**4. Venoarterial extracorporeal membrane oxygenation complications**

Although ECMO can improve survival to hospital discharge, several studies show significant morbidity with rates increasing with prolonged duration on support. A meta-analysis of 20 studies including 1866 patients demonstrated bleeding as one of the most common complications (40.8%), followed by requirement of dialysis (46%), significant infection (30.4%), limb ischemia (16.9%), and stroke (5.9%). Vascular complications, bleeding and blood transfusions were associated with significant in-hospital mortality [6]. Many of the complications relate to the vascular access site, with femoral cannulation requiring surgical intervention in 20% of the cases [14]. A negative downstream effect of cannulation is distal ischemia which can lead to arterial thrombosis and gangrene. This complication can be mitigated by preemptively placing a small antegrade perfusion cannula to bypass the area of obstruction from the ECMO arterial cannula [15]. Moreover, vascular complications can lead to unsuccessful weaning trials as serious bleeding events increase the need for blood product transfusions and the incidence of thrombotic

events. Specifically, thrombotic events were noted to occur in 17% of patients, mostly as lower extremity arterial thromboses, and can impact the duration on support, increase morbidity and affect overall outcomes [16, 17].

**LV distention in VA-ECMO.** When contemplating weaning trials to assess for LV recovery, consideration should be taken on the loading effect that VA-ECMO has on the left ventricle. Proper unloading of the LV can avoid complications from LV distention including pulmonary edema, worsening oxygenation, increased left ventricular wall stress, reduced myocardial blood flow and ventricular arrhythmias. In fact, acute pulmonary edema in the setting of peripheral VA-ECMO has been associated with mortality, with many patients dying within hours after implant or requiring conversion to central VA-ECMO [18]. In a study of 121 patients on ECMO with LV distention, 16% required decompression with an Impella device and cardiac recovery was inversely related to the degree of LV distention. Furthermore, those presenting with LV distention requiring decompression had lower survival in the first 30 days following VA-ECMO compared to those not requiring decompression. More so, the study noted that those presenting with acute decompensated heart failure had a delayed LV decompression strategy which was associated lower survival [19]. This may suggest that more aggressive unloading is required upfront when clinical signs of LV distention are present. In one study, adding an Impella device improved 30-day survival in those presenting with AMI compared to other groups. Additionally, in those with cardiogenic shock due to acute decompensated systolic heart failure, unloading can help to stabilize and bridge them to the next strategy. In a series of 52 patients with ADHF, 71% required an LV venting device with the vast majority transitioned to a durable device support [12].

### **5. Factors associated with successful weaning from VA-ECMO**

Determining successful weaning from VA-ECMO relies on multiple variables which can be partitioned into pre-implant and during support factors.

#### **5.1 Pre-ECMO factors**

**Patient selection.** Many risk scores have identified several variables that rely on clinical and biochemical markers. The SAVE score is a tool that discriminates between survivors and non-survivors of refractory cardiogenic shock on VA-ECMO. While younger patients, acute myocarditis, post-heart transplant, refractory arrhythmias and high diastolic blood pressure are protective factors, those with chronic renal disease, prolonged intubation, pre-ECMO organ failure, lower pulse pressure and lower bicarbonate are associated with poor survival. (http://www.save-score.com/) [20]. Similarly to SAVE, the ENCOURAGE survival score utilizes predictors for those presenting with CS due to AMI, however unlike SAVE it places more weight placed on gender, body mass index, Glasgow coma score and level of serum lactate. Survival was also directly proportional to the patient's risk score (probabilities of survival were 80%, 58, 25, 20, and 7% for classes 0–12, 13–18, 19–22, 23–27, and ≥28, respectively [21].

#### **5.2 During ECMO factors**

Once VA-ECMO support is initiated, there is a very narrow window to assess end organ function recovery and decide on need for advanced therapies. In a cohort of 124 consecutive patients receiving VA-ECMO for CS, about two thirds of the deaths occurred during the first 4 days due to multiorgan failure, however those

**159**

efforts [26].

*ECMO Weaning Strategies to Optimize Outcomes DOI: http://dx.doi.org/10.5772/intechopen.85614*

15.86; 95% CI, 3.56–70.73; *p* < 0.001) [26].

