Month: September 2017

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

The End of the “Emergency” Pelvic Exam

Enthusiasm, as measured by time-to-provider, for performing a pelvic examination in the Emergency Department is low. The logistics of a comfortable, adequate examination can be time consuming and detract from patient throughput. The yield of such examination is thought to be poor – enough so many providers, even absent sufficient evidence, choose to forgo the examination whenever reasonable, and depend on symptoms or advanced imaging to complete the evaluation.

This study aims to determine the acceptableness of the practice of forgoing the pelvic examination in a subset of vaginal complaints, those presenting with vaginal bleeding or abdominal pain in early pregnancy. From an ED standpoint, the typical most worrisome consideration is an ectopic pregnancy, with other diagnostic considerations important, but less salient. These authors developed a protocol in which women of fewer than 16 weeks gestation could be randomized to assessment with pelvic examination omitted or not. Their primary outcome was a composite pregnancy morbidity and utilization outcome at 30 days, with the trial designed to evaluate statistical equivalence between the two strategies.

Unfortunately, we have to give this trial a grade of “incomplete” for its ability to answer the research question – not the least because they under-enrolled their study cohort by over 500 patients. Of a planned enrollment of 720, they were only able to capture 202 due to slow enrollment due to a variety of factors. Furthermore, even if they had met their enrollment, I’m uncertain whether their composite outcome – chosen, almost certainly, to reduce the sample size needed to detect already rare outcomes – is clinically meaningful. Some elements of their composite morbidity outcome – unscheduled ED visits, hospital admissions, procedures relating to pregnancy – are of uncertain relationship to the decision to provide or withhold a pelvic examination at the time of first encounter. The most relevant of their composite is undoubtedly the identification of an alternative symptom source, but, again, this would require additional enrollment to detect a difference in such an infrequent outcome. Of the 202 patients included, 2 of 100 in the pelvic examination cohort had an alternative source for symptoms identified, but these are not specifically commented upon in the text.

Secondary outcomes relating to ED throughput and patient satisfaction favored the cohort omitting the pelvic examination, only ED length of stay suggests a potentially meaningful difference of approximately 20 minutes (not reaching statistical significance). Patient perceptions and concerns over embarrassment were not consistent across measures and assessment and probably not reliable.

Generally speaking, this study probably provides evidence supporting a strategy in which pelvic examinations are omitted, but this evidence is quite weak. The clinical significance of the information gleaned from a pelvic examination is unlikely to be of substantial clinical interested except in rare cases, and I would suggest the next steps in observational research to be to evaluate the clinical features of patients whose diagnosis or plan of care is changed by the pelvic examination.

“Is the Pelvic Examination Still Crucial in Patients Presenting to the Emergency Department With Vaginal Bleeding or Abdominal Pain When an Intrauterine Pregnancy Is Identified on Ultrasonography? A Randomized Controlled Trial”
http://www.annemergmed.com/article/S0196-0644(17)31387-2/fulltext

 

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

Predicting Poor Outcomes After Syncope

Syncope is a classic good news/bad news presenting complaint. It can be highly distressing to patients and family members, but rarely does it relate to an acutely serious underlying cause. That’s the good news. The bad news, however, is that for those with the worst prognosis, most of the poor prognostic features are unmodifiable.

This is a prospective, observational study of patients presenting with syncope to Emergency Departments in Canada, with the stated goal of developing a risk model for poor outcomes after syncope. The composite outcome of interest was death, arrhythmia, or interventions to treat arrhythmias within 30 days of ED disposition. Follow-up was performed by structured telephone interview, networked hospital record review, and Coroner’s Office record search.

To achieve a lower bound of the 95% confidence interval for sensitivity of 96.4%, these authors targeted a sample size of 5,000 patients, and ultimately enrolled 5,010 with complete outcome assessments. The mean age was 53.4, had a low incidence of comorbid medical conditions, and only 9.5% were admitted to the hospital. Within 30 days, 22 had died, 15 from unknown causes and the others from the pool of 91 patients diagnosed with a “serious arrhythmia” – sinus node dysfunction, atrial fibrillation, AV block, ventricular arrhythmia, supraventricular tachycardia, or requiring a pacemaker insertion.

