Clinical Management of VA ECMO

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Clinical Management of VA ECMO Marguerite M. Hoyler MD , Brigid Flynn MD , Erin Mills Iannacone MD , Mandisa-Maia Jones MD , Natalia S. Ivascu MD PII: DOI: Reference:

S1053-0770(20)30017-3 https://doi.org/10.1053/j.jvca.2019.12.047 YJCAN 5664

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Journal of Cardiothoracic and Vascular Anesthesia

Please cite this article as: Marguerite M. Hoyler MD , Brigid Flynn MD , Erin Mills Iannacone MD , Mandisa-Maia Jones MD , Natalia S. Ivascu MD , Clinical Management of VA ECMO, Journal of Cardiothoracic and Vascular Anesthesia (2020), doi: https://doi.org/10.1053/j.jvca.2019.12.047

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Review Article: Clinical Management of VA ECMO Author Names and Affiliations: Marguerite M. Hoyler (MD)a, Brigid Flynn (MD)b, Erin Mills Iannacone (MD)c, Mandisa-Maia Jones (MD)d, Natalia S. Ivascu (MD)e a

New York-Presbyterian/Weill Cornell Medical Center, Department of Anesthesiology, 525 East

68th Street, Box 124, New York, NY, 10065, USA E-mail: [email protected] b

University of Kansas Medical Center, Mail Stop 1034, 3901 Rainbow Blvd., Kansas City, KS,

66160, USA E-mail: [email protected] c

New York-Presbyterian/Weill Cornell Medical Center, Department of Cardiothoracic Surgery,

525 East 68th Street, M-404, New York, NY, 10065, USA E-mail: [email protected] d

Duke University Medical Center, Department of Anesthesiology, DUMC 3094, Durham, NC,

27710 E-mail: [email protected] e New York-Presbyterian/Weill Cornell Medical Center, Department of Anesthesiology, 525 East 68th Street, Box 124, New York, NY, 10065, USA E-mail: [email protected]

Corresponding author: Marguerite M. Hoyler, MD, New York-Presbyterian/Weill Cornell Medical Center, Department of Anesthesiology, 525 East 68th Street, Box 124, New York, NY, 10065, USA; Phone: 401-864-9181 Email: [email protected] 1

Abstract Venoarterial extracorporeal membrane oxygenation (VA ECMO) is a wellestablished technique to rescue patients in cardiogenic shock. As a form of temporary mechanical circulatory support, VA ECMO can be life saving, but is resource intensive and associated with substantial morbidity and mortality. Optimal clinical outcomes require specific expertise in the principles and nuances of ECMO physiology and management. Key considerations to be discussed in this review include hemodynamic assessment and goals, pharmacologic anticoagulation, ECMO weaning strategies and the prevention, evaluation and treatment of common complications.

Keywords: VA ECMO, extracorporeal membrane oxygenation, extracorporeal life support, cardiogenic shock, cardiac critical care, mechanical circulatory support, ECPR, anticoagulation

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Introduction Venoarterial ECMO (VA ECMO) is a form of mechanical circulatory support intended to temporarily replace cardiopulmonary function in patients in refractory cardiogenic shock. Since its first successful use in an adult in 1971, ECMO has become increasingly widespread, both in case volume and the number of participating centers.1,2 Although clinical outcomes have improved somewhat in this time period, VA ECMO continues to be associated with high rates of neurologic, hemorrhagic and thrombotic complications.3-5 Furthermore, in-hospital mortality remains between 50 and 70%.6-9 Despite its growing prevalence, VA ECMO care continues to be highly specialized. Patients treated at high-volume VA ECMO centers demonstrate significantly lower absolute mortality rates10 and risk-adjusted mortality odds than do patients treated at low volume centers.11 Transfer of VA ECMO patients to centers with comprehensive surgical and intensive care resources is recommended.12 Fortunately, early data suggest that clinical outcomes following transfer may be equivalent to “in house” VA ECMO cannulation at a quaternary care institution.13 Due to the significant clinical risks associated with VA ECMO, it is imperative that clinicians understand not only patient physiology, but also the physiologic modifications created by the VA ECMO apparatus and extracorporeal circulation. This review will focus attention on the key considerations involved in managing VA ECMO devices and, most importantly, caring for VA ECMO patients.

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Understanding VA ECMO

Indications and Contraindications to VA ECMO The most common indications for VA ECMO include failure to wean from cardiopulmonary bypass, refractory shock due to myocardial infarction, and extracorporeal cardiopulmonary resuscitation or “ECPR”.14-16 In these circumstances, VA ECMO can act as a “bridge” to recovery, permanent mechanical circulatory support (MCS) device placement or heart transplant. In patients whose global prognosis is unclear, as may be the case following cardiac arrest, VA ECMO offers a “bridge to decision” pending further clinical assessment. VA ECMO should only be utilized in patients who are expected to regain lifesustaining cardiac function or who are identified as potential candidates for heart transplant or permanent MCS devices. Indications and contraindications to VA ECMO are summarized in Table 1. The average duration of VA ECMO support is 4-5 days.7-9 Although prolonged support implies increased risk of device-associated complications, in-hospital mortality is not linearly associated with support duration, and patients may require and survive multiple weeks of VA ECMO support.7,8,17-20 Nonetheless, recent studies report peak survival among patients decannulated after four7 to seven days.17 These findings likely reflect the competing effects of early treatment failure in non-salvageable patients and the mortality risk associated with ECMO-induced complications after extended periods of cannulation. Case reports demonstrate that indications and contraindications for VA ECMO are evolving, as VA ECMO is offered to patients previously not considered candidates.21-23 As

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these territories are explored, the potential benefits of VA ECMO must be carefully and ethically weighed against the attendant risks of ischemic, hemorrhagic, infectious and neurologic complications.5,12,24,25 Prior to cannulation, a thorough goals of care discussion is advisable to inform the patient or surrogate about the limits of the support, potential complications, and circumstances in which discontinuation of life support may be recommended. Emergent initiation of VA ECMO may limit informed consent and may be a less desirable time to push the boundaries of previously established contra-indications.

VA ECMO Physiology VA ECMO has multiple interrelated physiologic effects that vary depending on cannula location. Figure 1 demonstrates common VA ECMO configurations; Table 2 describes the specific physiologic changes associated with each. VA ECMO decreases native cardiac output and augments total systemic blood flow and oxygen delivery. Mean arterial pressure (MAP) increases with additional flow through resistance vessels, and the left ventricle (LV) must overcome the afterload created by the arterial outflow of VA ECMO and increased MAP. While decreased LV preload results in improved myocardial perfusion and reduced stroke work, the additional afterload can impair LV function and recovery through decreased stroke volume, increased ventricular end-diastolic pressure (LVEDP), pulmonary edema and resultant hypoxemia, and decreased myocardial oxygen delivery. If LV ejection and pulsatility remain low for a prolonged period of time, due to high VA ECMO flows or extremely poor function, the patient is at risk for ventricular or aortic root thrombus and embolic stroke, even in the setting of therapeutic anticoagulation.

