# How We Would Treat Our Own Lung Transplantation:
A Multidisciplinary and International Perspective

Archer K. Martin, Anna Katja Reed, Konrad Hoetzenecker, Julien Fessler

► To cite this version:

Archer K. Martin, Anna Katja Reed, Konrad Hoetzenecker, Julien Fessler. How We Would Treat Our Own Lung Transplantation: A Multidisciplinary and International Perspective. Journal of Cardiothoracic and Vascular Anesthesia, 2023, 37 (11), pp.2207-2214. 10.1053/j.jvca.2023.07.042. hal-04229531

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# Journal of Cardiothoracic and Vascular Anesthesia
## How We Would Treat Our Own Lung Transplantation: A Multidisciplinary and International Perspective

--Manuscript Draft--

<table><tr><td>Manuscript Number:</td><td></td></tr><tr><td>Article Type:</td><td>Special Article</td></tr><tr><td>Keywords:</td><td>Lung transplantation; ECMO; multidisciplinary team; prehabilitation; analgesia; enhanced recovery; end-stage lung disease</td></tr><tr><td>Corresponding Author:</td><td>Archer Kilbourne Martin, M.D.<br>Mayo Clinic<br>Jacksonville, FL UNITED STATES</td></tr><tr><td>First Author:</td><td>Archer Kilbourne Martin, M.D.</td></tr><tr><td>Order of Authors:</td><td>Archer Kilbourne Martin, M.D.<br>Anna Katja Reed, MD, PhD<br>Konrad Hoetzenecker, MD, PhD<br>Julien Fessler, MD</td></tr><tr><td>Abstract:</td><td>Lung transplantation is the ultimate treatment for end-stage lung disease (ESLD) arising from a wide variety of etiologies. This manuscript will focus on selected aspects of a theoretical perioperative lung transplantation plan, highlighting data-driven and theoretical techniques we would employ if we were the index patient undergoing surgery. Beginning with looking for a transplant center utilizing internet search, patient advocacy organizations, and artificial intelligence guidance, we lay out a course for multidisciplinary care throughout the entire patient journey, ending with ideal approaches to recovery 6-months post-transplantation. While the index case will focus on a theoretical patient with pulmonary fibrosis, the principles of general management will be applicable across the entire spectrum of patients with ESLD presenting for lung transplantation.</td></tr></table>
Dear Professor Kaplan:

On behalf of my co-authors, I am submitting this special article at the invitation of Dr. Gabor Erdoes regarding the
following article in the *Journal of Cardiothoracic and Vascular Anesthesia*, "How We Would Treat Our Own Lung
Transplantation: A Multidisciplinary and International Perspective". All authors agree and are responsible for the
enclosed manuscript.

Thank you for your consideration of this special article submission to the *Journal of Cardiothoracic and Vascular Anesthesia* within the "How We Would Treat" series.

Dr. Archer Kilbourne Martin, M.D.

Dr. Anna Katja Reed, M.D., PhD

Dr. Konrad Hoetzenecker, M.D., PhD

Dr. Julien Fessler, M.D.
**Statements of funding, Declarations of Interest, and Acknowledgements:** No funding sources to declare. The authors JF, AKR, and KH have no interests to declare. AKM serves on the Scientific Advisory Board of Attgeno AB, with all consulting fees paid to Mayo Clinic.
**Title of article:** How We Would Treat Our Own Lung Transplantation: A Multidisciplinary and International Perspective

**Full names of authors in preferred order:** Archer Kilbourne Martin, MDª, Anna Katja Reed, MD, PhDᵇ, Konrad Hoetzenecker, MD, PhDᶜ, Julien Fessler, MDᵈ

**Author title and institution:**

A) Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic College of Medicine and Science, Jacksonville, Florida

B) Department of Cardiothoracic Transplantation and Mechanical Support, Harefield Hospital, Royal Brompton & Harefield Hospitals, Part of Guy's and St Thomas' NHS Foundation Trust & Imperial College, London, UK

C) Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria

D) Department of Anesthesiology, Hôpital Foch, Suresnes, France, and Université Versailles-Saint-Quentin-en-Yvelines, Versailles, France

**Corresponding Author:** Archer Kilbourne Martin, MD. Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, USA. 32224. martin.archer@mayo.edu

