Extracorporeal membrane oxygenation: Perioperative clinical practices and the Indian overview

Extracorporeal membrane oxygenation (ECMO) has emerged as a mechanical circulatory support system with rapid advancements in its technology. It has become an essential tool in the care of adults and children with severe cardiac and pulmonary dysfunction refractory to conventional therapy. The ease of implementation and cost effectiveness makes it highly desirable alternative for bridge to recovery or decision especially in developing countries like India. However complications and challenges related to ECMO, require more rigorously designed studies towards redefining management of patients. Anaesthesiologist being the perioperative physician has an impotant role in managing patients with ECMO. This review focuses on fundamental principles, technology, indications, management, weaning, transport protocols, complications, future directions as well as Indian scenario with ECMO utilization. © 2020 Published by Innovative Publication. This is an open access article under the CC BY-NC license (https://creativecommons.org/licenses/by-nc/4.0/)


Introduction
Extracorporeal membrane oxygenation (ECMO) has become an invaluable tool for managing patients with severe cardiac and respiratory failure who fail to respond to the maximum conventional therapy. [1][2][3] Extracorporeal membrane oxygenation is a form of extra corporeal cardiopulmonary bypass support system with special oxygenator which supports the diseased heart and or lungs and aids in recovery. However, it should be understood that ECMO is a supportive therapy rather than disease modifying modality. Trained and experienced physicians should be the part of ECMO program in any tertiary health center bearing in mind the cost involved. The remarkable progress in the field of ECMO necessitates a thorough understanding.
India has smaller allocation of financial expenditure towards health care. Malnutrition and infectious diseases are a big burden extracting a larger proportion of our

Definition of ECMO
Extracorporeal membrane oxygenation is by definition a cardiopulmonary support mechanism, wherein the blood is drained from the venous system and circulated outside the body by means of a mechanical pump. During this process, the hemoglobin moieties get fully saturated with oxygen and carbon dioxide generated is flushed out. Once fully saturated, the blood is re-infused back into the circulation. The flow rate of the mechanical pump is the determinant factor for oxygenation whereas the rate of countercurrent gas flow through the oxygenator determines carbon dioxide (CO 2 ) elimination at the same time. 1

History and Evolution of ECMO
The earliest understanding can be recollected back to 1944. This was the period when experiments by Kolff and Berk projected that the blood became oxygenated after passing through cellophane chambers of the artificial kidney. 5 However, it was Gibbon who in 1953 for the first time managed to successfully perform open heart surgery using artificial oxygenation and perfusion. 6 In 1965 Rashkind et al were able to reproduce similar results in a neonate with respiratory failure using bubble oxygenator. 7 First successful application of ECMO was in 1972 to treat an adult who had developed post traumatic respiratory failure. 8 This was soon followed by the first ever successful trial of ECMO in neonates who were suffering with severe neonatal respiratory distress by Bartlett et al. in 1975. 9 Thus the platform was set for further research.
These earlier studies however failed to show promising results as the patient population studied was limited. Subsequently conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) trial in 2006 set the standards for the perioperative usage of ECMO. 10 The trial showed improvement in the mortality rate and severe disability 6 months after randomization of patients who were suffering from severe respiratory failure treated with ECMO. The trial was conducted in an expert center with high case turnover. 10

Cardio-respiratory physiology and ECMO
ECMO can be either veno-arterial (VA) or veno-venous (VV) type based on the underlying pathology to be treated. The VV-ECMO ( Figure 1) is mostly instituted for respiratory failure. These patients have impaired gaseous exchange at the alveolar-capillary membrane, leading to hypoxia, hypercarbia and pulmonary vasoconstriction. Here the amount of blood that is removed and returned to the circulation remains essentially equal, thereby maintaining preload. The VV-ECMO improves oxygenation and increases CO 2 clearance thereby decreasing pulmonary vascular resistance, reducing right ventricle workload and improving performance. This process reduces the intrinsic work burden on the diseased lungs especially that caused by the high pressures delivered by mechanical ventilation. The period of rest provided by the extracorporeal gas exchange provides optimal conditions for healing process to occur. It should be emphasized at this point that VV-ECMO does not have direct action on left ventricle (LV) performance. Improvement in LV function can be attributed to improved right ventricle (RV) performance. This can be explained on the basis of ventricular interdependence. Veno-arterial ECMO on the other hand is mainly indicated for treating severe cardiac or cardio-respiratory failure. It is classified into central ( Figure 2) and peripheral ( Figure 3) VA ECMO. The oxygenated blood will return to the aorta and thereby causes significant reduction in the preload to reduce the left ventricular end diastolic volume (LVEDV) and wall stress of the failing heart. This type of extracorporeal circuit aims at providing partial cardiac support and hence the left ventricle continues to have certain amount of intrinsic activity and generates 20-30% of stroke volume. The rest 70-80% of the cardiac output is produced by the extracorporeal circuit. Thus some cardiac ejections continue to occur, such that venous return to the right heart continues and passes through the pulmonary system.
There are however certain physiological consequences of the VA-ECMO. At the onset, there is negligible resistance to retrograde ECMO return flow. Improved functioning of the heart will increase native antegrade aortic flow. This will prevent the oxygenated blood returning from ECMO circuit to traverse the aortic arch. If the cardiac function improves before the pulmonary function, the left ventricle will be ejecting poorly oxygenated blood from pulmonary circulation into the ascending aorta leading to hypoxemia. This is called as Harlequin syndrome. 11 This problem can be overcome by using 2 venous cannulae from SVC and IVC; and aortic or arterial cannula called as veno-venoarterial (V-VA) ECMO.