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Extracorporeal circulation also induces a markedly pro-inflammatory state through the activation of Factor XII, release of kallikrein and bradykinin, and the activation of the complement system, among other inflammatory cascades.26 These pro-inflammatory mediators lead to endothelial injury and diffuse neutrophil activation, possibly contributing to pulmonary and other end-organ dysfunction.27 Extracoroporeal circulation triggers mast-cell degranulation and may result in systemic vasoplegia.26 Vasopressors may be required to counteract this state of decreased systemic vascular resistance (SVR). Vigilant monitoring for other etiologies of vasodilation, including sepsis and acidosis, is essential. Finally, these inflammatory cascades induce both a pro-thrombotic state and consumptive coagulopathy; the latter is compounded by pharmacologic anticoagulation.

ECMO Configurations In simplest terms, the VA ECMO circuit consists of venous (“inflow”) and arterial (“outflow”) cannulae connected in series by tubing, a pump, and a membrane oxygenator with attached gas blender (Figure 1). Clinicians can independently adjust pump speed, delivered oxygen concentration (FDO2), and the rate of countercurrent air and oxygen “sweep” gas flow, to help achieve targeted pump flows, arterial oxygen tension, and carbon dioxide (CO2) clearance, respectively. Additional circuit components include flowmeters and pressure monitors, a heat exchanger and sampling ports. Femoral venous and arterial cannulation, by Seldinger technique or surgical cutdown, is often performed as a bedside procedure and is the strategy of choice in ECPR.14 Arterial outflow can also be achieved utilizing the ascending aorta (central VA ECMO) or the subclavian or axillary arteries.28-30 Cannulation of the subclavian or axillary arteries

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reduces the risk of upper body hypoxemia,28 may reduce LV afterload compared to retrograde perfusion from femoral cannulation,30 and may facilitate mobilization in select VA ECMO patients.29 Venous cannulation is typically femoral or internal jugular. The femoral venous cannula ideally terminates in the intra-hepatic segment of the inferior vena cava (IVC) in order to avoid suction of the right atrium or intra-abdominal IVC. Certain circumstances may warrant additional cannulae or “hybrid ECMO.”31,32 In patients with severe hypoxemia and a distal mixing zone of oxygenated and deoxygenated blood, an additional venous outflow cannula can provide oxygenated blood to the upper body (“VAV ECMO”) (Figure 1). A second venous drainage limb (“VVA ECMO”) can be used to augment pump flows, offload the right ventricle or decrease LV preload to reduce ventricular distension.

Overview of ECMO Monitoring Patients on VA ECMO require invasive and non-invasive monitoring similar to other intensive care unit patients. However, interpretation of data is frequently specific to VA ECMO physiology. Table 2 identifies caveats of monitoring and physiology in various configurations of VA ECMO; Supplementary Table 1 summarizes monitoring parameters and goals. Electrocardiogram (EKG) waveform changes and ectopy may be the first signs of myocardial ischemia or LV distension, which may be unlikely to cause hemodynamic perturbations while on high flow VA ECMO. The arterial pressure waveform can aid in assessing the pulsatility of the LV and the estimated location of the mixing zone. Monitoring arterial blood gas samples from two locations on separate sides of the body can

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provide the first evidence of upper body hypoxemia. Temperature monitoring is important as extracorporeal circulation has a cooling effect, and even low-grade temperature elevations while on ECMO may be a sign of infection. Alternatively, hypothermia may worsen coagulopathy and platelet dysfunction.33 Pulmonary artery catheters (PACs) are useful in assessing ventricular loading and function, especially in response to ECMO flow adjustments. Trends in PA pressures and pulse pressures may reflect changes in RV ejection, transpulmonary flow volume, and LV function.34 However, calculation of cardiac output by thermodilution is inaccurate.35,36 Transcranial doppler and near-infrared spectroscopy (NIRS) cerebral oximetry monitoring may provide early indications of decreased cerebral perfusion, neurologic injury, or upper body hypoxemia.37-40 NIRS has also been shown to identify lower extremity ischemia in the setting of peripheral arterial cannulation.37,40 Frequent echocardiography is a mainstay of VA ECMO monitoring, and enables assessment of biventricular function, aortic valve opening, cannula position, pericardial and pleural effusions and ventricular thrombus formation.41,42 Serial transthoracic echocardiography (TTE) is especially useful when adjusting or weaning flows. Additional uses of bedside echo are presented in Table 3.

Management Considerations in VA ECMO

Flows in VA ECMO Total systemic flow while on VA ECMO equals the sum of the pump flow plus the native cardiac output. Venous cannulae between 21 and 25 French and arterial cannulae

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between 17 and 21 French can provide flows up to 4-6 liters per minute (LPM) to most adult patients. Such “full flow” VA ECMO is typically sufficient to meet a patient’s metabolic needs, even as oxygen requirements in critically ill patients may exceed the 3-4cc/kg/min expected for a resting adult.15 Targeting supranormal cardiac output and oxygen delivery is controversial in non-ECMO patients, with early studies of goal-directed volume and pharmacologic therapy showing no mortality benefit in the critically ill,43 but demonstrating enhanced organ perfusion and decreased morbidity and mortality in highrisk surgical patients.44,45 More research is needed prior to endorsing supraphysiologic hemodynamic goals in VA ECMO patients When possible, pump flow should be maintained at less than 80% of total body blood flow to lessen risk of stasis and thrombosis in the pulmonary vessels or cardiac chambers.15 Adequate pulmonary blood flow should result in visible pulsatility on arterial and PA pressure monitoring.15 Adequate systemic perfusion is marked by normalizing lactate levels, maintenance of blood pressure and stable or improving end organ function. Insufficient ECMO flows can be due to insufficient pump preload, excessive afterload or obstruction in the circuit. Inadequate preload, typically from intravascular volume depletion, often manifests as refractory hypotension with increasing vasopressor requirements or suction of the cannula (“chattering”). Decreased preload may also result from pneumothorax, tamponade or abdominal compartment syndrome.46 Decreasing pump speed will relieve the suction while volume status is evaluated and optimized.