75% with VAD implant [18].

who were supported for more than 6 days had a reduced in-hospital mortality, with 50%, achieving successful device wean. In addition, prolonged support provided an opportunity for improved patient selection with 60% reaching cardiac recovery, 26% undergoing heart transplantation and 14% ventricular assist device (VAD) implant. After a median follow up of 2.4 years, survival at 1 year was 78% for those who achieved cardiac recovery, 51% for those who underwent heart transplant and

**LV unloading.** Ventricular decompression with an IABP during implant can allow for weaning and survival, bridge to LVAD or transplantation, while its non-use has been associated with increased risk for death during support or after VA-ECMO is withdrawn [22]. A recent meta-analysis of 17 observational studies comprising 3997 patients with 42% receiving an LV unloading device (IABP 92%, percutaneous VAD 5.5%, trans-septal left atrial cannulation 3%) showed a reduction in mortality when utilizing LV unloading devices compared to those without LV unloading (54 vs. 65%, RR 0.79, CI 95% 0.72–0.87). Secondary outcomes for limb ischemia, bleeding, need for renal replacement therapy, multiorgan failure, stroke or transient ischemic attack were not different among all cohorts [23].

**Echocardiography.** Several echocardiographic indicators exist when consider-

**Hemodynamics parameters.** Multiple hemodynamic variables have been found to be predictive of successful weaning. Presence of a pulse pressure greater than 50 mmHg, elevated systolic pressure greater than 100 mmHg has been associated with good prognosis and survival [25]. Maintaining a perfusion mean arterial pressure (MAP) >60 mmHg with minimal inotropic support is critical [27]. Right heart catheterization data shows that a pulmonary capillary wedge pressure <24, PVR < 1.1 WU, mean pulmonary arterial pressure <25, transpulmonary gradient <10 are recommended parameters to achieve prior to a weaning trial and that inotropic agents as well as pulmonary vasodilators can be of assistance during weaning

**Biomarkers.** Serological markers of poor perfusion have been associated with worse prognosis. Lactate has been recognized as a biomarker for macrovascular tissue perfusion and early clearance at 24 hours after VA-ECMO initiation has been correlated with weaning and survival [28]. Loforte et al., analyzed 228 patients supported on VA-ECMO primarily post-cardiotomy CS. The authors found that blood lactate level (>3 mmol/L) and a CK-MB index of 10% 72 hours after ECMO initiation, was predictive of a 50% probability of 30-day mortality [29]. An elevated creatinine on the day of withdrawal or weaning trial has been associated with poor outcome with a four-fold risk of death when the level is above 1.4 mg/dL [18]. **Tissue perfusion.** Derangements in the microvasculature have been noted in both severe sepsis as well as cardiogenic shock, with measures of microcirculation emerging as new markers for tissue perfusion [30]. In those supported by VA-ECMO, there is observational data suggesting that preserved microcirculation

ing a weaning trial. Improvement in underlying LV function with an ejection fraction ≥35%, LV outflow tract velocity-time integral >10 cm, tissue Doppler peak systolic velocity of the mitral annulus ≥6 m/s, absence of LV dilatation, and no cardiac tamponade while on minimal support have been shown as good predictors of successful weaning [24, 25]. Similarly, significant improvement in right ventricular function during weaning identifies greater opportunity for survival. In a study of 46 patients on VA-ECMO, RV ejection fraction (RVEF) was assessed by 3D echocardiography. RV free wall strain, RV fractional area change, and central venous pressure were found to be independently associated with RVEF. A cutoff RVEF of >24.6% was found to be a predictor for weaning success after first cannulation with lower values associated with increased all-cause mortality at 30 days (HR

#### *ECMO Weaning Strategies to Optimize Outcomes DOI: http://dx.doi.org/10.5772/intechopen.85614*

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

events. Specifically, thrombotic events were noted to occur in 17% of patients, mostly as lower extremity arterial thromboses, and can impact the duration on

