Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02527031 |
| Other study ID # |
HParis |
| Secondary ID |
2012-A00829-34 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 29, 2016 |
| Est. completion date |
July 3, 2020 |
Study information
| Verified date |
September 2022 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Cardiac arrest (CA) affects approximately 40,000 people in France. It is still a major cause
of death in a young population. Management of CA is defined by international recommendations,
detailed by learned societies in each country. It includes several links that are
interconnected for its optimisation. Despite all these improvements, no progress, or little
has been made in the survival of CA victims over the past few years in industrialised
countries, and the survival rate in France is 3% to 5%.
Refractory cardiac arrest is defined as failure, after 30 minutes of specialised
resuscitation. It used to be the standard to admit that there was no hope of spontaneous
cardiac activity and satisfactory neurological recovery after this period, except in cases of
CA with neuroprotection (intoxication, hypothermia).
External circulatory support such as "extracorporeal membrane oxygenation" (ECMO) makes it
possible to replace the circulatory activity of the myocardium and the respiratory activity
of the lungs.
In in-hospital cardiac arrest (CA) some teams use ECMO with an improvement in the survival
rate of 20% in comparison to standard resuscitation. This use demonstrates the possibility of
neurological recovery independent of the recovery of spontaneous cardiac activity which can
be differed.
These results encouraged the use of ECMOs in cases of out-of-hospital refractory cardiac
arrests. Patients who are victims of CA are resuscitated for 30 minutes on the spot where the
CA occurs. They are then transferred to a specialised centre. The significant improvement in
survival noted in in-hospital CAs was not observed in the French series of studies concerning
out-of-hospital CAs. This survival is currently estimated at 4%. This difference can be
partly explained by the difference in time between the beginning of cardiac massage and the
implementation of circulatory support by ECMO ("low flow" period). This time period is
directly correlated to survival.
To demonstrate the superiority of this strategy in terms of survival, investigators would
like to conduct a randomised comparative study of two strategies: 1) installation of an ECMO
between the 20th minute to the 30 minute of CA, directly at the site of the CA, by emergency
physicians and/or specifically trained resuscitators 2) On-site resuscitation optimised with
secondary transfer to the hospital for the implementation of support. The purpose is to
increase by 5% to 20% the survival of victims of out-of-hospital refractory cardiac arrests
with a good neurological prognosis.
Main objective:
The hypothesis is that pre-hospital ECMO will result in survival for 20% of the patients,
considering that the percentage of survival with in-hospital ECMO is less than 5%.
Main judgement criterion:
Survival with good neurological outcome (CPC 1 or 2) on discharge from intensive care or at 6
months
Secondary judgement criteria:
Success rate of the implementation of ECMO ECMO implementation time Immediate complications:
haemorrhage, infection Number of organ harvesting The quality of survivors' neurological
status according to the CPC neurological classification at D 28, 2 months and 1 year
Predictive indicators of the prognosis during cardiac arrest via cerebral and biological
monitoring Methodology, type of study: This is a prospective randomised study of current care
Sample size (SS, power, risk): A total number of 105 patients in each group will make it
possible to demonstrate at the alpha risk of 5% and a power of 1-β=90%, a significant
difference in favour of early pre-hospital ECMO compared to the current practice with
in-hospital ECMO.
Description:
1 STATUS OF THE QUESTION 2.1 Circumstances surrounding the problem: 2.1.1 The limits of
conventional resuscitation in cardiac arrests. Sudden adult death, unexpected cardiac arrest
(CA) most often related to cardiovascular causes, affects more than 40,000 people in France
every year.
The prognosis of out-of-hospital sudden death is particularly sombre. Only 5 to 20% of the
patients survive without neurological sequel. This prognosis can be partially improved by an
efficient organization of management that implements the concept of the "survival chain". An
early alert by witnesses of the CA, carrying out the first interventions, cardiopulmonary
resuscitation (CPR), defibrillation by the public or persons qualified in first-aid, followed
by specialized resuscitation by a medical team (such as the ambulance service) increase the
amount of survivors. The reduction in the time that passes before the first interventions
(called the no-flow period) and the duration of resuscitation before return of spontaneous
circulation (ROSC) called low-flow, are considered to be the primary predictive factors of
survival in CA.
