The use of extracorporeal membrane oxygenation for lung transplant patients with respiratory failure has become routine part of ICU therapy. This chapter reviews indications, complications and outcomes.
Ex-vivo lung perfusion for donor lungs is a successful strategy to identify suitable donor organs.
KeywordsEx-vivo lung perfusion Marginal donor lung Donor lung utilisation ECMO Principles and indication Perioperative ECMO use
Extracorporeal membrane oxygenation (ECMO) was made possible due to the introduction of membrane oxygenation during open heart surgery in the 1950s by John Gibbon. Initially such support was restricted to intra-operative use during heart operations. Earlier treatment attempts for patients with severe respiratory disease in an intensive care unit (ICU) setting carried a very high mortality and were deemed unsuccessful . Technical advances and increased experience from the use of cardiac bypass machines during surgery allowed the reintroduction of the concept of ECMO for critically ill patients with respiratory failure. More recently the H1N1 flu epidemic in 2009 saw an increased use of ECMO circuits in ICUs worldwide, with a global gain in expertise. The Extracorporeal Life Support Organization (ELSO) was founded thereafter and has created internationally accepted treatment guidelines . The use of ECMO for lung transplant candidates and recipients has become a routine part of the therapeutic options.
4.2 Circulatory Set Up of ECMO Support
ECMO provides maintenance of oxygen and carbon dioxide gas exchange in the case of cardio-respiratory failure. A centrifugal pump transports blood via cannulae and tubing to an external membrane oxygenator and heat exchanger and then returns it to the body.
Different types of ECMO circuits exist: A venous-venous (VV) or venous-arterial circuit (VA) will be chosen based on the patient’s pathophysiological needs. Each of these set-ups has its own risks and benefits, which will need to be carefully considered.
The VV ECMO circuit membrane is in series with the patient’s lungs. Both the organ and the artificial membrane contribute towards gas exchange. The blood is drawn from the superior vena cava or inferior vena cava to the artificial membrane and returned to the right atrium. The rate of the gas exchange is in large part dependent on the patient’s cardiac output. Therefore this type of support is only suitable for patients with respiratory but not cardiovascular failure. VV ECMO is the most commonly used mode with patients who suffer from respiratory failure.
Central VA ECMO requires direct placement of a cannula into the right atrium and a second cannula into the aorta. Sterile surgical approach in theatre is required to set up VA ECMO. Central VA ECMO is most commonly used in lung transplant recipients to treat cardio-respiratory shock during the transplant operation. It may be used as a planned upgrade from other ineffective forms of ECMO. The circuit of peripheral VA ECMO delivers oxygenated blood to the aorta via the femoral artery in retrograde fashion. The potential haemodynamic complications as a result of this include: separate perfusion of the lower and upper part of the body (watershed phenomenon), and distention of the left ventricle, and resulting pulmonary oedema due to increased afterload produced by ECMO. The latter requires close monitoring and careful adjustment of the flows, peripheral vascular resistance, vasopressor support and oxygenation. More advanced configuration of peripheral VA-ECMO employing three cannulas can be used to optimize cardiorespiratory support and deal with the aforementioned problems.
4.3 Indications for VV ECMO
This chapter will focus on VV ECMO, as it is the most common type of ECMO therapy in lung transplant candidates and recipients.
General indications for the use of VV ECMO include: reversible hypoxic respiratory failure when the risk of mortality is 80% or greater and reversible CO2 retention on mechanical ventilation despite maximal safe ventilation.
ELSO guidelines suggest to consider the use of ECMO when the ratio of PaO2 to FiO2 is <150. ECMO is indicated when the ratio is <80. A PaCO2 >80 mmHg or end-inspiratory plateau pressure >30 cm H2O are also considered to be indications for ECMO in patients with ARDS.
