a fairly obvious point (verging on being boring). I was wrong. The literature continues to brim with time-to-intervention studies. A new time-to-intervention study in sepsis surfaces every 3-6 months, often in major journals and to the receipt of substantial fanfare. The most prominent recent example was Seymour 2017.1
Time-to-intervention studies are methodologic junk. I’d like to perform a study correlating survival with door-to-commode time in septic shock. The study would evaluate thousands of patients, looking at the delay between hospital admission and the time when the patient was first able to sit on a commode to move their bowels. Shorter door-to-commode time would correlate with survival (because sicker patients take longer to recover enough to sit up). The obvious conclusion, of course, is that if we want septic patients to survive we need to give them a bunch of laxatives and force them onto a commode to have a bowel movement. Problem solved!
Other correlative studies are bad too
Time-to-intervention studies might be the most obvious offenders, but the literature is replete with other observational studies which gingerly attempt to imply causation. For example, let’s explore Levy 2018, a fresh study released online a few days ago:2
In 2013, New York State mandated that hospitals follow a sepsis protocol and report outcomes. This study correlates compliance with the sepsis bundle with reduced mortality. The implication is that to reduce sepsis mortality we must enforce sepsis bundles using mandated reporting.
The number of confounding factors here is legion. For example, compliance with the sepsis protocol may simply be a surrogate marker of better care. Based on the retrospective, correlational construction of this study, it’s impossible to distinguish between causation and confounding.
If we look a bit deeper into the study, it becomes clear that the results are weird and nonsensical. Let’s take a look at the bundle elements that they studied:
- Three-hour bundle:
- 3A) Administration of antibiotics
- 3B) Drawing blood cultures before administration of antibiotics
- 3C) Measuring blood lactate levels
- Six-hour bundle:
- 6A) Administration of 30 cc/kg fluid for patients with hypotension or elevated lactate
- 6B) Vasopressors for refractory hypotension
- 6C) Repeat lactate measurement
Early antibiotics, fluid, and vasopressors are probably the most useful elements here.3 Blood cultures can be helpful, but their yield is low among all comers with sepsis – so it’s unlikely that blood cultures would improve mortality much. Lactate is useful to identify sick patients, but once patients are already enrolled into a sepsis protocol the value of serial lactate levels is dubious.
The study results are shown above. According to this data:
- The most important elements are blood cultures and lactate measurement. Alternatively, vasopressor administration for refractory hypotension doesn’t matter at all.
- Checking a blood culture within three hours is equally as beneficial as completing the entire three-hour bundle (red boxes). So, if you check a set of blood cultures you don’t need to bother giving antibiotics.
This doesn’t make sense. We seem to be unraveling a complex nest of associations, rather than isolated causal relationships.
To add insult to injury, the study seems to imply that the reason the physicians were performing these interventions was because of mandated public reporting. However, there is no control group to test this hypothesis (e.g. comparison to another state which didn’t mandate reporting). Would the doctors have provided the same care without mandated reporting? Or perhaps better care? It’s impossible to tell, so any conclusion here is pure speculation.
Why keep generating hypotheses, when the hypotheses already exist?
Observational studies described above are correlational studies, which can never prove causation. As such, they are solely useful for hypothesis generation. However, hypotheses about these topics have already been generated – in fact they’ve been around for years. So, what is the purpose of a hypothesis-generating study, when hypotheses already exist?
Scientifically, these studies serve no discernable purpose. These studies instead appear to be thinly veiled attempts to prove established hypotheses using correlational data. This isn’t scientifically valid, but that doesn’t matter. If you repeat something enough times in major journals, people will start believing it’s true. Thus, these studies function largely as fake news: an insubstantial story which is dressed up to look and feel like scientific proof.
Multicenter RCTs are real news
The most rigorous way to answer questions about sepsis treatment is multicenter RCTs. Unfortunately, recently one of the most promising such studies has been threatened.
The CLOVERS trial is a prospective multi-center RCT comparing liberal crystalloids versus early vasopressors in septic shock. It is sponsored by the NHLBI and the PETAL investigators, highly esteemed organizations. Its authors are a who’s who of prominent researchers, with enrolling sites that include dozens of leading institutions (e.g. MGH, Brigham, Stanford, Duke, UPMC). The rationale for the trial is explained in a thoughtful article in the Annals of Emergency Medicine. In short, this is an extremely promising study.
