Articles
Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial

https://doi.org/10.1016/S2213-2600(17)30469-1Get rights and content

Summary

Background

Emergency medical services (EMS) personnel have already made substantial contributions to improving care for patients with time-dependent illnesses, such as trauma and myocardial infarction. Patients with sepsis could also benefit from timely prehospital care.

Methods

After training EMS personnel in recognising sepsis, we did a randomised controlled open-label trial in ten large regional ambulance services serving 34 secondary and tertiary care hospitals in the Netherlands. We compared the effects of early administration of antibiotics in the ambulance with usual care. Eligible patients were randomly assigned (1:1) using block-randomisation with blocks of size 4 to the intervention (open-label intravenous ceftriaxone 2000 mg in addition to usual care) or usual care (fluid resuscitation and supplementary oxygen). Randomisation was stratified per region. The primary outcome was all-cause mortality at 28 days and analysis was by intention to treat. To assess the effect of training, we determined the average time to antibiotics (TTA) in the emergency department and recognition of sepsis by EMS personnel before and after training. The trial is registered at ClinicalTrials.gov, number NCT01988428.

Findings

2698 patients were enrolled between June 30, 2014, and June 26, 2016. 2672 patients were included in the intention-to-treat analysis: 1535 in the intervention group and 1137 in the usual care group. The intervention group received antibiotics a median of 26 min (IQR 19–34) before arriving at the emergency department. In the usual care group, median TTA after arriving at the emergency department was 70 min (IQR 36–128), compared with 93 min (IQR 39–140) before EMS personnel training (p=0·142). At day 28, 120 (8%) patients had died in the intervention group and 93 (8%) had died in the usual care group (relative risk 0·95, 95% CI 0·74–1·24). 102 (7%) patients in the intervention group and 119 (10%) in the usual care group were re-admitted to hospital within 28 days (p=0·0004). Seven mild allergic reactions occurred, none of which could be attributed to ceftriaxone.

Interpretation

In patients with varying severity of sepsis, EMS personnel training improved early recognition and care in the whole acute care chain. However, giving antibiotics in the ambulance did not lead to improved survival, regardless of illness severity.

Funding

The NutsOhra Foundation, Netherlands Society of Internal Medicine (NIV).

Introduction

Sepsis is a complex syndrome associated with high morbidity and mortality. Although there has been a decline in mortality in the past two decades, the total number of deaths from sepsis is still rising due to increasing incidence.1, 2, 3, 4, 5, 6 However, this rise in incidence and decline in mortality can partly be attributed to the coding artifact, wherein milder cases are also recognised and coded as sepsis.7 Hospitalisations8, 9 for this condition are accounted as the most expensive of all conditions.10 Wang and colleagues11 reported that more than half of patients with severe sepsis in the USA are initially seen in the emergency department. Additionally, over half of the patients with sepsis presenting at the emergency department arrive by ambulance.12, 13, 14

Early recognition and initiation of therapy is crucial in the management of sepsis. One of the cornerstones of therapy is the timely administration of antibiotics, preferably within 1 h after arrival at the emergency department. This approach was endorsed by the Surviving Sepsis Campaign (SSC) guidelines15 after retrospective studies16, 17, 18 showed that prompt antimicrobial therapy was associated with improved survival, and that any delay in administration of antibiotics after development of septic shock was associated with an increase in mortality of almost 7·6% per hour.16 However, all studies which concluded that early antibiotic administration was associated with improved survival were retrospective and uncontrolled and thus selection bias might have affected the results. Whereas prospective observational studies have failed to show any association between early antibiotics and mortality benefit,19, 20, 21 the mainstream doctrine of early antibiotic administration within an hour of sepsis recognition is still upheld.22 To date, no prospective randomised controlled trial has been done to investigate the effects of early antibiotic administration in patients with suspected sepsis.

