**4. Complications**

The use of ECMO for long-term support can lead to any number of complications. Although a multitude of complications can occur during long-term ECMO support, the typical complications are related either to cannulation, anticoagulation, concomitant organ failure, or infection. A meta-analysis by Cheng et al. reports complication rates on 1866 adult patients receiving ECMO as rescue therapy for the treatment of cardiogenic shock [18]. The rates of complications from this analysis are as follows: lower extremity ischemia—16.9%, lower extremity fasciotomy or compartment syndrome—10.3%, lower extremity amputation—4.7%, stroke—5.9%, neurologic complication—13.3%, acute kidney injury—55.6%, kidney injury requiring renal replacement therapy—46.0%, major bleeding—40.8%, re-thoracotomy for bleeding or tamponade—41.9%, and significant infection—30.4%. These complications are discussed below.

in ECMO patients may present as bleeding at cannulation sites (or at the sites of other vascular access), or may present as a retroperitoneal hematoma, mediastinal hemorrhage (especially in post-operative patients), cardiac tamponade, pulmonary hemorrhage, gastrointestinal (GI)

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Minor bleeding is defined by ELSO as a loss of less than 20 mL/kg/day of blood or a requirement of 10 mL/kg or less of PRBC transfusion per day. The most significant concern of minor bleeding events is progression to a major bleeding event, and thus these harbingers must be investigated. Any major bleeding event while on ECMO therapy is known to greatly increase

Thrombosis is a common occurrence and a concern for patients on prolonged ECMO therapy. Exposure of the patient's blood to foreign substances, non-physiological shear stress, endothelial injury, immobility, alteration of normal blood flows, and critical illness increases the risk of a thrombotic event. In order to mitigate this risk, most modern ECMO circuits are lined with antithrombotic surface coatings that reduce the risk of thrombosis. While cannulated, patients are typically anticoagulated with unfractionated heparin, although there is the risk of developing heparin-induced thrombocytopenia. For these patients, or other patients with a contraindication to unfractionated heparin, direct thrombin inhibitors or factor XIIa inhibitors should be used. Naturally, these options carry a risk of hemorrhagic complication, may be more difficult to titrate, and may pose difficulty in the reversal of anticoagulation if necessary

The development of thrombus not only occurs within the patient's native vasculature, but thrombus can develop throughout the ECMO circuit. Oxygenators, connectors, and stopcocks are needed for thrombus formation, due to disrupted local blood flow patterns, non-physiologic shear stresses, and foreign surfaces. Thrombus developed within the ECMO circuit can embolize, and cerebrovascular event such as ischemic stroke and limb ischemia secondary to

Cerebrovascular events, while on prolonged ECMO therapy can be devastating, leading to increased mortality, permanent neurological deficits, and, in bridge-to-transplant patients, loss of transplant candidacy. Any sudden change to neurologic function in the ECMO patient warrants further workup, including full neurological examination and imaging. If applicable, sedation should be weaned to facilitate accurate neurological examination. Cerebrovascular events can be broadly categorized into hemorrhagic or ischemic stroke. The prolonged exposure to therapeutic anticoagulation places these patients at an increased risk of hemorrhagic stroke [19]. As discussed, hemorrhagic stroke is classified as a major bleeding event, and

Despite therapeutic anticoagulation, patients are also at risk for ischemic stroke, as a result of thromboembolism. As discussed in the section on thrombosis, prolonged ECMO therapy

bleeds, intracranial hemorrhage, epistaxis, and hematuria, among others [18].

patient mortality [22].

for hemorrhage or procedures [22].

**4.4. Cerebrovascular events**

immediate management is necessary.

thromboembolism are of major concern [19].

**4.3. Thrombosis**

#### **4.1. Vascular complications**

Vascular trauma secondary to cannulation is highly dependent on the selected cannulation strategy. Complications such as perforation of major vessels and arterial dissection are serious issues that can lead to extensive local bleeding, retroperitoneal hematoma formation, and limb ischemia. Perforation of the right atrium is relatively rare, while perforation or dissection of the femoral vessels, subclavian vein, or carotid artery is the more common form of vascular trauma [19, 20].

