When Aggressive Sepsis Treatment Kills

Much has been made of efforts to detect and treat sepsis as early as possible after presentation, with many post-hoc analyses seeming to demonstrate time-sensitive mortality benefits associated with receiving the various components included in our “quality” measures. However, just like early goal-directed therapy back in the day, it has never truly become clear which element of early sepsis care confers the survival benefit. Absent specific data regarding how to best tailor therapy to the individual patient, we simply bludgeon everyone with the same sepsis bundle.

And, as we see here, that generalization is likely harmful.

This is a small randomized trial from Zambia – not to be confused with Nambia – in which 212 patients presenting with suspected infection, at least 2 systemic inflammatory response syndrome criteria, and hypotension were randomized to an early resuscitation protocol or “usual care”. The early resuscitation protocol sounds, generally speaking, similar to our modern approach to sepsis care – early intravenous fluid boluses with frequent intravascular volume assessment, vasopressors, and transfusions for severe anemia. The usual care cohort received, essentially, the same, only less so.

The two groups enrolled were roughly equivalent – but nothing like our sepsis cohort here in the United States. Approximately 90% of the patients enrolled were positive for the human immunodeficiency virus, half of the positive culture results were tuberculosis, the mean hemoglobin was 7.8 g/dL, and the majority of patients had been bedridden for over a week prior to presentation. Intravascular volume status and response to resuscitation was assessed by evaluating jugular venous pressure, tachypnea, and peripheral oxygenation. Finally, unlike many modern settings, most patients received dopamine as their vasopressor of choice and were admitted to general medical wards rather than intensive care units. In short, these are patients and care settings unlike in most industrial nations.

Mortality, not unexpectedly, was high – but it was much higher in those randomized to the early resuscitation cohort. Mortality in those receiving early resuscitation was 48.1%, compared with 33.0% in those receiving usual care. This mortality different then persisted out to 28 days, with over 60% mortality in the early resuscitation group at that time, compared with just over 40% in usual care.

This trial does not necessarily call into question the general principles of modern sepsis care, but it certainly provides a couple valuable lessons. The first, and most obvious, is the cautionary tale regarding generalizing research findings from one setting to another. Even a reasonably important, beneficial effect size can be transformed into a greater magnitude of harm if applied in another clinical setting. Then, this should clearly make us re-examine our current approach to sepsis care to ensure there is not a subgroup for whom early resuscitation is, in fact, the wrong answer. Our blind pursuit of checking boxes for quality measures, while generating an overall beneficial effect, is probably resulting in waste and harms for a substantial subgroup of those presenting with sepsis and septic shock.

“Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension”
http://jamanetwork.com/journals/jama/fullarticle/2654854

It’s Sepsis-Harassment!

The computer knows all in modern medicine. The electronic health record is the new Big Brother, all-seeing, never un-seeing. And it sees “sepsis” – a lot.

This is a report on the downstream effects of an electronic sepsis alert system at an academic medical center. Their sepsis alert system was based loosely on the systemic inflammatory response syndrome for the initial warning to nursing staff, followed by additional alerts triggered by hypotension or elevated lactate. These alerts prompted use of sepsis order sets or triggering of internal “sepsis alert” protocols. Their outcomes of interest in their analysis were length-of-stay and in-hospital mortality.

At first glance, the alert appears to be a success – length of stay dropped from 10.1 days to 8.6, and in-hospital mortality from 8.5% to 7.0%. It would have been quite simple to stop there and trumpet these results as favoring the alerts, but the additional analyses performed by these authors demonstrate otherwise. In the case of both length-of-stay and mortality, both of those measures were trending downward independently regardless of the intervention, and in their adjusted analyses, none of the improvements could be conclusively tied to the sepsis alerts – and some relating to diagnoses of less-severe cases of sepsis probably prompted by the alert itself.

What is not debatable, however, is the burden on clinicians and staff. During their ~2.5 year study period, the sepsis alerts were triggered 97,216 times – 14,207 of which in the 2,144 subsequently receiving a final diagnosis of sepsis. The SIRS-based alerts comprised most (83,385) of these alerts, but only captured 73% of those with an ultimate diagnosis of sepsis, while having only a 13% true positive rate. The authors’ conclusion gets it right:

Our results suggest that more sophisticated approaches to early identification of sepsis patients are needed to consistently improve patient outcomes.

