Journal Feed Weekly Wrap-Up

We always work hard, but we may not have time to read through a bunch of journals. It’s time to learn smarter. 

Originally published at JournalFeed, a site that provides daily or weekly literature updates. 

Follow Dr. Clay Smith at @spoonfedEM, and sign up for email updates here.

#1: ANDROMEDA-SHOCK – Capillary Refill vs. Lactate

Spoon Feed
Capillary-refill time (CRT) guided resuscitation was better than lactate clearance in patients with septic shock in regard to improving organ dysfunction at 72 hours (SOFA score) and barely missed statistical significance in reducing 28-day mortality.

Why does this matter?
Lactate clearance is a common resuscitation goal in septic shock. Would a low-tech, physical exam finding, CRT*, do just as well? It has been shown in a small RCT to decrease fluid administration compared to standard treatment in patients with septic shock.

Andromeda: I’d like to see Poseidon try to chain me naked to a rock!
This was a multicenter RCT with 424 patients with septic shock randomized to a step-by-step resuscitation protocol** guided by improvement in peripheral perfusion (CRT) or lactate clearance. For the primary outcome, mortality at 28-days was 34.9% (74 patients) in the CRT group and 43.4% (92 patients) in the lactate group; hazard ratio (HR), 0.75 (95% CI, 0.55-1.02; p = 0.06; risk difference, -8.5% (95% CI, -18.2%-1.2%). The mean SOFA score dropped by 1 point at 72 hours in the CRT group and was statistically significant. Even though the results didn’t quite reach statistical significance for the primary outcome of mortality, it was really close with just checking CRT. In per-protocol analysis, the HR was 0.72 (0.56 to 0.93), p = 0.01.

Another Spoonful
Remember, a p value of 0.05 as “significant” means that 5% of the time the result of a study could have been due to chance. To quote Bryan Cotton on Twitter, “When are we gonna accept p<0.05 was pulled out of nowhere? No diff w/ p=0.06? Please…I know which freakin group I wanna be in! How about you?”

*”CRT was measured by applying firm pressure to the ventral surface of the right index finger distal phalanx with a glass microscope slide. The pressure was increased until the skin was blank and then maintained for 10 seconds. The time for return of the normal skin color was registered with a chronometer, and a refill time greater than 3 seconds was defined as abnormal.”

**Here is the protocol.


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 Feb 19;321(7):654-664. doi: 10.1001/jama.2019.0071.

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#2: CENSER RCT – Early Norepinephrine for Shock

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This small single-center RCT showed that early administration of norepinephrine resulted in improvement in shock control* at 6 hours compared with standard therapy.

*Shock control = MAP >65 + urine output >0.5mL/kg/h for 2 consecutive hours, or decreased serum lactate >10% from baseline

Why does this matter?
Does starting norepinephrine earlier improve outcomes? Current recommendations are to give an adequate fluid challenge first and start pressors if that fails. What if we started pressors earlier? Retrospective data suggests this might be beneficial. The CLOVERS trial is a phase III study currently underway to answer this more definitively. Until then, this is encouraging news that early vasopressors may be of benefit.

CENSER – not just for incense anymore
This was a phase II, double blinded, placebo controlled RCT with 310 adults with sepsis and hypotension, MAP <65. Groups were well matched with randomization. They got either norepinephrine 0.05 μg/kg/min infused for a period of 24 hours without titration or an identical appearing bag started with IV fluid boluses. They were all given standard Surviving Sepsis treatments, including up to 30mL/kg isotonic fluid, source control, etc. If they remained hypotensive after fluid, open label pressors were started at the treating physician’s discretion. The primary outcome was measured 6 hours from the time of initial diagnosis and was called the “shock control rate,” defined above. As would be expected, norepinephrine was started much earlier in the treatment arm: 93 minutes vs 192 minutes in the controls. A little over half of the patients in each arm were finally admitted to the ICU; the rest went to the floor (though they allowed infusion of vasopressors on the general ward). For the primary outcome of shock control, the norepinephrine group fared better: 76.1% vs. 48.4% (OR 3.4; 95% CI, 2.09–5.53). The relative risk was 0.761/0.484 = 1.57; NNT = 4. There was no statistically significant difference in 28-day mortality: 24/155 (15.5%) in the norepinephrine group vs 34/155 (21.9%) in controls (p = 0.15); although, that trend is interesting. The norepinephrine group had statistically (and clinically) significantly fewer complications of cardiogenic pulmonary edema and new-onset arrhythmia, each occurring about half as often than controls. There were loads of exclusion criteria; so, this was a select group. Also, this was fairly small, single-center study, with half of the patients in each group well enough after treatment to go to the floor. They also used a non-standard composite for the primary outcome, though it does reflect macro and micro-circulation. Overall, I think starting pressors early is promising. Hopefully, the CLOVERS trial in progress will shed more light.

Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial. Am J Respir Crit Care Med. 2019 Feb 1. doi: 10.1164/rccm.201806-1034OC. [Epub ahead of print]

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#3: Does IV Fluid Help Migraine Pain?

Spoon Feed
A bolus of IV normal saline did not improve pain control in patients with migraine headache beyond usual treatment with IV prochlorperazine + diphenhydramine.

Why does this matter?
Saline boluses are often given to help migraine patients. Many are volume depleted due to nausea, poor fluid intake, or vomiting. We know dehydration enhances perception of pain. So, how effective is NS as a treatment for migraine-related pain?

What doesn’t help a migraine
This was a small pilot RCT with 50 patients randomized to receive 1L of NS over 60 minutes vs 10mL/hr over 60 minutes plus usual treatment for all with IV prochlorperazine + diphenhydramine. Pain on a 0-10 scale at 60 minutes dropped 4.5 points in the fluid group and 4.9 in the no-fluid group, which was not statistically different. Keep in mind, this study was small and meant to be exploratory. They also were very choosy in patient selection, with 413 patients excluded for failing to meet the third International Classification of Headache Disorders definition of migraine. It indicates that IV fluid did not help relieve pain from migraine. However, many patients with migraine also have nausea or vomiting. So, use of IV fluid may still be helpful for patients in other ways. But as a pain reliever, it appears ineffective.

Intravenous Fluid for the Treatment of Emergency Department Patients With Migraine Headache: A Randomized Controlled Trial. Ann Emerg Med. 2019 Feb;73(2):150-156. doi: 10.1016/j.annemergmed.2018.09.004. Epub 2018 Oct 26.

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For more on evidence-based headache therapies, please see this emDocs post.

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