Abstract
Objective. Early and long-term survival in patients suffering from cardiogenic shock is poor. Treatment with mechanical assist devices is complicated and expensive but claim to improve survival. We reviewed our experience of venoarterial extracorporeal membrane oxygenation (ECMO) in patients with acute cardiogenic shock. Design. ECMO was used in 52 patients with cardiogenic shock. They were divided into those not operated upon previously (n=19) and those having had cardiac surgery prior to circulatory collapse (n=33). Results. Twenty-six patients were weaned from ECMO. Early mortality for all patients was 48%. Mortality beyond 30 days was 5.8%, with no mortality in the non-cardiotomy group. Long-term survival for patients in the non-cardiotomy group was 63%, as compared to 33% in post-cardiotomy patients (p=0.07). Age over 55 years, female gender or cannulation site did not appear to influence survival. Conclusion. Mortality for patients in cardiogenic shock is very high. Treatment with ECMO in patients with refractory cardiogenic shock can be performed with good survival especially in non-surgical patients.
Cardiogenic shock is a condition with dismal prognosis independent of its cause. Cardiogenic shock due to acute myocardial infarction (AMI) has an early mortality of about 50% in a recent study Citation[1], with only 20% survival if the patient develops renal failure. The high proportion of patients dying from this condition has stimulated interest in temporary cardiac support systems to allow for recovery or bridging. Bartlett et al. reported in 1977 how to rescue some of these patients with extra corporeal membrane oxygenation (ECMO) Citation[2].
Centrifugal or pulsatile temporary support was used in the 1980s and 1990s, but results were not encouraging and survival rates were low. Early ECMO systems carried disadvantages with device-related complications such as leakage from the oxygenators, the risk for limb ischemia and thrombo-embolic events. There was renewed interest in ECMO in the new millennium because of improved technology (e.g. magnetically supported rotors, oxygenators with better durability etc.) and increased knowledge of how to manage the patients in the intensive care unit. Another reason for using ECMO instead of uni-ventricular mechanical support is the easy access via femoral percutaneous cannulation which is rapid and safe.
We report our results with venoarterial ECMO for temporary support in patients with cardiogenic shock in the time period 2000 – 2007. Our interest was especially focused on whether there was a discernible group of patients having more benefit than others from this type of treatment.
Material and methods
This study was conducted in accordance with the standards of our ethical Committee for the protection of human subjects. Informed consent for demographic and hospital-outcome data analyses was not obtained because this observational study did not modify existing diagnostic or therapeutic strategies.
Patients
Medical records of patients receiving temporary circulatory assist with venoarterial ECMO during the time period 2000 – 2007 were collected and reviewed from two institutions. Both centres have programs for long-term left ventricular assist device (LVAD) and heart transplantation. Our review was focused on patients with primarily acute heart failure. Therefore, patients with accidental deep hypothermia, non-emergent patients (i.e. high risk cardiac interventions such as percutaneous coronary intervention) and patients with a primary pulmonary problem (i.e. lung transplantation, adult respiratory distress syndrome, etc) were excluded. No patients receiving venovenous ECMO were included in the study and patients receiving LVAD and right ventricular assist device (RVAD) were also excluded from the study. This was done since interpretation of results will be even more difficult if acute heart failure is mixed with other diagnoses that can be treated with centrifugal circulatory support. Elderly patients were not considered for ECMO as heart transplantation was the final option in the case of failed recovery but also due to the experience from the SHOCK study with dismal results in patients older than 75 years Citation[3]. Postcardiotomy shock was defined as any need of mechanical assist in a patient recently subjected to cardiac surgery. Venoarterial ECMO support was initiated under the following circumstances: 1) acute refractory cardiogenic shock complicating acute myocardial infarction; 2) postcardiotomy cardiogenic shock; 3) immediate posttransplant cardiac graft failure; 4), aortic aneurysm/acute aortic dissection; 5) myocarditis; 6) arrhythmia; 7) and miscellaneous conditions. The ECMO was instituted either in the catheterisation laboratory or in the operating room.