“Impact of an emergency department electronic sepsis surveillance system on patient mortality and length of stay”
https://academic.oup.com/jamia/article-abstract/doi/10.1093/jamia/ocx072/4096536/Impact-of-an-emergency-department-electronic

Now It’s Fluids that Matter in Sepsis?

A few weeks ago, there was an article in the New England Journal of Medicine that dredged a retrospective data set to generate an association between timeliness different elements of a sepsis bundle and outcomes. In their analysis, antibiotics, but not fluid administration, was associated with a mortality increase. This has, at least, face validity – although, the association between timely blood cultures and serum lactate a little less so.

Now, conversely, we have another sepsis registry review attempting to tie time to fluid administration to mortality. This quality improvement registry prospectively identified patients with sepsis – and retrospectively abstracted their clinical data – between 2014 and 2016, resulting in a database of 11,182. In their analysis, mortality for patients receiving their first crystalloid within 30 minutes or within 30-120 minutes was ~18%, while mortality for patients whose fluids were initiated beyond the 120 minute limit was 24.5%.

Again, however, because these are comparisons performed on observational data, it is still subject to the slings and arrows of unmeasured confounders. Most patients whose fluid administration was started early had their care initiated in the Emergency Department – and, in clearly co-linear processes, had major elements of their care completed appropriately. This included repeat lactate measurements, antibiotics within 180 minutes of time zero, and, not only IVF within 120 minutes, but frankly, any IVF at at all. Nearly 60% of patients analyzed for their >120 minute cohort received <5 mL/kg or zero IVF in their first six hours from measurement time zero.

This is, probably, another study just cherry picking out one single feature of an entire process predicated on timely identification and treatment of sepsis. These patients did not simply have a mortality advantage because of the timeliness of IVF – it ties in to all aspects of care and attention given sepsis patients properly identified. The effect size here is probably less associated with delays just in IVF, but a comprehensive delay in diagnosis – and all its associated therapeutic misadventures.

“Patterns and Outcomes Associated With Timeliness of Initial Crystalloid Resuscitation in a Prospective Sepsis and Septic Shock Cohort”

http://journals.lww.com/ccmjournal/Abstract/publishahead/Patterns_and_Outcomes_Associated_With_Timeliness.96558.aspx

What Does a Sepsis Alert Gain You?

The Electronic Health Record is no longer simply that – a recording of events and clinical documentation.  Decision-support has, for good or ill, morphed it into a digital nanny vehicle for all manner of burdensome nagging.  Many systems have implemented a “sepsis alert”, typically based off vital signs collected at initial assessment. The very reasonable goal is early detection of sepsis, and early initiation of appropriately directed therapy. The downside, unfortunately, is such alerts are rarely true positives for severe sepsis in broadest sense – alerts far outnumber the instances in a change of clinical practice results in a change in outcome.

So, what to make of this:

This study describes a before-and-after performance of a quality improvement intervention to reduce missed diagnoses of sepsis, part of which was introduction of a triage-based EHR alert. These alerts fired during initial assessment based on abnormal vital signs and the presence of high-risk features. The article describes baseline characteristics for a pre-intervention phase of 86,037 Emergency Department visits, and then a post-intervention phase of 96,472 visits. During the post-intervention phase, there were 1,112 electronic sepsis alerts, 265 of which resulted in initiation of sepsis protocol after attending physician consultation.  The authors, generally, report fewer missed or delayed diagnoses during the post-intervention period.

But, the evidence underpinning conclusions from these data – as relating to improvements in clinical care or outcomes, or even the magnitude of process improvement highlighted in the tweet above – is fraught. The alert here is reported as having a sensitivity of 86.2%, and routine clinical practice picked up nearly all of the remaining cases that were alert negative.  The combined sensitivity is reported to be 99.4%.  Then, the specificity appears to be excellent, at 99.1% – but, for such an infrequent diagnosis, even using their most generous classification for true positives, the false alerts outnumbered the true alerts nearly 3 to 1.

