Do Prehospital Antibiotics Matter?

In short, probably not, but still not completely disproven.

This randomised controlled open-label trial looked at giving 2 grams of IV ceftriaxone to patients that met SIRS criteria (save for WBC- testing unavailable to EMS) with suspected infectious illness. Patients were randomly assigned (1:1) to the intervention group or usual care group using block-randomisation with blocks of 4. This study took place across ten large regional ambulance services serving 34 secondary and tertiary care hospitals in the Netherlands over a 2 year period. They screened 3228 patients of which 2698 were eligible (pregnancy, beta-lactam or ceftriaxone allergy, suspected prosthetic joint infection, among others); 1150 in the usual care arm (IV fluids, supplemental oxygen prn), and 1548 in the intervention group (2g ceftriaxone plus usual care). 13 patients in each arm were excluded from final analysis or excluded due to withdrawn consent or being lost to follow up. The primary outcome was all-cause mortality at 28 days.

So, while they screened over 3,000 patients over 2 years (a massive undertaking!), unfortunately, only 37 (3.3%) patients in usual care and 66 (4.3%) patients in the early antibiotics group had septic shock. Perhaps you could make an argument that the intervention group was slightly sicker with 22% vs 17% having 2 or more qSOFA criteria. Despite a median time to antibiotics of 70 minutes in the ED (thus, probably close to 90+minutes faster in the intervention cohort), and with 14% having antibiotics >3hrs from presentation and 14% having none at all (suspected viral syndrome) – there was 8% mortality in both arms at 28 days and 12% at 90 days in both arms. No difference.

When you look at mortality for septic shock it was 27% (10/37) in the prehospital antibiotic cohort vs 28.8% (19/66). Again, not statistically significant. While prehospital antibiotics might make a difference in a larger cohort, its probably going to be very hard to ever do that study – this was a 2 year study looking at over 3,000 patients and they were barely able to accumulate over 100 septic shock patients.

While an American might argue “they only gave ceftriaxone, you need a real drug like Pip-tazo and vancomycin!” – slow down. The authors acknowledge that ceftriaxone may not have been appropriate because it was “a big gun” that they could all agree on and most patients were rapidly narrowed to receive, most commonly, amoxicillin–clavulanic acid with ciprofloxacin and ceftriaxone the second and third most common antibiotics given. They did not have culture reports back at time of publication, but having low mortality, and 9% of each cohort were not given antibiotics from the ED due to suspected viral illness makes me suspect that they do not have nearly the resistance problem (or concerns) that the Americans do, likely do to appropriate stewardship. Likewise, while one may be concerned about missed diagnosis due to premature closure, there was a miss rate of 1.4% in the intervention group vs 1.7% in the usual care group, also not statistically significant.

In the end, the authors provide a sensical view of the current state of prehospital antibiotics, “Studies showing that early antibiotic treatment is beneficial for reducing mortality found this positive association mainly in patients with more severe illness and a (time to antibiotic) of more than 5–6 hours… However, we currently do not advise antibiotic administration in the ambulance to patients with suspected sepsis.“

While it is certainly plausible that prehospital antibiotics may be beneficial for those with septic shock, it is a near certainty that, at least in the USA, sepsis hysteria would further ensue and the inertia of giving everyone a dose of broad spectrum antibiotics will likely occur – not to mention our continued fixation with iatrogenic salt-water drowning. The cost to the system – including other patients in the department – of responding to these prehospital alerts for those not in shock will likely be the hidden cost infrequently published or discussed by administrations.

Critical Care, Improving Outcomes, Mythbusting

No benefit for Keppra in Status Epilepticus?

This was a prehospital, randomized, double blind, placebo controlled trial of adults with convulsions lasting >5minutes comparing 2.5g (!) of levetiracetam (Keppra) or placebo in combination 1mg of clonazepam. If convulsions lasted another 5 minutes, another 1mg of clonazepam was given. The primary outcome was cessation of convulsions within 15 minutes of initial drug injection. The trial was stopped early due to no evidence of a treatment difference after an interim analysis showed no difference (68 patients in intent-to-treat analysis per arm). Convulsions were stopped at 15 minutes in 57/68 (84%) patients receiving clonazepam vs 50/68 (74%) of patients receiving levetiracetam.

This study was funded by UCB, who manufactures Keppra.

As someone who embraces aggressive treatment of status epilepticus (escalating benzos + early dilantin / keppra followed by early intubation if needed) – particularly with Keppra since it can be given relatively quickly – this makes me go back to the literature rethink my treatment algorithm.


Ativan v. Versed

Quick, the patient in room 2 started seizing. They do not have IV access. What do you ask for?

If you say Ativan, keep reading.

2mg IM Midazolam (Versed) did not need rescue therapy when administered by EMS 73.4 % of the time compared to 63.4 % for 2mg of IV Ativan for pre-hospital seizures. The primary reason I have heard from attendings to lean towards Ativan rather than Versed has been that Versed would be more likely to have a recurrence of seizures given that it is short acting.  The reality is that there is a 11.4% vs 10.6% recurrence and the need for an advanced airway is 14.1 % vs 14.4 % (for Versed and Ativan, respectively). The caveat being that if they have an IV, time to cessation of convulsions for Ativan is 1.6 minutes vs 3.3 minutes for IM Versed (I’d imagine IV Versed would be less than 3.3 minutes, but alas, that was not studied). Adverse event rates were similar in the two groups.

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Importantly, intubation and recurrence are the same.  However, less rescue therapy is required in the Versed group, so, in theory, I could see this saving a few hospitalizations just based on the fact that a provider is uncomfortable discharging someone that required two or more meds / rounds of meds for stabilization. 




Intramuscular versus intravenous therapy for prehospital status epilepticus. PMID: 22335736