Artificial Lungs for Lung Failure in the Era of COVID-19 Pandemic: Contemporary Review

Abstract

In patients with severe acute respiratory distress syndrome caused by coronavirus 2019 (COVID-19), mortality remains high despite optimal medical management. Extracorporeal membrane oxygenation (ECMO) has been widely used to support such patients. ECMO is not a perfect solution; however, there are several limitations and serious complications associated with ECMO use. Moreover, the overall short-term mortality rate of patients with COVID-19 supported by ECMO is high (~30%). Some patients who survive severe acute respiratory distress syndrome have chronic lung failure requiring oxygen supplementation, long-term mechanical ventilation, or ECMO support. Although lung transplant remains the most effective treatment for patients with end-stage lung failure from COVID-19, optimal patient selection and transplant timing for patients with COVID-19-related lung failure are not clear. Access to an artificial lung (AL) that can be used for long-term support as a bridge to transplant, bridge to recovery, or even destination therapy will become increasingly important. In this review, we discuss why the COVID-19 pandemic may drive progress in AL technology, challenges to AL implementation, and how some of these challenges might be overcome.

BACKGROUND

When outbreaks of the novel severe acute respiratory syndrome coronavirus 2 evolved into the worldwide coronavirus 2019 (COVID-19) pandemic, there were huge impacts on healthcare systems. Total case numbers had reached 600 million as of November 1, 2022.¹ Many patients with COVID-19 developed severe acute lung failure requiring mechanical ventilation. The mortality of these patients remains high despite advances in medical management.^2,3 Extracorporeal membrane oxygenation (ECMO) has been widely used for patients suffering from severe acute respiratory distress syndrome (ARDS).^4,5 However, ECMO is not a perfect solution to ARDS because there are several limitations and complications associated with ECMO use. Moreover, the short-term survival rates for patients supported by ECMO for ARDS as a result of COVID-19 have been low.^6–8 Additionally, some patients who survive ARDS have chronic lung failure requiring oxygen supplementation, long-term mechanical ventilation, or long-term ECMO support.

The pathophysiology of chronic lung failure caused by COVID-19 is not fully understood. There are 2 etiologies of COVID-19-related lung failure: COVID-related acute respiratory distress syndrome (CARDS) and post-COVID pulmonary fibrosis (PCPF).⁹ The characteristics of patients with lung failure caused by COVID-19 are not necessarily identical to the characteristics of patients with traditional indications for advanced lung failure therapies such as lung transplant or mechanical respiratory support. Concerns include thromboembolic events, involvement of cardiovascular system, relapse or reinfection of COVID-19, difficulty in diagnosing irreversible lung damage, pretransplant deconditioning because of severe respiratory failure, and multiorgan dysfunction because of severe infection. Although the vaccines against COVID-19 provide protection against COVID-19 infection and severe illness, COVID-19 has remained a global health challenge because of viral mutation and a lack of definitive treatments.^10,11 Furthermore, improvements in survival after acute COVID-19 could lead to an increasing number of patients suffering from chronic lung failure.

PURPOSE OF THIS REVIEW

Given the circumstances caused by the COVID-19 pandemic worldwide, an artificial lung (AL) that is specifically designed for long-term use in patients with lung failure caused by COVID-19 will become increasingly important. Research on ALs for long-term use has been advancing rapidly; however, there are several obstacles that must be overcome to develop an AL for clinical use. Moreover, issues that are unique to COVID-19 must be overcome. Additionally, the lessons learned from COVID-19 pandemic may be applied to lung failure caused by other viral infection. In this review, we discuss why the COVID-19 pandemic may drive progress in AL technology, challenges to AL implementation, and how some of these challenges might be overcome.

WHAT IS AL?

AL is a device system that supports oxygenation and carbon dioxide removal in patients with acute or chronic lung failure in the broadest sense. This includes cardiopulmonary bypass for open heart surgery, extracorporeal carbon dioxide removal for patients with hypercapnia,¹² extracorporeal lung support system (ie, ECMO), paracorporeal lung support system,^13,14 and implantable lung support system (still under development).^15,16

Since the first successful open heart surgery with cardiopulmonary bypass in the 1950s,¹⁷ systems evolved over the decades and membrane oxygenators were introduced in the 1970s.¹⁸ Membrane oxygenators used in open heart surgery account for the majority of ALs in current clinical use.¹⁹ Improvement and advances in membrane oxygenators enabled ECMO to be used for days to weeks outside the operation room.²⁰ Thanks to positive outcomes of ECMO, extracorporeal ventricular-assist device (VAD), paracorporeal VAD, and implantable VAD in the field of heart failure,^21,22 interest in long-term ALs has increased. Indeed, paracorporeal ALs have been successfully placed in patients.^13,14,23 Further development of technology may make implantable ALs a possible analogue of implantable VADs.

