Each year, the medical evidence piles inexorably higher. Even though it’s literally impossible to keep up, we still try. Without further ado, a short list of new developments from 2019:

What to Do When Benzodiazepines Fail

This year saw the publication of several studies involving second-line treatment for status epilepticus when patients’ seizures are refractory to benzodiazepines. There has been a general shift toward using levetiracetam (Keppra), likely due to ease of administration and perceived advantages implicit to its newness. Three pediatric studies tested levetiracetam against other second-line agents.^1–3 Two of these studies were head-to-head comparisons against phenytoin, and one added a third arm featuring valproic acid. Across all three studies, despite minor variations in secondary outcomes, no clear “winner” was found. An individualized choice of any of these agents may be considered reasonable while we await further developments in antiepileptic therapy.

The State of Pulmonary Embolism (PE) Exclusion

Thankfully, we are continuing to make progress toward reducing the use of advanced imaging in the evaluation of PE. Two studies published in the past year illustrate potential strategies to address imaging overuse.^4,5 The first looks at the use of the YEARS protocol for the evaluation of PE in pregnant women, using the combination of high-risk features and two different D-dimer thresholds to increase the number of women we can safely conclude do not require imaging. While this prudent application of YEARS was shown to improve imaging stewardship, it also illuminated the regrettable over-triage of pregnant women to evaluation for PE and an underlying baseline culture of pervasive advanced imaging. Further useful work in this field may incorporate trimester-adjusted D-dimer in addition to further decision support.

A second study parallels the YEARS concept except it uses the Wells Score as the foundation, dividing the cohort into low-, intermediate-, and high-pretest likelihood for PE. The D-dimer Testing Tailored to Clinical Pretest Probability in Suspected Pulmonary Embolism (PEGeD) study doubled the D-dimer imaging threshold cutoff for patients with a low-pretest likelihood, and no cases of missed PE were observed. While this is a successful demonstration of their strategy, considering clinical equipoise for PE allows a miss rate of around 1 percent to balance harms and benefits, even more aggressive strategies are likely reasonable. At the least, this study still represents another important step further establishing pretest-adjusted D-dimers as appropriate.

Finally, the most concise update is from the realm of syncope. Several years ago, a systematic evaluation of hospitalized patients with syncope found a prevalence of PE of 16 percent.⁶ Now, another prospective study finds the prevalence of PE at presentation (which is mainly what we care about when making decisions about who to work up) to the emergency department to be much lower: only 1.4 percent in these data.⁷ An evaluation for PE is necessary only as otherwise clinically indicated in the context of syncope.

Post-Arrest Care

When patients present following cardiac arrest, a continuing controversy has been the utility of emergency coronary angiography. In patients presenting with suspected ST-segment elevation myocardial infarction, the advantage seems clear. In those presenting with nondiagnostic electrocardiographic findings, the observational evidence likewise seems to support intervention. However, the first randomized trial evidence is trickling out now, and the Coronary Angiography after Cardiac Arrest (COACT) study found no clear benefit.⁸ This is the first of what are likely to be many forthcoming study reports, but it is the highest-quality evidence we have to date.

Another recent study reports on the expansion of therapeutic hypothermia to those presenting to the emergency department after cardiac arrest with a nonshockable rhythm.9 The overall survival of this population is dismal, comparatively, with 90-day mortality of greater than 80 percent. The use of targeted temperature management (TTM) in this population was observed to provide a small absolute advantage in neurologically intact survival, increasing the justification of using TTM in this population. However, deviations from TTM resulted in febrile episodes in the normothermia cohort only. Failure to prevent these episodes may have contributed to poorer outcomes and muddies the reliability of this trial’s observations. It may still be that the most critical thing we can do is to prevent fevers in these patients. 

Sepsis Steps Forward and Backward

Despite abundant face validity to the observation that all patients suffering overwhelming infection are not the same, our sepsis protocols offer little room for reasonable variation. Researchers at the University of Pittsburgh finally provided some hard data to back up better differentiation of those presenting with sepsis, performing a complex analysis of cytokine and gene expression in response to infection.¹⁰ Their data show clear differing phenotypes among what we currently just call “sepsis,” with a wide range of mortality for each phenotype, as well as variable enrichment of clinical trials with the differing phenotypes. While their analysis does not provide any specifically actionable utility, this demonstration should help future research better tailor interventions to specific subgroups of sepsis patients.

Meanwhile, the Early Goal Directed Therapy Using a Physiological Holistic View (ANDROMEDA-SHOCK) investigators put the classic lactic acid clearance target as a marker of sepsis treatment success to the test.¹¹ In one arm of this study, patients were resuscitated per protocol as guided by serial lactic acid measurements, or to clinical peripheral perfusion targets. In the other arm, investigators used glass slides and held manual pressure to the distal tips of patients’ fingers, then observed the length of time necessary for capillary perfusion to occur. At 28-day follow-up, all-cause mortality was 43.4 percent in the lactic acid clearance arm compared to 34.9 percent in those resuscitated to peripheral perfusion targets. The study was small enough that this difference in mortality could have occurred by chance alone, but it certainly provides a note of concern regarding even the most well-known practices underpinning our current approach to sepsis.

Lastly, we are beginning to receive the first trickle of results regarding the importance of high-dose vitamin repletion in sepsis. The Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI) trial started before much of the hullabaloo over combining steroids, thiamine, and vitamin C for patients with septic shock, and it looked solely at the use of vitamin C for reducing organ failure in a subgroup of patients with septic shock and acute respiratory distress syndrome.¹² In this small study, there were no differences in sequential organ failure scores within 96 hours, but 28-day mortality was 29.8 percent in the vitamin C arm compared to 46.3 percent with placebo. These data must be considered exploratory, however, owing to the structure of the trial, and we will need to await more robust results to have reliable information regarding the utility of vitamins in sepsis. (Turn to page 1 for more on recent research on vitamin C and sepsis.)

The opinions expressed herein are solely those of Dr. Radecki and do not necessarily reflect those of his employer or academic affiliates

References

1. Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet. 2019;393(10186):2125-2134.
2. Dalziel SR, Borland ML, Furyk J, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet. 2019;393(10186):2135-2145.
3. Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med. 2019;381(22):2103-2113.
4. van der Pol LM, Tromeur C, Bistervels IM, et al. Pregnancy-adapted YEARS algorithm for diagnosis of suspected pulmonary embolism. N Engl J Med. 2019;380(12):1139-1149.
5. Kearon C, de Wit K, Parpia S, et al. Diagnosis of pulmonary embolism with d-dimer adjusted to clinical probability. N Engl J Med. 2019;381(22):2125-2134.
6. Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med. 2016;375(16):1524-1531.
7. Badertscher P, du Fay de Lavallaz J, Hammerer-Lercher A, et al. Prevalence of pulmonary embolism in patients with syncope. J Am Coll Cardiol. 2019;74(6):744-754.
8. Lemkes JS, Janssens GN, van der Hoeven NW, et al. Coronary angiography after cardiac arrest without ST-segment elevation. N Engl J Med. 2019;380(15):1397-1407.
9. Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019;381(24):2327-2337.
10. Seymour CW, Kennedy JN, Wang S, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321(20):2003-2017.
11. Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA. 2019;321(7):654-664.
12. Fowler AA 3rd, Truwit JD, Hite RD, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA. 2019;322(13):1261-1270.