Sepsis is one of the most frequent reasons for referral to emergency departments (EDs) worldwide. The incidence of sepsis is likely to rise in the upcoming years. Sepsis has a tendency to become more serious when left untreated with a high mortality rate, exceeding even those of myocardial infarction and stroke. Therefore, much effort has been put in to start with appropriate therapy as early as possible. Early goal-directed therapy (EGDT) in the emergency department with fluid resuscitation, administration of vasopressors/vasodilators and intravenous antibiotics in patients with severe sepsis and septic shock has indeed decreased mortality substantially. Emergency medical services (EMS) personnel have already made a significant difference in improving care for patients with acute coronary syndrome, multiple trauma and stroke. Patients with severe sepsis or septic shock could also benefit greatly from timely pre-hospital care. Earlier recognition and initiation of treatment by EMS personnel may improve survival even more.

Interestingly, the first hour of ED presentation seems to be the most critical hour. Administration of antibiotics and fluid resuscitation in the pre-hospital setting will reduce the time to administration substantially. In adults, to the best of our knowledge, no studies on the effect of pre-hospital administration of antibiotics have been performed. In children with meningitis, some uncontrolled studies show contradictory results, most probably due to bias by severity. We propose a non-blinded randomised multicentre clinical trial study on the efficacy of early, pre-hospital intravenous administration of broad spectrum antibiotics (ceftriaxone), which are effective against a wide variety of infectious pathogens that cause most common community-acquired infections) in patients referred to the ED with suspected severe sepsis or septic shock.

Objective: To evaluate whether early, pre-hospital administration of antibiotics, together with training of ambulance personnel in recognizing and initiating treatment reduces 28-day mortality in patients referred to the ED with suspected severe sepsis or septic shock

Study design: Non-blinded randomized multicentre clinical trial nested within a stepped wedge design

Study population: All patients above the age of 18 years, with suspected severe sepsis or septic shock and transferred to the ED by ambulance, are eligible for study inclusion

Intervention: prehospital antibiotics (ceftriaxone 2000 mg intravenously)

Main study parameters/endpoints: 28-day mortality, hospital length of stay, admission to intensive or medium care unit (ICU/MC), time to administration of antibiotics. Follow up of one year. QoL after one month after discharge.

Introduction Sepsis is one of the most common and life-threatening diseases in the world, causing more deaths than AIDS, breast cancer and prostate cancer put together (8-10). Despite the fact that the mortality of sepsis is ten times higher than myocardial infarction and to five times higher than stroke, relatively little attention is given to sepsis (23-25). In recent years successful clinical care management pathways have been developed for patients suffering from a myocardial infarction, stroke or a trauma. Even though there is strong evidence in scientific literature to support the need for a series of time-dependent actions, for sepsis this is still not the case.

On 13 September 2012, the first ' World Sepsis Day ' was held with as main objective : 'to increase awareness for sepsis as a potentially lethal condition, which should be considered as a medical emergency ' (26). Prompt recognition and treatment are extremely important for improving survival, while patients who survive sepsis can still continue to suffer from physical or psychological symptoms. The likelihood and severity of these complications depends on a number of factors including the severity of sepsis and the length of stay in hospital stay and in ICU.

Definition Sepsis is defined as a proven or strongly suspected infection that is associated with a 'systemic inflammatory response syndrome ' (SIRS) (29,30). SIRS exists if at least two of the four criteria are met: abnormal body temperature, increased heart rate (over 90 beats per minute), increased respiratory rate (more than 20 per minute) and an abnormal white blood cell (WBC) count. There are different degrees of sepsis on the basis of severity. Sepsis may develop to severe sepsis or septic shock, if treatment is not timely initiated. Severe sepsis is defined as sepsis with failure of one or more organ systems and septic shock and severe sepsis with persistent low blood pressures despite adequate resuscitation. In particular organ failure and shock cause high mortality.

In the Netherlands, more than 10,000 patients with sepsis are admitted to a hospital annually, with an average length of stay (LOS) of 15 days. The medical costs being approximately $ 20,000 per person, the total cost of severe sepsis in the Netherlands is estimated at nearly 170 million per year (1-3).

Mortality can be very high if sepsis is not timely or adequately treated, especially among the vulnerable elderly population. The mortality rates vary from 20 to 60 percent, depending on the age and other underlying diseases such as diabetes and cancer. Even in the VUmc the mortality rates are almost up to 40%. Multiorgan failure due to sepsis and septic shock is the leading cause of death in the ICU (31,32). The incidence of sepsis has increased in recent years and it is expected that this trend will continue, partly due to the aging population and partly because of increasing numbers of immune-compromised patients who are highly susceptible to all kinds of (opportunistic) infections.

