Post-cardiac arrest extracorporeal life support

Accepted Manuscript Post-cardiac arrest extracorporeal life support Nicolò Patroniti, MD, Fabio Sangalli, MD, Leonello Avalli, MD

PII:

S1521-6896(15)00063-4

DOI:

10.1016/j.bpa.2015.09.004

Reference:

YBEAN 869

To appear in:

Best Practice & Research Clinical Anaesthesiology

Received Date: 8 July 2015 Accepted Date: 22 September 2015

Please cite this article as: Patroniti N, Sangalli F, Avalli L, Post-cardiac arrest extracorporeal life support, Best Practice & Research Clinical Anaesthesiology (2015), doi: 10.1016/j.bpa.2015.09.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Post-cardiac arrest extracorporeal life support Nicolò Patroniti, MD a,b,* Fabio Sangalli, MD b, Leonello Avalli, MD b

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Department of Health Science, University of Milano-Bicocca, via Cadore 48, 20048, Monza

(MB), Italy b

Department of Emergency Medicine and Intensive Care, San Gerardo Hospital, via Pergolesi 33,

20900, Monza (MB), Italy *

Corresponding author: Department of Health Science, University of Milano-Bicocca, San Gerardo

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a

Hospital, via Pergolesi 33, 20900, Monza (MB), Telephone ++39-039-2339273; FAX: ++39-039-

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2332297; e-mail: [email protected]

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ABSTRACT

Sudden cardiac arrest is a complex, life-threatening event requiring a multidisciplinary approach. Despite the use of conventional cardiopulmonary resuscitation, survival for both in-hospital and

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out-of-hospital cardiac arrest remains very low. In refractory cardiac arrest, defined by the absence of return of spontaneous circulation in spite of resuscitation manoeuvres, mortality approaches 100 %. In the last years an increasing number of case series, and few propensity matched cohort studies

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have reported encouraging results on the use of venoarterial extracorporeal membrane oxygenation for refractory cardiac arrest. Extracorporeal circulation allows maintaining adequate blood flow, to

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perform diagnostic and therapeutic interventions even before a return of spontaneous circulation is achieved, and to rest the heart by unloading the ventricle while ensuring myocardial perfusion after return of spontaneous circulation. Rational, indications, evidence, and management of

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extracorporeal support for cardiac arrest will be reviewed.

KEYWORDS

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Cardiopulmonary resuscitation, extracorporeal membrane oxygenation, refractory cardiac arrest,

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extracorporeal life support

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RATIONALE

FOR THE

USE

OF EXTRACORPOREAL

CARDIOPULMONARY

RESUSCITATION IN CARDIAC ARREST AND GENERAL CRITERIA FOR PATIENT SELECTION

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Sudden cardiac arrest (CA) is a complex, life-threatening event requiring a multidisciplinary approach. Outcome from such catastrophic event depends on a sequence of interventions called the “chain of survival” [1,2], which includes early access to the Emergency Medical System (EMS),

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early cardiopulmonary resuscitation (CPR), early defibrillation and appropriated state-of-the-art advanced care [3-5]. Early bystander CPR [6-9], and advanced interventions such as Targeted

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Temperature Management (10), careful control of normocapnia [11,12] and normoxia [13-14], might improve outcome.

However, survival for both in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) remains very low. More than 75% of patients with good functional recovery from CA achieve a return of spontaneous circulation (ROSC) within 15 minutes from collapse. This is the time window where

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conventional resuscitative manoeuvres have the highest chance to be effective [15]. For CA times above 15 minutes, the probability of good functional recovery among all attempted resuscitations falls to around 2%.

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In case of refractory cardiac arrest (RCA) defined by the persistent (longer than 10-30 minutes) absence of ROSC, mortality approaches 100% [16]. For these latter patients extracorporeal life

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support (ECLS) gained a place to sustain organ perfusion while diagnosis is ascertained and therapeutic interventions carried out. Derived from the pioneering applications of heart-lung machines firstly applied in 1930s by Gibbon, veno-arterial extracorporeal membrane oxygenation (VA ECMO) was first applied in 1976 by Mattox [17] to resuscitate moribund patients, obtaining a recovery of cardiac function and good survival in 15 out of 39 patients. VA ECMO was proposed in recent years as an additional ring in the chain of survival, initially for IHCA and subsequently also for OHCA patients (extracorporeal cardiopulmonary resuscitation, ECPR). ECMO represents a unique option in the absence of ROSC because it promptly restores circulation. Moreover, VA

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ECMO plays a pivotal role in the post-resuscitation period. In fact, it allows leaving the heart at rest allowing ventricular unloading while ensuring myocardial perfusion. Moreover, ECMO allows to perform diagnostic and therapeutic interventions even before a ROSC is obtained [18-20]

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Although results from the use of ECMO in RCA improved over time, criteria for the selection of candidates are still debated. Up to now, studies failed to provide precise indications and contraindications to ECMO in this setting, however, correct patient selection is paramount to avoid

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futile treatments.

