We come now to the end of 2021, a year of hope, dismay, followed again by hope, then dismay—and now, perhaps, is it yet safe finally to hope? Regardless, the medical journals burst forth with the tireless work of researchers from around the world. Here are a few of the highlights from 2021.

The Essential, Not-So-Effective Tranexamic Acid

Tranexamic acid (TXA) use is ubiquitous throughout the scope of medicine in which patients are bleeding. In major trauma, postpartum hemorrhage, or traumatic intracranial hemorrhage, TXA likely exhibits a beneficial effect, albeit quite small. Two trials published this year evaluated its use in two additional types of bleeding: nontraumatic subarachnoid hemorrhage (SAH) and epistaxis. The first application, the ULTRA trial, evaluated functional outcomes of patients given TXA as soon as possible following diagnosis of nontraumatic SAH.¹ At the primary clinical endpoint of six-month follow-up, no difference was seen in functional outcomes as measured by the modified Rankin Scale. Small, nonsignificant reductions in early aneurysmal rebleeding were seen favoring the TXA cohort. There may be patients in whom early TXA treatment has value, but they were not identified in this specific trial.

Epistaxis is a frequent clinical presentation to the emergency department, particularly across the population prescribed oral anticoagulants. The NOPAC trial randomized patients who had failed first-line topical vasoconstrictor therapy to either TXA-soaked packing or placebo.² Unfortunately, no advantage was seen with TXA-soaked packing, nor were any specific subgroup effects evident. It is likely any perceived benefit to topical TXA is as much confirmation bias as a true effect.

The Brain Gain

Every year is an exciting one for stroke neurology, and this year is no different. A set of trials tackled one of the current hot controversies: whether patients destined for endovascular treatment should first be treated with systemic thrombolysis. Endovascular treatment, after all, owes its existence as a treatment for acute ischemic stroke specifically to the gross ineffectiveness of systemic thrombolysis for large vessel occlusions. Two trials published this year, the SKIP and DEVT trials, addressed this question.^3,4 The SKIP trial was performed in Japan, while the DEVT trial was in China, and neither trial demonstrated an advantage to systemic thrombolysis prior to endovascular intervention. The SKIP trial was statistically inconclusive due to a small sample size, but the DEVT trial was stopped early due to the advantage demonstrated in the cohort treated by endovascular alone. The active debate over the interpretation of these trials will likely lead to substantial institutional and individual practice variation.

The other prominent trial making headlines this past year concerned mobile stroke units. The BEST-MSU trial out of Houston demonstrated dramatic differences favoring those treated by a mobile stroke unit, with 55 percent of those dispatched a mobile stroke unit achieving functional independence compared to 44 percent of those dispatched a traditional EMS.⁵ Digging deeper into the supplemental results, however, shows the leap of faith required to take these results at face value: Those evaluated by a mobile stroke unit had an excess final diagnosis of “stroke reversed by tissue plasminogen activator” equal to the final effect size. Were these stroke mimics treated so early they never had a chance for spontaneous improvement, or were they true cerebral ischemia whose effects evaporated without a trace? Interpretation of this trial hinges on that particular perspective.

Fluid Dynamics

We do love to give our patients in the emergency department intravenous fluids. Frequently, these fluids come at the behest of our “quality” overlords, ensuring no patient escapes the emergency department without receiving 30 cc/kg. One prominent concern has been which fluid is the “best,” stemming from concerns relating to the hyperchloremic metabolic acidosis from high-volume resuscitation with 0.9 percent saline solution. The most recent information comes from the BaSICS trial, conducted in Brazil, evaluating a “balanced” fluid solution versus “normal” saline.⁶ In this trial, no clinically important impacts on mortality or secondary outcomes were observed. For the vast majority of our patients, the initial choice of fluid probably does not matter.

In a slightly more esoteric vein, the SALSA trial looked at the treatment of moderate-to-severe hyponatremia, evaluating any advantage conferred by administering hypertonic saline as either a slow continuous infusion or as repeated intermittent boluses.⁷ By the researchers’ measure of “overcorrection” in the first 24–48 hours, the intermittent boluses were less likely to exceed the target rate than the continuous infusion. This supports intermittent boluses as the current approach recommended by consensus guidelines.

New Approaches to Old Infections

Some of the most common indications for antibiotics remain some of the least completely described. A diagnosis of community-acquired pneumonia is hardly infrequent, yet little evidence truly defines clinical practice. Should children be prescribed a five-day course or a 10-day course? The SAFER trial tested this straightforward, yet unanswered question and found clinical cure rates were virtually identical regardless of length of antibiotic therapy.⁸ In low-risk outpatients requiring antibiotics for pneumonia, five days of high-dose amoxicillin is an appropriate first step.