Just recently, better knowledge of post-cardiac arrest syndrome also contributed to an
improvement in the prognosis and the quality of survival. The introduction of early
angioplasty and the generalisation of therapeutic hypothermia now complete management for
which coding is steadily improving through international and national recommendations that
are updated every 5 years. However, in order to show what it is capable of, this conventional
management of CA requires spontaneous cardiac activity to be re-established as quickly as
possible. Therefore, a return of spontaneous circulation (ROSC) must be obtained in the field
in out-of-hospital sudden deaths.
Classically, in the absence of ROSC after 30 minutes of correctly administered resuscitation,
the CA is considered to be refractory and the treatment options are limited. Just recently,
it was shown that the chances of survival are non-existent after 16 minutes of resuscitation.
In most cases, resuscitation is discontinued and the patient is declared dead on the spot.
The regulatory inclusion of a physician on ambulance service teams relieves the difficulty of
this decision. It is often simple to make and is medically indisputable when it is obvious
that the prognostic factors are very unfavorable (notably, an extended no-flow period) and/or
the conditions (advanced age, severe chronic disease, etc...) are not compatible with
prolonged resuscitation. This decision is much more difficult when the prognostic factors are
favorable and prolonged resuscitation efficiently provides spontaneous circulation (signs of
the patient awaking during CPR). Under these circumstances, in France and several other
European countries, the decision can be made to continue extracorporeal membrane oxygenation
(ECMO) and transport the refractory CA victim. It was made possible by the development of
mechanical external cardiac massage devices such as Autopulse ® and Lucas® which enable
prolonged cardiac compression during transport by the emergency service. However, this
continuation of resuscitation can only be considered if it enables another subsequent
treatment for the patient. Two options are possible. The patient can be declared dead and
become a potential organ donor in the framework of an organ harvesting procedure in a patient
after "cardiac death". This harvesting, which is highly organized according to regulations,
can only be done in certain hospitals authorized by the French Biomedicine Agency.
Or, resuscitation can be prolonged by the use of extracorporeal circulatory support.
2.1.2. The progress of extracorporeal circulatory support and cardiac arrest
Circulatory support is a technique that has been in common use for many years now
perioperatively in cardiac surgery. One of its simplest forms, extracorporeal membrane
oxygenation (ECMO) is being used more and more often outside of this field, notably in
paediatrics and in the care of Acute Respiratory Distress Syndrome (ARDS) or refractory shock
in adults. This technique has notably been widely introduced in general intensive care in the
treatment of malignant influenzas that affect young subjects (H1N1 virus). In parallel with
this extension of the indications for ECMO, the technical development of equipment was a
major factor. ECMO devices, which are particularly easy to use, miniaturized and energy
autonomous, are available. They make it possible to use ECMO during inter-hospital transport
by ambulance or helicopter. In France, several teaching hospitals have therefore developed
mobile teams called mobile circulatory support unit (UMAC) that enable the implementation of
ECMO in intensive care units where there was none, and the transport of patients on
circulatory and respiratory support to a reference center.
2.1.3. The implementation of extracorporeal membrane oxygenation (ECMO) in Cardiac Arrest
(CA)
It quickly became evident that the possibility of having artificial circulatory activity that
enables efficient perfusion by oxygenated blood was important for CA victims whose heart had
stopped beating. The first research, conducted primarily during refractory CAs that occurred
in the hospital setting, demonstrated the unexpected possibility for survival in patients
who, without this option would be dead, and for whom resuscitation would have been stopped.
In 2003 in Taiwan, Chen et al. noted a survival rate of almost 30% in a series of CAs that
occurred in the hospital setting. In Caen, France, the same phenomenon was noted: the
survival of 8 out of 40 patients who benefited from ECMO following refractory CA. This
technique proved to be highly adapted when the cause of the CA was potentially reversible.
Mégarbane et al. noted the survival of 3 out of 12 victims of CA following acute intoxication
with cardiotoxic drugs.
In international recommendations, circulatory support is still only recommended in
paediatrics. However, these indisputable successes in adults led to an attempt to rationalise
the use of therapeutic ECMO in France. The indications considered as possible include the
existence of hypothermia, intoxication, signs of life during Cardio-Pulmonary Ressucitation
(CPR), and CPR (low-flow) of less than 100 minutes.
