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.