Extra corporeal membrane oxygenation system
Two different pump systems were used, the Medtronic Bio-Medicus® Centrifugal Pump (Medtronic, Minneapolis, MN, U.S.A.) and Levitronix® CentriMag® (Levitronix LLC, Waltham, Mass). The Bio-Medicus® pump cannulas are heparin coated whereas the CentriMag cannulas are not. The Levitronix ventricular assist device is a centrifugal pump designed for extracorporeal support that operates without mechanical bearings or seals. The rotor is magnetically levitated so that rotation is achieved without friction or wear, which seems to minimize blood trauma and mechanical failure. It is CE-approved for use up to 14 days. Both systems were combined with an oxygenator to create an ECMO circuit, allowing peripheral cannulation and total cardiopulmonary bypass. Two different oxygenators were used; Affinity (Medtronic, Minneapolis, MN, USA.) and Quadrox hollow-fiber membrane oxygenator (Maquet, Jostra Medizintechnik AG, Hirrlingen, Germany). Affinity is a micropourus polyprolene oxygenator regularly used in cardio pulmonary bypass (CPB) circuits. The Quadrox D oxygenator has a poly-methylpentene hydrophobic hollow-fiber diffusion membrane with an effective surface area of 1.8 m2, which allows long-term high gas exchange performance. This oxygenator is compact with a decreased heat exchange surface area of the membrane, thus reducing the risk of clot formation Citation[4].
Surgical technique
Support was initiated when all other treatment modalities were either considered or applied and subsequently failed and the patient was dying, but the decision was not specifically based on hemodynamic data. Thirty-one patients had femoral venoarterial cannulation, which was achieved using a cut-down technique in most patients (80%). Heparin, 10 000 units, was administered intravenously before cannulation. The cannulation procedure was started by securing arterial lines in the femoral artery (distally and proximally) and a femoral venous line. Thereby we were able to cannulate patients quickly, even during ongoing cardiopulmonary resuscitation (CPR). When it was impossible to cannulate percutaneously a cut-down technique was used and a side-graft (8-mm Dacron) was used to secure distal perfusion of the leg. The tip of the arterial cannula was aimed at the aorto-iliac junction, and the tip of the venous cannula was placed between the inferior and the superior caval veins in the middle portion of the right atrium. The positioning was confirmed by transesophageal echocardiography. The preferred approach for patients in the surgical group was central venoarterial cannulation (n = 21), in most cases using the same cannulation sites as for cardiopulmonary bypass.
Patients were anticoagulated with heparin and the dosage was adjusted according to the activated clotting time (ACT, target range: 160 – 200 s).
During ECMO the ventilator was set to a peak end expiratory pressure of 10 cm, frequency 12/minute, FiO2 50% and peak inspiratory pressure < 30 cmH2O. Blood gas samples were drawn from the right radial artery for analysis.
Weaning procedure
Patients were evaluated daily for hemodynamic improvement and the possibility of weaning from the circulatory support. If the patient's hemodynamic condition improved and transesophageal echocardiography revealed good recovery of heart contractility, the pump flow was reduced stepwise until 2 L/min. Heparin was administered until activated clotting time (ACT) reached > 300 s and the pump flow was further reduced while observing hemodynamic variables and assessing heart function by echocardiography. Inotropic and vasodilator support was increased if needed. When the hemodynamic situation was assessed as acceptable (normalisation of systemic blood pressures, left ventricular ejection fraction > 40% and mixed venous saturation > 65%) the patient was taken to the operating room and the device was explanted.
Follow-up
Patient data was collected retrospectively from the medical charts. Follow-up was 100% complete. Conditions, such as pre-ECMO CPR, pre-ECMO intra aortic balloon pump (IABP), and outcome, such as time on ECMO support, short, intermediate and long time survival and complications following treatment were analyzed.