Indication and contraindication of ECMO
Based on the data obtained from the international ELSO registry, 4 institution of ECMO may give promising results and outcome wherein understanding of the pathological processes is clear. The indications of ECMO can be categorized into cardiac, respiratory or combination of the two ( Table 1). The contraindications are summarized in Table 2.   Oxygen line is connected to the oxygenator 3 Gas flow started ≥5-6L/min 4 Sterile loop is opened and handed to cannulating surgeon 5 Circuit is cut between two clamps allowing sufficient length on the access line and return line to prevent any tension on the circuit 6 Ensure no air in circuit 7 VV ECMO-target flows must provide adequate arterial oxygenation 8 VA ECMO-target flows must provide adequate oxygen delivery 9 Routine patient and circuit arterial blood gases to be performed 10 Step down on ventilator settings Haemodynamic observations MAP-70-100 mmHg in adults, 40-60 mmHg for neonates and small child. Pre pump pressure-up to -20 mmHg is acceptable. Delta pressure-it is the difference between pre and post oxygenator pressure it is strictly maintained as recommended in order preventing excessive haemolysis. It should be less than 300 mmHg 3.
Evidence of hypovolaemia in the form of fluctuating flow rates and 'shaking' of ECMO tubes 4.
Temperature-Core and peripheral 8.
Chest X-Ray

Technique for assembling ECMO
The VV ECMO circuit is connected in series to the heart and lungs. When we are using a single venous cannula, the access cannula extracts blood from the vena cava or right atrium, circulates through the extracorporeal circuit and returns the blood to right atrium via the return cannula.
In two venous cannula systems in VV ECMO (Figure 1), drainage occurs usually via the cannula placed in the common femoral vein and infusion of oxygenated blood continues through the right internal jugular or other femoral vein. The positioning of the cannula should also be taken into consideration in all the scenarios. Ideally the cannula tip, when using one venous cannula, should rest in the infra-diaphragmmatic part of IVC. The proximal opening should be positioned in the superior vena cava (SVC) or SVC-RA junction, thus directing the opening towards the tricuspid valve. Blood flow is set at 3-6L/min for acceptable oxygenation. Oxygen flow rates are set at twice the value. The circuit of VA-ECMO is assembled in parallel to heart and lungs. The cannulation is either central or peripheral type (Figures 2 and 3). The access cannula extracts venous blood from the large central veins or right atrium and after oxygenation in the membrane oxygenator; the pump returns the blood to a major artery. Central cannulation is performed at ascending aorta whereas femoral, axillary or carotid arteries are used during peripheral cannulation 12,13 Central cannulation is preferred approach in post-cardiotomy ECMO. The flow rates may vary from low flows of 2-3L/min to as high as 4-6L/min. This determines whether partial assistance to native circulation will suffice or is there a demand to totally replace the patient's cardiac output. Ideal site for cannula placement is in ascending aorta just above aortic valve. However we should avoid cannulating the same side of groin for arterial and venous access, as this may carry the risk of venous congestion due to femoral venous compression by the adjacent arterial cannula. As discussed previously, ECMO circuit is designed in such a manner that it can provide partial support as in asthma to total support in failing heart. The flow rates corrected to body surface area (BSA) are 3L/m2/min. The age based calculation of flow rates are: for neonates 100ml/kg/min; pediatrics 80ml/kg/min; adults 60ml/kg/min. Adequate systemic perfusion is best measured by venous saturation values targeted above 70%.