The time interval from collapse to the beginning of CPR (the so-called “no-flow” time) represents

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the first issue to be considered in the decision tree for ECLS indication. The duration of no-flow can only be exactly determined only in witnessed CAs and the best candidates to ECMO in this setting are those receiving immediate CPR by bystanders, since the no-flow is negligible in these patients. Indications about the duration of no-flow are lacking or inhomogeneous in literature. In the French guidelines [21] no-flow is matched with the rhythm of presentation. The authors suggested a no-

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flow below 5 minutes as a cut-off for ECMO application when patients are found asystolic, while for non-asystolic patients with a no-flow longer than 5 minutes the duration of CPR (the so-called “low-flow time”) is evaluated. Le Guen et al [22] also suggested a no-flow of less than 5 minutes as

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an inclusion criterion for ECMO in their OHCA population. The duration of no-flow time may lose its importance when vital signs such as spontaneous movements or spontaneous respirations occur

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during CPR. Moreover, the role of no-flow time appears less critical during hypothermia because of its protective effects from ischemia on cerebral and cardiac tissues [23-27]. The second most important factor to consider is the low-flow time. There is no definitive consensus on the optimal low-flow time limit: the shorter the low-flow time, the better the outcome, but its duration vary between authors and also relates to the quality of CPR. Some studies showed a more favorable outcome in patients treated with ECMO after IHCA compared with those after OHCA [28, 29], with longer delays between collapse and the start of ECMO in the latter. VA ECMO FOR REFRACTORY IN-HOSPITAL CARDIAC ARREST

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In 2005, Massetti et al. published their 10 years’ experience on 40 patients with refractory IHCA treated with VA-ECMO. ECMO was discontinued in 22 patients due to brain death or multiorgan failure, 18 patients survived to the first 24 hours of support, and only 8 patients (20 %) were alive

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without any sequel at 18 months follow-up [30]. Chen et al. [31] obtained slightly better results in a 3-year prospective observational study. They compared use of ECMO versus conventional CPR in 92 patients suffering IHCA of cardiac origin (Table 1). Patients were analyzed by a matching

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process based on propensity score to equalize potential prognostic factors. Survival rate was significantly higher in the ECMO matched group than in the conventional treatment group at

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discharge, after 30 days and after 1 year. They also found a negative correlation between CPR duration and the survival rate: survival rate in the ECPR group was 41.7%, 30%, and 17.7 % respectively with CPR duration of 30 minutes, between 30 and 60 minutes, and after 60 minutes, demonstrating that need of initiating ECMO as soon as possible. A few years later, Shin et al [32] (Table 1) confirmed these results in a retrospective study applying a similar propensity score and

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reviewing data collected between 2003 and 2009 on 120 IHCA patients. Lin et al [33] compared patients who had return of spontaneous beating (ROSB) after ECLS with those that had ROSC after conventional CPR: no difference in survival at hospital discharge, after 30 days, 6 months and 1

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year was found between groups. However, it is important to note that 50 of 113 patients did not have ROSC in the conventional CPR group against to only 4 of the 59 patients receiving ECMO.

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These results suggest that the survival advantage of ECMO maybe more related to the effectiveness in reestablishing heart beating than in the management of post-resuscitation phase. Chou et al [34] compared the survival outcome of 43 patients who received ECPR with that of 23 patients who underwent conventional CPR after acute myocardial infarction. They failed to find a significant difference between patients who received ECPR (34.9%) and patients who received conventional CPR (21.8%) However, increased survival rates to hospital discharge were seen in patients with ST segment elevation or initial rhythm of ventricular tachycardia/ventricular fibrillation (VT/VF) during resuscitation.