**LV distention in VA-ECMO.** When contemplating weaning trials to assess for LV recovery, consideration should be taken on the loading effect that VA-ECMO has on the left ventricle. Proper unloading of the LV can avoid complications from LV distention including pulmonary edema, worsening oxygenation, increased left ventricular wall stress, reduced myocardial blood flow and ventricular arrhythmias. In fact, acute pulmonary edema in the setting of peripheral VA-ECMO has been associated with mortality, with many patients dying within hours after implant or requiring conversion to central VA-ECMO [18]. In a study of 121 patients on ECMO with LV distention, 16% required decompression with an Impella device and cardiac recovery was inversely related to the degree of LV distention. Furthermore, those presenting with LV distention requiring decompression had lower survival in the first 30 days following VA-ECMO compared to those not requiring decompression. More so, the study noted that those presenting with acute decompensated heart failure had a delayed LV decompression strategy which was associated lower survival [19]. This may suggest that more aggressive unloading is required upfront when clinical signs of LV distention are present. In one study, adding an Impella device improved 30-day survival in those presenting with AMI compared to other groups. Additionally, in those with cardiogenic shock due to acute decompensated systolic heart failure, unloading can help to stabilize and bridge them to the next strategy. In a series of 52 patients with ADHF, 71% required an LV venting device

support, increase morbidity and affect overall outcomes [16, 17].

with the vast majority transitioned to a durable device support [12].

**5. Factors associated with successful weaning from VA-ECMO**

which can be partitioned into pre-implant and during support factors.

classes 0–12, 13–18, 19–22, 23–27, and ≥28, respectively [21].

Determining successful weaning from VA-ECMO relies on multiple variables

**Patient selection.** Many risk scores have identified several variables that rely on clinical and biochemical markers. The SAVE score is a tool that discriminates between survivors and non-survivors of refractory cardiogenic shock on VA-ECMO. While younger patients, acute myocarditis, post-heart transplant, refractory arrhythmias and high diastolic blood pressure are protective factors, those with chronic renal disease, prolonged intubation, pre-ECMO organ failure, lower pulse pressure and lower bicarbonate are associated with poor survival. (http://www.save-score.com/) [20]. Similarly to SAVE, the ENCOURAGE survival score utilizes predictors for those presenting with CS due to AMI, however unlike SAVE it places more weight placed on gender, body mass index, Glasgow coma score and level of serum lactate. Survival was also directly proportional to the patient's risk score (probabilities of survival were 80%, 58, 25, 20, and 7% for

Once VA-ECMO support is initiated, there is a very narrow window to assess end organ function recovery and decide on need for advanced therapies. In a cohort of 124 consecutive patients receiving VA-ECMO for CS, about two thirds of the deaths occurred during the first 4 days due to multiorgan failure, however those

**158**

**5.1 Pre-ECMO factors**

**5.2 During ECMO factors**

who were supported for more than 6 days had a reduced in-hospital mortality, with 50%, achieving successful device wean. In addition, prolonged support provided an opportunity for improved patient selection with 60% reaching cardiac recovery, 26% undergoing heart transplantation and 14% ventricular assist device (VAD) implant. After a median follow up of 2.4 years, survival at 1 year was 78% for those who achieved cardiac recovery, 51% for those who underwent heart transplant and 75% with VAD implant [18].

**LV unloading.** Ventricular decompression with an IABP during implant can allow for weaning and survival, bridge to LVAD or transplantation, while its non-use has been associated with increased risk for death during support or after VA-ECMO is withdrawn [22]. A recent meta-analysis of 17 observational studies comprising 3997 patients with 42% receiving an LV unloading device (IABP 92%, percutaneous VAD 5.5%, trans-septal left atrial cannulation 3%) showed a reduction in mortality when utilizing LV unloading devices compared to those without LV unloading (54 vs. 65%, RR 0.79, CI 95% 0.72–0.87). Secondary outcomes for limb ischemia, bleeding, need for renal replacement therapy, multiorgan failure, stroke or transient ischemic attack were not different among all cohorts [23].

