Extracorporeal membrane oxygenation (ECMO) has revolutionized the treatment of severe cardiac and respiratory failure, having undergone tremendous technological advances since the 1970s.1 Because of the myriad variations and modifications in ECMO devices, ECLS is a more appropriate term. Depending on the circuit configuration, venovenous (VV) or venoarterial (VA) modes could be employed. Venovenous ECLS is usually maintained beyond a week because of the natural history of severe acute respiratory distress syndrome (ARDS).2 The relatively longer duration poses problems, and understanding the interaction between the circuit and the patient’s cardiopulmonary system is crucial. This review aims to share our experience and knowledge in the management of adult respiratory failure using VV ECLS.
The earliest evidence for VV ECLS in respiratory failure was derived from observational studies and uncontrolled clinical trials.3–6 More recently, Australasian investigators had considerable success using ECLS during the 2009 H1N1 Influenza pandemic.7 Two studies from the United Kingdom have subsequently shown that transferring patients with severe but potentially reversible respiratory failure to a designated ECLS center may lead to better survival.8,9 Although the evidence for ECLS in H1N1-induced ARDS remains untested in a randomized control trial (RCT), it has been widely adopted, especially in younger patients with severe hypoxemia.10
Early paralysis and proning have gleaned some success in reducing ARDS mortality but the mainstay of treatment remains lung protective ventilation strategy.11,12 Even so, ARDS patients are at high risk of deterioration and death.13–15 Airway pressure release ventilation, a rescue ventilatory mode lacks conclusive evidence of benefit, while high frequency oscillation ventilation has been demonstrated by two RCTs not to have survival benefit.16,17 These findings somewhat galvanized the role of ECLS as a recourse in the treatment of refractory respiratory failure. Nevertheless, more evidence is needed to evaluate the actual impact of ECLS on mortality as compared with optimization of conventional strategies. This is the objective of the ongoing Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome (EOLIA) trial (NCT01470703).
Extracorporeal carbon dioxide removal has been used alongside an ultraprotective ventilation strategy using tidal volumes below 6 ml/kg of predicted body weight. Modest physiologic improvements have been observed but this has not translated into any tangible clinical outcome.18–21 The Strategy of UltraProtective Lung Ventilation With Extracorporeal CO2 Removal for New-Onset Moderate to seVere ARDS (SUPERNOVA) trial (NCT02282657) is underway to address its role in ARDS management.
Clinical Applied Physiology
Venovenous ECLS achieves its oxygenation effect by increasing oxygen saturation of hemoglobin before native gas exchange. This effect is thus measured by oxyhemoglobin saturation in blood reaching the pulmonary artery. Native lungs play an additional role in oxygenation, which in most disease states requiring ECLS is understandably small or negligible. There are four key determinants affecting pulmonary arterial oxygen saturation (SpaO2), 1) ECLS flow (FE), 2) recirculation (FR), 3) native cardiac output (CO), and 4) venous saturation (SvO2). Key physiological equations are elaborated below.
If we assume zero recirculation (FR = 0), the equation could be simplified as follows:
Finally, the patient’s SaO2 is dependent on SpaO2, and the interaction between the lungs and ventilator.
As we do not know the extent of recirculation, patient’s CO or SvO2, SpaO2 cannot be accurately determined. Nevertheless, the device delivers a fixed amount of oxygen in any setting. In other words, SaO2 changes during VV ECLS (provided settings remain unchanged) are caused by a limited number of anticipated factors, i.e., native CO, SvO2, and residual lung function (Figure 1).
The average metabolic carbon dioxide (CO2) production at rest in humans is 200 ml/min, and each 100 ml of blood passing through normal lungs removes only 4 ml of CO2. However, the efficacy in CO2 removal during ECLS far exceeds the lung; no more than 2 L of blood flow is needed to remove all metabolically produced CO2. If blood flow remains constant, sweep gas flow rate is the chief determinant in the inverse relationship between oxygenation and ventilation in the artificial lung.