Statistical analysis
The continuous variables are reported as mean ± SD. Early mortality was defined as hospital mortality, which is all-cause death within any time interval after the mechanical assist operation or death within 30 days of surgery. Observed survival for patients was analyzed using life table technique and Kaplan-Meier estimates and constructed with the computer program Statistica and log rank test was used to compare the two groups. Chi-square test was used to compare categorical variables (age over 55 years, female gender, cannulation site, early mortality, and differences between patients with AMI who underwent CABG and PCI). A p-value of < 0.05 was considered as statistically significant.
Results
Fifty-two patients (44 males) were identified and included in the study (). Mean age was 50 years (range 13 – 75). Indication for assist implantation was acute refractory cardiogenic shock in 33 post-cardiotomy patients and in 19 non-cardiotomy patients. The diagnoses leading up to surgery in the operated patients and the diagnoses leading to acute cardiogenic shock in the non-cardiotomy group are given in . All patients were treated with ECMO.
Table I. Patient characteristics in patients with cardiogenic shock after cardiac surgery (post-cardiotomy) and in patients who did not undergo surgery (non-cardiotomy). There were significantly more patients in the non-cardiotomy group who had acute myocardial infarction compared to postcardiotomy patients, p < 0.05.
The distribution of patients with AMI complicated with cardiogenic shock treated with ECMO is seen in . Sixty-three percent of patients who underwent PCI survived to discharge compared to 29% in CABG patients (p = 0.2).
Figure 1. Distribution of patients with acute myocardial infarction (AMI) complicated with refractory cardiogenic shock treated with extracorporeal membrane oxygenation (ECMO). Seven patients with AMI underwent coronary artery bypass grafting (CABG) and 8 patients had percutaneous coronary intervention (PCI).
Fifteen patients (29%) had their assist device inserted during ongoing CPR. There were statistically more patients with ongoing CPR at ECMO institution in the non-cardiotomy group, (p = 0.025). Eighteen patients (35%) had IABP prior to implantation of the centrifugal pump. The survival was 47% in the group of patients with on-going CPR and 49% in the group not in need of CPR. There was no significant difference in early mortality between patients with CPR compared to patients with no CPR at ECMO institution ().
Table II. Outcome in post-cardiotomy and non-cardiotomy patients. There were significantly more patients in the non-cardiotomy group who underwent pre-ECMO CPR compared to patients in the post-cardiotomy group, p < 0.05.
Mean time on ECMO support for all patients was 8 (range 0 – 80), days. Mean time on support for the post-cardiotomy group was 5.5 days (1 – 26 days) and for the non-cardiotomy group 11.6 days (1 – 80 days) (). Two patients had two or more episodes of treatment, which were added in the analysis. Twenty-six patients (50%) could be weaned from the circulatory support. The use of pre-ECMO IABP did not influence outcome, weaning rate or mortality. Surviving patients were on ECMO for an average of 9.9 days (2 – 80 days), and non-survivors 5.7 days (1 – 14 days) (p = 0.2).
Total (all cause) mortality for all patients was 56% at a mean follow-up time of 2.7 years (). Early mortality was 48%. Early survival in post-cardiotomy patients and non-cardiotomy patients was 45% and 63%, respectively (p = 0.2). There was a tendency towards higher long-term survival for patients in the non-cardiotomy group, 63%, as compared to the post-cardiotomy group, 33% (p = 0.07). The outcomes in all 52 patients with their respective diagnose group are seen in . The cause of death is shown in . There were no statistical differences regarding survival in patients younger or older than 55 years (p = 0.47) or cannulation site (p = 0.5). There was a statistical significant better survival for female gender (p = 0.03).
Figure 2. Kaplan-Meier survival curve in patients with cardiogenic shock after cardiotomy (n = 33) and non-cardiotomy patients (n = 19) treated with extracorporeal membrane oxygenation (ECMO) and the number of patients at risk. The median follow-up time was 2.7 years. Complete (○) = dead, censored (+) = follow-up time.
Figure 3. Outcomes of the 52 patients with refractory cardiogenic shock supported by extracorporeal membrane oxygenation (ECMO). Post Htx = post transplant graft failure, AA = aortic aneurysm, misc = miscellaneous, AMI = acute myocardial infarction.