**Statements of funding, Declarations of Interest, and Acknowledgements:** No funding sources to declare. The authors JF, AKR, and KH have no interests to declare. AKM serves on the Scientific Advisory Board of Attgeno AB, with all consulting fees paid to Mayo Clinic.
Abstract:

Lung transplantation is the ultimate treatment for end-stage lung disease (ESLD) arising from a wide variety of etiologies. This manuscript will focus on selected aspects of a theoretical perioperative lung transplantation plan, highlighting data-driven and theoretical techniques we would employ if we were the index patient undergoing surgery. Beginning with looking for a transplant center utilizing internet search, patient advocacy organizations, and artificial intelligence guidance, we lay out a course for multidisciplinary care throughout the entire patient journey, ending with ideal approaches to recovery 6-months post-transplantation. While the index case will focus on a theoretical patient with pulmonary fibrosis, the principles of general management will be applicable across the entire spectrum of patients with ESLD presenting for lung transplantation.

**Keywords:** Lung transplantation; ECMO; multidisciplinary team; prehabilitation; analgesia; enhanced recovery; end-stage lung disease;
## Introduction:

The present manuscript aims to provide a review about selected aspects of the perioperative course of my own (AKM) theoretical transplantation, such as the selection of a world-renowned multidisciplinary team (AKR, KH, JF), optimal transplantation center, preoperative preparation of the journey, the adaptation of the intraoperative management of the specific end-stage lung disease (ESLD), pain management, blood management, utilization of extracorporeal life support (ECLS), and application of an enhanced recovery after surgery program. To illustrate this approach, the authors will use an index case that provides opportunity to examine a specific ESLD¹ and its various considerations throughout the perioperative course.

The management of a lung transplant recipient is particularly challenging due to the complex clinical situations requiring multidisciplinary coordination that can occur throughout the entire perioperative period. Adding to this challenge is the scarce evidence available to guide the multidisciplinary team (MDT) because of the difficulty of conducting high-quality, large volume studies examining lung transplantation. This research challenge results in most recommendations stemming from retrospective studies or database analyses that do not allow causal relationships to be established. Furthermore, the vast majority of these studies are single center, resulting in significant influence of the practices of each center and the profiles of the recipients recruited in each center.

## Index Case:

The patient is a 40-year-old male with idiopathic pulmonary fibrosis who presents for bilateral lung transplantation. His baseline oxygen requirement has been steady over the past few months at 4 L/min, however, he has had an increase over the past 2 weeks in oxygen requirements on exertion to 8 L/min. Concomitantly, he has had a consistent decrease in functional capacity, with occasional orthopnea in the past few weeks. His past medical history is significant for gastroesophageal reflux. His transthoracic echocardiogram from 6 months ago showed a mildly increased right ventricle with intact systolic function, left ventricular ejection fraction of 65%, and mild tricuspid regurgitation. A right heart catheterization performed only a couple of days ago showed a pulmonary arterial pressure of 38/18 (mean 25), pulmonary capillary wedge pressure of 5 mm Hg, and calculated 4.2 Woods
Units. His current vital signs are as follows: heart rate 95, systemic blood pressure 122/59, respiratory rate 24, oxygen saturation 94%.

## Review of the Clinical Context

### How We Would Choose our Lung Transplantation Center

Determining the selection of one's lung transplantation center focuses on many different factors including personal preference, social support network, existing medical relationships, and expertise of the local center. Utilizing online search, patient advocacy organizations, and artificial intelligence tools, we would prioritize the foundational principles of selection for our theoretical center including the center outcomes and philosophy of care. Centers are often judged on reported mortality outcomes, but a deeper theoretical evaluation would include a composite assessment of long-term outcomes, rates of primary graft dysfunction (PGD), perioperative morbidity related to complications, quality-of-life scores, return to work rates, and MDT philosophy of lung transplantation care. Yang et al recently examined the relationship between 1-year survival outcome and lung transplantation center volume.² The retrospective study of the United Network for Organ Sharing (UNOS) database examined over 10,000 patients at 71 transplant centers. Increasing transplant center volume was associated with improved 1-year survival outcomes (hazard ratio [HR] 0.989, 95% confidence interval [CI], 0.980 to 0.999 per case), but no benefit was observed once a center had crossed 33 lung transplantations per year.² Beyond 1-year survival metrics, our lung transplantation center would also be evaluated on the composite outcomes of morbidity. PGD, most recently defined by the International Society for Heart and Lung Transplantation (ISHLT) in 2017, is a multifactorial perioperative syndrome (graded within 72 hours after transplantation) that is associated with increased rates of morbidity, mortality, and chronic rejection when high grade at 72 hours.³ PGD, in combination with perioperative morbidity related to procedural complications, should be minimized through careful attention to anesthetic and surgical technique.⁴ In order to achieve a decrease in composite morbidity, our transplantation center would have an MDT approach that would focus on improving communication⁵, coordinating specialized team-based training⁶, implement the latest principles in resource stewardship⁷, and ultimately improving outcomes.⁸
Practical implementation of this diverse strategy within our lung transplantation center of choice would start in the preoperative phase, with a tailored MDT approach to the recipient's etiology of ESLD⁹, ¹⁰ to include optimal donor/recipient matching, short waiting list times, ex-vivo lung perfusion capabilities, pre-operative ECLS bridging planning, physiotherapy, psychosocial resources, frailty assessment, and utilization of complementary medicine.