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ECPR hence appears feasible in patients with refractory IHCA and seems to improve the outcome when compared to conventional treatment – despite longer low-flow times – thus supporting the hypothesis that ECMO provides a sort of “controlled reperfusion”, as suggested by Chen in his

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2008 study [35].

VA ECMO FOR REFRACTORY OUT-OF-HOSPITAL CARDIAC ARREST

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Sudden cardiac death represents one of the leading causes of death in adults in the US [36]. Each year, millions of people around the world experience out-of-hospital cardiac arrest (OHCA), with

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an estimated incidence of 50-60 cases of treated OHCA per 100000 inhabitants per year [37]. These figures are obviously underestimated, as they do not take into account patients who are declared dead on the scene without being admitted to hospital.

For those who reach the emergency department with a sustained ROSC survival rates range between 10.6 and 31.4 %, whereas in patients with a RCA who reach the hospital under CPR

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mortality nears 100 percent.

ECPR gained a place even in this setting, but despite an improved survival with respect to conventional resuscitative maneuvers [38, 39] (Table 1), several series revealed dismal results when

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compared to those obtained in in-hospital cardiac arrest patients (IHCA) [28,29, 40, 41] (Table 2). Several reasons contribute to these differences.

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The time intervals from collapse to CPR (no-flow) and from collapse to ECMO (low-flow) are shorter in IHCA patients [28]. In fact, Kagawa and colleagues observed similar outcomes between IHCA and OHCA patients after adjusting for patient factors and the time delay in instituting ECMO, while crude data showed a worst outcome in OHCA patients [29]. Haneya and colleagues reported on the 5 year experience in Regensburg and found worst outcome for ECPR in OHCA than IHCA [41]. In their report, the median duration of CPR was 25 (20-50) minutes in IHCA and 70 (55-110) minutes in OHCA patients. No-flow time – and to a lesser extent low-flow time – hence appear as strong determinants for good outcome in ECPR [22,29].

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The negative effect of CPR duration on survival has important consequences also for the selection criteria. In most studies a CPR duration longer than 10 minutes is required before consideration for ECMO. It is worth noting that in studies requiring CPR duration longer than 20 minutes [28, 29]

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lower survival rate were observed. As recently shown by Reynolds et al. [15], the probability of good functional recovery after 15 minutes of CA in OHCA is less than 2%. These observations suggest that to increase chance of obtaining a good outcome ECMO should be consider after 10

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minutes, but not beyond 15 minutes of CPR, avoiding also an excessive delay of ECMO implantation.

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Together with the duration, the quality of chest compressions during CPR represents another paramount factor. Mechanical chest compression devices have been advocated as useful tools in enhancing the quality of CPR and hence possibly improving survival. In this regard, recent randomized trials compared state-of-the-art conventional CPR with mechanical chest compression devices showing comparable results in terms of safety and efficacy, without a benefit on outcome

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[42-44]. However none of these study has investigated the combination of mechanical chest compression with E-CPR. As recently highlighted in an observational study from Tranberg and colleagues [45], these studies show that mechanical CPR is feasible, safe and allows for continuous

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high-quality CPR in a hostile environment such as the out-of-hospital setting, where the recommendation for uninterrupted high-quality chest compressions is seldom possible to achieve

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with conventional CPR [44]. These features may be particularly important in the setting of a E-CPR program for OHCA where CPR time durations are longer than with conventional CPR. In a recent prospective observational trial, Staub et al. reported the results of a E-CPR program for both, OHCA and IHCA, that combine mechanical CPR, intra-arrest therapeutic hypothermia, and E-CPR [19]. They were able to achieve ROSC in 25 of 26 included patients (96%), while survival with good neurological outcome at hospital discharge occurred in 54% of patients [19]. The efficacy of mechanical chest compression, combined with pre-hospital intraarrest cooling, E-CPR and early

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invasive treatments, compared to conventional CPR in OHCA patients is under investigation in an

VA ECMO FOR SPECIAL CIRCUMSTANCIES

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on ongoing European randomized controlled trial [46].

While the evidence for ECPR in adults with CA was considered insufficient to support its use in the

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general 2010 guidelines [47], use of VA-ECMO for CA associated to accidental hypothermia and

VA ECMO for accidental hypothermia

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intoxication has been established [48].