Management during ECMO
At the commencement of ECMO it is prudent to follow a checklist as mentioned in Table 3. Anticoagulation is monitored vigilantly. The ACT is measured every hour to titrate heparin infusion rate in the first 24hrs and there after every 6 th hourly over 24hr. Target ACT of 180-200sec is maintained in non-bleeding patient having platelet count >80,000/mm3. 14 After 24hrs, APTT is primarily used to guide heparin therapy with target values of 45-55sec. Continuous monitoring of the patient guides us on outcomes and prognosis. The essential monitoring parameters are listed in Table 4. Apart from these, general management can be protocolized based on institutional norms. The protocol in our cardiac surgical ICU is listed in Table 5. These patients should also be thoroughly investigated on a daily basis with CXR, ABG and hematology tests. Blood cultures are sent as required or at least thrice a week from existing lines or circuit.
Analgesics, sedatives, anticoagulants, and antimicrobial agents should be administered to patients receiving ECMO as required with special attention to pharmacokinetics. Hemodilution from ECMO initiation, drug sequestration within the circuit, altered protein binding, and end organ dysfunction may all influence the pharmacokinetics of particular drugs as being reviewed under the antibiotic   15,16 Volume optimization is crucial to support LV decompression and allow improved end-organ function and should begin immediately after VA ECMO support initiation, as more positive fluid balances in this period have been associated with worse outcomes. 17 Optimal fluid status may be achieved through diuretics or renal replacement therapy. If dialysis is required, dialysis filter is added directly to the ECMO circuit avoiding additional risks of cannulation.

Monitoring during ECMO
Constant and vigilant monitoring is necessary during ECMO care. The monitoring must include parameters for ECMO system and its effect on various vital organs of the patient. Different monitoring are mentioned in the Table 6.
Blood flow is monitored by ultrasonic detectors. The pre-oxygenator saturation is used to monitor the adequacy of tissue oxygen extraction. The post-oxygenator blood saturation and PaO 2 signify oxygenator function.

Echocardiography in ECMO
Transesophageal echocardiography (TEE) is a useful tool in initiation of ECMO. It guides in correct placement of guide wires and subsequently the cannula. Color flow Doppler using TEE imaging is used to demonstrate flow of blood at the tip of return cannula and side holes of the access cannula. Any turbulence will guide for repositioning the cannula (Figure 4). Cardiac functions can be monitored and any improvement should be documented during the conduct of ECMO. The prime focus of assessment during VV-ECMO is RV size and systolic function. The preferred views for assessing the same are the focused apical 4chamber view at end-diastole. The size is best estimated by measuring the maximal short axis dimension at the level of the base. Tricuspid annular plane systolic excursion (TAPSE) as a measure to RV systolic function can be assessed by using M-Mode at the tricuspid annulus level. The peak systolic integral of the tricuspid lateral annular plane should also be obtained using tissue Doppler imaging (RV TDI S'). During VA-ECMO, assessment of biventricular function and dimensions becomes prudent. Measurement of serial LV dimensions is helpful as any increase in dimensions is suggestive of stasis of blood flow within cardiac chamber. This acts as a guide to initiate or escalate inotropic support or need for other mechanical device to increase forward flow. While on ECMO support, position of the cannula should be constantly monitored as it will help in preventing inadvertent injuries to vital structures.

Medications, nutrition and special care 2.9.1. Sedation and analgesia
The goals of sedation and analgesia are to alleviate discomfort, avoid hypertension and prevent excessive movement in patients, while allowing for neurological evaluation and periodic interaction with family members. Deep sedation sufficient to inhibit respiratory movement is required initially. This requires an infusion of fentanyl or morphine, Midazolam and muscle relaxation (vecuronium or atracurium or cisatracurium) during cannulation, decannulation, surgical re-exploration and excessive movement

Medications
Vasopressors and inotropes should be adjusted to the desired hemodynamic for the patient. Negative fluid balance is adopted to reduce tissue edema by hemofiltration and frusemide infusion (0.2-0.3mg/kg/hr).Low dose dopamine (2-3mcg/kg/min) is occasionally preferred by some clinicians.
Antibiotics use to be followed as per the institute protocol. The adoption of wide range coverage for the organisms is essential due to the open sternum, ECMO cannula and tubes. No tubing or circuit should hang on the floor. Personnel handling the ECMO should have antiseptic hand wash and strict aseptic precautions. Antibiotic may be added separately to ECMO priming and circuit. No alcohol should be applied on the circuit as it can damage the circuit integrity

Nutrition
Enteral feeding is first choice. It retains integrity of gut mucosa, limit translocation of enteric bacteria into blood stream, reduce frequency of cholestasis and offers low cost. If not tolerated total parenteral nutrition (TPN) is to be initiated. Stress ulcer prophylaxis in the form of pantoprazole may be used.