*Preoperative Preparation for the Journey – Frailty Assessment and Improvement Through Pre-habilitation*

Pulmonologists are the team leads in charge of the patient optimization prior to official listing for lung transplantation. One of the key assessments of frailty pre-listing is the utilization of multiparametric scores reflecting a composite of physical, cognitive and social factors that quantify patient vulnerability to stressors that result from an accumulation of physiologic deficits across multiple interrelated systems.¹¹ Physical assessment is predominantly based on clinical markers such as sarcopenia¹², physical weakness, slow locomotion, easy fatigability, and low baseline levels of physical activity. Such scales predict death during enrollment, early complications, disability, poor quality of life, and postoperative mortality.¹³, ¹⁴

The most commonly used tests are the short physical performance battery (SPPB)¹³, ¹⁵ and the Fried frailty phenotype (FFP).¹⁶ The latter integrates the respiratory component of the disease, limiting physical capacities. Moreover, this evaluation must be adapted to the heterogeneity of the candidates¹⁷ and the pathology.¹⁸ Interestingly, Singer et al have developed a 3-candidate scale measure incorporating readily available clinical data, then adding muscle mass, and finally, research-grade biomarkers in a multicentric cohort. They found that their lung transplant frailty scale (LT-FS) model exhibited superior construct and predictive validity compared to the SPPB and FFP. Thus, we choose the LT-FS model to assess our index patient for frailty and prepare him for pre-habilitation.

Our patient's frailty assessment must also make it possible to identify factors that can be reversed by pre-habilitation programs.¹⁵ The aims of our assessment are to identify impairments and provide interventions that increase baseline functional level, enhance quality of life, and provide psychological support to improve postoperative recovery including adherence to immunosuppressant therapy.¹⁵ Additionally, our evaluation must be
repeated over time and consider the dynamic notion of frailty. Once evaluated with LT-FS, we would employ the Toronto pre-habilitation program to increase our index patient's chances of having a positive outcome.¹⁹ Pre-habilitation exercise programs should follow the ‘FITT’ principle, consisting of the cornerstones of frequency, intensity, time (duration), and type of exercise. The use of adjunct technology to objectively track exercise progress, such as accelerometers, would be utilized for our index patient.²⁰ Finet et al showed that such devices are feasible in thoracic surgery and could encourage patients in a physical reconditioning program to clearly predefined goals.²¹, ²² The multi-modal pre-habilitation program should also include nutritional optimization and psychological well-being.²³

In lung transplantation, the anesthesiologist is an active stakeholder at an advanced stage of this preparation phase, particularly during the synthesis of all the preoperative assessments and MDT decision concerning perioperative strategy. A recent study discussed the importance of the preoperative anesthesia consultation to discuss the different stages of a lung transplantation and initiate the appropriate complementary techniques to aid the recipient during the potentially painful events related to the procedure. This holistic engagement provides the opportunity to make the patient an actor in their own care and provides them various tools to adapt to their own personal strategy including self-hypnosis, sophrology, relaxation, or transcutaneous electrical stimulation.²⁴ While their study was not designed²⁵ to demonstrate the effectiveness of this strategy on pain or quality of life, we would decide to utilize it for our index patient as a complementary strategy within our comprehensive pre-habilitation program.