And, that classification scheme is the crux of determining the value of this approach. The primary outcome was defined as either treatment on the ED sepsis protocol or pediatric ICU care for sepsis. Clearly, part of the primary outcome is directly contaminated by the intervention – an alert encouraging use of a protocol will increase initiation, regardless of appropriateness. This will not impact sensitivity, but will effectively increase specificity and directly inflate PPV.

This led, importantly, for the authors to include a sensitivity analysis looking at their primary outcome. This analysis looks at the differences in overall performance if stricter rules for a primary outcome might be entertained. These analyses evaluate the predictive value of the protocol if true positives are restricted to those eventually requiring vasoactive agents or pediatric ICU care – and, unsurprisingly, even this small decline in specificity results in dramatic drops in PPV – down to 2.4% for the alert alone.

This number better matches the face validity we’re most familiar with for these simplistic alerts – the vast majority triggered have no chance of impacting clinical care and improving outcomes. It should further be recognized the effect size of early recognition and intervention for sepsis is real, but quite small – and becomes even smaller when the definition broadens to cases of lower severity. With nearly 100,000 ED visits in both the pre-intervention and post-intervention periods, there is no detectable effect on ICU admission or mortality. Finally, the authors focus on their “hit rate” of 1:4 in their discussion – but, I think it is more likely the number of alerts fired for each each case of reduced morbidity or mortality is on the order of hundreds, or possibly thousands.

Ultimately, the reported and publicized magnitude of the improvement in clinical practice likely represents more smoke and mirrors than objective improvements in patient outcomes, and in the zero-sum game of ED time and resources, these sorts of alerts and protocols may represent important subtractions from the care of other patients.

“Improving Recognition of Pediatric Severe Sepsis in the Emergency Department: Contributions of a Vital Sign–Based Electronic Alert and Bedside Clinician Identification”

http://www.annemergmed.com/article/S0196-0644(17)30315-3/abstract

Angiotensin II for Refractory Shock

If you blockade the angiotensin receptor system, you have a treatment for hypertension. If you agonize that same system, it logically follows you may have a corresponding treatment for hypotension. So, this is ATHOS-3, a phase 3 trial of synthetic human angiotensin II infusion in patients with catecholamine-resistant shock.

Roughly speaking, this is a trial evaluating the effectiveness of angiotensin for improving hemodynamic parameters in adult patients in vasodilatory shock – defined by the trialists as based on sufficient cardiac index, intravascular volume measurements, and persistent hypotension. Enrolled patients also needed to display ongoing hemodynamic derangement despite “high-dose vasopressors”. Exclusion criteria abound. The primary outcome was achievement of mean arterial pressure targets at 3 hours after initiation of angiotensin or placebo infusion.

Over the ~1.5 year study period, 404 patients were screened to ultimately initiate study protocol in 321. There’s little ambiguity with respect to the primary outcome – 69.9% of patients met MAP targets in the angiotensin cohort compared with 23.4% with placebo. Improvement in MAP led to corresponding downtitration of catchecholamine vasopressors in the intervention cohort. The intervention cohort displayed improvements in the cardiovascular SOFA, but no difference in overall SOFA at 48 hours. Mortality was quite high, regardless of group assignment, and no reliable difference was noted. Adverse events were common in each group with, again, no reliable differences detected.

This trial is mostly just interesting from a scientific awareness standpoint. The beneficial or harmful effects of angiotensin infusion are not established by these data. The enrolled population – approximately one patient every four months per site, on average – cannot be reliably generalized. As with any sponsored trial replete with conflict of interest among the authors – and particularly those with slow enrollment due to extensive exclusions – skepticism is particularly warranted. That said, this novel vasopressor clearly warrants additional study and comparative effectiveness evaluation.