Indications, Contraindications, and Timing of Application
Severe Gas Exchange Impairment
Venovenous ECLS indications include severe type I or II respiratory failure despite optimal mechanical ventilation. Clinical studies used PaO2/FiO2 (PF) ratios 50–80 on a high level of ventilatory support.7,9,10,22 Typical ventilatory parameters upon initiation are FiO2 >80%, and positive end-expiratory end pressure (PEEP) >10–15 cm H2O. Respiratory acidosis, commonly a corollary of low tidal volumes is another frequent indication. Venovenous ECLS must be considered when such physiologic derangements are first observed, as an ensuing short period of persistent dismal parameters (2–6 hours in studies) would warrant its use.22 Support must be readily available to ensure a prompt initiation when the need arises.
Any patient below 60–65 years old with a previously active life could be considered. Venovenous ECLS contraindications are generally relative. Specific contraindications are similar to those of lung transplantation, e.g., immunocompromised or severely malnourished state, thoracic empyema, and intractable disseminated infection. In young, previously healthy patients, the aim is a bridge to recovery or lung transplantation. Initiating ECLS in patients aged more than 60–65 poses a potential dilemma because of their immediate preclusion from lung transplantation. The physician should ideally possess a higher degree of certainty in disease reversibility in these patients. Other relative contraindications include conditions precluding an acceptable quality of life if the patient recovers (e.g., irreversible neurological injury, advanced malignancy with limited life expectancy), inability to tolerate anticoagulation, and a poor premorbid status.
However our predicted trajectory of a patient’s clinical course is not always correct, and physicians’ values and perception of life may differ from what is held by patients and families. Meaningful discussions between the medical team and the patient’s family are pivotal in preventing conflict that may arise from clinical decisions. Although we aspire to act in their best interest, we should not fail to acknowledge societal and cultural bearings, or beliefs held by patients and their families.
Timing of Initiation
The timing of VV ECLS initiation is intuitively crucial to the outcome of ARDS patients, who often experience a rapidly progressive course. However, the trigger point remains a contentious issue. The recommendations from Extracorporeal Life Support Organization (ELSO) (PF ratio <150 with FiO2 >0.7 and PEEP >10) are deemed by some to be too liberal and arbitrary, which may lead to unnecessary ECLS use.23 Some experts have deemed a lower PF ratio <100 to be a more appropriate trigger.24 The authors are of the opinion that the decision for VV ECLS initiation hinges not only on the severity of oxygenation impairment, i.e., PF ratio but also the anticipated clinical course. We agree that a PF ratio <100 is a reasonable trigger. However, we would not withhold VV ECLS in a patient with a PF ratio of 150, but whose clinical status is deteriorating rapidly and anticipated to pursue a precipitous trajectory. We use Figure 2—a hypothetical depiction of a patient suffering from ARDS and ventilator-induced lung injury (VILI)—to illustrate this point. The take-home message here is that a single cross-sectional reading such as PF ratio may be less useful than the trend of its trajectory. For example, if a patient’s PF ratio is 120 on day 7 of mechanical ventilation with a deteriorating trend since day 1, the intensivist could have anticipated with reasonable confidence at an earlier time point that the oxygenation impairment would eventually reach the VV ECLS threshold. In such an instance, we opine that earlier ECLS initiation could potentially reduce ongoing VILI and improve patient outcomes. Early consult with the ECLS team is advised in all cases where deterioration is deemed likely. This is to ensure that the flow of ECLS events—not unlike the Chain of Survival in cardiac arrest, from ECLS team notification to actual cannula insertion and circuit initiation—is timely and expedient.25
Clinical Strategies During VV ECLS
Mechanical Ventilation and Tracheostomy
The main indication for VV ECLS is ARDS that has failed conventional therapy.26 Therefore ventilatory settings must be adjusted to a minimum level after initiation to reduce further VILI.27 No evidence-based guidelines exist but reasonable targets are low FiO2, tidal volumes not exceeding 6 ml/kg of predicted body weight, peak plateau pressure <30 cm H2O, and a PEEP of 5–15 cm H2O. An ultraprotective ventilation strategy using tidal volumes as low as 3 ml/kg appears promising, but we await the SUPERNOVA trial to determine its efficacy.19