Patients listed for lung transplantation may undergo VV ECMO therapy as a bridge to lung transplantation . In such cases the patient’s overall clinical state and the problems of urgent organ allocation need to be considered: An older, frail patient with worsening pulmonary fibrosis would in most institutions not be treated with ECMO therapy as a bridge to transplant. Individual centres differ in their approach and advanced age alone is not a universally accepted contraindication. Younger patients with catastrophic respiratory failure due to cystic fibrosis or ARDS are more likely to be placed on ECMO therapy as bridge to transplantation. It is not uncommon that a transplant centre is asked to consider a patient for lung transplantation who is already on ECMO therapy at time of the referral. This poses a significant challenge, as the usually thorough assessment process needs to be performed in a very short time and in most cases with a patient who is deeply sedated and unable to give a history. To prevent this, a proposed strategy could be that Lung Transplant Units are consulted about all patients being placed on VV ECMO for respiratory failure so that a decision can be made about their candidacy for potential bridge to lung transplantation early.
The specific indications for a lung transplant recipient in the postoperative period for VV ECMO therapy include: treatment of primary graft dysfunction, broncho-pulmonary fistulas, Sepsis, anastomotic dehiscence and severe air leak. These conditions are regarded as potentially reversible. In many cases of primary graft dysfunction, VV ECMO therapy is started in theatre when the transplanted lungs fail to achieve sufficient oxygen and carbon dioxide exchange. Whilst the patient is treated with VV ECMO therapy, the treating physicians can address the causes of primary graft dysfunction, allow the lungs to recover and if required, further operative management can be safely planned.
4.4 Complications of VV ECMO Therapy
With its invasive nature, ECMO has a vast array of complications, affecting almost every organ system. Generally VV ECMO is better tolerated than VA ECMO. The complications of ECMO therapy can be divided into 2 groups: Those caused by the condition requiring ECMO therapy or as a result of the ECMO therapy.
Bleeding is the most common complication. The blood loss may occur because of surgical trauma due to cannula placement, surgery or as a complication of the essential anticoagulation, haemolysis, or thrombocytopenia. Pulmonary bleeding is a common complication and may require repeated bronchoscopy and washouts.
Thrombus formation in the extracorporeal circuit is rare and more significant in VA ECMO compared to VV ECMO, as thrombus may enter the systemic circulation.
Neurological complications due to intracranial haemorrhage, focal infarction and generalized brain oedema may occur. Renal failure and oliguria may require additional support with dialysis, which then further complicates systemic blood pressure and fluid management. Gastrointestinal complications include malnutrition, bleeding and ileus.
The risk of sepsis due to the presence of a large intravascular foreign body plays a particularly important role in the immunosuppressed lung transplant recipient. As the ECMO circuit temperature is actively regulated, the patient’s body temperature is not an indicator of sepsis and regular blood culture samples are part of an ECMO management protocol. The ECMO circuit may influence the serum concentration of medications due to the altered volume of distribution. Drugs may be absorbed by the inner surface lining of cannula and tubing. Monitoring of therapeutic drug levels is often required and drugs with a narrow therapeutic range may need to be avoided . Mechanical failure may occur in the key components of the ECMO circuit such as the pump or the oxygenator.
The significant pathophysiological consequences of deep sedation and inability to participate in physiotherapy often result in severe loss of muscle bulk and the emergence of non-respiratory organ involvement. The period during which an ECMO dependent patient can be safely transplanted is therefore limited and a daily review of the patient’s likelihood to successfully undergo lung transplantation needs to be performed . Patients on ECMO therapy as a bridge to lung transplantation are regarded as most urgent and this is reflected in the relevant national lung allocation system.
In selected centres there has been growing expertise in providing ECMO support to patients who are awake whilst receiving ECMO therapy. Such patients can participate in rehabilitation and have a longer period during which they may be successfully transplanted. Case reports of patients who were successfully transplanted after a very long period of ECMO support are published .
4.5 Outcome of VV ECMO Use for Respiratory Failure
General indication for VV ECMO therapy
Reversible respiratory failure with a mortality of higher than 80%
Reversible CO2 retention on mechanical ventilator support
Indications for VV ECMO therapy for lung transplant recipients
Bridge to lung transplantation
Primary graft dysfunction (PGD)
Contraindications for VV ECMO therapy
Unsupportable cardiac failure/cardiac arrest
Treatment resistant pulmonary hypertension, in a non-transplant candidate
Irreversible respiratory failure, in a non-transplant candidate
Chronic lung allograft dysfunction in a transplant recipient
Irreversible CNS comorbidities
4.6 Ex-Vivo Lung Perfusion
The initial assessment of a potential donor lung is based on a combination of clinical donor information, blood gas measurements and imaging results. The final decision to accept donor organs is made during the retrieval operation and surgical inspection. Donor lungs are typically transported in a static hypothermic environment after the retrieval. In the past, a functional assessment of the organ could not be performed prior to implantation. Many potentially suitable organs have not been used due to the uncertainty about marginal results in the organ assessment. Such marginal results may have been due to reversible causes such as fluid overload or tolerable levels of aspiration. Up to 40% of such lungs which have been rejected due to marginal criteria were in a research setting later found to be useable for transplantation . The demand for donor organs greatly exceeds the availability of donor lungs and therefor the identification of suitable organs with reversible dysfunction will lead to an increase in donor numbers.