ACUTE LUNG FAILURE CAUSED BY COVID-19

Indication for Mechanical Circulatory and Respiratory Support

ECMO has been used to support patients with ARDS refractory to medical management. Indications and parameters for ECMO necessitated by COVID-19 were initially based on the previous literature and prior experiences with ECMO for ARDS necessitated by H1N1 influenza infection and other causes.^4,5,24,25 Although ECMO has an important role in treating certain patients with CARDS, short-term mortality is still high in this population (30%–40%).^8,26 Moreover, there are significant complications related to ECMO support. Because there has not been a randomized controlled trial of ECMO support in patients with CARDS, appropriate patient selection criteria remain controversial. The Extracorporeal Life Support Organization published the guidelines for ECMO in patients with COVID-19.²⁷ In general, patients who still exhibit respiratory failure after conventional therapies for ARDS, including mechanical ventilation with a lung protective strategy and prone positioning, are considered as candidates for ECMO. Once ECMO is indicated, ECMO installation should not be delayed because delayed ECMO initiation and prolonged exposure to mechanical ventilation before ECMO may lead to worse outcomes or longer duration ECMO support.^26,27 Exclusion criteria or contraindications for ECMO vary from hospital to hospital, and ECMO initiation should be considered on a case-by-case basis. Major contraindications include age >65 y old, mechanical ventilation support >7 to 10 d, the inability to receive anticoagulation, immunocompromise, multiple organ failure, and life expectancy of <5 y. ECMO should not be considered in facilities without experienced medical staff.

Types of Mechanical Support for Acute Decompensated Lung Failure

Venovenous ECMO

Venovenous ECMO (VV-ECMO) comprises >90% of mechanical support for CARDS.^26,28 VV-ECMO is indicated in the patients without significant heart dysfunction or significant pulmonary artery hypertension. There are 2 primary configurations used for cannulation. The first is a conventional, 2-site cannulation strategy. The other is 1-site cannulation strategy using a double-lumen cannula. In many patients, the right internal jugular vein is cannulated for outflow, and the common femoral vein is cannulated for inflow. Cannulation can be done at the bedside using ultrasound guidance for the first puncture. The clinicians do not need to bring the patient to the catheterization laboratory or operation room, which lowers both the risk of viral spreading and the risk of their respiratory condition worsening during transport. On the contrary, blind cannulation increases the risk of cannula migration or vessel injury, which can be lethal. Furthermore, groin cannulation is associated with a higher rate of cannulation site infection and makes it more challenging for cannulated patients to sit in a chair or ambulate. Changing the cannulation site or switching to a double-lumen cannula should be considered in patients supported by ECMO for a long duration. The 1-site cannulation strategy requires fluoroscopy or transesophageal echocardiography guidance for placement. Only the right internal jugular vein is cannulated, which allows the patient to get out of bed, sit, and even ambulate, and decreases the risk of cannulation site infection by avoiding groin cannulation. ECMO-related complications also include thromboembolism and bleeding. Systemic anticoagulation therapy is used to prevent clot formation in the ECMO circuit. However, thromboembolic events or bleeding complications can happen even when anticoagulation is administered within the established therapeutic range. Moreover, a hypercoagulation state caused by COVID-19 can make anticoagulation therapy difficult.^11,27,29 A higher range of partial thromboplastin time (PTT) or a higher flow rate through the ECMO circuit should be considered to decrease the risk of thrombosis and the risk of oxygenator failure. On the contrary, a higher PTT goal can increase the risk of bleeding including the risk of intracranial hemorrhage,^30,31 and higher rotational speed of the ECMO pump can worsen blood damage including increased degradation of von Willebrand factor multimers and hemolysis.^32,33 Schmidt and colleagues⁸ reported a case series of ECMO support for CARDS during an early stage of the pandemic. Major bleeding occurred in 42% of the patients, and hemorrhagic stroke occurred in 5%.