Compartment syndrome of the cannulated limb can occur in a subset of patients. Secondary complications of compartment syndrome include, but are not limited to, limb ischemia, neurologic deficits, or amputation of the affected limb. The first line of treatment for compartment syndrome is an urgent fasciotomy of the affected limb to release the elevated pressure and restore tissue perfusion [18, 19, 21]. Often, it is the detection of compartment syndrome that is challenging, especially if the patient is intubated and sedated, as they cannot report the altered sensation. As such, it is prudent to document distal perfusion after cannulation with a pulse exam (and Doppler if necessary) and to reexamine at frequent intervals (every few hours by nursing). Laboratory signs such as an elevated lactate, creatine phosphokinase, or myoglobin may be suggestive of compartment syndrome, and further investigation may be necessary. Of note, measurement of compartment pressures often provides little clinical guidance.

Limb ischemia can occur in the absence of compartment syndrome and is a frequent complication of ECMO therapy. The presence of a cannula within an artery (especially with percutaneous femoral artery cannulation) may lead to inadequate distal perfusion. This inadequate perfusion is exacerbated by hemodynamic instability, the need for vasopressors, thromboembolism, compression of the femoral artery and vein, or vascular trauma during cannulation. This risk is mitigated by the usage of a distal perfusion cannula, which is a standard practice at many high-volume ECMO centers [20].

#### **4.2. Hemorrhage**

Despite widespread use of antithrombotic surface coatings on ECMO equipment, it remains standard of care that patients on ECMO are on therapeutic anticoagulation. In the majority of patients, unfractionated heparin is used to mitigate the risk of thrombotic events, with the subsequent increased risk of both minor and major bleeding events. The 2014 Extracorporeal Life Support Organization (ELSO) guidelines on anticoagulation therapy provide definitions of both major and minor bleeding events. Major bleeding events are defined as a drop in hemoglobin by at least 2 g/dL within 24 hours, loss of 20 mL/kg of blood within 24 hours, the requirement of at least one 10 mL/kg packed red blood cells (PRBC) transfusion within 24 hours, or the need for reoperation or re-cannulation secondary to bleeding [22]. Blood loss in ECMO patients may present as bleeding at cannulation sites (or at the sites of other vascular access), or may present as a retroperitoneal hematoma, mediastinal hemorrhage (especially in post-operative patients), cardiac tamponade, pulmonary hemorrhage, gastrointestinal (GI) bleeds, intracranial hemorrhage, epistaxis, and hematuria, among others [18].

Minor bleeding is defined by ELSO as a loss of less than 20 mL/kg/day of blood or a requirement of 10 mL/kg or less of PRBC transfusion per day. The most significant concern of minor bleeding events is progression to a major bleeding event, and thus these harbingers must be investigated. Any major bleeding event while on ECMO therapy is known to greatly increase patient mortality [22].

### **4.3. Thrombosis**

requiring renal replacement therapy—46.0%, major bleeding—40.8%, re-thoracotomy for bleeding or tamponade—41.9%, and significant infection—30.4%. These complications are

Vascular trauma secondary to cannulation is highly dependent on the selected cannulation strategy. Complications such as perforation of major vessels and arterial dissection are serious issues that can lead to extensive local bleeding, retroperitoneal hematoma formation, and limb ischemia. Perforation of the right atrium is relatively rare, while perforation or dissection of the femoral vessels, subclavian vein, or carotid artery is the more common form of vascular

Compartment syndrome of the cannulated limb can occur in a subset of patients. Secondary complications of compartment syndrome include, but are not limited to, limb ischemia, neurologic deficits, or amputation of the affected limb. The first line of treatment for compartment syndrome is an urgent fasciotomy of the affected limb to release the elevated pressure and restore tissue perfusion [18, 19, 21]. Often, it is the detection of compartment syndrome that is challenging, especially if the patient is intubated and sedated, as they cannot report the altered sensation. As such, it is prudent to document distal perfusion after cannulation with a pulse exam (and Doppler if necessary) and to reexamine at frequent intervals (every few hours by nursing). Laboratory signs such as an elevated lactate, creatine phosphokinase, or myoglobin may be suggestive of compartment syndrome, and further investigation may be necessary. Of note, measurement of compartment pressures often provides little clinical

Limb ischemia can occur in the absence of compartment syndrome and is a frequent complication of ECMO therapy. The presence of a cannula within an artery (especially with percutaneous femoral artery cannulation) may lead to inadequate distal perfusion. This inadequate perfusion is exacerbated by hemodynamic instability, the need for vasopressors, thromboembolism, compression of the femoral artery and vein, or vascular trauma during cannulation. This risk is mitigated by the usage of a distal perfusion cannula, which is a standard practice