Finally, psychosocial pre-habilitation based on supportive behavioral therapies and improved mental wellbeing have been shown to improve outcomes in cancer and reduce postoperative chronic pain.²⁶ For example, in this present case, the index patient would choose to enter the operating room in a calm and benevolent atmosphere, where the team would play his preferred choice of music: Zuill Bailey's rendition of Bach's Cello Suite No. 1 Prelude in G Major. This choice highlights the importance of tailoring even the most minute details of the prehabilitation plan to the individual patient's objective disease and subjective preferences by the MDT.
Our index case patient suffers from idiopathic pulmonary fibrosis (IPF), which is a disease process with unique comorbidities to consider when evaluating for an anesthetic.⁹,¹⁰ Prior to evaluating the patient, the anesthesiologist should review the history and preoperative diagnostic work-up for signs of IPF-related comorbidities including gastroesophageal reflux, gastroesophageal dysmotility, coronary artery disease, right ventricular dysfunction, or signs of adhesions on preoperative thoracic imaging.⁹,¹⁰ Combining these factors as well as published predictors for intraoperative course related to recipient ESLD should inform the anesthesiologists' discussion with the patient in the preoperative area. Data have shown that cystic fibrosis (CF) and chronic obstructive pulmonary disease/emphysema (CE) have a simpler intraoperative journey, leading to an increased likelihood in extubation in the operating room as compared to IPF patients, with IPF patients also having a higher incidence of unplanned intraoperative and postoperative extracorporeal membrane oxygenation (ECMO).²⁷ Preparing for an informed discussion with the patient, one should consider discussing the entire range of possibilities, ranging from a fast-track extubation to a prolonged ECMO course.²⁸

One of the primary aspects of the clinical exam is to determine the impact of the etiology of ESLD on the function of the cardiopulmonary unit. Our index patient's history suggests numerous things that point towards a relatively acute decline in cardiopulmonary function in the past several weeks – decreased functional capacity, increased supplemental oxygen requirements, worsening orthopnea, and elevated pulmonary arterial pressures on the recent right heart catheterization. These recently obtained clinical data must be considered within the temporal context of the transthoracic echocardiogram, which was performed 6 months prior to the hospitalization. Abu et al described the differences between echocardiography versus right heart catheterization in preoperative evaluation of lung transplantation patients. Utilizing a retrospective cohort of nearly 400 recipients, the echocardiographic estimation of pulmonary arterial systolic pressure was limited as compared to right heart catheterization.²⁹ Combining these data with the temporal decline or improvement of the patient's clinical status allows the anesthesiologist to better formulate a real-time assessment of the cardiopulmonary unit function.

However, these data do not preclude the utilization of real-time echocardiography during the immediate preoperative evaluation phase. On the contrary, the utilization of point of care ultrasound (POCUS) is a necessity for the anesthesiologist during the immediate preoperative evaluation.³⁰ Evaluation of the impact of increased right ventricular afterload secondary to pulmonary hypertension should look for both acute and chronic changes in right

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ventricular anatomy and function. Acute changes include the presence of a relative increase in right ventricular chamber diameter, new onset flattening of the interventricular septum, relative increases in tricuspid regurgitation, and relative decrease within indices of right ventricular function. The most important chronic change to assess for is right ventricular hypertrophy, as these patients may present with dynamic right ventricular outflow obstruction during the intraoperative phases of care including induction, implantation, or following pulmonary arterial clamp release.³¹ Beyond evaluation of the heart, the evaluation with POCUS should include gastric ultrasound to assess aspiration risk, lung ultrasound to assess for the presence or absence of pulmonary edema/effusion, pulmonary atelectasis, or diaphragmatic function.³⁰,³² Once a thorough history and physical has been performed, the induction strategy should focus on an approach tailored to ESLD in order for the anesthesiologist to predict and avoid pitfalls associated with the recipient ESLD co-morbidities.