Venoarterial ECMO

Unlike ARDS caused by other viruses (eg, H1N1 influenza and Middle East Respiratory Syndrome), myocardial involvement after COVID-19 infection is a well-documented occurrence.³⁴ Myocardial involvement can lead to fulminant myocarditis with cardiogenic shock.^35,36 Other causes of cardiac complications include stress-induced cardiomyopathy, acute coronary syndrome due to thromboembolism, pulmonary embolism, and right-sided heart failure because of pulmonary hypertension. Patients with reduced heart function and severe pulmonary hypertension are considered for venoarterial ECMO (VA-ECMO) to support both respiration and circulation. The benefits of VA-ECMO use in patients with septic shock and vasodilatory shock are not clear, and the indications for VA-ECMO should be carefully considered for those patients.

VA-ECMO is typically installed peripherally via the femoral artery and vein. A distal perfusion catheter is often inserted to reduce the risk of limb ischemia on the cannulation side of the arterial perfusion (outflow) cannula.^26,28 Additional concerns associated with peripheral VA-ECMO include arterial injury requiring a new cannulation site and vascular repair, leg ischemia, central hypoxia, limited ambulation because of groin cannulation, and increased left ventricular afterload that precludes recovery of the left ventricle.³⁷ These VA-ECMO-specific complications might be linked with the higher mortality observed with VA-ECMO support as compared with VV-ECMO.^26,28

Right Ventricular-assist Devices With an Oxygenator

Increased right ventricular afterload caused by ARDS and thromboembolic disease and decreased right ventricular contraction because of myocardial involvement of COVID-19 can cause right-sided heart failure. A right ventricular-assist device with an oxygenator (RVAD-Oxy) can be installed peripherally in patients with right-sided heart failure without significant left-sided heart failure using either a 1-site or 2-site cannulation strategy. RVAD-Oxy supports the right side of the heart by draining blood from the right atrium and perfusing it into the pulmonary artery. A long, dual-lumen cannula (PROTEK Duo cannula, CardiacAssist, Pittsburgh, PA) can be placed via the right internal jugular vein to the pulmonary artery for single-site cannulation.^38,39 It is more technically challenging than ECMO cannulation because the tip of the cannula must be placed in the main pulmonary artery. There is also a risk of injury to the right ventricle or pulmonary artery by the maneuver. The other complications associated with RVAD-Oxy are the same as for ECMO support.

CLINICAL COURSE AFTER ACUTE LUNG FAILURE

Some survivors of the acute phase of CARDS are weaned from ECMO support and decannulated. Many of these decannulated patients recover fully⁴⁰; however, some patients still require oxygen supplementation, tracheostomy, and hospital stay. The other survivors require long-term ECMO support. The longer they are on ECMO support, the more the risk of complications increases.

Some patients suffer from chronic lung failure after surviving the acute stage of COVID-19 illness. End-stage lung failure in patients with COVID-19 may be the result of multiple factors including nosocomial pneumonia, ventilator-induced lung injury, microvascular thromboembolism, pulmonary embolism, and severe pulmonary fibrosis because of significant inflammation. Histopathological findings in lungs damaged by severe COVID-19 include diffuse interstitial fibrosis, focal microscopic honeycomb changes, and extensive lung infarction with diffuse alveolar damage, fungal or bacterial infection, and microthromboembolism.^41–43 Currently, lung transplantation is the only definitive treatment option for severe, irreversibly damaged lung tissues.

LUNG TRANSPLANTATION FOR COVID-19–RELATED LUNG FAILURE

Lung transplantation is an option for some patients with acute lung failure (CARDS) or chronic lung failure (PCPF) caused by COVID-19.^41,42,44 As of October 2022, a total of 140 lung transplants for CARDS and 74 lung transplants for PCPF had been performed in North America, according to the United Network for Organ Sharing (UNOS).⁴⁵ Roach et al⁴⁵ reported posttransplant outcomes using data from the UNOS registry. In their study, 7% of lung transplants from August 2020 to September 2021 were performed for COVID-19–related lung failure. Of those, 4.6% were for CARDS and 2.4% for PCPF. Short-term outcomes were comparable with the outcomes of lung transplant for the other underlying etiologies.