In a study by Morita et al. [49] hypothermic patients treated with extracorporeal rewarming between 2001 and 2009 were compared with patients treated with conventional rewarming from historical extracorporeal

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data collected between 1992 and 2001. In the small subgroup of patients with CA

rewarming was associated with a significant higher survival (85% vs 14.3%). With the limitations of an historical comparison, the study convincingly suggests the effectiveness of extracorporeal

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technique in these patients. Nevertheless, the several published case series reports inconsistent results [49-56]. This is due to the inclusion in the same series of both, patients who suffered a

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primary hypoxic arrest with concomitant hypothermia (submersion, avalanche), and patients in whom CA is a direct consequence of cold exposure. Dunne et al. have recently review the topic pooling data from several case series and reporting survival and neurologic outcome differentiated between hypoxic (157 patients) and exposed to cold (90 patients) patients [57]. Survival at discharge and good neurological outcome were respectively 67.7% and 61.5 % in cold exposed patients, but only 23.4 % and 9.4 % respectively in hypoxic hypothermic patients. The better prognosis in cold expose patients compared to patients suffering primary hypoxic arrest support the idea that hypothermia may have a neuroprotective role, and explain survival reported for prolonged

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cold exposure [57]. These data clearly support the use of VA ECMO for resuscitation of patients suffering CA arrest following cold exposure. In addition to restore recirculation and organ perfusion, in patients suffering hypothermic CA, VA ECMO offers the unique feature of controlling

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the speed of rewarming. It is important to consider that, differently than for other indications, time from CA to ECMO institution is less an issue in CA from cold exposure, while a plasma potassium level higher than 10

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mmol/L following hypothermic CA is considered an exclusion criteria or a reason to withhold

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ECMO [57].

VA ECMO for intoxication

Another established indication to VA ECMO is CA associated with intoxication [58-62]. Most of reports come from single cases and only few case series are available [61, 62]. In the most recent

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published series, Daubin et al. reported a survival rate of 71% in 17 patients suffering from CA following drug poisoning [62]. Of note, this successful outcome was obtained with a CPR duration of before ECMO of 101±55 minutes. Megarbane et al. reported a lower, but still satisfactory,

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minutes) [61].

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survival rate (24%), that was obtain in spite of CPR duration before ECMO even longer (120±60

VA ECMO AND ADJUNCTIVE THERAPIES FOR CARDIAC ARREST We have already discussed how determinant are patient selection criteria, quality of CPR, and time from CA to ECMO initiation to achieve rapid ROSC and obtain patient survival whit minimal neurological impairment. However, initiation of ECMO and ROSC are not sufficient alone to achieve these objectives in most of patients. In most recent trials on CA patients, VA ECMO is not assessed alone but in combination with other adjunctive therapies among which percutaneous

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coronary intervention (PCI) and therapeutic hypothermia [19, 20]

Percutaneous Coronary Intervention

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As soon as VA ECMO has started it is crucial to identify, in time, any reversible treatable cause of CA. As acute coronary syndrome is a frequent cause of CA, emergent coronary revascularization performed during ECPR may have a great impact on outcome. In a recent paper from the group of

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Kagawa and colleagues, the Authors obtained a ROSC in all patients who underwent intra-arrest PCI, even if its direct effect on survival was blurred due to many confounding factors [63]. No

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randomized trials included STEMI patients who suffered cardiac arrest. In fact, such patients were deliberately excluded from clinical trials due to concern over their higher risk for poor outcomes. However, multiple reports advocate immediate PCI for all patients with evidence of STEMI [6366]. Whether to perform cardiac angiography in patients without an evident ST elevation at ECG might appear more questionable. However recent data suggest that almost one-quarter of patients

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resuscitated from cardiac arrest but without ST-segment elevation, show a culprit lesion [67].In the prospective Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry, 96% of patients with STEMI and 58% without STEMI after OHCA revealed at least one significant coronary artery

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lesion, and hospital survival rates were significantly higher if immediate PCI was performed successfully [66,68]. This led to a recommendation both from the European Association for

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Percutaneous Cardiovascular Interventions (EAPCI) [69] and from the joint ESC/EACTS 2014 Guidelines on myocardial revascularization [70] stating that OHCA patients should undergo coronary angiography in less than two hours and PCI, if appropriate, should be performed irrespective of the ECG pattern if no obvious non-cardiac cause of the arrhythmia is present.