Early Goal Directed Therapy (EGDT)

The advent of antibiotics was a major step forward in the treatment of sepsis, causing a mortality decrease by approximately 25 percent (33,34). It is noteworthy that in the decades hereafter very little progress in the treatment of sepsis was made, until the introduction of the 'Early goal directed therapy (EGDT). A study by Rivers and colleagues (4) shows that by applying EGDT during the first six hours after detection of sepsis, an absolute mortality reduction of almost 16% is achieved. This EGDT consists of a number of interventions, which have the purpose to optimize hemodynamics as quickly as possible by means of tight monitoring of arterial / venous pressures and oxygen saturation. The cornerstones of this treatment include aggressive fluid resuscitation, administration of vasopressors, giving protective ventilation and administration of broad-spectrum antibiotics. Several large clinical trials have confirmed the value of EGDT with sometimes even greater mortality reduction (35-38).

Survival Sepsis Campaign Timely recognition and rapid treatment of sepsis appears crucial, but recognizing sepsis still remains a challenge: the symptoms are often non-specific and various other diseases might fit as well. Therefore the "Surviving Sepsis Campaign" (SSC) was launched in 2003 (13), with the aim of creating awareness for sepsis for better recognition and treatment of sepsis to improve the prognosis. Through this campaign a directive was developed wherein a somewhat modified form of the EGDT was incorporated. This directive also states that broad-spectrum antibiotics should be administered as soon as possible, preferably within one hour after arrival in the emergency room.

Despite extensive attention in the last few years (major campaigns of VMS) in shortening time to administration of antibiotics (the so called "onset to needle time"), there are still delays in the start up of antibiotic therapy in the emergency department (ED) (6-7). EDs are still not functioning optimally, with waiting times sometimes exceeding 6 hours. This is also the conclusion of the report: 'Haastige spoed niet overal goed' from 2004 (Inspectie der Volksgezondheid). Herein EDs in the Netherlands are described as the weakest link in the emergency care, and in addition according to this report, little progress in the quality of care in the emergency department was made from 1994 to 2004. After much effort and recommendations, progress was made in the last few years but not sufficiently enough (see report '' Ziekenhuizen goed op weg met implementatie normen voor afdelingen spoedeisende hulp' "). Our study will therefore be able to contribute to the improvement of both in-hospital and pre-hospital acute care chain. Not only will we save costly time in the trip till reaching the hospital, but moreover we will also overcome (potential) delays in the emergency department by starting therapy in the ambulance. Delays which can amount from one to even six hours.

Why antibiotics should be administered early? The first hour of presentation in the emergency room, also known as the 'Golden Hour' seems to be the most critical one in the treatment of a septic patient. Retrospective studies have shown that rapid antibiotic administration could mean better chance of survival as well as a reduction in the chance of lasting physical problems. Moreover, rapid intervention may shorten hospital stay as well and even prevent the need for ICU admission (1-5). In daily practice however, implementation of the SSC directives is not always easy, and there may be several reasons to delay the start of treatment (6.15). The so-called 'onset to needle time' can be as high as several hours. A recent pilot study in the VUMC showed that 25% of patients had to wait longer than three hours at the emergency department before treatment was initiated with antibiotic therapy (16). Not only in the pilot study of our university but also in a retrospective study conducted by Kumar and colleagues only 32.5% of the patients received the first gift within the first 3 hours (6) Any delay in the administration of antibiotics, causes an increase in mortality rate with almost 8 percent per hour!(6).

The later the treatment is initiated, the greater the chance of multiorgan failure. Besides higher mortality-rates, multiorgan failure is directly correlated with more complications, longer hospital stay and higher use of costly healthcare facilities (10). Therefore it is probably important that the onset to needle time is as short as possible.

Moreover in the long term sepsis can cause much damage (17-20). Patients who survive sepsis often suffer for months of complications that arise during or after a prolonged hospitalization in intensive care (eg. critical illness neuropathy, problems with speech or swallowing by prolonged ventilation). The quality of life can also sharply deteriorate after experiencing sepsis (18).

An important point to note is that all the studies which state that early antibiotic administration is associated with improved survival, were retrospective and uncontrolled studies, making occurrence of selection bias probable. One of the reasons why the doctors may not be very keen on initiating the antibiotics early (before a definitive diagnosis is made) may be the fact that they consider current evidence insufficient and incomplete. In order to investigate the optimal timing of antibiotic administration, prospective randomized controlled studies should be performed at the emergency department. However, it may be unethical to randomize patients and delay initiation of antibiotic therapy at the ED. An alternative and perhaps a better option is to perform a prospective randomized trial in the pre-hospital setting, i.e in the ambulances. In current practice, initiation of antibiotic therapy starts at the emergency department (ED) and not in the ambulances. Pre-hospital antibiotic administration on the one hand may be a solution to avoid delays in treatment at the ED and on the other hand a way to finally perform a randomised trial to examine the effect of onset to needle time on clinical endpoints such as improved survival, shorter hospital stay and better quality of life.