Patient selection criteria, optimal timing, and outcomes of lung transplantation in this population are still unclear, and further studies are essential for appropriate decision-making. Early lung transplant could lead to worse outcomes because of the recipient’s critically ill condition. Deconditioning from the severe illness caused by COVID-19 has a negative impact on outcomes after lung transplant.⁹ Allowing sufficient time for the lung recovery and rehabilitation may not only prevent unnecessary lung transplant but also facilitate quicker recovery if a lung transplant is necessary. Although the time necessary for lung recovery is unclear, it is evident that it can take several months.^40,44 On the contrary, long-term ECMO support increases the risk of complications. Given this dilemma, access to a mid-to-long-term AL device with a lower complication risk may be advantageous and has garnered great interest.

THE PROMISE OF AN AL FOR COVID-19–RELATED LUNG FAILURE

Ideal ALs and Future Direction

Ideally, AL technology could be used as a bridge to recovery (BTR), bridge to transplant (BTT), or destination therapy (DT) in patients with COVID-19–related lung failure (Figure 1). Giving a patient time to recover from acute or acute-on-chronic lung failure using mechanical support is defined as a BTR strategy. BTR is applied to most patients with lung failure because of COVID-19 because the most common etiology is the acute viral infection. A BTT strategy is defined as supporting a patient who does not recover from lung failure while using a mechanical support device and remaining on support while waiting for a suitable organ donor and a successful lung transplant. According to the UNOS registry, 64.5% of the patients who underwent lung transplant for lung failure with COVID-19 were supported by ECMO as a BTT.⁴⁵ Once patients are no longer contagious and isolation for COVID-19 is discontinued, physical therapy is required to recondition the patients. Although ECMO support can allow for improvement in a patient’s clinical condition and enables some patients to be involved in aggressive physical therapy, patients still need to stay in the intensive care unit to access adequately trained medical staffs and resources, which affects the patient’s quality of life. DT is a treatment strategy for patients who are not candidates for lung transplant because of factors such as age or comorbidities. COVID-19 causes not only lung failure but also multiple organ dysfunction including the cardiovascular and kidney dysfunction. In general, patients with multiple organ failure are deemed poor candidates for lung transplant. For these patients, DT using long-term AL could improve survival and quality of life. VADs clearly have improved the outcomes of patients with heart failure.^21,22 VADs can be used either as a BTR, BTT, or DT. Durable (implantable) VADs allow patients to be discharged home, live with good quality of life, and even work. Currently, there is no single analogous AL device that can be used as long-term respiratory support.

FIGURE 1.

Mechanical respiratory-assist options for supporting patients with lung failure because of coronavirus 2019 (COVID-19). These are ideal device options for supporting patients with lung failure caused by COVID-19; however, there are still unmet needs. AL, artificial lung; BTR, bridge to recovery; BTT, bridge to transplant; CARDS, COVID-19–related acute respiratory distress syndrome; DT, destination therapy; ECMO, extracorporeal membrane oxygenator; PCPF, post-COVID pulmonary fibrosis; RVAD-Oyx, right ventricular-assist device with an oxygenator.

ECMO is an established therapy for a short-term respiratory support, but is not a perfect solution. The longer a patient is supported with ECMO, the higher the risk of complications gets. The scarcity of organ donors and uncertainty about the optimal timing and optimal patient selection for lung transplant after COVID-19 has led to a growing interest in an AL that can be used as a long-term support.

Table 1 details the characteristics of an ideal AL designed to overcome COVID-19-related issues. There are mainly 2 directions in the development of ALs. One approach is to develop bioengineered lungs without artificial surfaces or tubing that exits from patient’s body cavity. The ultimate goal of ALs is to develop bioengineered lungs with autologous cells. Nichols and colleagues⁴⁶ transplanted bioengineered lungs to pigs. They created acellular lung scaffolds from porcine lungs and seeded the scaffold with autologous porcine cells. The bioengineered lungs were transplanted to pigs in an orthotropic fashion. Although only the tracheas were anastomosed and pulmonary vessels were not reattached in their study, the implanted lungs showed good microvascular and alveolar tissue formation as early as 2 wk after transplant. Moreover, none of the implanted lungs showed evidences of rejection. These findings will be warranted by the further studies. The other approach is to improve and refine conventional AL systems that consist of membrane oxygenator, tubing for blood circulation, and tubing for gas exchange. Research gaps in this way include long-term antithrombogenicity, with less bleeding risk, portability, implantability, and durability. Cypel and colleagues⁴⁷ published a case report detailing combined support with central VA-ECMO (right atrial drainage and aortic return) and a low-resistance pumpless oxygenator (drainage from the pulmonary artery and return to the left atrial) in a patient with cystic fibrosis. The patient underwent bilateral pneumonectomy to control a lung infection and was supported by the mechanical support described earlier for 6 d until a suitable donor was found. This was an important step toward long-term support for lung failure because it proved that living without lungs was possible using technologies. We have previously discussed indications for long-term AL support, configurations of circuits, approaches for device placement, and limitations in the current development of long-term AL in a review article.¹⁵ Here, we will provide an update on recent AL development focusing on device designs and hypercoagulability related to COVID-19 illness.