Successful induction of our index patient should deploy appropriate pre-induction monitoring and anesthetic strategy for presumed worsening right ventricular dysfunction in the setting of increased acute pulmonary hypertension. Hargrave described the considerations for pre-induction monitor placement as well as strategy (Figure 1) in this patient population.³³

<figure><img src="image_2.png" /></figure>

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Figure 1: Possible physiologic effects of general anesthesia induction and positive-pressure ventilation on right ventricular function in patients with pulmonary hypertension and compromised right ventricular function. Adapted from Hargrave with permissions.³³

Data are lacking regarding ideal monitoring strategy, however, in our index patient we would place an awake right arterial line to allow for real-time beat to beat monitoring. We would avoid placement of an awake central venous cannula or pulmonary arterial cannula for several reasons. First, patient discomfort may lead to increased sympathetic activity. This increased sympathetic activity may lead to increased pulmonary arterial pressures, as would any potential hypoventilation resulting from sedating medications used to decrease patient anxiety, although this may be attenuated by utilizing our self-hypnosis toolbox for the patient. Second, an acute failing right ventricle may be prone to increased arrhythmias related to central venous wire and/or pulmonary arterial catheter placement. Once monitors are placed, the induction strategy would focus on minimizing alterations in systemic perfusion pressure, tachycardia, and right ventricular volume overload. While medication preferences differ, the utilization of an ongoing low-dose norepinephrine infusion during induction would help our index patient achieve these goals. The airway would be acquired as rapidly as possible, as hypoxic episodes during induction can quickly lead to cardiac arrest in ESLD patients. In the immediate post induction period, caution would be noted to maintain the balance of hemodynamics in the setting of positive pressure ventilation, which must be balanced to avoid both decrease in right ventricular preload and increase in right ventricular afterload. Achieving this balance in our index patient would be guided by a dynamic composite evaluation utilizing intraoperative transesophageal echocardiography (TEE), pulmonary arterial pressures via a Swan-Ganz catheter, and systemic arterial pressures while avoiding the integration of central venous pressure monitoring due to its inadequacy as a useful hemodynamic monitor.³⁴

Guiding Hemostasis with Coagulation Point of Care Management

During dissection phase of lung transplantation, and in preparation for explantation, we would have a special attention to optimizing perioperative hemostasis. Although perioperative transfusion to the donor and recipient has been widely associated with an increased risk of PGD and 1-year mortality³⁵⁻³⁷, it is difficult to determine whether the impact of transfusion is related to the nature of the products administered or to the bleeding
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that led to the transfusion. Notwithstanding, the intraoperative hemoglobin threshold is not clearly defined, with
most centers advocating for a restrictive strategy. The first step in avoiding intraoperative transfusion is preoperative
optimization, and our index patient would undergo evaluation for and correction of any underlying anemia at a
specialized outpatient clinic. The next step focuses on intraoperative strategy, where a goal-directed transfusion
strategy would be deployed based on point-of-care coagulation testing (POCCT). Smith et al evaluated POCCT in
lung transplantation when they examined a retrospective cohort of 93 patients comparing a specific algorithm based
on rotational thromboelastometry (ROTEM) and platelet aggregometry assays to standard of care. All lung
transplantations were conducted with cardiopulmonary bypass (CPB), and the POCCT-based strategy resulted in
fewer blood transfusions without significant changes in outcome. They also performed a cost-analysis, which
demonstrated an overall reduction of cost of transfusion after introducing this strategy.³⁸ A randomized controlled
trial by Durila et al also examined POCCT in lung transplantation when they compared ROTEM to standard of care.
Although the study was complicated by differing fluid resuscitative strategies between the two arms (albumin 5% in
POCCT group versus crystalloids in non-POCCT), the study was stopped prematurely after interim statistical
analysis due to superior results in the POCCT/ROTEM group.³⁹ Their findings of decrease in perioperative blood
loss and blood product consumption guide our recommendation to engage a POCCT-based strategy within our index
patient's case. While ROTEM has been the predominantly studied POCCT, an ongoing multicentric randomized
controlled trial (NCT05798286) with Quantra technology may provide another POCCT monitor to guide
coagulation strategy in lung transplantation.