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Mean Arterial Pressure (MAP) In the context of VA ECMO, mean arterial pressure (MAP) reflects arteriolar tone and the sum of LV ejection and pump blood flow. The MAP goal represents a balance of adequate systemic, coronary, and cerebral perfusion against left ventricular work caused by increased afterload. An assessment of adequate MAP should incorporate perfusion indices such as mixed-venous oxygen saturation (SvO2) and arterial lactate, as well as LV pulsatility and clinical and laboratory evidence of end-organ function. The MAP goal ranges between 65mmHg and 90mmHg for most patients on VA ECMO.47 Pump blood flow and MAP may be augmented with vasopressor infusions, judicious fluid boluses, blood product transfusions or a combination of these. In obese or profoundly vasodilated patients, additional venous cannulae (“VVA ECMO”) can increase venous drainage to support adequate flows and blood pressure. Hypotension in the setting of low flows should always raise suspicion of possible hemorrhage. Hypotension in the setting of adequate or high flows suggests a decreased SVR and should prompt a workup for infection. Changes in volume status and ventricular loading have variable effects on MAP, depending on the extent of underlying cardiac injury. Native cardiac output contributes less to MAP than does VA ECMO flow, but positive inotropes may be beneficial in supporting blood pressure through increased biventricular contractility and forward flow. This is especially true during ECMO weaning. PA catheter measurements and serial TTEs are particularly useful in evaluating cardiac performance under various loading conditions. 36,41

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Oxygenation For patients on VA ECMO, systemic oxygenation reflects the combined function of the native lung and the membrane lung in the ECMO circuit. Extracorporeal gas exchange occurs when venous blood bathes gas-filled microtubules in the membrane oxygenator, and oxygen and carbon dioxide (CO2) diffuse down their respective concentration gradients. Due to high blood solubility and rapid diffusion, CO2 levels are easily managed by titrating sweep gas flow. By contrast, oxygenation depends on FDO2, oxygenator blood flow and exposed surface area. Accordingly, an oxygenator’s “rated flow” refers to the maximal volume of 70% saturated venous blood that will achieve 95% saturation after passing through the device. Oxygenation is relatively unaffected by adjustments in sweep. Recent advances in membrane lung technology have yielded more efficient oxygenators with decreased resistance to flow, decreased platelet and plasma protein consumption and decreased inflammatory properties.15,48 Air embolism may develop in the membrane lung if sweep gas pressure exceeds membrane lung blood perfusion pressure. Many ECMO circuits are equipped with gas inflow pressure alarms as well as bubble detectors on the blood return line to prevent this complication. In addition, it is recommended to place the membrane lung below the level of the patient to reduce the risk of air entrainment in the event of pump failure or another low-pressure event.49 In peripheral VA ECMO, lung-oxygenated blood is ejected by the heart and mixes with membrane-oxygenated blood in the thoracic aorta. The location of the mixing zone varies according to the balance of flows from the LV and the arterial cannula. In patients with respiratory insufficiency but relatively preserved cardiac output, the mixing zone may

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be distal to the left subclavian artery leading to delivery of poorly oxygenated blood to the aortic arch vessels. Isolated cyanosis of the upper extremities, head and neck may develop, as well as cerebral and coronary ischemia.50 Referred to as upper body hypoxia, “Harlequin” or “North-South” syndrome, this phenomenon is particularly likely in femorally-cannulated patients in the setting of cardiac recovery, when initiating or increasing the dose of positive inotropic medications, and during the ECMO weaning process. To rule out upper body hypoxia, arterial blood gas analyses and pulse oximetry monitoring should be performed on the right upper extremity, or otherwise on the opposite side of the mixing zone relative to the ECMO circuit’s arterial outflow (Table 2). Cerebral oximetry may also help diagnose this phenomenon.5,40 There are no firm guidelines regarding optimal oxygen levels in adult VA ECMO patients.15 Hyperoxia is associated with increased mortality following adult cardiac arrest and in pediatric VA and adult VV ECMO populations.15,51,52 However, this association has not been consistently demonstrated in adult VA ECMO patients.53 In the setting of ECPR, some sources recommend titrating FDO2 to an initial peripheral oxygen saturation between 90 and 95% in order to avoid the adverse effects of hyperoxia seen in other patient populations.15 VA ECMO is not an independent indication for mechanical ventilation, and patient may be extubated on VA ECMO support. Indeed, as few as 41% of VA ECMO patients “bridged” to heart transplant are mechanically ventilated immediately prior to transplant surgery.54 For VA ECMO patients who do require mechanical ventilation,29 data are limited regarding optimal ventilation strategies. Extrapolating from the VV ECMO literature, lung protective ventilation is commonly recommended, with tidal volumes of 4-6cc/kg, peak

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inspiratory pressures less than 20-25cmH20 and/or plateau airway pressure less than 30 cm H2O.55 At high ECMO flows, respiratory rates as low as 5-10 breaths per minute can help avoid alkalosis and minimize ventilator-induced lung injury.15,55 At lower flows, the ventilator may need to provide more assistance. Positive-end expiratory pressure (PEEP) should be provided to optimize oxygenation and prevent atelectasis.55 However, high levels of PEEP may lead to elevated pulmonary vascular resistance and right heart strain, as well as decreased venous return and compromised pump flows due to elevated intrathoracic pressure.

Pulsatility Pulsatility is a marker of LV contraction and native cardiac output. A lack of pulsatility on arterial waveform signals excessive afterload or minimal left ventricular preload or contractility and cessation of cyclical opening of the aortic valve. This can result in intracardiac or aortic root thrombosis due to stasis and risks potential embolism. A cardiac output of 20% of total flow, corresponding to a goal pulse pressure of at least 10mmHg, may significantly reduce these risks.15 When decreased pulsatility reflects poor LV function or excessive afterload, LV distension may develop due to decreased stroke volume, incomplete ejection of systemic venous return, drainage from Thebesian and bronchial veins, and even trace aortic regurgitation.34 LV distension is associated with increased LVEDP, wall stress, and oxygen demand that together impair myocardial recovery and VA ECMO weaning, and contribute to overall poor outcomes.34,36,56 In addition to decreased pulse pressure, signs of LV distension include a dilated and hypokinetic LV on echocardiogram, refractory ventricular

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arrhythmias, elevated pulmonary capillary wedge pressure (PCWP) and pulmonary edema.42 Medical interventions to decompress the heart include positive inotropes, vasodilators, and volume removal through aggressive diuresis. Renal replacement therapy (RRT) may be required to manage hypervolemia. ECMO flows may be decreased to reduce LV afterload, or increased to reduce preload, usually in conjunction with the addition of vasodilator. If these techniques do not result in adequate LV pulsatility, or if elevated filling pressures, arrhythmias or pulmonary edema persist, mechanical LV off-loading or “venting” should be performed.42,57 Options for offloading the LV include intra-aortic balloon pumps (IABPs), atrial septostomy, percutaneous ventricular assist devices (pVADs) such as the Impella® and surgical LV venting with an LV apical cannula. To date, no randomized controlled trial has evaluated LV unloading compared to VA ECMO alone.56 However, a recent meta-analysis of 17 observational studies reported a significant mortality benefit associated with LV unloading compared to isolated VA ECMO (54% versus 65% mortality rate, risk ratio 0.79, 0.72-0.87).58 IABP was the unloading device utilized in 91% of patients included in the analysis, but the review found no significant mortality difference in IABP patients compared to percutaneous VAD patients (5.5% of patients) or atrial septostomy or pulmonary vein cannulation patients (2.8%). Anecdotal reports and early studies of prophylactic LV venting also suggest that this practice is associated with a mortality benefit compared to ECMO alone, and may be increasingly common.42,57,59