As most patients would be paralyzed and proned before ECLS, we suggest neuromuscular blockade be continued no longer than 48 hours. A short duration of paralysis may minimize VILI in the early phase of ARDS but prolonged paralysis would lead to longer times spent on controlled ventilation modes, protracted deep sedation, and continued immobilization. Diaphragmatic atrophy and muscle wasting ensue, and chronic disuse may lead to ventilator dependence.28–31
The beneficial physiologic effects of proning are well studied. Acute respiratory distress syndrome predominantly affects dependent parts of the lungs, resulting in a preferentially higher dorsal to ventral pleural pressure ratio when the patient is supine. Proning counteracts this phenomenon via a more even distribution of transpulmonary pressure across the lungs; ventral alveoli experience less overdistension while dorsal ones undergo less atelectasis.32 It was not until recently that proning was shown to have mortality benefit in a patient subgroup with severe ARDS.33 Insufficient evidence exists to recommend routine proning in VV ECLS patients because of their exclusion from the Effect of Prone Positioning on Mortality in Patients With Severe and Persistent Acute Respiratory Distress Syndrome (PROSEVA) study. Proning would entail continued neuromuscular blockade, which we advise against in favor of prompt awakening and liberation from mechanical ventilation, followed by early physical therapy. Finally, concerns abound over potential kinking and dislodgement of vascular cannulas although previous studies reported no adverse events.34–36
Patients should be assessed for liberation from mechanical ventilation using a protocolized approach with daily sedation cessation and suitability assessment to undergo a spontaneous breathing trial.33,37 The ideal outcome is early, successful liberation—resulting in so-called awake EMCO but this strategy was largely studied in patients on ECLS as a bridge to lung transplantation.38 Unfortunately, this is often unachievable in reality. Tracheostomy, performed after a short interruption in anticoagulation, appears to be safe.39 If liberation is an unlikely clinical outcome in the next 5–7 days, we perform early tracheostomy to alleviate patients’ discomfort from the endotracheal tube, reduce the amount of sedatives or analgesics required, and facilitate early intensive care unit (ICU) mobilization and rehabilitation.
Management of Hypoxemia on Extracorporeal Life Support
There is no widely accepted SaO2 target during VV ECLS. Recommendations range from ≥80% to >88%.23,24 As every patient’s hypoxic threshold differs, any target is at best arbitrary and should be tailored to the clinical and physiological status. We believe that “less is more” in ECLS management, which explains why we often tolerate SaO2 levels <80% in stable patients, obviating relentless troubleshooting that may cause more problems. More importantly, we should take caution in avoiding sudden rapid decreases in PaCO2 (deemed to be more than 27 points in the study) after initiation because of an observed association with intracranial bleeds.40 However, in an attempt to simplify concepts for a general readership, we have chosen a minimal SaO2 target of 80%.
In practice, we assess hypoxic intolerance via clinical and physiological parameters, e.g., mental status, respiratory rate, and lactate. Cerebral tissue oxygenation monitoring via near-infra red spectroscopy may be helpful but more evidence is needed before its use becomes routine.41,42 Two crucial points exist in the timeline of a VV ECLS patient whereby hypoxemia is commonly encountered. The first occurs immediately after ECLS initiation with a failure to achieve a desired SaO2 target, while the next is an unexpected SaO2 deterioration in a previously stable ECLS patient.
We have devised two algorithms (Figures 3, 4) to illustrate our proposed management. In Figure 3, the post-ECLS SpO2 target is set according to the depth of sedation, and the flow is titrated to 60 ± 20 ml/kg/min, which roughly estimates 60% of the CO.43 If the desired SaO2 could not be achieved, preoxygenator blood gas analysis is done to exclude significant recirculation. Hypovolemia is also excluded before cannula manipulation. In the absence of excessive recirculation, a trial of increasing the pump revolutions per minute (RPM) and observing the SaO2 response could determine if drainage insufficiency is indeed the problem.
