In 2000 Fazzini et al published a paper comparing the use of ionization vs photoelectric smoke alarms in rural Alaskan homes (1). The authors noted that at the time of the article’s publication. the fire fatality rate for native Alaskans was 9.6 times the national rate and 3.5 times higher than the general rate in Alaska. Since working fire alarms have been shown to reduce the rate of death due to household fires, and early identification is key, smoke detectors which rapidly notify occupants of danger have the potential of saving lives. The authors compared two types of smoke detectors placed in four rural Alaskan villages. The ionization alarm is thought to be more sensitive to a roaring fire and potentially react more quickly. The photoelectric alarm is said to be less sensitive with fewer false or nuisance alarms. At the end of the 6-month observation period, the authors noted that families with the photoelectric alarm were far more likely to have a functioning smoke detector than those with an ionization alarm. This was not due to the superior durability of either device, but rather because families given the ionization alarms, bombarded with false alarms, inevitably removed the battery rendering the device useless. With this is mind, we turn to a recent article examining prehospital antibiotics for patients with suspected sepsis.
The PHANTASi Trial, published by Alam et al in the Lancet, examined the effects of prehospital antibiotics in a cohort of patients with suspected infection (2). The authors randomized patients with a diagnosed or suspected infection, a temperature higher than 38C or less than 36C, and at least one other criterion of the systemic inflammatory response syndrome (heart rate >90 beats per min or respiratory rate >20 per min, or both), to either a usual care (typically IV fluid resuscitation and supplemental O2) or traditional care with the addition of an infusion of 2g of ceftriaxone IV.
Between June 2014 and June 2016, the authors enrolled 2698 patients, of whom 1548 were assigned to the intervention and 1150 to the usual care group. The prehospital administration of antibiotics effectively reduced the time-to-antibiotic administration by 96 minutes. Despite these temporal benefits, the authors reported no difference in their primary outcome, 28-day mortality, between the prehospital antibiotic group and standard care (8% in both groups). Nor did they observe a difference in 90-day mortality (12% in both groups), the rate of ICU admissions (10% vs 9%), 28-day readmission rate, hospital or ICU length of stay. The authors performed a subgroup analysis examining whether patients with more severe sepsis benefited from earlier administration of antibiotics, but were unable to demonstrate any meaningful difference between the prehospital antibiotic group and the controls.
One of the stranger aspects of this study was that the total number of patients randomized to each group was noticeably discordant (1137 in the traditional care group and 1535 in the prehospital antibiotic group). The authors explained this anomaly by reporting that the paramedics were so convinced by the efficacy of the prehospitally administered antibiotics they continued to open the envelopes which determined group assignments until the patient was assigned to the prehospital antibiotic group. This unseemly allocation practice certainly injects a degree of bias in the trial, as sicker patients who the prehospital providers felt would benefit from early antibiotics were more likely to be assigned to the prehospital group. Despite these imbalances, when the authors analyzed the 800 patients enrolled in the two largest prehospital systems where appropriate allocation etiquette was maintained, the results were consistent with the overall findings.
On first glance these results seem to be in stark contrast to the prior observational cohorts demonstrating a consistent benefit in the timeliness of effective antibiotic delivery. But upon closer evaluation one would see that these trials are not so different after all.
The most infamous of the time-to-antibiotic studies was the Kumar et al paper, published in Critical Care Medicine in 2011 (3). The authors conducted a retrospective review of patients admitted to the ICU with septic shock and examined the effect of time-to-antibiotic administration on mortality. They described a 7.6% absolute increase in mortality for every hour delay in appropriate antibiotic administration. And while these numbers are impressive, due to their retrospective design it is impossible to truly quantify the exact benefit timely antibiotics provide in this patient population. More importantly, this was a highly select population of patients admitted to the ICU with septic shock. These results do not directly translate to the more general population of patients presenting to the Emergency Department with a suspected infection.
In 2017, Seymour et al published a retrospective analysis of the Greater New York Sepsis Collaborative Database examining the effects of delays to completing an ED based sepsis bundle on mortality of patients presenting to the Emergency Department with severe sepsis or septic shock. Like Kumar et al, the authors found a statistically significant increase in mortality for every hour delay to administration of antibiotics in patients presenting with severe sepsis or septic shock from 2014 to 2016 (P<0.001). But unlike the Kumar et al paper, while statistically significant these findings are far less clinically impressive. The authors reported an increase in the odds of death for every hour delay in administration of antibiotics of 1.04 (95% CI, 1.03 to 1.06). This means delays in the administration of the appropriate antibiotics would have to occur in 148 patients before one dies or an NNH of 148. In fact, even this small temporal benefit dissolves when the patients with septic shock are excluded from the analysis.
Despite the retrospective observational nature of these trials, their findings likely reflect the importance of timely, appropriate antibiotic therapy in critically ill patients presenting in septic shock. In addition, the authors demonstrate these temporal benefits are unfounded in septic patients without signs of shock. When viewed from this perspective the results of the PHANTASi trial are unsurprising. The authors enrolled patients with suspected infection, a temperature higher than 38C or less than 36C, and at least one additional modified SIRS criteria (heart rate >90 beats per min or respiratory rate >20 per min). Only 57% of the population had severe sepsis and only 3-4% had septic shock. If Seymour et al’s data is to believed, the absolute benefit of shortening the duration of antibiotics by one hour would yield a mortality benefit in 1 out of 147 patients or an absolute reduction in mortality of 0.68%. The likelihood that prehospital antibiotics would work in the cohort of patients that the PHANTASi authors selected is minimal.
The PHANTASi Trial is simply the result of applying imperfect retrospective data, to a population of relatively healthy patients, all the while utilizing a remarkably optimistic power calculation that would be unlikely to detect a benefit even if one exists. I have no doubt that the use of timely, appropriate antibiotics is of vital importance in patients presenting with septic shock, but the PHANTASi Trial serves as a demonstration of the futility of broadly applying these concepts to the more general population presenting to the Emergency Department. It reminds us that screening and treating all patients in the Emergency Department with the potential for sepsis is logistically cumbersome and is unlikely to make a significant difference in patient centered outcomes.
- Fazzini TM, Perkins R, Grossman D. Ionization and photoelectric smoke alarms in rural Alaskan homes. West J Med. 2000;173(2):89-92.
- Alam N, Oskam E, Stassen PM, et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med. 2017;
- Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-96.
- Seymour CW et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. NEJM, May 21, 2017