Anticoagulation and monitoring

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Contact between blood and foreign surfaces leads to endothelial activation and initiation of the clotting cascade. In addition, ECMO patients are known to have elevated levels of procoagulant mediators, notably Factor VIII, as well as decreased levels of antithrombin and activated Protein C.60 Hence, anticoagulant medications are utilized to mitigate the hypercoagulable state induced by ECMO, and to prevent ECMO circuit thrombosis and embolic complications15 A bolus of unfractionated heparin (40-100u/kg) is typically administered prior to cannulation,15,61 though this may be modified or omitted in already heparinized patients, after major surgery or when signs of severe bleeding are present. There are no authoritative guidelines for dose or level of anticoagulation required for VA ECMO, and the milieu of each patient’s intrinsic clotting/bleeding profile varies greatly. Anticoagulation is most often achieved with unfractionated heparin (UFH). Activated clotting time (ACT) is the historical standard for anticoagulation monitoring with a goal ACT of 180-220 seconds. The ACT should be checked several times a day, once at target. Notably, the ACT is less accurate when monitoring lower doses of heparin, as in ECMO, compared to cardiopulmonary bypass.61,62 A recent review of 120 VA-ECMO patients did not reveal any difference in serious bleeding events or clotting complications between ACT or activated partial thromboplastin time (aPTT) driven protocols.63 However, the ACT protocol was associated with a higher transfusion rate, suggesting a greater degree of overall blood loss even in the absence of severe hemorrhagic events. The aPTT monitoring method is more commonly utilized in high volume ECMO centers.61 The goal for aPTT should be 1.8-2.0 times normal.15 Notably, the aPTT may not be a reliable indicator of heparin level in the setting of Factor XII deficiency, lupus

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anticoagulant, acquired factor deficiency, hemodilution, liver disease or disseminated intravascular coagulation.61 In cases of suspected heparin resistance, anti-thrombin III levels should be obtained. If anti-thrombin III levels are found to be low, as may occur after prolonged heparinization, replacement with fresh frozen plasma or synthetic antithrombin III can be initiated.64,65 Anti-Factor Xa levels directly monitor the final common pathway of the coagulation cascade. Except in the setting of high free hemoglobin or bilirubin levels, anti-Factor Xa levels are more sensitive to UFH than the aPTT.62 In the case of bleeding or clotting while seemingly at therapeutic levels of Heparin, anti-Factor Xa levels can more specifically define the heparin effect.61 Compared to anti-Factor Xa levels and aPTT, viscoelastic testing provides a more comprehensive coagulation profile and may identify factor and quantitative platelet deficiencies, hypofibrinogenemia, hyperfibrinolysis and heparin effect.66 Viscoelastic monitoring has been suggested to reduce transfusions in cardiac surgical patients,67 but data are limited regarding the role of viscoelastic testing in VA ECMO management.68 Early results in VV ECMO suggest that viscoelastic testing may not predict bleeding more accurately than traditional coagulation studies.69 Additionally, VA ECMO patients have been found to have only slightly elevated D-dimer levels, suggesting that viscoelastic testing for fibrinolysis may not be routinely useful.60

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Complications and Trouble-Shooting in VA ECMO

While longer durations of ECMO impose greater risk, complications may occur at any time.70 If severe complications persist, removal of ECMO and alternative support methods may be necessary. A few complications warrant further discussion. Table 4 summarizes the common complications and suggested trouble-shooting algorithms.

Bleeding and Chattering Hemorrhage is the most commonly reported complication in VA ECMO.16 Although bleeding complications are not consistently defined in the VA ECMO literature, large studies report that “serious bleeding” occurs in 40-56% of ECMO patients.71,72 Bleeding occurs due to required anticoagulation, along with the thrombocytopathy, thrombocytopenia and clotting factor activation and consumption that occurs with extracorporeal circulation. Shock and ECPR patients also experience disruption of the glycocalyx which results in a relatively coagulopathic state.62 Bleeding complications may be evident in laboratory values or on physical exam. A slow downtrend in hemoglobin may be due to a persistent small amount of blood loss at cannulation or surgical sites.62 Alternatively, the first signs of bleeding may involve ECMO “chatter” due to relative hypovolemia in the circuit. During times of very low flow or a suction event, hemodynamic instability and hypoxia can rapidly ensue. Immediately decreasing the set flows to 1 -2 L/min can allow for circuit filling until fluids or exogenous blood can be administered; some modern ECMO machines will reduce flows automatically.

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Physical examination and imaging can aid in identifying sources of bleeding with special attention to cannulation sites, retroperitoneal, gastrointestinal, pleural and pericardial spaces. If bleeding is identified, anticoagulation may need to be held until hemostasis is achieved. Indeed, an emerging body of literature suggests that avoiding routine anticoagulation in VA ECMO patients may well-tolerated among patients who do not have alternate indications for anticoagulation, with decreased transfusion requirements and no increased risk of clinically significant thrombosis.73 Platelets, fresh frozen plasma, anti-fibrinolytics and factor concentrates have also been described for treatment of life-threatening bleeding in VA ECMO patients.74 In particular, small studies suggest that recombinant Factor VIIa may be effective in halting hemorrhage refractory to other medical treatments, without a significant increase in thrombotic events.74,75

Hemolysis Hemolysis is the product of turbulent blood flow and should prompt assessment of clot in the oxygenator or high ECMO flow rates through small, kinked or poorly positioned cannulae. Plasma free hemoglobin or haptoglobin, as well as bilirubin and lactated dehydrogenase (LDH) should be routinely checked, especially in the case of down-trending hemoglobin. The first clinical sign may be pink-tinged urine due to hemoglobinuria. Increasing anticoagulation, increasing cannula size and decreasing ECMO flow rates can lessen the degree of hemolysis, as can replacing the oxygenator or circuit if there is visible evidence of thrombus. However, device exchange requires temporary cessation of ECMO support and invariably leads to blood loss.

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Thrombosis ECMO induces a hypercoagulable state through an imbalance in pro- and anticoagulant factor levels, activation of the clotting cascade, and risk of stasis in the setting of poor cardiac contractility.60 The risk of cerebral infarction in patients on VA ECMO is nearly double that of cerebral hemorrhage, occurring in nearly 4% of compared with cerebral hemorrhage occurring in less than 2% of patients.76 In addition to routine neurologic and clinical examination of VA ECMO patients, the oxygenator membrane and all tubing should be scanned for fibrin stranding daily with a flashlight.15 Thin white strands of fibrin are the earliest sign of thrombus formation and are common especially around connection sites and stopcocks. These fibrin strands are typically benign and do not warrant circuit exchange or increased anticoagulant dosing. Thrombi frequently appear as black spots on the oxygenator inflow and must be carefully monitored and documented. These clots should cause particular concern when they are mobile or are associated with decreased function of the membrane lung. Large clot burden warrants oxygenator assessment with arterial blood gas analyses of both pre- and post-oxygenator samples, while on 100% FDO2. The post-oxygenator PaO2 should measure around 500 mmHg. Likewise, the trans-membrane pressure gradient at these two sites should be measured. It is normally < 50 mmHg. High gradients may indicate substantial clot within the oxygenator membrane, particularly if the premembrane pressure is > 300 mmHg and post-membrane pressure is normal.46 Clots in the arterial cannula carry the highest risk of embolization and may require circuit exchange or termination of ECMO support. A malfunctioning oxygenator or circuit tubing can be exchanged at bedside with a brief cessation of ECMO flow. Many centers