Management of ventilation during ECMO
Mechanical ventilation depends on level/ flow of ECMO support. The ventilatory goals are FiO 2 weaned to <0.5, PIP < 30cmH2O, PEEP < 10-15cmH2O and respiratory rate 6-10bpm. All adjustments are to be performed as per ABG findings. In practice, an arterial PaO2 of 50-55mmHg or an oxygen saturation of 85-90% is acceptable. Patients with severe air leak from lungs benefit from CPAP.

Complications of anticoagulation
The activated clotting time (ACT) during ECMO support should be maintained between 200-250seconds. Risks of clot formation are observed if ACT is less than 200sec.Activated clotting time above 300sec increases risk of bleeding. The standby circuits should not be stopped rather recirculation continued to avoid stasis due to stagnation of blood. Use of blood and blood components may alter the coagulation level.

Weaning from ECMO
Weaning should be initiated when the disease process for which ECMO was initiated has sufficiently resolved such that patient can be safely and adequately managed with low amounts of ventilatory and inotropic support. There are no universally accepted weaning guidelines. While weaning from VV-ECMO, flow rates are maintained and patient's full ventilation is resumed. Oxygen supply to the oxygenator is turned off. After observing for hemodynamic/ respiratory stability for at least six hours, decannulation is performed.
In VA-ECMO, during weaning period ACT is maintained at >400sec to avoid clotting. Flow rates are decreased by one liter and LV function assessed using TEE. After providing a period of low flow of less than 1.5 liters/ min and exclusive mechanical ventilation, if patient remains stable, decannulation should be considered after 6h. Arterial cannula should be removed by open surgical procedure with vessel wall repair. Transesophageal echocardiography is a useful guide while weaning. During the period of trial of reduced blood flow to 1litre/min for 30 minutes, the goal should be to maintain left ventricular ejection fraction (LVEF)>25%, aortic VTI>12cm and TDI lateral S' >6cm/sec. Strain and strain rate calculation could also be a predictive marker for successful weaning. The aim should be an increase of 20% over baseline with concomitant increase of EF. 18

Complications during ECMO
The complications can either arise due to primary pathology or from ECMO condition [19][20][21][22] and are listed with the management in Table 7. There are complications specific to VV-ECMO like hypoxia or hypercarbia due to leakage, oxygenator failure and higher demand on flows. Complications specific to VA-ECMO are cerebral or coronary hypoxia, thrombus formation and cannulation related injuries like dissections. VV-ECMO has better outcomes as compared to VA-ECMO and should be preferred when permissible. Left Ventricular myocardial stunning during VA ECMO is observed in some patients with white lungs and distension of chamber. The treatment is unloading of LV and increasing coronary oxygen content. 23

Transport of a patient on ECMO
Role of ECMO in saving many lives is worth the efforts.
However not all centers are specialized in providing such a support and many patients need to be transported to specialized centers. Patients suitable for ECMO support are generally in critical condition with ventilator support and multiple ongoing therapies. There are two types of transport facilities: 1. Primary transport-assessment of the patient, cannulation and initiation of ECMO at the referring hospital followed by transport to the ECMO centre. 2. Secondary transport-transport of patient already on ECMO between different specialized centers.
Primary ECMO transport is briefly performed in the following order: 24 1. Call for help from the referring hospital and launch of mobile ECMO team 2. Arranging transport vehicle (ground ambulance, fixed wing aircraft, helicopters) with sufficient electrical supply for electrical equipments, oxygen supply, adequate lightning, suction and climate control 3. Composing the transport team as per the ELSO guidelines-cannulating physician, surgical assistant, ECMO physician, ECMO specialist and a transport nurse, respiratory therapist. If it is an international transport every member should carry valid transport and viable currency for emergency situations 4. Check list before initiating transport-disposable ECMO circuitry, spare emergency ECMO circuit, surgical equipment for cannulation, electrical cautery, blood products, devices for monitoring blood gases and anticoagulation monitoring, transport ventilator, infusion pumps, pharmaceuticals and patient monitoring devices. 5. After initiating ECMO at the referring centre, patient should be transported to the ECMO facility with utmost safety with time being of secondary importance. 6. The transport team must also be well versed with the management of complications, both anticipated and unanticipated, during such transports. The complications are summarized in Table 8.