**Echocardiography.** Several echocardiographic indicators exist when considering a weaning trial. Improvement in underlying LV function with an ejection fraction ≥35%, LV outflow tract velocity-time integral >10 cm, tissue Doppler peak systolic velocity of the mitral annulus ≥6 m/s, absence of LV dilatation, and no cardiac tamponade while on minimal support have been shown as good predictors of successful weaning [24, 25]. Similarly, significant improvement in right ventricular function during weaning identifies greater opportunity for survival. In a study of 46 patients on VA-ECMO, RV ejection fraction (RVEF) was assessed by 3D echocardiography. RV free wall strain, RV fractional area change, and central venous pressure were found to be independently associated with RVEF. A cutoff RVEF of >24.6% was found to be a predictor for weaning success after first cannulation with lower values associated with increased all-cause mortality at 30 days (HR 15.86; 95% CI, 3.56–70.73; *p* < 0.001) [26].

**Hemodynamics parameters.** Multiple hemodynamic variables have been found to be predictive of successful weaning. Presence of a pulse pressure greater than 50 mmHg, elevated systolic pressure greater than 100 mmHg has been associated with good prognosis and survival [25]. Maintaining a perfusion mean arterial pressure (MAP) >60 mmHg with minimal inotropic support is critical [27]. Right heart catheterization data shows that a pulmonary capillary wedge pressure <24, PVR < 1.1 WU, mean pulmonary arterial pressure <25, transpulmonary gradient <10 are recommended parameters to achieve prior to a weaning trial and that inotropic agents as well as pulmonary vasodilators can be of assistance during weaning efforts [26].

**Biomarkers.** Serological markers of poor perfusion have been associated with worse prognosis. Lactate has been recognized as a biomarker for macrovascular tissue perfusion and early clearance at 24 hours after VA-ECMO initiation has been correlated with weaning and survival [28]. Loforte et al., analyzed 228 patients supported on VA-ECMO primarily post-cardiotomy CS. The authors found that blood lactate level (>3 mmol/L) and a CK-MB index of 10% 72 hours after ECMO initiation, was predictive of a 50% probability of 30-day mortality [29]. An elevated creatinine on the day of withdrawal or weaning trial has been associated with poor outcome with a four-fold risk of death when the level is above 1.4 mg/dL [18].

**Tissue perfusion.** Derangements in the microvasculature have been noted in both severe sepsis as well as cardiogenic shock, with measures of microcirculation emerging as new markers for tissue perfusion [30]. In those supported by VA-ECMO, there is observational data suggesting that preserved microcirculation at time of VA-ECMO cannulation may be more specific than hemodynamic measures for identifying successful VA-ECMO weaning and survival. This discordance between the micro and macro-circulation has been described previously as a loss of hemodynamic coherence in part due to heterogeneous flow the organs receive during support, alterations in capillary density and presence of tissue edema [31]. Specifically, one study which assessed microcirculation serially, found that even in the presence of preserved lactate, tissue perfusion as estimated by parameters of microcirculation did not improve on VA-ECMO and those with compromised microcirculation—measured as perfused capillary density and proportion of perfused vessels—could not be weaned from VA-ECMO [32]. A separate study looking specifically at 28-day survival in cardiogenic shock patients placed on VA-ECMO, found that while MAP, pressor requirement and lactate did not differ, microcirculation was better preserved in survivors compared to non-survivors within 12 hours of VA-ECMO support [33]. However, further research is needed to determine if microcirculatory assessment can help guide timing of VA-ECMO weaning.

#### **5.3 Post VA-ECMO wean**

Survival post VA-ECMO is predicated on correcting the underlying cause for shock or cardiac arrest, ultimately allowing device removal. However, weaning does not always signify that individuals will survive. Individual factors have to be considered to predict long term survival such as age, comorbidities, complications arising during circulatory support, underlying ventricular function and end organ function. On the latter, renal failure (signified by elevated creatinine level) or hepatic failure (marked by elevated total bilirubin and elevated INR) at the time of wean can impact short-term and long-term survival with multiorgan failure being the predominant mode of death after weaning [22]. If myocardial recovery is unlikely but other factors have been controlled and improved (including renal and hepatic function, lactate and resolution of pulmonary edema), durable VAD or heart transplantation should be taken into consideration, as longer duration on VA-ECMO can reduce the likelihood of survival to discharge or success towards a bridging option. In a small observational study, survival to discharge was higher for those transitioned within 14 days from VA-ECMO support to a VAD compared to those transitioned longer than 14 days (92 vs. 25%, *p* < 0.05) [34].