Figure 4 summarizes the approach to SaO2 deterioration in a patient previously stable on VV ECLS. This algorithm aims to delineate the causes of hypoxemia, which include drainage insufficiency, oxygenator failure, increased CO, worsened lung function, and decreased SvO2. However, this algorithm only serves as a guide. In practice, we often avoid using a neuromuscular blocking agent or beta-blocker because of concerns over prolonged ventilation or unwanted hypotension. Our unit also abides by a conservative transfusion practice of not giving blood to patients with a hemoglobin level of ≥7 g/dl.
A few cannulation strategies are commonly employed in VV ECLS. Dual and single cannulation are performed percutaneously these days.44 The former uses two cannulas (drainage, return) in a femoro-jugular or femoro-femoral configuration while the latter only needs a single bicaval dual lumen cannula, thus obviating the need for a second venous puncture. It must be mentioned that the single bicaval dual lumen cannula is not readily available in Korea. However, the authors’ experience with this cannula in the United States and Singapore have frequently been marred by inadequate flow capacity and consequently, suboptimal oxygenation. Moreover, the significantly higher cost and increased technical difficulty in insertion are factors limiting a widespread clinical uptake of this cannula.45 While it may seem intuitive that a femoral cannula in situ would preclude patient mobilization, a study performed at our center has demonstrated that physiotherapy and mobilization are feasible and safe for patients with femoral cannulas.46
The femoro-jugular configuration consists of a long venous drainage cannula inserted into the femoral vein, and a short arterial return cannula into the right internal jugular vein. It is conventional wisdom to position the tip of the drainage cannula near the junction of the inferior vena cava (IVC) and the right atrium (RA), i.e., intrahepatic IVC to reduce venous collapse around the cannula. Similarly, the return cannula tip is located at the junction of the superior vena cava (SVC) and RA, or just distal to it in the RA. The cavo-atrial direction of blood flow (blood is drained from the IVC and returned to the RA) is preferred as the opposite has been shown to have significant recirculation problems in early adult ECLS studies.47
The femoro-femoral approach entails the insertion of two long venous cannulas into bilateral femoral veins. This configuration is less preferred because of a higher incidence of recirculation.48 By convention, the drainage cannula is also situated within the intrahepatic IVC, and the return cannula within the RA. Traditionally, a minimum distance of 10 cm between the cannula tips has been advocated. However, it is our routine practice (regardless of configuration) to position both the drainage and return cannula tips within the RA, just distal to the junction between the SVC or IVC and the atrial cavity. We opine that the 10 cm distance recommendation is arbitrary and suffers from imprecision of two-dimensional estimation. In our practice, recirculation rarely poses a significant problem even when cannula tips lie within the RA nearer to each other than what is advised. We postulate that recirculation is less likely when the drainage cannula is located within a cardiac chamber as compared with a large vessel, i.e., IVC, SVC because of the larger denominator blood volume. Extracorporeal life support cannulas are sized in French units (F) based on their external diameters, and available sizes come in even or odd numbers depending on the manufacturer. The authors strongly advocate three essential principles in VV ECLS cannulation. First, the drainage cannula must be sufficiently large to meet the patient’s clinical demands. A rough guide would be >24 F in an adult patient of body surface area >1.8 m2, and 21–24 F for most others. In comparison, the size of the return cannula is less crucial in VV ELCS compared with VA ECLS. An 18 F cannula would often suffice in most circumstances. This is because the cannula afterload is markedly higher in VA ECLS compared with VV ECLS, i.e., mean arterial pressure versus central venous pressure. Second, as explained earlier, our preferred drainage cannula tip position is in the RA rather than the intrahepatic IVC. We believe this seemingly insignificant technical point plays a pivotal role in ensuring a stable ECLS