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administer an intravenous bolus dose of heparin prior to an exchange to prevent clot formation during this time. After an oxygenator exchange there will be consumption of platelets and clotting factors on the newly exposed surface. Due to bleeding risk, it may be prudent to avoid oxygenator exchange at the time of other surgical procedures. Most centers utilize intravenous heparin due to predictable pharmacodynamics. If heparin-induced thrombocytopenia (HIT) is suspected due to dropping platelet counts or there is evidence of arterial or venous thrombi, a heparin alternative (e.g. bivalirudin, argatroban) may be necessary.77

Hypoxemia In central VA ECMO, hypoxemia suggests a mechanical failure with the ECMO cannulation, circuit or oxygenator. In isolated cardiac failure treated with peripheral VA ECMO, hypoxia in the absence of flow changes may indicate pulmonary insufficiency due to pulmonary edema, pneumonia or atelectasis. Treatment of global hypoxemia includes increasing ECMO flows, FDO2, inhaled oxygen and PEEP, and optimizing ventilator settings in intubated patients. Oxygen carrying capacity can be increased with judicious red blood cell transfusions.15 North-South syndrome is managed by optimizing pulmonary function, increasing ECMO flows and decreasing native cardiac output. The latter interventions push the mixing cloud proximally, such that membrane oxygenated blood perfuses the arch vessels and coronary arteries. Diuresis and careful reductions in inotropic support may also help achieve these aims, though decreased contractility can itself exacerbate pulmonary congestion. Upper

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body venous drainage may also indirectly improve cerebral oxygenation by ensuring that SVC blood enters the ECMO circuit.78,79 In cases of severe pulmonary dysfunction, conversion from VA to VAV ECMO may be required. In patients whose cardiac function has recovered but whose lung function remains profoundly insufficient (e.g. PaO2/FiO2 < 100 on 21% FDO2), conversion from VA to VV ECMO may be indicated.80

Hypercarbia CO2 removal is controlled by adjusting the rate of sweep gas flow through a functioning oxygenator. Acute increases in carbon dioxide can be caused by condensation building up in the hollow fibers of the oxygenator membrane, which occurs more commonly at low sweep flows. This can result in acute hypercarbic acidosis with cardiopulmonary instability in a matter of minutes. Purging the oxygenator by increasing the sweep flow to 10 L/min for a few seconds usually rids the excess moisture and restores decarboxylation capacity.81 To prevent acute hypercarbia, a purge should be performed every 1-3 hours depending on the sweep flow.

Limb ischemia Limb ischemia due to peripheral arterial cannulation occurs in up to 20% of patients.82 The risk of mechanical flow obstruction in the cannulated artery is compounded by the frequent need for vasopressors during VA ECMO and by peripheral vascular disease, common among cardiac patients. A distal-limb perfusion cannula is commonly employed to provide anterograde blood flow past the arterial cannula. Alternate strategies to prevent

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lower limb ischemia include subclavian or axillary arterial cannulation, or placement of an end-to-side femoral artery graft, commonly called a T-graft, through which the ECMO cannula is positioned. The latter requires surgical intervention to place and to remove. Rapid diagnosis and treatment of limb ischemia is paramount. In addition to decreased temperature and pallor on clinical exam, NIRS has been shown to effectively identify lower extremity ischemia.37,40 Arterial embolism can be diagnosed with a Doppler study and warrants urgent embolectomy. Swelling and erythema may indicate rhabdomyolysis or compartment syndrome and require prompt measurement of compartment pressure. If compartment syndrome is suspected, urgent fasciotomy is indicated. Creatine phosphokinase (CK), potassium and metabolic acidosis should be measured and treated to help prevent kidney injury.

Renal Failure and Volume Overload If RRT is indicated due to metabolic derangements or volume overload, the apparatus can be incorporated into the ECMO circuit.83 In one schema, a hemofilter is attached downstream from the ECMO pump, and filtered blood is returned to the prepump venous inflow. Due to recirculation, however, pump speeds in this configuration will not accurately reflect arterial outflow. A preferable alternative involves splicing a hemodialysis machine and circuit between the ECMO pump and oxygenator, in a sequence that will prevent air entrapment in the pump and possible air embolism beyond the oxygenator. Compared to an independent CRRT circuit, a joint CRRT/ECMO configuration avoids the bleeding and infectious risks associated with an additional central venous catheter. It

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may also facilitate more reliable ECMO flows and more accurate monitoring of fluid balance.83 Most dialysis machines are equipped with a pressure alarm system and may require re-programming to account for the positive pressure provided by the ECMO pump. However, it can provide additional protection against high outflow pressures within the ECMO circuit.84 A diagram of a joint ECMO-RRT configuration is depicted in Figure 3.

Weaning VA ECMO

The decision to initiate VA ECMO weaning entails evaluation of cardiac, hemodynamic, respiratory and end organ function.15,85 Rates of successful weaning vary according to etiology of cardiogenic shock, and reported values range from 38% to 65%.8587

Patients who are successfully weaned from VA ECMO still face levels of inpatient

mortality between 30% and 40%.85,86 There are no formal guidelines for VA ECMO weaning, and multiple approaches are described in the literature.15,80,85,88,89 An algorithm for weaning VA ECMO is presented in Figure 4. Proposed criteria for initiating a wean include ventricular pulsatility on arterial waveform or echocardiography for at least 24 hours, MAP >60mmHg in the setting of lowdose vasopressors and inotropes, and a PaO2/FiO2 > 200mmHg on 21% FDO2 and less than 60% FiO2.80,90 If a patient meets these criteria, or otherwise demonstrates signs of cardiac recovery and relative hemodynamic and clinical stability, it is reasonable to begin to decrease flows by 0.5LPM or 1LPM every 4 to 24 hours, targeting a rate of 2LPM. Prior to weaning VA ECMO flows, mechanical ventilation and inotropic support should be optimized. An inhaled pulmonary vasodilator may be initiated in cases of right

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ventricular failure. Volume may need to be removed to aid right ventricular function and to optimize respiratory mechanics. While the wean is in progress, pulmonary artery catheter data, lactate and SvO2 should be carefully trended for signs of worsening cardiac function and poor systemic perfusion. Serial TTEs should be performed to evaluate LV size and biventricular function. Arterial blood gas analysis should be obtained with near total pulmonary support being delivered by the ventilator. The ventilator should be adjusted to compensate for decreased membrane lung assistance, and sedation may need to be adjusted to improve synchrony with the ventilator as respiratory dynamics change. Inotrope and vasopressor requirements may increase as flows are reduced. Factors predictive of successful weaning include an aortic velocity time integral (VTI) of at least 10cm and LV ejection fraction EF > 20–25% with VA ECMO flows less than 1.5LPM.85,90,91 Factors that may predict failure to wean include right ventricular distension and associated decreased LVEDV.91 Indications to halt the ECMO wean include impaired oxygenation or ventilation, progressive ventricular dilation or worsening valvulopathy, increasing filling pressures, lack of increase in arterial pulse pressure, and marked hypotension. If the patient tolerates the initial wean to 2LPM, flows should be further decreased to 1L/m under echocardiographic guidance at bedside.88 Importantly, full anticoagulation is recommended when titrating ECMO flows below 2 LPM, and a bolus of heparin (2550U/kg) may be administered to ensure thrombus formation does not occur. If the patient maintains stable hemodynamics and oxygenation and demonstrates adequate cardiac contractility and minimal increase in ventricular distention for fifteen to thirty minutes, it is reasonable to return flow to 2L/m and plan for decannulation.