“Angiotensin II for the Treatment of Vasodilatory Shock”
http://www.nejm.org/doi/full/10.1056/NEJMoa1704154

Blood Cultures Save Lives and Other Pearls of Wisdom

It’s been sixteen years since the introduction of Early Goal-Directed Therapy in the Emergency Department. For the past decade and a half, our lives have been turned upside-down by quality measures tied to the elements of this bundle. Remember when every patient with sepsis was mandated to receive a central line? How great were the costs – in real, in time, and in actual harms from these well-intentioned yet erroneous directives based off a single trial?

Regardless, thanks to the various follow-ups testing strict protocolization against the spectrum of timely recognition and aggressive intervention, we’ve come a long way. However, there are still mandates incorporating the vestiges of such elements of care –such as those introduced by the New York State Department of Health. Patients diagnosed with severe sepsis or septic shock are required to complete protocols consisting of 3-hour and 6-hour bundles including blood cultures, antibiotics, and intravenous fluids, among others.

This article, from the New England Journal, looks retrospectively at the mortality rates associated with completion of these various elements. Stratified by time-to-completion following initiation of the 3-hour bundle within 6 hours of arrival to the Emergency Department, these authors looked at the mortality associations of the bundle elements.

Winners: obtaining blood cultures, administering antibiotics, and measuring serum lactate
Losers: time to completion of a bolus of intravenous fluids

Of course, since blood cultures are obtained prior to antibiotic administration, these outcomes are co-linear – and they don’t actually save lives, as facetiously suggested in the post heading. But, antibiotic administration was associated with a fraction of a percent of increased mortality per hour delay over the first 12 hours after initiation of the bundle. Intravenous fluid administration, however, showed no apparent association with mortality.

These data are fraught with issues, of course, relating to their retrospective nature and the limitations of the underlying data collection. Their adjusted model accounts for a handful of features, but there are still potential confounders influencing mortality of those who received their bundle completion within 3 hours as compared to those who did not.  The differences in mortality, while a hard and important endpoint, are quite small.  Earlier is probably better, but the individual magnitude of benefit will be unevenly distributed around the average benefit, and while a delay of several hours might matter, minutes probably do not.  The authors are appropriately reserved with their conclusions, however, only stating these observational data support associations between mortality and antibiotic administration, and do not extend to any causal inferences.

The lack of an association between intravenous fluids and mortality, however, raises significant questions requiring further prospective investigation. Could it be, after these years wandering in the wilderness with such aggressive protocols, the only universally key feature is the initiation of appropriate antibiotics? Do our intravenous fluids, given without regard to individual patient factors, simply harm as many as they help, resulting in no net benefit?

These questions will need to be addressed in randomized controlled trials before the next level of evolution in our approach to sepsis, but the equipoise for such trials may now exist – to complete our journey from Early Goal-Directed to Source Control and Patient-Centered.  The difficulty will be, again, in pushing back against well-meaning but ill-conceived quality measures whose net effect on Emergency Department resource utilization may be harm, with only small benefits to a subset of critically ill patients with sepsis.

“Time to Treatment and Mortality during Mandated Emergency Care for Sepsis”

http://www.nejm.org/doi/full/10.1056/NEJMoa1703058

Vitamin C for Sepsis

This is just a quick post in response to a tweet – and hype-machine press-release – making the rounds today.

This covers a before-and-after study regarding a single-center practice change in an intensive care unit where their approach to severe sepsis was altered to a protocol including intravenous high-dose vitamin C (1.5g q6), intravenous thiamine (200mg q12), and hydrocortisone (50mg q6). Essentially, this institution hypothesized this combination might have beneficial physiologic effects and, after witnessing initial anecdotal improvement, switched to this aforementioned protocol. This report describes their outcomes in the context of comparing the treatment group to similar patients treated in the seven months prior.

In-hospital mortality for patients treated on the new protocol was 8.5%, whereas previously treated patients were subject to 40.4% mortality. Vasopressor use and acute kidney injury was similarly curtailed in the treatment group. That said, these miraculous findings – as they are exhorted in the EVMS press release – can only be considered as worthy of further study at this point. With a mere 47 patients in both treatment groups, a non-randomized, before-and-after design, and other susceptibilities to bias, these findings must be prospectively confirmed before adoption. When considered in the context of Ioannidis’ “Why Most Published Research Findings Are False”, caution is certainly advised.