Brain protection and Therapeutic Hyperthermia Finally but obviously paramount for the ultimate outcome of OHCA patients are minimization and quantification of neurological damage. Neurological outcome depends on several factors. The most

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relevant is the primary insult determined by the cardiac arrest time and the low-perfusion time during CPR. However, relevant damage might still happen after ROSC or ECLS implementation. In this regard, therapeutic hypothermia at 32-34°C for 24 hours with controlled rewarming is

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recommended by current guidelines [71] in all comatose patients after cardiac arrest, in order to reduce cerebral metabolism and prevent secondary insults. The optimal target temperature to aim to was recently questioned by the large TTM (Targeted Temperature Management) Trial comparing a

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temperature of 33°C according to current guidelines to a temperature of 36°C [10]. The TTM Investigators showed no difference in mortality nor in neurological outcome in either group of

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patients. Irrespective of the ideal target temperature, the key message derived from this as well as from other studies was to attain a strict temperature control and prevent hyperthermia. Multimodal neurological monitoring is warranted in all patients to promptly detect and treat neurological problems and allow prognostication [72]. Such approach might improve the prognosis even in

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patients with initial poor prognostic indicators [73].

VA ECMO FOR CARDIAC ARREST AND ORGAN DONATION As already stated, outcome after ECPR has improved over time and in most recent studies, the rate

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of patient with good neurological outcome approaches the survival rate. In a study by La Guen et al. one third of non-survivors after ECPR died from postanoxic brain damage [22]. These patients may

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be good candidates for organ donation. Mègarbane et al. reported only 1 survivor with good neurological outcome out of 66 patients considered for VA-ECMO [74]. However, among 6 patients with proven brain death 3 were suitable for organ donation. Given the duration of CA, none of these patients would have been suitable for donation without ECMO. Many ECMO centers are now implementing a program for organ donation in CA patients with brain death after ECPR [7577]. Given the high costs of maintaining an ECMO program for CA patients, the increase in organ donation should be considered when assessing justification costs for VA ECMO.

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PRACTICAL ISSUES AND MANAGEMENT OF VA ECMO In this section, we will discuss most important technical and clinical issues related to institution and

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management of VA ECMO that are relevant for application in CA (Table 3).

ECMO team organization and expertise.

In spite of technological improvement, VA ECMO remains a costly and challenge technique,

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especially for CA indications characterized by poor outcome and need of fast implantation. Due to complexity and the required expertise, E-CPR programs should be started in experienced and high-

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volume ECMO centers. Strong linking and cooperation with pre-hospital EMS is paramount in order to optimize indications and coordination and, ultimately, patients’ outcome. To maximize resource utilization it is necessary to implement, within the local emergency health network, an ECMO center with all necessary experts (intensivists, cardiac surgeons, perfusionists) available 24 h/7 d. Selection criteria must be clear, and, as soon as a candidate to VA ECMO is identified, the

Cannulation technique

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ECMO team must be alerted to be possibly already available at the arrival of patient in the hospital.

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For CA arrest, most centers place the cannulas by percutaneous technique. However, a surgical back-up must be always available. Commonly the drainage cannula (>19 Fr) is placed in the right

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atrium/inferior vena cava through the femoral; the returning arterial cannula is placed in the lower aorta through the femoral artery. The choice of the cannula size must balance the advantages (less resistance, less hemolysis) and risk (distal limb perfusion) of bigger cannula. For full VA ECMO support, arterial femoral cannula of 15 or 17 Fr are sufficient in most patients [78]. A frequent complication of femoral artery cannulation is ischemia of the distal leg. Adequacy of perfusion of the leg must be frequently monitored. In case of sign of ischemia, or in some center preventively, a reperfusion cannula may be inserted distally to the femoral cannula [78].

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Anticoagulation After initial unfractionated heparin bolus given during the placement of arterial cannula, continuous intravenous infusion is performed to keep an activated clotting time between 160 and 180 [28] or

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160 and 200 s [29] or even higher when extracorporeal blood flow is reduced [ 29, 30,35].