24

Patients who are centrally cannulated and successfully weaned may not tolerate chest closure. Patients with decreased space between the right ventricle and sternal table should be considered for delayed chest closure. A trial of chest closure is prudent in patients who require a moderate level of inotropic support. Some patients may need further circulatory assistance in the form of an intra-aortic balloon pump, temporary ventricular assist devices, durable MCS, or less commonly, heart transplantation. Planning for these devices should occur prior to attempted decannulation. Palliation is indicated for patients who are not candidates for long-term support or transplantation and not expected to have cardiac recovery. Organ donation can be considered for some patients. Respectful and thoughtful discussion with family is essential for moving toward withdrawal of mechanical circulatory support in these unfortunate circumstances.

Conclusion By temporarily replacing cardiopulmonary function, VA ECMO offers potentially lifesaving support for patients suffering from refractory cardiogenic shock. The management strategies for VA ECMO are likely to change in coming years, as technology progresses and VA ECMO is applied in a wider range of clinical contexts. However, understanding the physiologic principles of the human body, and also the devices that support it, will remain imperative.

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Declarations of Interest: None

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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FIGURE LEGENDS

Figure 1. Configurations for VA-ECMO. a) peripheral ECMO involving femoral vein and femoral artery. The arterial outflow can be accomplished with a cannula or with a T-graft anastomosis; b) central cannulation with outflow cannula in jugular vein or via sternotomy in right atrium; inflow cannula may be carotid, subclavian, axillary or directly to aorta; c) VAV ECMO configuration used in cases of severe lung disease, the inflow cannula from the oxygenator can be spliced to allow for oxygenated and decarboxylyzed blood to be delivered to a major vein, generally the internal jugular in hopes of increasing oxygenated blood circulating in cerebral and other major vasculature. This method may also be useful in cases of “North-South Syndrome”. O2 = oxygen, FdO2 = fraction of device oxygen, CO2 = carbon dioxide

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Figure 2. North-South Syndrome in VA ECMO

Figure 3. Configurations of RRT and VA ECMO A. RRT Machine and circuit placed between ECMO pump and oxygenator B. Hemofilter placed distal to ECMO pump, with filtered blood returned to pre-pump venous inflow

37

Does the patient meet criteria for weaning VA ECMO? •

• •

Clinical evidence of cardiac recovery: • Ventricular pulsatility on arterial waveform or TTE for > 24 hours • Stable to decreased inotrope requirement • MAP >60mmHg on low- or moderate-dose vasopressors • Increased CO/CI Adequate pulmonary function to support systemic oxygen demand: • PaO2/FiO2 > 200mmHg on 21% FDO2 FiO2 < 60% Stable or improving renal, hepatic and neurologic function

Is the patient optimized for weaning VA ECMO? •

• •

Optimize pulmonary function • Adjust ventilator settings and sedation • Consider volume removal (diuresis, CVVH) Anticipate increased vasopressor and inotrope requirement during and after wean Manage and Pre-Empt RV strain • Consider an inhaled pulmonary vasodilator • Consider volume removal

Wean VA ECMO • • • •

Decrease flows 0.5 – 1.0LPM every 6-24 hours Obtain TTE with every flow decrement Bolus heparin (25-50U/Kg) when flows < 2LPM Maintain flows < 1.5 LPM for at least 15 - 30 minutes

Halt VA ECMO Wean

ECMO Wean Not Tolerated •

• • • • • • •

Hypotension (MAP < 60mmHg) requiring significant increases in vasopressors or inotropes No observed increase in arterial or PA pulse pressure Rising left or right-sided filling pressures Progressive ventricular dilation New or worsening mitral or tricuspid regurgitation Hypoxia Hypercarbia Elevated peak or plateau pressures if mechanically ventilated

ECMO Wean Tolerated •

• • • • • •

Minimal increases in vasopressor and inotrope requirements Increased systemic and PA pulse pressures Stable left- or right-sided filling pressures No new ventricular dilatation Aortic VTI > 10cm LVEF > 25% Adequate oxygenation

Decannulation Permanent MCS, Orthotopic Heart Transplant

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Figure 4. VA ECMO weaning algorithm

Table 1. Indications and Contraindications to VA ECMO in the Adult Patient Indications Failure to wean from cardiopulmonary bypass Cardiogenic shock secondary to:      

    

Myocardial infarction/Acute Coronary Syndrome Myocarditis Pulmonary Embolism Drug overdose (e.g. beta blockers) Fulminant endocrinopathy (e.g. thyroid storm, diabetic ketoacidosis, pheochromocytoma) Treatment-refractory malignant arrhythmias (e.g. ventricular tachycardia, fibrillation or storm) Takatsubo cardiomyopathy Peripartum cardiomyopathy Acutely decompensated chronic cardiomyopathy Traumatic injury Septic cardiomyopathy

Refractory, witnessed cardiac arrest (“ECPR”) attributable to reversible cardiac etiology, including those listed above Primary graft failure following heart transplantation Preoperative support pending urgent or emergent repair of acute cardiac defects, including:  

Absolute Contraindications Inconsistent with patient’s goals of care Cardiac lesions worsened by VA EMCO:  

Aortic insufficiency Aortic dissection

Low likelihood of cardiac recovery in patients who are not candidates for heart transplant or durable mechanical support device Neurologic injury incompatible with life End-stage renal or hepatic failure in non-transplant candidates Multiorgan failure with low likelihood of recovery Uncontrolled hemorrhagic shock Uncontrolled, metastatic malignancy

Relative Contraindications Advanced age Inability to tolerate anticoagulation Malignancy, controlled or in remission Anatomy precluding or limiting cannulation:  

Morbid obesity Severe peripheral arterial disease

Prolonged CPR (> 1530 minutes) Neutropenic sepsis

Ventricular septal defect (e.g. post-infarct) Acute valvulopathy (e.g. following papillary muscle rupture, endocarditis)

Pre- or postprocedure circulatory support for high risk interventional procedures (e.g. TAVR, PCI) Septic shock Anaphylactic shock TAVR = transcatheter aortic valve replacement; PCI = percutaneous coronary intervention

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Table 2. VA ECMO Configurations, Physiologic Effects, and Monitoring Considerations

Cannula Location

Hemodynamic Effects

Oxygenation Effects

Monitor Placement

Additional Considerations

Central VA ECMO

Inflow: Right atrium Outflow: Ascending aorta; left atrium -

Anterograde aortic flow Large caliber vessels and cannula enable highest ECMO flow ratesMost effective biventricular offloading