These authors ride the standard merry-go-round of statistical analysis, bootstrapping, and logistic regression to determine a prediction rule – the Canadian Syncope Arrhythmia Risk Score – an eight element additive and subtractive scoring system to stratify patients into one of eleven expected risk categories. They report the test characteristics of their proposed clinically useful threshold, greater than 0, to be a sensitivity of 97.1% and a specificity of 53.4% – a weak positive predictive value of 4.4% considering the low incidence of the composite outcome.

This is yet another product of obviously excellent work from the risk model machines in Canada, but, again, of uncertain clinical value. The elements of the risk model are frankly those that are quite obvious: elevated troponin and conduction delays on EKG, along with an absence of classic vasovagal features. These are patients whose cardiac function is obviously impaired, but short a time machine to go back and fix those hearts before they became sick, it’s a bit difficult to see the path forward. These authors feel their prediction rule aids in safe discharge of patients with syncope, although these patients are already infrequently admitted to the hospital in Canada. The various members of their composite outcome are not equally serious, preventable, or treatable, limiting the potential management options for even those falling into their high-risk group.

As with any decision instrument, its value remains uncertain until it is demonstrated the clinical decisions supplemented by this rule lead to better patient-oriented outcomes and/or resource utilization than our current management in this cohort.

“Predicting Short-Term Risk of Arrhythmia among Patients with Syncope: The Canadian Syncope Arrhythmia Risk Score”

https://www.ncbi.nlm.nih.gov/pubmed/28791782

Azithromycin Ruins Everything

For some reason – and by “some reason”, I mean extensive evaluation of immunomodulatory properties – there is an obsession with azithromycin use for more than simply its anti-bacterial indications. It has been hypothesized to diminish inflammation and have antiviral properties, and, of course, functions as a floor wax and dessert topping.

This is a randomized, controlled trial of azithromycin versus placebo in pre-school children with acute wheezing as a primary diagnosis. The primary outcome was time to resolution of respiratory symptoms, and secondary outcomes included any use of short-acting beta-agonists, adverse events, and time to any repeat exacerbation of wheezing.  These authors enrolled 300 before funding ran out, and were able to follow-up 222 with completed symptom diaries. Patients were generally similar between the two groups, and over 80% of each cohort had prior episodes of wheezing, and a similar percentage used or was prescribed a beta-agonist at discharge from the Emergency Department.

The winner: nothing and no one. Azithromycin did not improve any outcomes versus placebo, and should not be used for suspected viral wheezing in the hopes of anti-inflammatory symptom improvement until better evidence of benefit emerges.

“Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: A placebo-controlled randomized trial”
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182411

Enough with the Coughing!

Every Emergency Physician who has worked a night shift knows this all too well – the child brought to the ED in the middle of the night for a cough, keeping the entire family up, and the cough has been going on for weeks.

And, the not-at-all-satisfying answer: “This is pretty normal.”

This is yet another publication describing the natural history of symptoms following an upper respiratory illness. These authors in Australia enrolled children evaluated in the Emergency Department for an upper respiratory infection featuring cough. They enrolled 839 children and attempted to follow them for four weeks after the index visit, as well as through follow-up with a pulmonology specialist if seen for persistent, unresolving cough. Nearly 300 of the initially enrolled cohort was lost to follow-up over the course of the month, but of those who were contacted, two-thirds still had cough at 7 days, and a quarter were still coughing at day 21. Ultimately 171 – or 20.4% – were still coughing at day 28 and eligible for pulmonologist evaluation. Of these, about a third were identified to have a previously undiagnosed underlying chronic respiratory disorder (asthma, bronchiectasis, etc.) and about half were given the diagnosis of persistent bacterial bronchitis.

The general takeaway here is that coughs generally linger – but once a cough has persisted beyond 2-3 weeks, it is reasonable to consider alternative precipitating diagnoses other than the initial URI.

“Chronic cough postacute respiratory illness in children: a cohort study”
https://www.ncbi.nlm.nih.gov/pubmed/28814419