Month: June 2019

Ye Big High-Sensitivity Troponin Evaluation

After many years of various studies of moderate size looking at the diagnostic performance of high-sensitivity troponin assays, now we have a new entry: the Calculation of Myocardial Infarction Risk Probabilities to Manage Patients with Suspicion of Myocardial Infarction (COMPASS-MI) project.

This is not new data, but rather the power team of Roche and Abbott pooling the results of 15 prior studies to describe the diagnostic performance of their Elecsys and Architect high-sensitivity platforms. Then, there are really two parts of this article. There is an initial analysis looking at the performance characteristics of differing combinations of initial and serial sampling of each. After that, these authors pull in several age- and comorbidity-matched comparison populations and describe the long-term 1- and 2- year outcomes of patients with differing levels of troponin concentrations.

The main product of their work, however, boils down to a set of mildly confusing wheels of data regarding the negative predictive value of various combinations of initial troponin level and serial troponin change, divided up based on whether repeat sampling was performed early or late. These cut-offs are further divided on the wheel regarding the proportion of the population with a certain risk level for 30-ay MI or death.

The end result, combined with the various massive supplementary appendicies, are massive amounts of data to help systems using these assays tailor their practice patterns to their desired level of sensitivity and specificity. The authors are not specifically prescriptive in any one cut-off, but rather try to provide as much data as possible. Prevalence of nSTEMI in their population was about 14%, meaning the negative predictive values are only generalizable to to similar patient demographics.

If you’re using these assays, this is quite important work to help assist in interpretation. If not, considering there’s no comparative data to conventional assays, it seems to have limited utility.

It should finally be noted virtually all the listed authors of this work receive some financial support from the manufacturers of these assays.

“Application of High-Sensitivity Troponin in Suspected Myocardial Infarction”
https://www.nejm.org/doi/full/10.1056/NEJMoa1803377

Yet Another Febrile Infant Rule

The Holy Grail in the evaluation of infants of less than 60 days remains safe discharge without a lumbar puncture. Boston, Philadelphia, Rochester, Step-by-Step and others have tried to achieve this noble goal over the years. And now, the Febrile Young Infant Research Collaborative has tossed their hat into the ring.

In this retrospective query of their Pediatric Health Information System and other electronic medical records, these authors identified 181 non-ill appearing patients across 11 Emergency Departments with invasive bacterial infection, defined as bacteremia in either blood or cerebrospinal fluid. Using 362 matched controls as a comparison cohort, these authors used the typical logistic regression route to tease out the strongest predictors of IBI – age in days, observed temperature, absolute neutrophil count, and urinalysis result. Subsequently, they condensed the continuous variables into cut-offs maximizing area under the curve. These cut-offs were then incorporated into a scoring system based on the strength of their adjusted odds ratio, and then the final output was validated on the derivation set using k-fold cross-validation with 10 sets.

The final result using their best cumulative score cut-off: sensitivity of 98.8% (95% CI 95.7-99.9) with 31.3% specificity. The two cases missed were that of a 3-day old and a 40-day old otherwise afebrile in the ED with normal UA and an ANC <5185. The authors ultimately conclude their score, if validated, may have best value as a one-way prediction tool primarily to reduce current routine invasive testing, owing to its poor specificity. Certainly, I agree it does not have much value in those who might otherwise not undergo testing; a more specific risk score may be better, if not clinician gestalt.

The other tidbit I might mention is whether there could be value in incorporating time-of-onset of fever into their evaluation. We’ve seen in other studies a few of the fallouts with regard to sensitivity of IBI stem from recency of illness onset, and it may be falsely reassuring to find a normal ANC early in an illness course. Furthermore, these authors do not specifically mention whether the lack of fever in the ED could have been associated with prehospital antipyretic use. Finally, their data collection does not appear to incorporate respiratory swab results; readily available respiratory viral panel results may also prove useful in ruling out IBI.

While these data are certainly alluring, considering the desire to avoid invasive procedures in young infants, substantial prospective work is still likely required.

As a sad aside, the authors state:

However, these criteria were developed >25 years ago, and the epidemiology of serious bacterial infections has changed considerably since that time.

Unfortunately, as vaccination frequency continues to decline, even since patients were enrolled for this study, our “modern” cohort may better begin to resemble that of 25 years ago.

“A Prediction Model to Identify Febrile Infants ≤60 Days at Low Risk of
Invasive Bacterial Infection”

https://www.ncbi.nlm.nih.gov/pubmed/31167938

Upping Your CSF Game

WBCs? Glucose? Gram stain? Next-generation genetic sequencing?

It’s the NEJM again, so you know the fingerprints of financial and professional conflict of interest pervade, but this study is still fairly typical of the types of infectious disease diagnostics on the horizon. Why wait for any specific organism to grow – over the course of days – when you can simply try and match DNA fragments floating around to those of various viral and bacterial pathogens?