flow subsequently. As PEEP is usually lowered after ECLS initiation to minimize further VILI, alveolar derecruitment may cause a dramatic fall in both intrathoracic pressure and end-expiratory lung volume, and finally resulting in a relative downward migration of the cannula tip. If the tip had initially been within the intrahepatic IVC, its eventual position would likely be much lower down in the IVC. Drainage flow restriction because of suck-down of the cannula may ensue and manifest as line chattering at the bedside. This would trigger a reflexive fluid challenge, which may be detrimental in ARDS, especially if too many repeated fluid boluses are administered.49 Third, the choice of either a femoro-jugular or femoro-femoral configuration has to be individualized. The former may be preferred because of less recirculation and easier physical mobilization. Nonetheless, great caution should be exercised when accessing the internal jugular vein in any of the following circumstances: 1) severe hemodynamic instability, 2) extremely high PEEP setting on the ventilator, and 3) a body mass index at or beyond the extremes of the ideal range. Well-recognized complications such as an iatrogenic pneumothorax or hematoma could prove lethal in such instances. As a rule of thumb, we routinely perform femoro-femoral cannulation in non-ICU environments, semi-emergent situations, e.g., mobile retrieval from another hospital, or cases whereby the anatomy is unfavorable for safe internal jugular vein puncture.
Cessation of Sedation and Early Mobilization
Early mobility reduces length of ICU/hospital stays, and improves functional outcomes at discharge.50 Sedation cessation allows early mobilization and rehabilitation, which has been shown to benefit ECLS patients awaiting lung transplantation.51,52 Physical therapy and rehabilitation during ECLS have also been demonstrated to be feasible and safe.46 As shown in Figure 5, a patient not under heavy sedation could experience a desired clinical course whereby ECLS is easily weaned off. In contrast, prolonged mechanical ventilation results in ongoing muscle loss, critical care neuropathy, and delirium. Chronic ventilator dependence and institutionalization may ensue, increasing ventilator-associated events further. Early rehabilitation is instinctively a superior option as compared with rehabilitation in an impoverished and ventilator-dependent patient.
Pharmacokinetics and Drug Dosing
Critically ill patients experience significant pharmacokinetic (PK) changes because of physiologic insults arising from various etiologies.53 Hemodynamic derangements, capillary leak, and hypoproteinemia render drug levels and therapeutic effects unpredictable. By introducing an external circuit, ECLS complicates the issue by affecting the volume of distribution (Vd) of both hydrophilic and lipophilic drugs.54 Volume expansion from circuit priming, infusion fluids, and blood transfusions results in hemodilution, leading to an increased Vd in hydrophilic drugs. In contrast, the Vd of lipophilic drugs is increased because of sequestration by the circuit.55–57
It is important to keep drug levels optimal during ECLS as infective pneumonias are the commonest cause of ARDS.58,59 Most studies investigating PK changes during ECLS were done in neonates, and data in adults remain scant.54,55 A study using ex vivo ECLS circuits found that sequestration was most significant for fentanyl and midazolam, with 70% and 50% of drugs lost respectively in the first hour of initiation.57 In comparison, morphine levels remained stable. Meropenem was observed to degrade at 4 hours in whole blood at physiologic temperatures, with further drug loss noted when antibiotic-infused blood traversed the circuit. Vancomycin was relatively unaffected by sequestration but a study by our group found that vancomycin trough levels often do not reach desired therapeutic levels under in vivo conditions.60 Oseltamivir dosing is not affected by the circuit.61 The ASAP-ECMO study will examine the PK alterations to commonly used sedatives, analgesics, and antibiotics in ECLS patients.62 Meanwhile, it would suffice to say that the effects of morphine may be more predictable than fentanyl, and when using meropenem, higher or frequent dosing may be required to maximize its concentration-dependent bactericidal effect. Similarly, a higher vancomycin loading dose or a shortened initial dosing interval may be necessary.