TABLE 1.

An ideal AL: challenges and possible solutions

Issues/problems	Solution
Thromboembolism and bleeding	• Coating to prevent clot formation and protein adsorption • New anticoagulation drugs with lower bleeding risk • Oxygenator designs with less stagnation • Bioengineered lungs without artificial surfaces
Deconditioning due to severe illness	• Ability for long-term use/longer durability • Avoid groin cannulation for easier ambulation • Improve portability with a shorter circuit (implantable or paracorporeal) • Oxygenators that last longer without decrease in gas exchange capacity and antithrombogenicity • Bioengineered lungs without tubing or driveline
Fibrosis	• Coating devices with antifibrotic agents (Note: uncertain efficacy of the agents and technical feasibility of applying coating)

AL, artificial lung.

Hypercoagulability Associated With COVID-19

An AL must have a large and densely packed artificial surface for gas exchange, which unfortunately leads to rapid clot formation when compared with a VAD. Moreover, COVID-19 promotes hypercoagulability.^11,29 Changes in the coagulation system can increase the risk of blood clot formation in ECMO circuits and oxygenators leading to early failure of the devices.²⁹ Clot formation can be reduced by setting higher anticoagulation thresholds, increasing blood flow, and reducing stagnation, shear stress, and surface area in the circuit. Currently, unfractionated heparin is used as the standard anticoagulant for temporary mechanical support devices (ie, ECMO), and warfarin is used for durable mechanical support devices (ie, VADs). Bivalirudin is an alternative agent for temporary mechanical support devices. Researchers reported Bivalirudin used for ECMO was associated with less major bleeding events, less frequent blood transfusion, and more consistent therapeutic range of PTT than heparin.^48–50 Nonetheless, thromboembolic events and hemorrhagic events can still occur in some patients receiving anticoagulation therapy within the therapeutic range defined as appropriate. These complications and subsequent organ dysfunction can lead to a loss of candidacy for durable support or transplant. Several strategies have been investigated to reduce clot formation including novel coagulation inhibitors, device coatings, and drug delivery systems.

New Anticoagulation Agents

A therapeutic that could inhibit thrombosis without increasing bleeding risks would be an ideal anticoagulation agent. Coagulation factor XII (FXII) has attracted attention as an appealing target for a new anticoagulation agent. FXII is the initiating protease of the intrinsic coagulation pathway. After blood contacts artificial surfaces and FXII is adsorbed on the surface, FXII is activated to FXIIa, and the intrinsic pathway is initiated.⁵¹ Patients with FXII deficiency, a rare disease, have a longer PTT but no hemorrhagic symptoms. FXII knock-out animals also exhibit reduced thrombogenicity without an increased bleeding tendency.⁵² Wilbs et al⁵³ demonstrated that selective FXIIa inhibition significantly decreased clot formation with no effect on bleeding time in a small animal study using ECMO circuits. The FXIIa inhibitor increased activated clotting time to >1000 s, whereas bleeding time was similar to that seen in untreated animals and shorter than in animals treated with systemic heparin to a target activated clotting time of 230 to 300 s. The FXIIa inhibitor is still under development and no clinical trial has been conducted; however, inhibiting FXIIa may prevent clot formation without increasing the risk of bleeding.

Device Coatings to Block Thrombogenicity

In addition to systemic anticoagulation, artificial coatings that reduce protein adsorption and initiation of the coagulation cascade might decrease thromboembolic risks. Many circulatory-assist devices have coatings to decrease their thrombogenicity and reduce the doses of anticoagulation agents required for their use. Heparin coatings are widely used; however, heparin coatings are not perfect for long-term support due to degradation and chemical modifications that reduce heparin activity.⁵⁴ Researchers have been working on different coating strategies including nonfouling coatings.