The development of ECMO programmes for the treatment of refractory CA demonstrated a
difference in prognosis between in-hospital and out-of-hospital CAs. In-hospital CAs quickly
benefit from the implementation of ECMO. Out-of-hospital CA victims have late access to this
possibility of resuscitation. In fact they require resuscitation of at least 30 minutes in
the field to be considered as refractory, followed by transport under mechanical massage
until arrival at a center with ECMO. Le Guen et al. noted that in a series of patients who
were victims of sudden death in Paris in out-of-hospital settings, only 2 out of 51 patients
survived in good neurological condition. Most of these patients had extended low-flow periods
before the implementation of ECMO. A negative correlation between the duration of
resuscitation before ECMO and survival explains this poor prognostic result. In addition,
resuscitation prolonged by mechanical massage is burdened by its own morbidity as Agostinucci
et al. emphasized. This negative influence before access to ECMO is also noted by Chen et al.
in the hospital setting. The prognosis rapidly decreases when resuscitation is prolonged:
more than 40% survival if resuscitation lasts less than 30 minutes; 17% when it surpasses 60
minutes. This difference in survival between in-hospital and out-of-hospital CA is also noted
in another series of French studies (Gay, AFAR abstract). The prognosis for out-of-hospital
CA is even worse when it is accompanied by prolonged CPR. Morbidity is also higher among
these patients. Cadarelli et al. included all the research and case histories published up
until 2008 in a meta-analysis and demonstrated the harmful effect of prolonged CPR. In this
analysis, the speed at which ECMO is implemented appears to be a prognostic factor similar to
patients' age and the total duration of circulatory support. Therefore, ECMO that is started
after more than 30 minutes of CPR results in a decrease in survival. Kilbaught et al.
emphasize that it is actually the time factor that makes the difference between in-hospital
and out-of-hospital CAs. In their pre-hospital emergency system, very rapid transport of
patients during CPR to start ECMO upon arrival in the emergency service is possible. With
this strategy, they demonstrate that the difference in prognosis between in-hospital and
out-of-hospital CAs is eliminated when the time for implementation of ECMO is comparable. As
a result, ECMO is used earlier and earlier in hospitals in Japan with results currently being
published that appear to be very positive for survival.
2.1.4 The concepts of pre-hospital extracorporeal membrane oxygenation (ECMO)
The analysis of the international literature shows that ECMO might be a management method
that improves the survival of CA victims.
However, in the context of out-of-hospital sudden death in a medicalised emergency system and
in the framework of French regulations, there are two limiting factors:
- the obligation for resuscitation for 30 minutes before categorically announcing that the
CA is refractory and whether or not to choose another treatment option.
- the possibility to have access to ECMO within the closest time period to the 30 minutes
of Cardio-Pulmonary Ressucitation (CPR), which appears to be an important threshold in
determining the prognosis.
Pre-hospital ECMO, which is the basis of the research concept being proposed, includes
arterio-venous cannulation and the implementation of the extracorporeal system (pump,
oxygenator) in a non-healthcare setting. It is therefore different from the in-hospital
transport of patients on ECMO since the preceding steps take place in a hospital. The
implementation of ECMO in hospital studies can be rapid, approximately 20 minutes in the
Japanese study series and according to our experience. ECMO for out-of-hospital refractory
CAs was the subject of a few clinical cases, in children and in sports events . Its
feasibility by the ambulance service pre-hospital teams was confirmed in our last studies.
The improvement in survival with early ECMO, close to a 30-minute period of CPR should also
be demonstrated. It is only based on the extrapolation of the results of very fast transport
and almost without specialised resuscitation of victims of sudden death close to a hospital
with ECMO.
Confirmation of this concept is therefore of particular importance and in fact:
- it would provide the prospect of a new treatment possibility for patients whose chances
for survival are extremely slim, because prolonged CPR is required to have access to a
hospital ECMO. It is an essential step before conducting a multi-centre randomised study
to demonstrate the beneficial effect on survival.
- it would make it possible to stress the pertinence of the French teams' approach in this
field, notably in comparison to European countries (Germany, Spain, etc...) that already
have a medicalised pre-hospital emergency system, or that are currently developing it,
like Japan.
- finally, it might also result in a better determination of the place of therapeutic ECMO
and as a result, clarify the indications for organ harvesting after "cardiac death" in
victims of pre-hospital sudden death.
In brief, the objective of this project is to evaluate the advantage of pre-hospital ECMO in
improving patient survival.