Mixing zone in the aortic root Optimal perfusion for coronaries and brain

Less important to have right UE oxygen monitor since ECMO outflow is in the ascending aorta -

Requires sternotomy for cannulation and decannulation Increased infectious risk associated with open chest

Pseudo Central VA ECMO

Inflow: Femoral or internal jugular vein-

Anterograde aortic flow Large caliber vessels and cannula enable highest ECMO flow rates-

Mixing zone in the aortic root Optimal perfusion for coronaries and brain -

Retrograde aortic flow More likely to strain LV, decrease pulsatility Small caliber up upper extremity vessels may limit deliverable flow volume -

Variable location of mixingzone; may occur distal to left subclavian artery Risk of “North-South” syndrome due to distal mixing zone Risk of afterload-induced pulmonary edema, compromised pulmonary function -

Coronary and cerebral oxygenation most accurately reflected in right upper extremity Right UE arterial pressure may be higher than systemic pressure Coronary and cerebral oxygenation most accurately reflected in right upper extremity Monitor lower extremity tissue saturations with femoral cannulation Ipsilateral upper extremity oxygenation will overestimate cerebral or systemic oxygenation Contralateral upper extremity arterial line values more reflective of systemic oxygenation -

Increased afterload/SVR can decrease LV cardiac output Facilitates increased pump flows -

Goal to enhance oxygenation May be indicated in management of “NorthSouth” syndrome Goal to enhance oxygenation especially of cerebral vasculature May be indicated in management of “NorthSouth” syndrome

Elevated venous inflow oxygenation suggests “recirculation” (direct flow from venous outflow to inflow cannula)

-

Pulmonary pressures, blood gas -

Peripheral VA ECMO

VVA ECMO

VAV ECMO

Outflow: Axillary, subclavian Inflow: Femoral or internal jugular veinOutflow: Femoral, axillary, subclavian -

Inflow: Femoral vein and internal jugular Outflow: Any large artery

-

Inflow: Femoral Vein; internal jugular vein; pulmonary artery Arterial outflow: variable

Relative increase in preload dueto additional venous outflow -

LV

Techniques include: pulmonary-

Decreased LV preload reduces -

Decreased pulmonary

Right upper extremity provides accurate whole body oxygenation assessment -

Can provide rapid cannulation at the bedside Femoral and iliac artery atherosclerosis may impair cannulation and flows Femoral artery cannula may obstruct distal perfusion May utilize surgical cut-down and end-to-side anastomoses Concern for CVA in carotid cannulation (less common in adults than children) Upper body cannulation facilitates patient mobility

Relative outflow to venous and arterial limbs can be adjusted with extrinsic manipulation (suture, clamp) Venous cannula tips in IVC, SVC should be > 15cm apart to prevent recirculation Relative flow from venting

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“venting”

vein cannula; LV apex cannula; atrial septal puncture (with possible LA cannula) Percutaneous techniques: Intraaortic balloon pump (controversial); Impella ( “ECPELLA”)

LV distension, enhance myocardial perfusion, may increase pulsatility Afterload is not increased

-

edema may enhance oxygenation Possibly increased whole body cardiac output (native + ECMO)

and chest x-ray to assess pulmonary edema Serial TTE to assess LVEDD

cannula versus vein cannula can be adjusted with extrinsic suture/clamps

(VA ECMO = veno-arterial extracorporeal membrane oxygenation; VVA = veno-venous arterial; VAV = veno-arterial venous; LV – left ventricular; IVC = inferior vena cava; SVC = superior vena cava; LA = left atrium; TTE = transthoracic echocardiogram; LVEDD = left ventricular end-diastolic diameter)

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Table 3. Uses of Bedside Ultrasonography in VA ECMO Management  Cardiac Biventricular Function o Ejection fraction o Cardiac output (LVOT VTI) o RV contractility (TAPSE) o LV contractility (MAPSE) o LV dilatation (LVEDD) o Flattening or paradoxical movement of the interventricular septum o Pulmonary arterial pressures o Regional wall motion abnormalities o Pre-existing versus new pathology  Cardiac Valvular abnormalities o Aortic Insufficiency, Mitral Regurgitation, Tricuspid Regurgitation  Cardiac Pulsatility o Aortic valve opening o LV distension (LVEDD) o Intraventricular or aortic thrombus  Mechanical considerations o ECMO Cannula position o Position of LV venting devices  Acute complications o Pericardial tamponade o Pneumothorax o Lower extremity arterial occlusion or embolism  Volume status o Biventricular filling (preload) o IVC collapse o Pulmonary edema, effusions LVOT VTI = left ventricular outflow tract velocity-time integral; LVEDD = left ventricular end diastolic diameter; MAPSE = mitral annular plane systolic excursion; TAPSE = tricuspid annular plane systolic excursion

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Table 4. Complications and Trouble-shooting Strategies for VA ECMO. Complication Bleeding

Signs - Decreased ECMO flows, “chatter” or suction events - Oozing from cannula sites- Anemia

Risk Factors - Anticoagulant therapy - Coagulopathy due to critical illness, liver dysfunction, DIC -Thrombocytopathy due to extracorporeal circulation

Assessment - Examine cannulation sites - Assess pericardial, pleural, abdominal and retroperitoneal spaces with imaging - Follow INR, PTT, hemoglobin, Xa levels - Check fibrinogen, platelets - Consider viscoelastic testing

Hemolysis

- Anemia without signs of bleeding - Hematuria - Jaundice - Elevated LDH and plasma free hemoglobin, undetectable haptoglobin - Clot visualized in oxygenator and/or cannulas

- High flow rates through small cannulas

- Follow LDH, plasma free hemoglobin, bilirubin daily - Examine circuit for clots or obstruction

- Low flows without full anticoagulation

- Examine cannulae and oxygenator daily - Serial neurologic examinations - Examination of digits and extremities for embolic signs - Check HIT antibody or serotonin release assay if suspected - If concern for heparin resistance and need for high heparin infusion rates, check antithrombin III level

- Verify anticoagulation status via PTT, ACT or anti-Factor Xa level - Increase anticoagulation goal - Exchange oxygenator if large clot burden or malfunctioning oxygenator - Exchange tubing or remove ECMO if arterial circuit contains clot - Switch to heparin alternative (argatraban or bivalirudin) in patient with suspected or confirmed HIT

- ABG with PaO2 < 60 mmHg while on 100% FdO2

- High fraction of flow through native circulation with impaired pulmonary function - Ventilator not optimized - Decreased LV function causing pulmonary edema

- Ensure adequate oxygen flow to oxygenator - Check pump flow and for signs of chatter - Check oxygenator for clot, as above - Check oxygenator function by analyzing pre- and postoxygenator pressures and ABG on FdO2 100% at both locations -- pre- should be < 300 mmHg with < 50 mmHg gradient -- oxygenator outflow should have pO2 > 500 mmHg on FdO2 100% - Check ventilator peak pressures and signs of failure to deliver tidal volume -- especially if peripherally cannulated - Assess echocardiography