The next generation ECMO
Major changes in technology have occurred in the past decade and the quest to achieve more is still on. There will be development of future generation of ECLS pumps which have advanced machinery for automation and servo regulation. The surface of the circuitry will inhibit platelet adhesion thereby decreasing the need for anticoagulation. The field is moving towards a portable extracorporeal gas exchange device. Also the choice of anticoagulant may switch over to direct thrombin inhibitors (DTI) such as Argatroban and Bivalirudin. 25 The long duration of ECMO support on patients who are awaiting transplant put burden on available resources as well need for more medical personals. We will be seeing a growth of ambulatory ECMO 26,27 where patient can be managed at home with some extra training.

E-CPR or ECMO supported CPR
This is defined as the implantation of VA-ECMO in a patient who experienced a sudden and unexpected pulse less condition attributable to cessation of cardiac mechanical activity. 28,29 E-CPR is recognized by both ELSO 30 and American Heart Association (AHA) guidelines in selected patients after cardiac arrest when the suspected etiology is potentially reversible. 31 It has demonstrated its superiority to conventional CPR in many retrospective studies 32 in the treatment of refractory cardiac arrest. However, despite the technicalprogress the acceptance is slow; as many ethical questions have to be addressed.

Implantable membrane lungs
These can be described as membrane devices that are attached by conduits directly to the circulation, either to the heart or peripheral vessels. They can be used as bridge to lung transplantation or as destination therapy. They can be utilized without blood pumps, depending either on pulmonary artery pressure or systemic blood pressure to drive blood through the membrane. 33 The application of such devices will transform the next generation of ECMO management. 34 It will be characterized by an awake and spontaneously breathing patient without systemic anticoagulation, and can be managed in general hospital or even at home.

Integrated ECMO
The ECMO circuit is combined with the CPB circuit and blood cardioplegia device (BCD) circuit and named as integrated ECMO ( Figure 5). The routine oxygenator is replaced by ECMO oxygenator. The integrated ECMO is used both in operation room and postoperatively in ICU. This model reduces the cost and time to setup ECMO circuit in the moment of emergent cardiopulmonary deterioration. This model is routinely used in authors' institute in management of regressed left ventricle patients.

Indian overview with ECMO
The perioperative clinical use of ECMO in India is stepping up gradually. The use is expanding from respiratory pathology to cardiac surgery, transplant, pulmonary alveolar proteinosis (PAP), management of poisoning, emergency resuscitation, transport of sick patient, organ donation and many more (Table 9).
ECMO has been successfully used for more than 19 years with fruitful outcomes in authors' institute. Initial application was limited to cases where weaning from cardiopulmonary bypass (CPB) failed following complex congenital heart diseases. However, there has been a paradigm shift with our understanding and application of ECMO. Teaching and training programs were initiated at the institute for training students about the principles and practices of ECMO.
Recent studies have reported data on outcomes of children with complex congenital heart disease weaned off on ECMO support after surgical repair. The authors have found a significantly increased survival rate in cases with planned integrated CPB-ECMO circuit ( Figure 5). We have initiated ECMO support as a bridge to transplant in patients in decompensated heart failure waiting for suitable donor to undergo heart transplant. Also it has been used in post heart transplant patients presenting with acute rejection with multi-organ failure. It has been successfully used in a patient with autoimmune PAP following renal transplant who presented with marked hypoxemia and was managed by whole lung lavage (WLL) under ECMO support. Recently it was used in patient with 28 weeks of gestation diagnosed with H1N1 influenza to provide respiratory support while waiting for fetal maturity. Apart from this it is being used in the department of pulmonary medicine in treating patients with ARDS not responding to conventional therapy with promising results. The publications related to perioperative clinical uses of ECMO from India are listed in Table no. 9. [35][36][37][38][39][40][41][42] Cost is the main hurdle in many of the indicated patients who are deprived of the benefit of ECMO support in India. Limited centers/ hospitals have the facility of ECMO. Trained personals still less in numbers. In India the patient survival is 40-50%, which is comparable with international standards. The innovation, research and economical support will boost the perioperative and routine use in India.

Conclusion
ECMO is an advanced life support system for pulmonary and cardiac diseases. Selecting the appropriate ECMO for the patient requires the clinical judgment. It should be used as a tool for reversible organ failure situation or as a bridge to transplantation or decision making. The establishment, maintenance and weaning should follow strict guidelines, monitoring, indications with involvement of trained personnel. Anaesthesiologist being the perioperative physician will come across in managing these patients and should play a leading active role. The developing countries like India are progressively using ECMO as a mechanical circulatory support. It needs dedicated centers and financial support for further technological development. The authors hope that with increase in knowledge in the perioperative use of ECMO, cardiac and pulmonary diseases can be better managed with improved outcome and survival in India in more number of patients

Source of Funding
None.

Conflict of Interest
None.