Despite widespread use of antithrombotic surface coatings on ECMO equipment, it remains standard of care that patients on ECMO are on therapeutic anticoagulation. In the majority of patients, unfractionated heparin is used to mitigate the risk of thrombotic events, with the subsequent increased risk of both minor and major bleeding events. The 2014 Extracorporeal Life Support Organization (ELSO) guidelines on anticoagulation therapy provide definitions of both major and minor bleeding events. Major bleeding events are defined as a drop in hemoglobin by at least 2 g/dL within 24 hours, loss of 20 mL/kg of blood within 24 hours, the requirement of at least one 10 mL/kg packed red blood cells (PRBC) transfusion within 24 hours, or the need for reoperation or re-cannulation secondary to bleeding [22]. Blood loss

discussed below.

trauma [19, 20].

guidance.

**4.2. Hemorrhage**

at many high-volume ECMO centers [20].

**4.1. Vascular complications**

222 Advances in Extra-corporeal Perfusion Therapies

Thrombosis is a common occurrence and a concern for patients on prolonged ECMO therapy. Exposure of the patient's blood to foreign substances, non-physiological shear stress, endothelial injury, immobility, alteration of normal blood flows, and critical illness increases the risk of a thrombotic event. In order to mitigate this risk, most modern ECMO circuits are lined with antithrombotic surface coatings that reduce the risk of thrombosis. While cannulated, patients are typically anticoagulated with unfractionated heparin, although there is the risk of developing heparin-induced thrombocytopenia. For these patients, or other patients with a contraindication to unfractionated heparin, direct thrombin inhibitors or factor XIIa inhibitors should be used. Naturally, these options carry a risk of hemorrhagic complication, may be more difficult to titrate, and may pose difficulty in the reversal of anticoagulation if necessary for hemorrhage or procedures [22].

The development of thrombus not only occurs within the patient's native vasculature, but thrombus can develop throughout the ECMO circuit. Oxygenators, connectors, and stopcocks are needed for thrombus formation, due to disrupted local blood flow patterns, non-physiologic shear stresses, and foreign surfaces. Thrombus developed within the ECMO circuit can embolize, and cerebrovascular event such as ischemic stroke and limb ischemia secondary to thromboembolism are of major concern [19].

#### **4.4. Cerebrovascular events**

Cerebrovascular events, while on prolonged ECMO therapy can be devastating, leading to increased mortality, permanent neurological deficits, and, in bridge-to-transplant patients, loss of transplant candidacy. Any sudden change to neurologic function in the ECMO patient warrants further workup, including full neurological examination and imaging. If applicable, sedation should be weaned to facilitate accurate neurological examination. Cerebrovascular events can be broadly categorized into hemorrhagic or ischemic stroke. The prolonged exposure to therapeutic anticoagulation places these patients at an increased risk of hemorrhagic stroke [19]. As discussed, hemorrhagic stroke is classified as a major bleeding event, and immediate management is necessary.

Despite therapeutic anticoagulation, patients are also at risk for ischemic stroke, as a result of thromboembolism. As discussed in the section on thrombosis, prolonged ECMO therapy creates disturbances to blood flow, presence of a foreign body, endothelial injury, chronic illness, and non-physiologic shear stress—all of which increase the risk of thromboembolism. For patients on venoarterial ECMO, or in patients with an atrial septal defect or pulmonary arteriovenous malformation, thrombus from the ECMO circuit can travel to the systemic circulation and potentially embolize in the cerebral vasculature.

Development of biofilms and reduced antimicrobial penetration within the ECMO circuit are

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Like all patients with organ failure, patients requiring ECMO therapy for cardiac or respiratory failure are critically ill and are subject to ICU-related complications, deconditioning, and muscle wasting. In the earliest applications of ECMO, patients were highly sedated and immobilized. With technological developments and advancements in ECMO patient management, the once sedated ECMO patient has now been awakened and extubated. In the population of patients with respiratory failure, the awake ECMO technique showed promising results, with improved survival over sedated ECMO patients and mechanically ventilated patients. Currently, patients on ECMO frequently receive physical therapy, with ambulatory