Nonfouling coatings prevent nonspecific protein adsorption and subsequent clot formation. These coatings create a hydration layer on the artificial surface, making an environment more like the physiological environment of a healthy endothelial surface. The hydration layer prevents adsorption on the hydrophobic artificial surface and thereby prevents the subsequent conformational changes and activation of proteins, which should lead to reduced activation of platelet and coagulation factors.

Of nonfouling coatings tested to date, polycarboxybetaine (PCB) coatings have demonstrated decreased protein absorption in in vitro and in vivo studies. Using 3,4-dihydroxyphenylalanine-linked PCB coating, Ukita et al⁵⁵ reported a significant reduction in clot formation and prevention of increased resistance in the oxygenator in small and large animal models. Naito et al⁵⁶ evaluated the combined use of an FXIIa inhibitor and 3,4-dihydroxyphenylalanine-linked PCB and showed additive effects with reduced clot formation without increasing tissue bleeding time.

Nitric oxide (NO)-releasing fibers⁵⁷ and the use of NO in the sweep gas⁵⁸ have also been examined and may reduce platelet activation and adhesion to the artificial surfaces of an AL. NO is a messenger molecule in the human body and regulates blood flow, vascular resistance, neural communications, and thrombosis. It is very short-acting substance with a half-life of 0.05 to 1.80 ms in the blood that can mimic the natural endothelium and, thus, reduce thrombosis at the fiber surface. The short half-life of NO allows for normal platelet function when the blood is returned to the patient. Lai and colleagues⁵⁷ performed a 72-h sheep study to evaluate the effects of oxygenator fibers with copper-catalyzed NO generation. They demonstrated that fibers with copper-catalyzed NO generation significantly delayed clot formation and maintained fiber-bundle patency. Further in vivo studies are warranted to evaluate the effects of copper on the human body especially in the liver. Major and colleagues developed an NO-releasing polymer coating (diazeniumdiolated dibutylhexanediamine) to prevent clot formation in ECMO circuits. A 24-h sheep study using a pumpless low-resistance AL with a diazeniumdiolated dibutylhexanediamine-coated circuit showed good hemocompatibility even without systemic anticoagulation.⁵⁸ In this study, NO in the sweep gas was used to prevent thrombosis in the oxygenator because the coating was not compatible with gas exchange in the hollow fibers. Zhang and colleagues⁵⁹ reported tests of an NO-eluting stent for coronary artery disease to prevent acute thrombosis and chronic in-stent restenosis. They coated stents with catechol-grafted chitosan, zinc sulfate, and Arg-Glu-Asp-Val peptide. This coating mimicked the endothelium and could continuously catalyze endogenous NO. A similar coating might be used for an AL.

The concept of biologic coatings, in which endothelial cell layers are coated on the artificial surface to improve hemocompatibility, is not new.⁶⁰ Biological surface coatings are attractive and may further AL development. Researchers have reported improved hemocompatibility, reduced platelet adhesion and activation, and reduced protein adsorption with biologic coatings.⁶¹ Despite promising development of these biologic-based technologies, there remain several obstacles that must be addressed before long-term use. First, the endothelial cells are exposed to shear stress and static pressure that impact the genotype and phenotype of the cells.⁶² Second, endothelial cells cannot remain intact on the surface under the mechanical force in the circuits. Third, seeding endothelial cells on oxygenator surfaces can decrease the oxygenator’s gas exchange capabilities. Lastly, the cost and time of the coating procedure may be prohibitive because of large surface area of the circuit, which includes both the tubing and the oxygenator.

Device Coatings for Drug Delivery

COVID-19 causes endothelial dysfunction, microvascular injury, and microthrombosis mediated by the immune system, a hyperinflammatory response, and direct invasion of the virus into the vascular endothelium through angiotensin-converting enzyme.^63,64 The use of anti-inflammatory drugs, anticytokine drugs, and angiotensin-converting enzyme inhibitors has been an attractive approach for treatment of COVID-19; however, there have been only limited clinical data.⁶⁴ Antifibrotic agents, including nintedanib and pirfenidone, used to slow idiopathic pulmonary fibrosis are considered candidate drugs to prevent the process of PCPF.^65,66 This approach is still under investigation, and further research is required. Antifibrotic agents might be more effective if they are delivered locally to targeted areas. Drug-eluting stents have been widely used for coronary artery disease⁶⁷ and antibiotic-coated grafts are under development to prevent infection of vascular grafts.⁶⁸ AL circuits coated with drugs that improve endothelial function or prevent fibrosis in the lungs could be created. Such an AL might have benefits for treating patients during both the acute and chronic phases of COVID-19-related lung failure.