#### **6. Weaning strategies**

#### **6.1 Pharmacological agents**

The pharmacologic agents that have been used to assist with weaning trials have primarily been inotropic agents including dobutamine, epinephrine, dopamine, milrinone and levosimendan. Epinephrine, dopamine and dobutamine are catecholamines, with epinephrine and dopamine having alpha-1 activity and thus some crossover with norepinephrine as vasoconstrictors. Dobutamine acts predominantly on beta-1 and beta-2 receptors. Milrinone and levosimendan on the other hand are inotropes without direct adrenergic receptor targets. Milrinone is a type-3 phosphodiesterase inhibitor and augments myocardial contraction by increasing intracellular concentrations of cAMP and calcium. Levosimendan on the other hand is a calcium sensitizer and is postulated to augment myocardial contractility without increasing intracellular calcium and myocardial oxygen consumption. Current evidence supports the use of both milrinone and levosimendan to assist with VA-ECMO weaning [35, 36].

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*ECMO Weaning Strategies to Optimize Outcomes DOI: http://dx.doi.org/10.5772/intechopen.85614*

Protocols for weaning VA-ECMO include:

can range from 10–15 min to 24 h.

afterload as flows decrease.

1.A stepwise reduction in VA-ECMO flows either by percent of support or by

3.Baseline parameter thresholds and subsequent measurements assessing for hemodynamic tolerance and myocardial adaptation to changes in preload and

5.Frequency of weaning trials may occur daily, but typically occur 24–72 hours after VA-ECMO institution to allow for reversal and recovery from the inciting

In addition to requiring full anticoagulation during weaning trials, flows cannot be turned down below 1–1.5 L/min because of concerns for thrombus formation within the VA-ECMO circuit. Thus, clinicians must monitor changes in hemodynamic and echocardiographic parameters as VA-ECMO flows are decreased and terminate weaning if evidence of hemodynamic compromise or intolerance to preload changes such as loss of pulsatility, ventricular dysfunction or increases in filling pressures are seen. Hemodynamic tolerance during the weaning trial is extrapolated to imply myocardial recovery has occurred and that decannulation will be tolerated by the patient. In order to allow clinical assessments off VA-ECMO support entirely, some centers are using arteriovenous cannula bridging strategies that form a circuit that bypasses the patient [41], or a separate technique pioneered in neonates that

Assessing the readiness for VA-ECMO weaning involves withdrawal or reversal of the inciting injury, maintenance or recovery of extracardiac organ function, and lastly myocardial recovery. Prior to weaning attempts, hemodynamic stability and adequate tissue perfusion defined as a MAP ≥ 60–65 mmHg while on minimal pressor support, arterial pulsatility and lactate levels < 2 mmol/L should be achieved. VA-ECMO flow should be reduced by 0.5–1.0 L/min in 5–10-min intervals with continuous invasive hemodynamic and echocardiographic monitoring. In instances where adequate transthoracic windows cannot be achieved, transesophageal echocardiogram should be performed, and biventricular size and function monitored. Because some parameters of left ventricular function including aortic VTI and TDSa are not easily obtained by both transthoracic and transesophageal echocardiography, we recommend measuring changes in ventricular size and visual assessments of ventricular function and valvular regurgitation. In instances where CVP rises to greater than 1518 mmHg (depending on ventilator settings) and the RV dilates with worsening function and tricuspid regurgitation, the weaning trial should be aborted. Left sided function and loading conditions may vary depending on venting strategies, however, in cases where PCWP rises above 20 mmHg and

4.Using continuous or intermittent transthoracic or transesophageal

reduces pump flow until the circuit runs retrograde [42, 43].

2.A pre-specified time interval in which the VA-ECMO flow is reduced for which

**6.2 Weaning trials**

0.5–1.0 L/min.

echocardiogram.

injury [29, 37–40].

**7. Proposed weaning protocol**