- Ensure pump flow is adequate (> 2/3 cardiac output) - Ensure FdO2 and ventilator FiO2 at 100% - Optimize mechanical ventilator mode - Consider cooling patient via ECMO cooler - Consider second access to provide VAV ECMO configuration - Transfuse patient to hemoglobin > 7 mg/dL

Clotting

Hypoxia

Management - Decrease or stop anticoagulation - Transfuse red blood if bleeding - Correct elevated INR and PTT with FFP or PCCs - Correct thrombocytopenia and low fibrinogen levels with platelets and cryoprecipitate - Correct surgical sources of bleeding - May need to remove ECMO if life threatening bleeding continues - Full anticoagulation if not bleeding - Transfuse red blood cells - Decrease ECMO flows or wean ECMO as able - Consider replacing cannulae with larger bore

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- Check hemoglobin - Compare ABG at furthest point from arterial cannulation, typically right radial, to lower body ABG - Obtain echocardiography evaluation of cardiac output - Monitor cerebral oxygen content with NIRS

Differential hypoxemia (North-South Syndrome)

- Lower PaO2 in upper body compared with lower body - Echocardiography demonstrating increased intrinsic cardiac output

- Occurs with severe respiratory failure and high cardiac output

Hypercarbia

- Steady increases in PaCO2 level - Acutely increased PaCO2 level - Acute increases in pressor requirement or PAP

- Failing oxygenator or oxygenator condensation

- Follow ABG frequently - Check pump flow (> 2/3 cardiac output) - Consider recirculation phenomena -- Check ABG at different arterial sites -- Evaluate cardiac function with echocardiography

Decreased ECMO Flows

- Chattering of cannulas - Flow numbers “bouncing” on ECMO platform - Blood pressure decreases

- Bleeding, as described above - Septic shock or other distributive shock state

Left ventricular distention / pulmonary edema

- Decreased pulsatility on arterial waveform - ventricular distension and

- Less risk with central cannulation - Blood stasis may result in ventricular or pulmonary

- Exclude kinked or malpositioned cannula - Rule out intra-abdominal compartment syndrome (i.e. decrease return) - Check pre- and postoxygenator pressure gradient -pre- should be < 300 mmHg with < 50 mmHg gradient between pre- and postoxygenator - Evaluate possible sources of bleeding - Evaluate invasive hemodynamic monitoring central venous pressure, pulmonary pressure, mixed venous saturation and lactate for signs of fluid status and perfusion - Ensure outflow and inflow cannulas are not too close in proximity creating a shunt - Daily chest x-ray and/or ultrasonography for B-lines - Monitor for changes in oxygenation on ABG - Monitor airway ventilator

- Increase ECMO flow to full cardiac output Optimize ventilator and FdO2 as above - Consider decreasing or discontinuing inotropic support - Consider changing to UE or central cannulation strategy - Consider switching to VV-ECMO if cardiac function adequate - Consider VAV-ECMO with additional inflow cannula to jugular vein if cardiac function not adequate Acute hypercarbia: - Purge or “sigh” (turn sweep flow to 10L/minute for 1-2 seconds) and monitor for water release from oxygenator - Sweep should be purged hourly in cases of low sweep flow of < 1 L/minute and every 2 hours at higher flows Subacute hypercarbia: - Increase ECMO flow - Increase minute ventilation on ventilator - Optimize cardiac function in peripheral ECMO - Optimize fluid status with resuscitation or ceasing diuresis - Maintain volume in the circuit by transfusing hemoglobin to 7 mg/dL if not bleeding or > 9 mg/dL if bleeding - Correct source of bleeding if identified -- may need to lessen anticoagulation or hold for a few hours if bleeding or hemoglobin decrease continues despite adequate transfusion - Change oxygenator if large preand post-membrane pressure gradient; can be due to clots - Reposition cannula or place second venous drainage cannula for VVA configuration

- Decrease or stop pulmonary vasodilators - Increase ECMO flows, consider adding systemic vasodilators - Increase inotropic support

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Peripheral limb ischemia

Vasoplegia

Infection

limited aortic valve opening on echocardiogram - hypoxia - Pink, frothy edema from endotracheal tube with severe pulmonary edema - Decreased pulses, pallor, dusky appearance or pain in cannulated extremities - Increased girth of extremity when measured serially at exact location

thrombosis

pressures - Echocardiography to evaluate function and LV diameter at end systole and end diastole, aortic valve opening - Monitor arterial line pulsatility (goal > 10mmHg)

- Increase diuresis or initiate renal replacement therapy if fluid overloaded - Consider LV unloading via IABP, Impella (Abiomed, Danvers, MA) , atrial septostomy or LV apical drain

- Small caliber femoral artery - Large arterial cannula - Absence of distal perfusion cannula

- Check CK level - Assess urine color and quantity - Ensure no arterial monitoring lines in cannulated extremity

- Place SaO2 monitor on cannulated extremities - Consider distal perfusion cannula - Consider decreasing cannula caliber size or placement of T-graft - Consider replacement of arterial cannula into UE artery - If CK > 10,000 U/L, consider hydration, avoidance of diuretic - Consider alkalinizing agent to obtain urine pH > 8.0 - May need renal replacement for severe acidosis or fluid overload

- Rule out infectious etiology with cultures and examination - Assess for adrenal insufficiency with ACTH stimulation test or with empiric hydrocortisone administration - Monitor for signs of perfusion: lactate, mixed venous saturation, acidosis - Pan-culture - Check serial lactate and mixed venous saturation

- Add vasopressin to norepinephrine for synergy - Fluid administration as able and consider stopping fluid removal - May require high doses of multiple pressors (norepinephrine, vasopressin, epinephrine) - Inotropic support if cardiac output can be enhanced - Empiric broad spectrum antibiotics if suspected infection while awaiting culture results - Positive blood cultures warrant exchange of indwelling catheters (central lines, arterial lines) if possible - Source control as able - Fluid administration as able - Infection suspected from ECMO circuit requires plan for ECMO alternative

- Warm or cold extremities - High pressor requirements, despite full VAECMO flow

- Leukocytosis - Fever (Note: May be masked by ECMO circuit temperature management) - Warm or cold extremities

- Higher risk if emergent ECMO cannulation or unsterile environment - Higher risk with prolonged cannulation, intubation, indwelling lines

FdO2 = ECMO device oxygen fraction, FiO2 = fraction of inspired oxygen from ventilator, ABG = arterial blood gas, RPM = revolutions per minute, NIRS = near infrared spectroscopy, PaCO 2 = partial pressure of carbon dioxide, LV = left ventricle, CK = creatine kinase, LDH = lactated dehydrogenase, HIT – heparin-induced thrombocytopenia/thrombosis, PTT = partial thromboplastin time, ACT = activated clotting time, DIC = disseminated intravascular coagulation, FFP = fresh frozen plasma, PCC = prothrombin complex concentrate, ACTH = Adrenocorticotropic hormone, IABP = intra-aortic balloon pump, CPB = cardiopulmonary bypass

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