Taking this idea one step further, this “less is more” principle was tested in a trial randomizing children with respiratory tract infections to an immediate antibiotic prescription, a “delayed antibiotic prescription,” or no antibiotics.⁹ By the authors’ conclusion, the delayed antibiotic strategy was a success. Children randomized to delayed antibiotics had the same outcomes as those provided an immediate prescription while caregivers filled the delayed prescriptions at a dramatically lower rate. Less appreciated, however, was that the “no antibiotics” cohort also did just as well, with even fewer antibiotic exposures in follow-up. A “delayed antibiotics” strategy is certainly reasonable but only showed an advantage when compared to the modern standard of rampant antibiotic overuse. Prudent stewardship for pediatric respiratory infections is the far superior strategy.

Antibiotics-first strategies for the treatment of appendicitis have been increasingly in vogue the past few years. Studies evaluating these strategies have generally reported a short-term failure rate for antibiotics around 35 percent. The concern, however, is the long-term durability of an antibiotics-first strategy. In this follow-up from the CODA trial, subsequent appendectomy occurred in a cumulative 46 percent of patients out to two years from enrollment.¹⁰ These additional data do not invalidate an antibiotics-first strategy as inevitably doomed, but they do provide valuable information for shared decision making with patients regarding the balance of risks and benefits to each strategy.

The Recently Mostly Dead

Mostly dead is still partly alive, and the desperate search continues for effective strategies to salvage good functional outcomes in these patients. The November 2021 issue of ACEP Now described outcomes from the Targeted Temperature Management-2 trial, along with the likely demise of “mild” hypothermia as part of the treatment of patients resuscitated from out-of-hospital cardiac arrest. However, it is an open question whether any current cooling practice involves not enough of a good thing. The CAPITAL CHILL trial tested “moderate” 31° C versus “mild” 34° C and was not able to discern a difference in either overall or neurologically intact outcomes.¹¹ The best bet at the moment remains “temperature management” rather than any sort of active cooling.

Work continues regarding whether patients recently resuscitated from cardiac arrest should undergo cardiac catheterization. The TOMAHAWK trial, similar to other previously reported trials, enrolled patients with out-of-hospital cardiac arrest of possible coronary origin and no evidence of ST-segment elevation.¹² Patients either underwent immediate coronary angiography or were hospitalized for intensive care assessment and observation. Even though nearly two-thirds of patients randomized to intensive care assessment subsequently underwent coronary angiography, both survival and neurological outcomes favored the delayed strategy. Given the totality of evidence, it ought to be clear resuscitated patients should only undergo coronary angiography based on specific indications rather than on a routine basis.

I’m looking forward to 2022 with a whole new set of research trial acronyms to summarize! 

References

1. Post R, Germans MR, Tjerkstra MA, et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet. 2021;397(10269):112-118.
2. Reuben A, Appelboam A, Stevens KN, et al. The use of tranexamic acid to reduce the need for nasal packing in epistaxis (NOPAC): randomized controlled trial. Ann Emerg Med. 2021;77(6):631-640.
3. Suzuki K, Matsumaru Y, Takeuchi M, et al. Effect of mechanical thrombectomy without vs with intravenous thrombolysis on functional outcome among patients with acute ischemic stroke: the SKIP randomized clinical trial. JAMA. 2021;325(3):244-253.
4. Zi W, Qiu Z, Li F, et al. Effect of endovascular treatment alone vs intravenous alteplase plus endovascular treatment on functional independence in patients with acute ischemic stroke: the DEVT randomized clinical trial. JAMA. 2021;325(3):234-243.
5. Grotta JC, Yamal JM, Parker SA, et al. Prospective, multicenter, controlled trial of mobile stroke units. N Engl J Med. 2021;385(11):971-981.
6. Zampieri FG, Machado FR, Biondi RS, et al. Effect of intravenous fluid treatment with a balanced solution vs 0.9% saline solution on mortality in critically ill patients: the BaSICS randomized clinical trial. JAMA. 2021;326(9):1-12.
7. Baek SH, Jo YH, Ahn S, et al. Risk of overcorrection in rapid intermittent bolus vs slow continuous infusion therapies of hypertonic saline for patients with symptomatic hyponatremia: the SALSA randomized clinical trial. JAMA Intern Med. 2021;181(1):81-92.
8. Pernica JM, Harman S, Kam AJ, et al. Short-course antimicrobial therapy for pediatric community-acquired pneumonia: the SAFER randomized clinical trial. JAMA Pediatr. 2021;175(5):475-482.
9. Mas-Dalmau G, Villanueva López C, Gorrotxategi Gorrotxategi P, et al. Delayed antibiotic prescription for children with respiratory infections: a randomized trial. Pediatrics. 2021;147(3):e20201323.
10. CODA Collaborative, Davidson GH, Flum DR, et al. Antibiotics versus appendectomy for acute appendicitis—longer-term outcomes [published online ahead of print Oct. 25, 2021]. N Engl J Med.
11. Le May M, Osborne C, Russo J, et al. Effect of moderate vs mild therapeutic hypothermia on mortality and neurologic outcomes in comatose survivors of out-of-hospital cardiac arrest: the CAPITAL CHILL randomized clinical trial. JAMA. 2021;326(15):1494-1503.
12. Desch S, Freund A, Akin I, et al. Angiography after out-of-hospital cardiac arrest without ST-segment elevation [published online ahead of print Aug. 29, 2021]. N Engl J Med.