Ex-vivo lung perfusion allows functional assessment prior to implantation and potentially treatment of reversible complications.
This highly sophisticated method of assessing donor lungs is based on the pioneering work of Professor Stig Steen, Sweden, who in the 1990s published conceptual data. The same group published the first case of successful transplantation of a donor lung which was rejected during the initial donor assessment in 2006 . EVLP systems have become commercially available and numerous institutions world-wide have now published short and long term outcome data.
The choice of perfusate is a current topic of research:
“Steen solution” contains human serum albumin to provide normal oncotic pressure as well as an electrolyte solution which resembles extracellular fluid. This solution has been found to be protective against pulmonary oedema. In addition, “Steen solution” contains dextran which is a mild oxygen scavenger which coats and protects endothelium from subsequent excessive leucocyte interaction and thrombogenesis. “Steen solution” itself is acellular. Adding donor blood to the “Steen solution” creates a cellular perfusate which contains red blood cells as oxygen carriers . The cellular solution may more closely mimic physiological conditions, but it has not been shown that either approach is superior.
Different institutions use either an open left atrium or a closed left atrium during the EVLP: Closing the left atrium with a funnel shaped device when connecting the cannulas creates a positive left atrial pressure which consequently is thought to be protective to the donor lung. It has been shown that the closed left atrium approach may lead to a lower pulmonary vascular resistance and less pulmonary oedema compared to an open atrium approach . Neither of the anatomical approaches has yet been accepted as international standard.
4.6.2 Assessment of Marginal Donor Lungs
A donor blood gas oxygen level below the local accepted minimum. (In our institution a level below 300 mmHg on a FiO2 of 100% and a PEEP of 5.)
High ventilator pressure requirements, without clinical or radiological explanation and otherwise acceptable donor organs.
Marginal changes on chest imaging, which require further inspection, exceeding what could be assessed in a routine transplant retrieval operation. Typical examples are minor structural lung changes or changes suggestive of infection.
Lungs from older donors with an expected long ischemic time.
To allow for prolonged explant operation.
Following donor lung retrieval and transportation back to the recipient hospital in the usual fashion the lungs are placed in the EVLP machine. The ex-vivo lung perfusion requires a sterile approach in the operating theatre, with a perfusionist, surgeon, transplant physician and anaesthetist being essential members of the team. The EVLP setup consists of a sterile chamber with connection to a mechanical ventilator and gas mixture. The perfusate is pumped through closed circuit cannulas, via an external heater into the pulmonary artery. A monitor displays temperature and pressure measurements from probes which are placed into the airway and pulmonary artery. Different types of ex-vivo lung perfusion set-ups exist, but the principle of the assessment process is identical. The local protocol determines the type of perfusate (cellular vs acellular), height of the target temperature, target ventilation, FiO2 used and if the left atrium remains closed during the assessment . The lungs are slowly warmed to body temperature and then perfused and ventilated. Oxygenation, airway pressure and lung compliance get regularly monitored. Repeated CXR images allow monitoring the progress of radiological changes. Therapeutic intervention such as recruitment manoeuvres on the ventilator, bronchoscopic removal of secretions and administration of antibiotics can be performed during the evaluation process.
Several institutions have now published their EVLP outcome data. There is a demonstrated net increase in transplantation overall as a consequence of EVLP use. The world wide data demonstrate that short term complications such as primary graft dysfunction , functional parameters such as the FEV1 and long term freedom from chronic lung allograft dysfunction do not significantly differ between lungs that underwent EVLP prior to transplantation and those which did not .
These are encouraging findings, justifying the use of these expensive resources for donor organ assessment.
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