Unfortunately, the study has recently met resistance from Public Citizen, a think tank in Washington DC founded by Ralph Nader.4 The group has sought media exposureto accuse the CLOVERS trial of turning patients into “unwitting guinea pigs in a physiology experiment that will not advance medical care for sepsis.” The group has various quibbles with study design, which don’t seem valid. For example, they fault CLOVERS for including only two arms, without including a third usual care arm. However, choosing two well-defined study arms is probably a wise decision, in order to ensure adequate separation of the arms and to maximize statistical power. A usual care arm would be murky, since it would consist of a hodgepodge of both strategies (depending on the whims of the treating clinician).
Methodologic foibles aside, halting a major RCT would set a dangerous precedent. There are already innumerable barriers in place to performing high-quality clinical research. Adding additional barriers (e.g., anti-research think tanks) could easily make it insurmountably difficult to accomplish clinical research in the United States.
History has taught us that RCTs frequently reveal surprising results, with major public health benefits. For example, the ORBITA trial recently compared stenting versus a sham procedure among patients with refractory chronic angina. If that study had been performed in the United States, groups like Public Citizen would undoubtedly have agitated that it was an unethical trial (perform a sham procedure to someone with refractory angina?!?). Of course, the trial revealed no benefit from stenting – proving that the study was in fact both ethical and enormously valuable.
As evidenced above, I have lots of opinions and I’m not shy about sharing them. However, I’ve never criticized a study which is in progress. There are already rigorous systems in place to ensure that trials are performed safely and ethically (e.g., IRB review, data safety monitoring boards). Interference with ongoing clinical trials is a slippery slope, because there’s always something to criticize about any study. It’s best for us to allow trialists to complete their studies unfettered by external criticism.
- Retrospective studies, which correlate the timeliness of an intervention with outcomes, have numerous confounding factors and cannot ever prove causation. This study design is extremely weak and probably doesn’t merit publication in major journals.
- Other forms of observational, correlative studies cannot prove causation either.
- There is little scientific value in performing repeated observational studies in attempts to prove an established hypothesis. The observational studies cannot either prove nor refute the hypothesis.
- Multicenter RCTs are needed to prove causality. We should encourage such studies and allow them to be performed without external interference.
Related heretical material about sepsis
- The fallacy of time-to-intervention studies (PulmCrit)
- Six myths promoted by the new Surviving Sepsis guidelines (PulmCrit)
- Petition to retire the surviving sepsis campaign guidelines (FOAMed consortium)
- Retract SSC 2018 (EMCrit podcast)
- Editorial in Annals of Emergency Medicine (Spiegel et al.)
- Sign the sepsis petition here.
- PulmCrit Hot Take: Steroid for severe pneumonia (CAPE COD trial) - March 21, 2023
- PulmCrit Blogitorial – SIESTA syndrome: Sedation Induced EEG Suppression with Transient Agitation - December 19, 2022
- PulmCrit Hot Take – Acetazolamide plus furosemide for decongestion of heart failure (ADVOR trial) - August 27, 2022
Excellent Josh, Is very important analyze design AND results of publications, not only follow the conclusions or statements. In low incomes settings or in some circunstances, not always are available lactate and cultures when start the management of the patient, AND Is possible obtain positive outcomes if use fluids, antibiotics, source control, and vasopressors, if need, opportunely.
anyone know who these two experts are?
see press release
Observational trials serve as hypothesis generating tools, yes, but also on the evidence ladder, a series of well-done set of them strengthens the potential presence of causality. In the absence of RCTs, that ain’t nothing. Sometimes there is a point.
I think that misses the point. True, there are situations in which we have to rely on observational evidence because RCTs logistically cannot be performed, but in these cases I agree that there seems little point to performing these types of analyses instead of RCTs…i.e. the “what this study adds to the field” box would be empty in the examples cited.
unless there is a consistent unmeasured confounder that is present in all of the trials. In the case of these sepsis measures, it is that uncomplicated sepsis is both easier to diagnose and have better outcomes. This has been studied and it explains why quicker treatment leads to better outcomes. Every retrospective study of folks who carry cigarette lighters in their pocket will show an association with lung ca, no matter how many you do.
Exactly! Which is why we can cure lung cancer by removing lighters from people’s pockets in under 60 minutes! Seriously, I have been so disappointed by all of this that I reached out to one of my academic, well-published friends for his take. He expressed that increasing correlation data suggests causality and he is way smarter than I am. But it just doesn’t pass the sniff test – are there lots of doctors out there saying,”yep, it’s sepsis for sure. . . . let’s hang those antibiotics in a few hours”? In a different view, the frequently cited Kumar paper… Read more »
Great, now I can’t shut up. . .