The promise probably doesn’t quite meet the hype in this study, based out of UCSF, where many of those working on the project hold shares of the patent on the technology. In this prospective multicenter study, these authors recruited patients, ostensibly, who were diagnostic challenges – “idiopathic meningitis, encephalitis, or myelitis in patients who had not received a diagnosis at the time of enrollment”. The vast majority of those enrolled were ultimately encephalitis and meningitis. Then, this wasn’t specifically a formal trial as much as it was a collected case series with a 1-year convenience time frame, constrained by funding and testing capacity.

The authors screened 482 patients for a final study population of 204. Of these 204, their next-generation sequencing methods made a diagnosis in 32. Of these 32, 19 had already been made by further directed clinical evaluation. Of those final 13, then, in which the NGS assay was the only method of diagnosis, this information augmented clinical management in 7. The supplementary appendix details these specific impacts on management – although, in reality, few of the vignettes are terribly compelling. A handful of cases confirmed a suspected diagnosis, leading to clinicians to narrow antibiotic or antifungal therapy, while others “reassured” clinicians they were on the right course. The NGS assay did, however, occasionally detect clinically important pathogens and guide directed treatment, including Nocardia and S. mitis meningitis whose conventional testing was otherwise negative. Unfortunately, despite the addition of this testing, no conclusive final diagnosis was ever made in half their cohort.

At present, this sort of testing is not likely to be within the scope of the Emergency Department – these represent complex cases with low diagnostic yield, and even while this method picks up some new diagnoses, it also misses others established by conventional means. That said, this sort of technology will likely yet only improve, decrease in cost, and additional applications will edge closer to mainstream care.

“Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis”

https://www.nejm.org/doi/full/10.1056/NEJMoa1803396

Choosing Wisely Hepatology, Eh?

The Choosing Wisely campaign is quite popular in theory, if not in practice – ranging widely across the specialties from Pediatric Hospital Medicine to our own, beloved, Emergency Medicine.

This list is from the Canadian Association for the Study of the Liver, and two of their five recommendations are somewhat relevant to EM. Without further ado:

Statement 1: Don’t order serum ammonia to diagnose or manage hepatic encephalopathy

This was their most highly ranked recommendation when members were surveyed at their annual meeting. They cite multiple confounders regarding ammonia levels, factors affecting accuracy of the measurement, and state “elevated ammonia levels do not add any diagnostic, staging, or prognostic value.” The diagnosis, they feel, ought to be made based on clinical history and response to therapy alone.

Statement 2: Don’t routinely transfuse fresh frozen plasma, vitamin K, or platelets to reverse abnormal tests of coagulation in patients with cirrhosis prior to abdominal paracentesis, endoscopic variceal band ligation, or any other minor invasive procedures

This is another one of my favorite pet topics – transfusion intended to “restore normal hemostasis” in a dysfunctional, but somewhat already rebalanced coagulation system. As they say, “Routine tests of coagulation do not reflect bleeding risk in patients with cirrhosis and bleeding complications of these procedures are rare.” In fact, I’ve seen several articles approaching even liver resection in the context of elevated coagulation parameters absent any major bleeding complications – so this ought certainly apply to minor procedures, including those in the Emergency Department.

No doubt the uptake of these recommendations will be highly variable among hospitals and specialty groups, but lists like these are great tools with which to start the conversation.

“Choosing Wisely Canada-Top Five List in Hepatology”
https://www.ncbi.nlm.nih.gov/pubmed/30596626

Vital Signs = Vital

That is how the authors frame it, after all: “‘Vital signs are vital’ is a common refrain in emergency medicine.”

And, these authors add to the body of work further exploring this axiom. In this simple, retrospective data analysis, they evaluate all adult visits to their Emergency Department to determine the effect of abnormal vital signs at disposition on short-term outcomes.

For discharges, about 3% of their cohort returned to the same ED within 72 hours. Only a handful – a little less than 15% – had any vital sign abnormalities at discharge. And, yes, those with vital sign abnormalities were slightly more likely to return than those who did not, with relative risk ratios centered generally around 1.2. Then, a little more than a quarter of patients were admitted on their return visit – and, again, vital sign abnormalities increased the likelihood of subsequent admission by a small amount. In this case, fever was more likely than the other abnormal vital signs to tip the scales towards admission.

Similarly, an analysis of inpatient visits and subsequent escalations in care noted vital sign abnormalities exhibited a greater risk of upgrade, with RRs centered around 2.

Overall, however, the vast majority of patients who were either admitted or discharged with abnormal vital signs did well. Abnormal vital signs are always worth recognizing and dedicating a bit of cognitive effort, but the aren’t strong enough predictors of subsequent outcomes to drive changes in management.

“Association of Vital Signs and Process Outcomes in Emergency Department Patients”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526877/