I sincerely hope prospective, external validation will yield similar findings – but will likewise not be surprised if they do not.

“Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study”
https://www.ncbi.nlm.nih.gov/pubmed/27940189

A qSOFA Trifecta

There’s a new sepsis in town – although, by “new” it’s not very anymore. We’re supposedly all-in on Sepsis-3, which in theory is superior to the old sepsis.

One of the most prominent and controversial aspects of the sepsis reimagining is the discarding of the flawed Systemic Inflammatory Response Syndrome criteria and its replacement with the Quick Sequential Organ Failure Assessment. In theory, qSOFA replaces the non-specific items from SIRS with physiologic variables more closely related to organ failure. However, qSOFA was never prospectively validated or compared prior to its introduction.

These three articles give us a little more insight – and, as many have voiced concern already, it appears we’ve just replaced one flawed agent with another.

The first article, from JAMA, describes the performance of qSOFA against SIRS and a 2-point increase in the full SOFA score in an ICU population. This retrospective analysis of 184,875 patients across 15 years of registry data from 182 ICUs in Australia and New Zealand showed very little difference between SIRS and qSOFA with regard to predicting in-hospital mortality. Both screening tools were also far inferior to the full SOFA score – although, in practical terms, the differences in adjusted AUC were only between ~0.69 for SIRS and qSOFA and 0.76 for SOFA. As prognostic tools, then, none of these are fantastic – and, unfortunately, qSOFA did not seem to offer any value over SIRS.

The second article, also from JAMA, is some of the first prospective data regarding qSOFA in the Emergency Department. This sample is 879 patients with suspected infection, followed for in-hospital mortality or ICU admission. The big news from this article is the AUC for qSOFA of 0.80 compared with the 0.65 for SIRS or “severe sepsis”, as defined by SIRS plus a lactate greater than 2mmol/L. However, at a cut-off of 2 or more for qSOFA, the advertised cut-off for “high risk”, the sensitivity and specificity were 70% and 79% respectively.

Finally, a third article, from Annals of Emergency Medicine, also evaluates the performance characteristics of qSOFA in an Emergency Department population. This retrospective evaluation describes the performance of qSOFA at predicting admission and mortality, but differs from the JAMA article by applying qSOFA to a cross-section of mostly high-acuity visits, both with and without suspected infection. Based on a sample of 22,350 ED visits, they found similar sensitivity and specificity of a qSOFA score of 2 or greater for predicting mortality, 71% and 74%, respectively. Performance was not meaningfully different between those with and without infection.

It seems pretty clear, then, this score doesn’t hold a lot of value. SIRS, obviously, has its well-documented flaws. qSOFA seems to have better discriminatory value with regards to the AUC, but its performance at the cut-off level of 2 puts it right in a no-man’s land of clinical utility. It is not sensitive enough to rely upon to capture all patients at high-risk for deterioration – but, then, its specificity is also poor enough using it to screen the general ED population will still result in a flood of false positives.

So, unfortunately, these criteria are probably a failed paradigm perpetuating all the same administrative headaches as the previous approach to sepsis – better than SIRS, but still not good enough. We should be pursuing more robust decision-support built-in to the EHR, not attempting to reinvent overly-simplified instruments without usable discriminatory value.

“Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit”

http://jamanetwork.com/journals/jama/article-abstract/2598267

“Prognostic Accuracy of Sepsis-3 Criteria for In-Hospital Mortality Among Patients With Suspected Infection Presenting to the Emergency Department”

http://jamanetwork.com/journals/jama/fullarticle/2598268

“Quick SOFA Scores Predict Mortality in Adult Emergency Department Patients With and Without Suspected Infection”

http://www.annemergmed.com/article/S0196-0644(16)31219-7/fulltext

Shenfu!