ECMO setting

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For CA indication, the main setting ECMO parameter is the pump blood flow (BF). The BF will determine both the mean arterial pressure and the organ perfusion. A target of 50 to 80 mmHg for

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arterial blood pressure is recommended. As the ECMO BF is directed backward toward the heart there is a competition between left ventricle output and BF. An excessive BF rate may lead to left ventricle distension and pulmonary congestion. For this reason, during VA ECMO it is crucial to monitor left ventricle output to identify any changes in outflow and to guarantee effective opening of aortic valve. Echocardiography is performed to verify cardiac contractility, ventricular

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distension, and valve opening: if necessary, low dose of inotropes and vasodilators are infused to assure adequate aortic valve opening, maintain pulsatile flow, decompress left heart and minimize the risk of intracardiac clot. If left ventricle remain dilated and lung congestion develop insertion of

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an intraortic balloon pump, or direct drainage of left ventricle may be necessary.

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Monitoring and management of organs perfusion Mild hypothermia [19, 28] is implemented during the first 24 h post-CA for neuroprotection. If residual cardiac output is too low, ventilation with physiologic minute ventilation will result in a relative alveolar hyperventilation. Controlled or spontaneous ventilation should be set to maintain an ETCO2 level of at least 20 mmHg. Positive end expiratory pressure should be set to avoid the atelectasis associated to the decreased ventilation, and to prevent pulmonary congestion. Renal function should be frequently monitored, as many patients during VA ECMO will require

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continuous renal replacement therapy. Most common indication are acute renal failure and management of fluid overload.

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Weaning from VA ECMO Weaning is attempted only when cardiac function improves. Weaning test is carried out by reducing ECMO blood flow, while monitoring cardiac contractility by echocardiography and by

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hemodynamic parameters. Sometimes, inotropic support is required to wean-off ECMO. If cardiac output increases while heart diameters remain stable under echocardiographic view, withdrawal of

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ECMO is conceivable [79].

CONCLUSIONS

VA ECMO is increasingly implemented for cardiopulmonary resuscitation of patient with refractory CA. In spite of the lack of a randomized controlled trial, available data comparing ECPR

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to conventional CPR strongly support the use of VA ECMO for both in and out of hospital CA. The rate of good neurological outcome reaches 40-50% for in hospital CA, and 15-30 % for out of hospital patient. The worst outcome of out of hospital CA is likely related to the longer duration of

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CA before ECMO installation. Patients with CA from cold exposure and intoxication show better outcome in spite of CA duration longer than 60 minutes. Maximization of outcome require well

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defined inclusion criteria, minimization of time from CA to ECMO implantation, and postresuscitation management integrating therapeutic hypothermia and percutaneous coronary intervention. In patient with poor neurological outcome, VA ECMO allows preservation of organs perfusion and the possibility of organ donation.

PRACTICE POINTS: • ECPR represents a valid and feasible option for IHCA and OHCA patients.

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• Especially for OHCA, due to clinical, organizational and economic issues, indications and exclusion criteria should be precise and restricted. • Due to complexity and the required expertise, ECPR programs should be started in

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experienced and high-volume ECMO centers. • Strong linking and cooperation with pre-hospital EMS is paramount in order to optimize indications and coordination and, ultimately, patients’ outcome

with CA duration longer than 60 minutes.

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• For CA due to accidental hypothermia or intoxication, ECPR should be considered even

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• Better outcome are obtained when ECPR is combined with mechanical CPR, therapeutic hypothermia, and percutaneous coronary intervention.

• An ECPR program should include the possibility of organ donation for patient recovering with poor neurological outcome.

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RESEARCH AGENDA

• Though a randomized controlled trial for ECPR in refractory CA seems unfeasible, efforts must be done to provide a stronger evidence supporting ECMO treatment for refractory CA.

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• Most of actual evidence comes from single center experiences. Multicenter international trials including larger population are needed.

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• Further research is warranted to improve management of patient before and after ECMO implantation.

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Care Med 2011;37:1738–1745

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TABLE 1: Studies comparing Extracopreal (E-CPR) vs conventional (CPR) cardiopulmonary resuscitation

Inclusion criteria

Sakamoto [38]

OHCA vs conventional

a) FV/TV

2008-2012

Prospective, observational.

b) No ROSC after 15 min c) Time from 119 call to hospital <45 min

IHCA vs conventional

a) Witnessed

2004-2006

Prospective, observational;

b) CPR >10 min

propensity score matched

IHCA vs conventional

a) Witnessed

2003-2009

Retrospective observational;

b) CPR >10 min

OHCA vs conventional

2000-2004

Prospective observational; Propensity score matched

Favorable Neurological outcome

unmatched

6 months *

E-CPR

260

11.2

CPR

194

2.6

matched

1 year *

E-CPR

46

21.