Table III. The cause of death in post-cardiotomy and non-cardiotomy patients treated with extracorporeal membrane oxygenation (ECMO).
In the beginning of our series two patients with femoral cut-down cannulation developed severe ischemia of the lower limb resulting in amputation. One survived.
Two patients had severe pulmonary complications that prolonged ECMO treatment but did not result in patient death.
Mechanical assist was deliberately terminated in two patients in whom brain death was diagnosed. The ECMO device in two post-cardiotomy patients was converted to a long-term left ventricular assist device as a bridge-to-heart transplantation and another two patients underwent heart transplantation.
Discussion
This retrospective, two-center study, describes the effect of treatment with venoarterial ECMO in patients in refractory cardiogenic shock. An important finding in this study was the surprisingly high survival rate, despite an expected poor prognosis. In addition, initiation of ECMO in the moribund post-cardiotomy patients resulted in a higher survival than expected from clinical experience Citation5–7. The number of long-term survivals is, to our knowledge the highest reported to date. There could be several reasons for these good results. One could be the selection of patients receiving ECMO. Recently, Chen et al. presented relatively poor survival of critically sick patients with AMI and refractory cardiogenic shock where ECMO was initiated during CPR Citation[8]. On the other hand almost half of the patients with ongoing CPR in our cohort of patients survived. Our study period is also more recent than the one described by Chen et al., getting advantage by the rapid developments in pump technology, properties of cannulas etc, which also could explain the improved outcome.
Acute myocardial infarction and cardiogenic shock is seen in approximately 10% of cases admitted to the emergency room and is hence a fairly common situation. Without aggressive treatment, cardiogenic shock results in high mortality Citation[1]. The survival in patients needing a post-cardiotomy assist device, such as LVAD or ECMO has previously been reported to be dismal and nearly always inferior to survival after cardiogenic shock of non-cardiotomy ethiology Citation5–8. Our study is well in accordance with those findings and shows that short-term circulatory assist can result in approximately 50% survival of patients who would otherwise have succumbed. However, most publications include patients with a wide variety of diagnoses, elective and emergent patients are mixed together with patients with a primary pulmonary problems and also, the reports contain different approaches to support the failing heart i.e. LVAD, RVAD and ECMO.
Another important finding was that if the patient survived the early postoperative period the long-term survival was excellent. This further supports an aggressive treatment of patients with cardiogenic shock in non-cardiotomy patients and stresses the need and importance of having an organization trained for the quick initiation of circulatory support. An increased survival was also noted for female gender. This could in part be explained by the fact that it was only two female in the post-cardiotomy group. The time from refractory cardiogenic shock to initiation of ECMO is very important and has been shown to be a risk factor for mortality Citation[9], Citation[10]. The risk for severe neurological damage increases in a time-dependent manner during CPR and therefore it is important to start the ECMO as soon as possible. After diagnosing severe brain damage in several patients who came to our hospital under CPR we now only consider ECMO in patients with in-hospital-witnessed cardiac arrest.
There are several therapeutic options for the rescue of critically ill patients depending on the clinical situation. Patients with AMI complicated with cardiogenic shock are treated conventionally with vasopressors and IABP support followed by angioplasty or CABG depending on the clinical situation and the decision of the cardiologist and the surgeon. This regimen has improved the survival in critical sick patients but the mortality is still significant Citation[11]. Therefore, the timing when to initiate ECMO in patients with refractory cardiogenic shock is difficult to determine and is still under debate. There are no controlled studies supporting a specific time when to initiate ECMO and our policy has been to use ECMO in patients refractory to the therapeutic algorithm described above. It is unknown if earlier initiation of ECMO would improve survival and it has to be considered that ECMO also is associated with complications, sometimes lethal, due to bleeding, infections, but also technical failures. Therefore, randomized studies aimed at the clarification of these issues would be of utmost importance. However, there are ethical problems associated with randomisation in a salvage therapy context.