I will readily admit I am stepping outside the bounds of my expertise with this post – with respect to the “shenfu injection” and its effects on physiology. The authors describe shenfu as “originated from Shenfu decoction, a well-known traditional Chinese formulation restoring ‘Yang’ from collapse, tonifying ‘Qi’ for relieving desertion”. More specifically, from a physiologic standpoint: “Ginsenosides and aconite alkaloids are the main active ingredients in Shenfu. Ginsenosides are the determinant contributor to the vasodilator benefit of Shenfu, whereas the alkaloids play a vital role in the cardiac electrophysiological effect of Shenfu by blocking ion channels”. In China, a pharmacologic shenfu distillate is used routinely to treat sepsis and septic shock as a 100mL daily injection – and this is a placebo-controlled trial endeavoring to demonstrate its efficacy.

At face value, the trial appears reasonable – a targeted enrollment of 160 patients with a goal of detecting a 20% difference in mortality at 28-days, based on an expected overall mortality of 40%. Their primary outcome, however, were the co-primary outcomes of “length of ICU stay, the duration of vasopressor use, illness severity, and the degree of organ dysfunction.” A proper study, of course, has a single primary outcome – and, considering the study was powered for a mortality difference, this patient-oriented outcome probably ought to have been made primary.

Regardless, from the results presented here, it is reasonable to suggest this is promising and worthy of additional evaluation. Several outcomes – ICU LOS, APACHE II score, and duration of vasopressor us – reached statistical significance favoring the intervention. The mortality outcome did not meet statistical significance with the intervention at 20.5% and the placebo at 27.8%. However, an absolute mortality improvement of 7.3% is nothing to sneeze at – and I would be happy to see more work performed to replicate or generalize these results.

“Shenfu injection for improving cellular immunity and clinical outcome in patients with sepsis or septic shock”

https://www.ncbi.nlm.nih.gov/pubmed/28029485

The Magic Bacterial Divining Rod

Antibiotic overuse is a real issue.  In modern countries, despite obsessing over antibiotic stewardship, we are still suckers for the excessive use of both narrow-spectrum antibiotics for ambulatory patients and broad-spectrum antibiotics for the critically ill.  In less resource-capable areas, the tests used to stratify patients as potentially bacterial or viral exceed the cost of the antibiotics – also leading down the path to overuse.

This breathless coverage, featured in Time, the AFP, and proudly advertised by Stanford Medicine, profiles a new panel of tests that is destined to bring clarity.  Rather than relying simply on a single biomarker, “our test can detect an infection anywhere in the body by ‘reading the immune system’”.

They used retrospective genetic expression cohorts from children and adults with supposedly confirmed non-infectious or infectious etiologies to derive and validate a scoring system to differentiate the underlying cause of sepsis.  They then further trim their model by eliminating infants and predominately healthy patients from outpatient cohorts.  Ultimately, they then test their model on a previously uncharacterized whole blood sample from 96 pediatric sepsis patients and report an AUC for viral vs. bacterial sepsis of 0.84, with a -LR of 0.15 and +LR of 3.0 for bacterial infections.  At face value, translated to a presumed clinical setting with a generally low prevalence of bacterial infection complicating SIRS, this is an uninspiring result.

However, these authors rather focus their discussion and press releases around the -LR of 0.10 and +LR of 2.34 produced as part of their ideal validation cohort, trumpeting its superiority over the -LR for procalcitonin of 0.29 as “three-fold improvement”.  This is, of course, nonsense, as the AUC from that same procalcitonin meta-analysis was 0.85, and these authors are simply cherry-picking one threshold and performance characteristic for their comparison.

Now, that’s hardly to say this is not novel work, and their confusion matrices showing clustering of non-infected SIRS vs. bacterial sepsis vs. viral sepsis are quite lovely.  Their approach is interesting, and very well could ultimately outperform existing strategies.  However, their current performance clearly does not match the hype, and they are miles away from a meaningful validation.  Furthermore, the sort of nano-array assay required is neither fast enough to be clinically useful nor likely to be produced cheaply enough to be used in some of the resource-poor settings they claim to be addressing.

It makes for a nice headline, but it’s better consigned to the “Fantasy/Science Fiction” shelf of your local bookstore for now.

“Robust classification of bacterial and viral infections via integrated host gene expression diagnostics”
http://stm.sciencemag.org/content/8/346/346ra91