Because of exposure of blood to large areas of nonendothelial surfaces during ECLS, the resulting inflammation activates the coagulation cascade and predisposes to thrombosis. Unfractionated heparin (UFH), the most commonly used anticoagulant, exerts its effect by combining with serine protease inhibitor antithrombin to inactivate activated coagulation factors (free thrombin and factor Xa).63, 64 It is inexpensive, widely available, and its short half-life of 60 minutes with the availability of an antidote (protamine) makes it ideal in ECLS patients who may often need emergency procedures or surgeries. Interindividual variability in the levels of antithrombin and heparin-neutralizing plasma proteins (e.g., histidine-rich glycoprotein and platelet factor 4), and differences in metabolism rates of the liver and reticuloendothelial system unfortunately render UFH to manifest a highly variable dose-dependent relationship.65 It is common practice to maintain an activated clotting time (ACT) or activated partial thromboplastin time (aPTT) 1.5–2 times of normal. A blood conservation protocol using low dose anticoagulation that targets an aPTT between 40 and 60 seconds has also been described to be safe.66 Heparin-induced thrombocytopenia (HIT) is a rare complication reported in up to 5% of patients, and screening tests have an unacceptably high false-positive rate while confirmation tests, i.e., HIT antibody assay, serotonin release assay are very costly.67 As the latter tests are not available at most centers including our own, we act on a positive HIT screening test only if there is clinical evidence of thrombosis. Our experience with HIT is that patients have a tendency to present with premature oxygenator failure—defined as thrombotic device occlusion or poor gas exchange within 2 weeks of use. Management of HIT includes prompt cessation of heparin and transition to a direct thrombin inhibitor, i.e., argatroban.
Interest in using direct thrombin inhibitors, i.e., argatroban and bivalirudin as first line anticoagulants is growing. These novel drugs selectively bind to circulating and clot-bound thrombin but not other plasma proteins. This direct mechanism of action renders antithrombin levels irrelevant, resulting in more predictable PK and better efficacy. Cons include a purportedly higher cost, lack of a tested reversal agent, and potential side effects, i.e., headache, nausea, cardiac arrhythmias, and hemodynamic instability. The therapeutic index of UFH/DTI is still commonly monitored via ACT or aPTT.
Traditionally, weaning from VV ECLS is considered once acceptable ventilator settings could be achieved without ECLS support. However, ongoing ECLS complications, i.e., bleeding and infection, may necessitate expedient weaning or more commonly, weaning under marginal or borderline conditions. One must anticipate all possible trajectories after weaning; discussions with the patient and family regarding management in the event of deterioration must be established preemptively. Adequate oxygenation (PaO2 >70 mm Hg) and ventilation (PaCO2 <50 mm Hg), and an acceptable acid-base status (pH >7.3) while on moderate ventilator settings (FiO2 <60%, PEEP <12) without exceeding injurious thresholds for tidal volumes and plateau pressures are some prerequisites. Cessation of sweep gas is the simplest example of a weaning trial.
At our center, the weaning trial entails 1) reducing blood flow to an idle rate, e.g., 2 L/min, and 2) clamping/disconnecting the tubing to the oxygenator as oxygen can sometimes leak around the flow meter despite being turned off. Decannulation is jointly decided by the primary and ECLS teams. Manual compression or a simple skin suture would usually suffice for removal of a venous cannula. When removing the cannula from the internal jugular vein, the Valsalva maneuver is recommended to reduce the risk of air embolism.
Venovenous ECLS has impacted greatly on the management of adult respiratory failure. Technological advances and growing experience during viral outbreaks have popularized its usage. However, an increased uptake of technology does not necessarily equate to improved overall clinical outcomes. As the Chinese adage goes, a bad workman blames his tools. Similarly, if success is desired, it is imperative that the ECLS physician has a thorough understanding of the complexities behind this tool that he wields.
The authors thank Su Hyun Cho, RN, for her invaluable comments on our study.
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