Next to general practitioners, emergency medical services (EMS) personnel are the first health-care providers that patients will encounter. In the past, EMS personnel have made substantial contributions to improving care for patients with other serious time-dependent conditions, such as acute coronary syndrome, poly-trauma, and stroke.23, 24, 25 Patients with (severe) sepsis and septic shock might also benefit from timely prehospital care by EMS personnel. Studies have shown that recognising sepsis and providing these patients with prehospital care by EMS personnel accelerated and improved care in emergency departments.26, 27 However, knowledge and awareness about sepsis among EMS personnel is low28 leading to poor recognition of sepsis in ambulances,13, 29, 30 which suggests that there is room for improvement.

Research in context

Evidence before this study

Sepsis is a common, life-threatening illness that affects millions of people globally. Prognosis of patients with sepsis can be improved by early recognition and early intervention. One of the cornerstones of therapy is the timely administration of antibiotics, preferably within an hour of sepsis recognition. Emergency medical services (EMS) personnel have already made substantial contributions to improving care for patients with time-dependent illnesses, such as trauma and myocardial infarction; patients with sepsis might also benefit from timely prehospital care. However, knowledge and awareness about sepsis among EMS personnel is low leading to poor recognition of sepsis in ambulances. We searched PubMed for studies investigating the association between the timing of antibiotic administration and mortality from inception to Aug 21, 2017, with the terms “sepsis AND (antibiotics or antimicrobial therapy) AND clinical trial AND adults” without language restrictions. We found no randomised controlled trials investigating the effect of early antibiotic therapy in patients with sepsis. Sterling and colleagues did a systematic review with a meta-analysis. They found no significant improvement in survival when antibiotic administration occurred within 3 h of emergency department triage or within 1 h of severe sepsis and septic shock recognition. Our search identified several other retrospective and prospective studies, although with conflicting results.

Added value of this study

The PHANTASi trial is the first randomised controlled trial investigating the effects of early antibiotic treatment after training EMS personnel in recognising sepsis. In patients with varying severity of sepsis, training EMS personnel significantly improved recognition of sepsis as well as reducing time to antibiotics (TTA). However, the intervention did not lead to a significant difference in mortality in our patient population with varying severity of sepsis.

Implications of all the available evidence

Currently, we do not advise antibiotic administration in the ambulance in patients with suspected sepsis. However, training EMS personnel improves early recognition of sepsis and processes of care in the emergency department.

Therefore, we designed the first prospective randomised controlled multicentre Prehospital Antibiotics against Sepsis (PHANTASi) trial to test the hypothesis that increasing the awareness of sepsis through training of EMS personnel in recognising and initiating treatment with early prehospital administration of antibiotics leads to increased survival of patients with sepsis, severe sepsis, or septic shock compared with those patients receiving usual care.

Section snippets

Study design and participants

We did this nationwide randomised controlled open-label trial in ten large regional ambulance services serving 34 secondary and tertiary care hospitals in the Netherlands, where 25 regional ambulance services provide prehospital service to 94 emergency departments.31

Patients were recruited by EMS personnel. Eligible patients were at least 18 years of age, had a diagnosed or suspected infection, a temperature higher than 38°C or less than 36°C, and at least one other criterion of the systemic

Results

2698 patients were enrolled between June 30, 2014, and June 26, 2016, of whom 1548 were assigned to the intervention and 1150 to the usual care group (figure 1). 18 were lost to follow-up, while eight withdrew consent, leaving 2672 for the intention-to-treat analysis (1535 in the intervention group and 1137 in the usual care group). Some patients who were eligible for the study were excluded for several reasons, for example patients with a language barrier, patients who were not able to give

Discussion

In this first prospective randomised controlled open-label trial that compared the effects of early prehospital antibiotics with usual care in patients with suspected sepsis, as well as training of EMS personnel, we found that giving prehospital antibiotics led to a time gain of 96 min, but did not lead to a difference in in-hospital, 28 day, or 90 day mortality. Only a small proportion of patients diagnosed with sepsis in the ambulance by EMS personnel had an alternative diagnosis during chart

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