Device Design and Resistance

ALs with improved portability that could be used for a longer duration may overcome challenges because of the deconditioning patients on ECMO for COVID-related lung failure experience, allow for physical rehabilitation as needed, and give patients a better quality of life. There are 2 main configurations for placing ALs: in series (pulmonary artery to pulmonary artery) and in parallel (pulmonary artery to left atrium).¹⁵ Although ALs can be either pump-driven or pumpless, a pumpless AL would make management of the circuits easier due to a shorter and simpler circuit. Placement of a pumpless AL in series is challenging in patients with severe pulmonary hypertension. Right ventricular dysfunction also makes pumpless AL placement more difficult. To combat this issue, there is a great need for a low-resistance AL device that enables pumpless AL placement or alleviates strain on the right side of the heart.

Computational fluid dynamics (CFD) enable researchers to investigate AL housing designs to determine whether they would have good hemocompatibility, a lower pressure drop with less resistance, and less stagnation of blood flow.⁶⁹ A low-resistance pediatric AL designed using CFD was tested in a pulmonary hypertension model in a juvenile lamb using an in-parallel configuration.⁷⁰ The AL improved cardiac output and right ventricular efficiency. Orizondo and colleagues⁷¹ evaluated an AL with an integrated blood pump designed using CFD in a sheep model. The device design was not finalized; however, Orizondo’s team was able to achieve a device small enough to be wearable (1.8 lbs with a priming volume of 135 mL). The device was installed with jugular vein cannulation using a double-lumen cannula and was tested for 28 to 30 d.

SUMMARY: THE NEED OF LONG-TERM ALS FOR END-STAGE LUNG FAILURE WITH ANY ETIOLOGIES

Although it has been >2 y since the COVID-19 outbreak started, many patients still suffer from new SARS-Cov-19 infections or chronic lung failure as a result of COVID-19 illness. During the first surge of COVID-19, the use of advanced lung failure therapy, mainly VV-ECMO, was focused on treating acute-to-subacute severe illness manifested in ARDS. The efficacy of lung support therapy using ECMO for a short period has been established. Additionally, multiple factors including effective vaccination, treatment of COVID-19 based on evidence-based practices, and viral mutations have greatly reduced the risk of severe COVID-19 illness. However, patients who survived critical COVID-19 illness as well as patients who had mild-to-moderate illness can develop progressive pulmonary fibrosis leading to chronic lung failure as a result of COVID-19. Given the ongoing pandemic and the large number of individuals who now survive acute phase COVID-19, a substantial number of individuals with PCPF and chronic lung failure are anticipated in the future. This might shift the priorities of advanced lung failure therapy in patients with COVID-19-related lung failure toward long-term support. There will be a growing interest in long-term ALs because of the scarcity of donor organs, more patients on the waiting list for a lung transplant, and more patients with chronic lung failure who are not transplant candidates. The demands for long-term ALs that COVID-19 pandemic brought to the forefront may drive technological development to overcome the obstacles to clinical application of long-term ALs. Long-term ALs would be of great use for patients suffering from lung failure with any etiologies as an analogue of durable VADs for heart failure. Lung transplant waitlist mortality of non-COVID-19 patients has remained between 15 to 20 deaths per 100 patient-y over the decade. Considering that durable VADs have improved waitlist mortality (from 17.4 deaths per 100 patient-y in 2008 to 8.3 deaths per 100 patient-y in 2019)⁷² and posttransplant mortality in heart failure patients,^73,74 we can expect BTT with long-term ALs will provide similar effects. Similarly, DT with long-term ALs is expected to improve survival rate and quality of life of lung failure patients. Lessons and knowledge learned from COVID-19 might make a significant contribution to the advance in the field of end-stage lung failure.

ACKNOWLEDGMENTS

The authors thank Shannon Wyszomierski for editing a draft of the article.