Strategy for Choosing and Managing Intraoperative ECLS

Lung transplantation can be performed with or without ECLS. Strategies vary from center to center, with
some preferring an off-ECLS approach, while others prefer a variety of ECLS ranging from veno-venous (VV)
ECMO, veno-arterial (VA) ECMO, or CPB. CPB was the first ECLS approach used historically in lung
transplantation. Mohite et al retrospectively examined outcomes between an off-ECLS approach with an “elective
CPB” versus “unplanned conversion to CPB” group.⁴⁰ A total of 302 patients across a 7-year cohort were examined,
and the reported conclusion was that off-ECLS improved early outcomes and survival as compared to CPB
utilization. Subsequently, Hoetzenecker et al compared off-ECLS approach with a planned VA ECMO approach in a
retrospective analysis.⁴¹ Their reported findings showed a greater survival in the planned VA ECMO group as
compared to the off-ECLS approach at 1-, 3-, and 5-year time intervals. Finally, Magouliotis et al reported a meta-analysis of 7 studies comparing CPB and ECMO.⁴² They reported improved rates of PGD and decreased rates of morbidity in the ECMO group as compared to the CPB group.

These reported data helped to shape our approach in considering how to choose and manage our index patient's lung transplantation ECLS strategy. Considerations for choosing the appropriate ECLS strategy include patient factors, ECMO cannulation strategy, and requisite team expertise for intraoperative management. Our index patient, suffering from IPF complicated by an acutely worsening cardiopulmonary unit secondary to increased pulmonary pressures, would clearly benefit from the environment of hemodynamic stability and protective ventilation strategy that VA ECMO provides.⁴¹ Additionally, the attenuation of the ischemic-reperfusion injury provided by VA ECMO has been suggested to decrease rates of PGD across multiple etiologies of recipient ESLD.⁴³, ⁴⁴ The cannulation for ECMO, which can vary significantly across ECMO types⁴⁵, would be a planned central VA ECMO after induction of anesthesia. In order to reduce the risk for ECLS-associated bleeding, anticoagulation would be limited to a single dose of 3,000 units of heparin before ECLS cannulation. Coated ECLS cannulas would be used, therefore activated clotting time (ACT) monitoring or repeated doses of heparin during the procedure would not be necessary.

Intraoperative management of ECMO should be guided through an organ-system based strategy to optimize cardiac, respiratory, neurological, and hematological function.⁴⁶ The balance of intrinsic cardiac output with VA ECMO flow can be guided by indices of systemic perfusion such as urine output, acid-base balance, lactate and end-tidal carbon dioxide combined with ongoing TEE assessment of the perfused pulmonary vein velocity time integral.⁴⁶ In general, ECMO blood flow of 40-50% of the calculated cardiac output should be the perfusion goal. This level of flow generally promotes hemodynamic support and facilitates protective ventilation strategies whilst maintaining a low transpulmonary flow, thus avoiding stasis and the risk of in situ thrombosis of the new implanted donor organ. We would choose to utilize a hybrid VA ECMO circuit, which provides the ability to perform VA ECMO at a significantly reduced cost as compared to a standard ECMO circuit.⁴⁷ Our cardiac strategy would focus on maintaining hemodynamic stability and systemic perfusion. Our respiratory strategy would employ a lung protective ventilation strategy tailored to both recipient ESLD pre-explantation and standard practice to protect the new grafts post-implantation.⁴⁸ Anesthetic depth would be monitored with electroencephalogram monitoring, with
cerebral oximetry employed to ensure localized perfusion of the brain.⁴⁶ Finally, appropriate hematological monitoring, both to limit transfusion burden as well as guide ECMO anticoagulation, would employ point of care techniques which have been shown to decrease perfusion and perhaps improve outcomes.³⁹, ⁴⁹

ECMO circuit considerations include the impact on TEE measurement accuracy⁴⁶, dosing of antibiotic therapy⁵⁰, and management of vasoplegia. Once the lungs are implanted, measuring the vascular anastomoses to assess their diameter and peak velocities is vital to ensure they are patent.⁵¹ However, due to the diversion of intracardiac preload to the ECMO circuit, measurements should be made once completely separated from VA ECMO. Two systematic reviews, separately reporting pulmonary arterial and venous recommendations, provide guidance for our assessment of anastomotic adequacy.⁵², ⁵³ The ECMO circuit has been noted to sequester anti-infective medications, which may theoretically impact overall dosing regimens. Lyster et al studied sequestration of commonly used anti-fungal medications within ECMO circuits using an ex-vivo model.⁵⁰ The results were notable in that the authors concluded it was possible that therapeutic levels of anti-fungal agents may possibly not be achieved with general standardized doses for patients whilst undergoing ECMO therapy. These data would lead us to consider a theoretical dosing strategy that would attenuate such a risk. Finally, vasoplegia has been reported to be associated with any form of ECLS in cardiothoracic surgery and was reported by Sef et al to be associated with poor outcomes.⁵⁴ While ideal treatment for vasodilatory shock associated with cardiothoracic transplantation has not been elucidated in the literature, we would prefer an early vasopressin⁵⁵ and angiotensin II strategy.⁵⁶