This core measure and high profile national campaign has led to everyone now carrying a diagnosis of sepsis, severe sepsis or septic shock and by including more patients that we used to call pneumonia with hypoxia or DKA and now labeling them severe sepsis, lo and behold, our mortality has gone down causing the surviving sepsis campaign to claim victory. . .
Nice rant Josh. While I agree with the majority of your post, I do believe there can be some utility to observational studies. Unfortunately, not all research questions can be answered by randomised clinical trials. They are not always feasible or ethical. In addition the questions answered from an RCT are very focused & narrowed. We know that smoking causes cancer, but there was never an RCT that proved this. This conclusion was based on multiple large well conducted observational studies that were consistent in their conclusions. (Could you imagine an RCT of smoking? As you are aware, there are… Read more »
I agree that observational/epidemiologic trials can be helpful, but we need to have a healthy respect for their limitations. Such studies may be adequate for answering a simple question (does smoking cause cancer) but not for an extremely complex question (do sepsis mandates improve outcomes compared to non-mandated personalized care?). A good example of this which I should have put in the blog is as follows. Between ~2005-2015, numerous observational trials came out implying that sepsis bundles involving invasive early goal-directed therapy seemed to reduce mortality (remember that jazz- stat central line, mixed venous oxygen sat, CVP, etc.). Several studies.… Read more »
Oh come on Josh, the different arms in ARISE, PROMISE, and PROCESS all got equivalent treatment. The only difference was in blood transfusion and dobutamine use, and these were used so infrequently the studies weren’t powered to show a difference. It was basically a study of early antibiotics (kind of funny given your rant but I agree with you in principle), moderate amounts of IV fluids titrated to CVP, and pressors vs early antibiotics, moderate amounts of IV fluids titrated to some other endpoint*, and pressors. Is it therefore really surprising that there was no difference in outcomes? As far… Read more »
I couldn’t agree more. This is partially a side effect of the requirement for publication to remain in academic medicine, which provides an incentive to publish garbage.
Yep, there are a lot of problems with the system:
– Academic incentivized to publish as many papers as possible
– Journals may be motivated to publish flashy articles (to boost their impact factor) rather than necessarily the methodologically best articles
– Many media sources will pick up journal articles and usually repeat them without much critical evaluation
FOAMed may have an important role here by providing timely and often critical feedback from a variety of perspectives.
We need more shouting about this topic. Immense harm comes from conflating retrospective, observational studies with real evidence. Remember hormone replacement therapy to prevent cardiac disease in post-menopausal women. Innumerable times observational studies have been disproven following the appropriate randomized prospective trial. For a concise list see Devereaux PJ, et al. The Need for Large Clinical Studies in Perioperative Medicine. Anesthesiology 6 2012, Vol.116, 1169-1175
Dear Josh, agree very much Plus, in addition to the inherent limitations of observational studies, they have serious methodological and statistical hacks,. I even think you need more methodological/stats knowledge in order not to do/publish/interpret nonsense. When I see a methodologically sound observational study, e.g. profSuissa’s studies on cardiovascular otucomes in copd medications- I think- never do this at home!. and when researchers use really complex methodology,( e.g. propensity match) I feel uncomfortable because I think there are not many people who are able to spot the methodological problems and publish their comments . For sure I am not able… Read more »
Just a comment on the New York State reporting – I work in several NYS hospitals and the only change their mandated reporting has brought about was the need for more paperwork. Since you are allowed to deviate from the “bundles” as long as you document why, the hospitals hire people to go around with papers and bother you during your shift to write down why any marker wasn’t met. So now we have another series of useless administrators running around increasing our paperwork burden and doing absolutely nothing to improve patient care or outcomes.
sounds awesome. we definitely need to implement this everywhere, STAT.
One more note about blood cultures:
They cannot be used as an intervention. They are a study, the results of which are not available for up to 5 days.
Thus, a blood culture is to be regarded as one would a picture; taking a picture is not an intervention, it’s an observation and has no effect on the early interventions measured.
Absolutely. It’s quite difficult for *any* intervention to improve mortality (https://emcrit.org/pulmcrit/mortality/). Would be quite strange for a diagnostic intervention with lowish yield to improve mortality.
scott asks an important question: who are these two internationally recognized sepsis experts, who were mentioned in the press release?
and i suggest reading the entire press release linked below in scotts brief comment.
the think tank, Public Citizen wants to shut down not only the CLOVERS trial, but put a “moratorium” on all NHLBI and PETAL funded trials.
read the press release.
they (public citizen) may have a point, or , if wrong and influential, there may be very grave, threatening issues ahead.
Putting a moratorium on all NHLBI & PETAL funded trials is insane.