Pre-hospital care, even in sepsis? Ambulance personnel have already made a significant contribution in improving care for patients with acute coronary syndrome, stroke and multiple trauma (42, 43). Patients with severe sepsis or septic shock can also benefit from early pre-hospital care (44). Pre-hospital care is the initial medical care, which is given by ambulance personnel once they reach the patient. Since time plays a crucial role in the treatment of sepsis, early recognition and initiation of treatment by the ambulance personnel may help to reduce mortality. The provision of pre-hospital care is associated with a shorter start-up time of EGDT and antibiotic therapy in the hospital (44-47). In addition, it appears that this pre-hospital care leads to quicker achievement of an optimal blood pressure, and oxygen saturation. Therefore, it can be expected that by the administration of broad-spectrum antibiotics in the ambulance, the survival of sepsis can be improved by greatly reducing the time to the administration of the necessary antibiotics.

To date no randomized controlled trials on the effect of antibiotics in the pre-hospital settings on adults have been conducted. In children with meningitis some uncontrolled studies have been done. In the studies by Strang and Cartwright (50,51), a clear beneficial effect on survival is seen after pre-hospital administration of antibiotics by general practitioners. Hamden and Sorensen (52.53) on the contrary showed that administration of antibiotics in the pre-hospital setting was associated with worse outcomes. A possible explanation for these divergent results is that there occurred a strong selection bias. The group of children receiving pre-hospital antibiotics could be in a more critical stage of illness.

A definitive answer to the question whether administration of antibiotics in pre-hospital setting is effective, can only be obtained by a prospective randomized controlled trial. In this form of study selection bias can be avoided.

However, recognition of sepsis is difficult, Suffoletto et al investigated how accurately the ambulance personnel in Pennsylvania were able to recognize a serious infection, the negative predictive value was 93%. In contrast, 69% of the patients with a severe infection were missed (8). A pilot study in Maastricht showed (54), that this situation can probably be extrapolated to the Netherlands as well: a large proportion of patients with septic shock was in fact not recognized as such and transported with a B-ride (low priority ride). The information transfer is hereby often incomplete or not entirely accurate (from the general practitioner to the ambulance personnel/hospital or from the ambulance to the ED) causing substantial delays in initiating treatment. Therefore, much can be gained by training ambulance personnel and getting them skilled enough in recognizing sepsis and improving the transfer of information.

Research Consortium

Through an intensive collaboration of some major Dutch medical centres and ambulance services, a research consortium has been established to start a nationwide project in the form of a multicentre randomized trial: the PHANTASi trial (PreHospital ANTibiotics Against Sepsi) This consortium has a joint goal namely evaluating the effect of early administration of antibiotics in patients with suspected sepsis in the pre-hospital setting compared to that with the regular treatment. Our hypothesis in this study is that administration of antibiotics in the pre-hospital setting will significantly shorten the time to administration of antibiotics, which subsequently will lead to improved survival. In addition, the pre-hospital administration of antibiotics shortens hospital stay which, simultaneously has a favorable effect on the cost and quality of life (QoL).

Importance of this project Sepsis is a major global health problem with an increasing incidence and high mortality rate. While in the past decades, modern medicine has become increasingly sophisticated, and the treatment and care around diseases, such as heart failure and cancer is greatly improved, treatment of sepsis remains a problem with a high mortality. Early administration of antibiotics in critically ill patients with sepsis could possibly change that. It is not clear what the best time of administration should be, because how early is early? Moreover, in practice it often happens that the time limits are not, or not sufficiently monitored closely, whilst increasing the risk of death.

Moreover, the treatment of an acutely ill patient requires teamwork and an optimally functioning acute-care chain. Through this project it will be possible to investigate whether pre-hospital antibiotic therapy leads to better outcomes for this category of seriously ill and vulnerable patients.

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Inclusion Criteria:

- All patients older than 18 years who are suspected of sepsis AND have an abnormal temperature (>38 degrees Celsius or < 36 degrees Celsius) in combination with at least one of the following two SIRS criteria, abnormal pulse (> 90 beats per minute) and/or abnormal respiratory rate (> 20 per minutes)

Exclusion Criteria:

• Age <18 years
• Known severe allergic reaction to ceftriaxone or to other beta lactam antibiotics
• Known pregnancy

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