## From Operating Room to Discharge: Strategy to Enhance Recovery and Pain Management

At the end of the surgery, we would aim de-escalate ECMO and try to extubate the index patient in the operating room to reduce the risk of morbidity as related to ongoing ECLS and mechanical ventilation. A recent study examined the results of an operating room extubation strategy, with 36% of their cohort achieving it across a wide variety of ESLD.²⁸ Prior to extubation, all patients had to pass a structured de-escalation trial. First, they reduced the ECMO to a minimum flow (around 1.5 L/min) and evaluated the patients for any ongoing deterioration in their right ventricular function or global cardiac output. The adequacy of the patient's intrinsic macrocirculation was assessed with TEE and mixed venous oxygen saturation while microcirculation was evaluated by evolution in

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blood lactate levels.⁵⁷ The assessment also included evaluation of graft function, utilizing arterial blood gas draws at minimal ECMO flows to ensure adequacy of proper gas exchange (PaO2/FiO2 > 200). Second, ECMO was removed and the patient was extubated if they met criteria for the Paul S. Myles magic bullet points.⁵⁸ Combining these published approaches, we would aim for our index patient to be normothermic, on a low-dose of vasopressor, blood lactate level below 2.6 mmol/L, de-curarized, and weaned from sedation utilizing a target control infusion based on anesthetic depth sedation monitoring.⁵⁹ Apart from reducing ventilator-induced lung injury, early extubation in the operating room would be helpful to quickly begin the post-rehabilitation program consisting of tailored physiotherapy, early oral feeding, and removal of invasive hemodynamic monitoring.⁶⁰,⁶¹

A key part of the post-transplantation recovery strategy for our patient is the control of analgesia.⁶² This is based on multi-modal analgesia, with a key focus on loco-regional tailored to surgical incision approach. The deployment of loco-regional must not only be aimed at attenuating pain at rest but also with movement postoperatively, thus allowing for active post-rehabilitation. This active post-rehabilitation, and the role multi-modal analgesia plays in optimizing it, is key to limit muscular deconditioning. In our case, preoperative epidural placement is the preferred approach. Combining a low-heparin VA ECMO strategy with preoperative catheter placement should have minimal hematoma risk, and the overall benefit/risk balance favors preoperative placement.⁶³,⁶⁴ A possible less invasive alternative would be chest wall blocks, such as a bilateral serratus block at the end of the procedure⁶⁵, although this would avoid the benefit of pre-emptive analgesia.⁶⁶ A final alternative to consider is cryoablation⁶⁷, but it remains controversial because of the risk of nerve damage, loss of respiratory muscle contraction, and chronic neuropathic pain.

A final consideration in the recovery of our index patient is the assessment and treatment of chronic pain, which has a high prevalence in the lung transplantation population. Laurent et al recently reported a prospective cohort study of 72 patients who had chronic pain (score > 3/10 in 57%) and chronic neuropathic pain in 26.5% of recipients at the 6-month post-surgical checkup.²⁶ This pain was associated with a poor quality of life and predicted only by maximal preoperative pain score. Smith et al examined the psychosocial consequences of poor quality of life in transplant recipients' mortality, and found that both depression and distress at the 6-month post-surgical checkup were associated with increased mortality risk.⁶⁸ The postoperative recovery strategy of our index patient, with immediate foundations of attenuating PGD and optimizing pain control, would also include an early enrollment

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within a parallel psychosocial program to encourage mental health, social engagement, and medication adherence in the outpatient setting.

## Conclusion

The foundation of how I would treat my own lung transplantation is the multidisciplinary team. The integration of the multidisciplinary team, which consists of a diverse set of physician/non-physician members and the patient, across the entire perioperative spectrum is key for optimizing patient outcomes. While our index case was theoretical, the evaluation of the topics discussed included data-driven recommendations as well as theoretical topics that demand investigation. As such, members of the lung transplantation team should always approach clinical strategy with a mix of humility and science, allowing for nuance to be discussed amongst ongoing collaborations between centers across the globe.

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