Before the era described in this report our strategy was to selectively support the failing ventricle, often ending up with bi-ventricular support. There are several reasons why we changed our routine in favour of venoarterial ECMO as circulatory support. One is the rapid development regarding the pump technology and the durability of the oxygenators. In an emergent situation it is easy to insert an ECMO system without first trying to distinguish between uni- or biventricular failure. Femoral percutaneous cannulation offers an easy approach that is preferable to sternotomy in patients with cardiogenic shock. Central cannulation was more common in post-cardiotomy patients because of the already opened sternum and easy conversion from cardiopulmonary bypass CPB to ECMO. There are some advantages with central cannulation as compared to peripheral cannulation. Peripheral cannulation may cause retrograde perfusion and conflicting flows, forcing the heart to pump against retrograde flow, which theoretically could inhibit heart recovery. Therefore it is important to closely investigate recovery of the heart and initiate the weaning procedure at an optimal time.
The duration of ECMO in our patients was longer compared to those described in other studies Citation7–13, Citation[15]. It was most obvious in the non-cardiotomy group; a finding also reported by other study groups Citation[10]. Our strategy was to provide sufficient time for the heart to recover from myocardial injury. The shorter duration on ECMO support in postcardiotomy patients was due to the lack of recovery in this very sick patient group. When there was no or very poor heart function after 4 – 5 days, the ECMO-treatment was electively terminated.
It has been proposed that LVAD would be an appropriate treatment option for patients in acute cardiogenic shock Citation[13]. The results reported in the literature are however not promising and it seems a better option to use temporary mechanical circulatory support in an emergency situation for stabilisation of the circulation, also allowing time for further evaluation of the total patient situation. In our experience, some patients on temporary mechanical support have been diagnosed with a more or less severe neurological damage, making LVAD implantation and/or transplantation contraindicated. Patients who were declared brain-dead became organ donors. On the other hand, with improved LVAD technology the use of LVAD may become a primary therapeutic option in selective post-cardiotomy patients who can not be weaned off CPB.
The use of IABP has been shown to be a predictor for better survival in patients with refractory cardiogenic shock Citation[14]. Based on the hypothesis of the beneficial effect of additional pulsatile flow, reduction of afterload, and better coronary flow, our policy is to use IABP routinely in patients undergoing ECMO Citation[15]. However, only 35% of the patients in our material had IABP prior to implantation of mechanical support which consequently was a deviation from our protocol. The decision to go directly for ECMO without previous IABP was based on the individual surgeon's preference, often when IABP was assessed not to be effective enough due to very poor or no circulation at all. Our hypothesis has to be proven in a randomized prospective study, which however is difficult to perform for ethical reasons.
Malperfusion of the leg resulting in ischemia may occur with cannulation of the femoral artery Citation[16]. It is therefore of utmost importance to follow the circulation in the cannulated leg. Insufficient circulation due to cannulation was not seen in patients who had been percutaneously cannulated, which seems to be a way of limiting distal malperfusion. The currently preferred method is to place a separate cannula distally in the femoral artery before placing the femoral artery cannula percutanously, thereby securing the peripheral circulation of the leg.
Study limitations
The follow-up was 100% complete and reliable regarding survival, however, since this study is a retrospective analysis there is always a risk of underestimating clinical events such as complications and other outcome data. There is also a limitation of the number of variables such as preoperative hemodynamics and laboratory values which could be retrieved from the medical records. Being a retrospective analysis of a relatively small group of patients over a seven-year period, our series of patients could not be compared to a control group nor has it been compared to other control series in the literature.
Conclusion
Mortality for patients in cardiogenic shock without mechanical assist is very high. ECMO treatment in patients in refractory cardiogenic shock seems to reduce mortality, especially in a non-cardiotomy group of patients and should therefore be an optional treatment. However, this should be further elucidated in randomized studies.
Acknowledgements
This study was supported by Sahlgrenska University Hospital and Karolinska University Hospital.
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