Physical therapy in the ECMO patient begins with stationary strengthening and mobility exercises, performed supine while in their ICU bed. These typically consist of core strengthening, limb raises, and stretching. The patient is then progressed to exercises while sitting on their bed, with strengthening of their core and limbs, as well as sitting balance as a goal. When tolerating this, the patient can be transitioned to a chair to be out of bed for a period of each

Patients who cannot ambulate due to either preexisting mobility deficits or incompatible cannulation sites can exercise using a stationary bicycle or an upper body hand bike. In general, access of the femoral vessels limits the ability of patients to ambulate while on ECMO, and for the long-term ECMO patient, transition to other cannulation sites may be necessary. Notably, femoral cannulation is not an absolute contraindication to ambulation, and many centers

The approach to ambulatory physical therapy begins with patient preparation, with many centers electing to free the femoral vessels from cannulation as a first step. With adequate ECMO oxygenation, patients may then be extubated if possible; if patients are not candidates for extubation, placement of a tracheostomy can facilitate secretion management, weaning from the ventilator, and weaning of sedation. Following these preparatory procedures, the patient is ready to begin active physical therapy, culminating in ambulation. This is a resource-intensive task, requiring physicians, nurses, perfusionists, respiratory therapists, physical therapists, and assistants. Particular attention must be paid to cannula management,

Since the earliest use of ECMO for short-term life support, the technology has produced ethical dilemmas. The earliest ECMO systems exposed patients to significant risk of morbidity

ambulate patients on ECMO despite venous and arterial access to the femoral vessels.

day. With assistance, the patient on ECMO can stand and then ambulate [27].

as cannula dislodgement has significant adverse consequences [28].

**6. Ethical considerations**

factors which contribute to difficult treatment of these patients [18, 19, 25, 26].

**5. Rehabilitation**

physical therapy the goal for many patients.

Cerebral ischemia can also occur without embolus. In patients on venoarterial ECMO with blood return in the femoral artery, it is possible for the great vessels to receive poorly oxygenated blood from the dysfunctional lungs, while the remainder of the body is perfused by well-oxygenated blood from the ECMO circuit. This phenomenon, known as Harlequin syndrome, can lead to chronic cerebral hypoxia [23]. Like other cerebrovascular events, this condition warrants immediate investigation and remedy. There are multiple solutions to this inadequate mixing, ranging from repositioning of the arterial return cannula within the femoral artery, conversion to veno-venoarterial ECMO (which delivers oxygenated blood to the right atrium as well as the arterial circulation), central cannulation of the aorta, or operative cannulation of the subclavian vessels.

#### **4.5. Acute kidney injury**

Acute kidney injury (AKI) secondary to ECMO therapy is a relatively common occurrence and is associated with a fourfold increase in mortality when it progresses to chronic kidney disease or end-stage renal failure. The development of AKI is common in critical illness and the underlying disease process necessitating ECMO initiation places the patient at risk for AKI. Additionally, ECMO itself can exacerbate the progression of AKI, due to potential changes to renal perfusion, chronic inflammation resulting in renal injury, changes to endocrine homeostasis, as well as the risk of exposure to nephrotoxic substances during a period of prolonged critical care [24].

#### **4.6. Infection**

Patients on long-term ECMO therapy are at significant risk of infectious complications. The combined presence of critical illness, chronic blood-contacting medical devices, and an ICU stay greatly increase the likelihood of infection. Patients on long-term ECMO who develop a systemic infection have an increased mortality rate, possibility for loss of transplant candidacy, and increased complexity of care. Many patients decompensate to a level requiring ECMO as a result of an infectious process, with pneumonia a common presenting condition. Due to the presence of indwelling cannulae, bloodstream infection is a major concern in caring for the ECMO patient. For the long-term ECMO patient, prolonged exposure to nosocomial pathogens is of particular concern, as these pathogens are likely to exhibit multidrug resistance. Cannula site infections may also occur, which require re-cannulation at a distant site, as well as debridement and drainage of the infected cannulation site. Infection at a cannulation site places patients at risk for vascular complications, such as hemorrhage, hematoma, arteriovenous fistula formation, or development of an aneurysm or pseudoaneurysm. Treatment of the infected ECMO patient can be a particular challenge, and consultation with Infectious Disease specialists is often required. The gas exchange requirements of the ECMO circuit result in the development of a large surface area, which results in a large foreign attachment site for bacteria. Development of biofilms and reduced antimicrobial penetration within the ECMO circuit are factors which contribute to difficult treatment of these patients [18, 19, 25, 26].
