Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01988428 |
| Other study ID # |
NL42001.029.13 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
November 5, 2013 |
| Last updated |
June 13, 2017 |
| Start date |
June 2014 |
| Est. completion date |
June 2017 |
Study information
| Verified date |
June 2017 |
| Source |
VU University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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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