CPR

46

5

matched

2 year *

E-CPR

60

20

CPR

60

5

matched

3 months *

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Maekawa [39]

a) Witnessed

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propensity score matched

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Shin [32]

Number of patients

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Chen [31]

Groups

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Study type

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Study

b) CPR >20 min

E-CPR

24

29.2

c) cardiac origin

CPR

24

8.3

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Abbreviatons: CPR, conventional cardiopulmonary resuscitation; E-CPR, Extracopreal cardiopulmonary resuscitation; OHCA, out of hospital

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cardiac arrest; IHCA, in-hospital cardiac arrest; VF, ventricular fibrillation; VT, ventricular tachycardia; ROSC, return of spontaneous circulation.

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Study

Study type

Inclusion criteria

Number of patients

Favorable Neurological outcome

Kagawa [29]

OHCA vs IHCA

a) FV

unmatched

1 year (p=0.07)

2006-2009

Retrospective observational;

b) Time from CA to CPR <15 min

OHCA

39

10

c) CPR >20 min

IHCA

38

26

unmatched

Discharge (p=0.55)

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Groups

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TABLE 2: Studies comparing the outcome between out-of-hospital vs in hospital cardiac arrest

OHCA vs IHCA

a)Witnessed

2007-2012

Prospective observational;

b) Time from CA to CPR <6 min

OHCA

39

25.8

c) CPR >10 min

IHCA

38

25.1

unmatched

Survival at Discharge *

OHCA

26

15.4

IHCA

59

42.4

unmatched

6 months *

OHCA

18

22

IHCA

24

38

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Wang [40]

OHCA vs IHCA

a) Time from CA to CPR <10 min

2007-2012

Retrospective observational

b) CPR >10 min

OHCA vs IHCA

2006-2011

Retrospective observational

a) Witnessed

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Avalli [28]

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Haneya [41]

b) CPR >30 min

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Abbreviations: OHCA, out of hospital cardiac arrest; IHCA, in-hospital cardiac arrest; CPR, conventional cardiopulmonary resuscitation; VF,

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ventricular fibrillation; CA, cardiac arrest.

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Table 3: Practical issues and management of VA ECMO

•

Experienced and high-volume ECMO centers

•

Strong link and cooperation with pre-hospital EMS

•

ECMO team and necessary experts 24h/7 d available

Selection criteria •

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ECMO team and organization

Selection criteria must be clear and all personnel involved must be acknowledged with the protocol.

Cannulation technique Most commonly percutaneous insertion

•

Drainage cannula: tip in the atrium/inferior vena cava; size > 19 Fr

•

Returning arterial cannula: through the femoral artery; 15-17 Fr can be insert percutaneously and allow sufficient

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•

blood flow; bigger cannula require surgical insertion •

Check frequently adequacy of leg perfusion

•

If sign of leg ischemia consider a distal reperfusion cannula

Anticoagulation

continuous intravenous infusion of unfractionated heparin target activated clotting time between 160 and 180 or

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•

160 and 200 s ECMO setting

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Blood flow:

Targeted on mean arterial pressure (50-80 mmHg) and adequacy of organ perfusion

•

Excessive blood flow may lead to left ventricle distension

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•

Gas flow: •

targeted on gas exchange

•

avoid excessive hypocapnia and alkalosis

Monitoring and management Heart •

Echocardiography to verify cardiac contractility, ventricular distension, and effective opening of aortic valve.

•

In case of left ventricle distension and pulmonary edema consider: o

low dose of inotropes and vasodilators

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o

intraortic balloon pump

o

direct drainage of left ventricle

Controlled or spontaneous ventilation

•

Targeted to maintain an ETCO2 level of at least 20 mmHg

•

Check for occurrence of pulmonary edema

•

Right radial artery should be used for blood gas analysis

•

PEEP should be set to avoid atelectasis and prevent pulmonary congestion.

Adjunctive therapies

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•

After ECMO starting rule out any reversible treatable is cause

•

Consider early, intraarrest coronary revascularization while on VA-ECMO

•

Attain a strict temperature control and prevent hyperthermia

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•

Weaning from VA-ECMO •

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Respiratoy management

Weaning test: by reducing ECMO blood flow, while monitoring cardiac contractility and organ perfusion.

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Abbreviations: EMS, emergency medical system; ETCO2 ,end tidal CO2, PEEP, positive end-expiratory pressure