Lung Transplantation for Pulmonary Artery Hypertension

Abstract

This manuscript discusses the role of lung transplantation in patients with pulmonary hypertension. The indications and timing for referral to a transplant unit and timing for wait-listing for lung transplantation are discussed. The type of transplantation—isolated (single or double) lung transplantation and situations when combined heart and double lung transplantation is indicated—will be elaborated. Escalation of medical therapy with the need and timing for bridging therapies such as extracorporeal membrane oxygenation until an appropriate organ becomes available will be discussed. Challenges in the postoperative period, specific to lung transplantation for pulmonary artery hypertension, will be reviewed. The outcomes following lung transplantation will also be considered in greater detail.

1. Introduction

Lung transplantation (LT) is a recognized therapy for appropriate patients with end-stage lung disease (ESLD) due to idiopathic pulmonary artery hypertension (IPAH) who remain symptomatic and continue to clinically worsen despite maximal medical therapy. It offers both symptomatic and survival benefits in such patients [1].

This review begins with a historical note on pulmonary hypertension (PH) and LT in general and for PH. The current global burden of the disease is discussed, along with the number of LTs done annually worldwide, to highlight the current supply-demand imbalance. The indications, with timing for referral and listing for transplantation and contraindications, are reviewed. Surgical considerations, along with possible complications and outcomes, are elaborated. The global and Indian scenarios are discussed, along with a mention of the possibilities for the future and the road ahead.

While data for all aspects of (PH) and LT are available for the developed countries, data are sparse and of rather modest quality from developing countries like India—whose economy is on the rise. We shall also discuss the global scenario and that of India with a brief mention of data from our unit.

2. Historical considerations

2.1 Historical aspects of PH

Despite being initially classed an “orphan disease,” numerous randomized controlled trials (RCT) for targeted therapy in PAH have been performed [2], and a lot of research done on this disease shows that from a global perspective, PH has indeed attained epidemic proportions.

Since the late 1800s, varied reports about PH have been available in the literature. A review article in 2019 highlighted the pivotal position of the development of right heart catheterization (RHC) and discussed the history of diagnosis of PH in 2 different eras—the pre-RHC and post-RHC eras [3].

2.1.1 Pre-RHC Era

Ernst von Romberg, a German physician, was the first to describe post mortem findings of sclerosed pulmonary blood vessels (pulmonary vascular sclerosis) in 1891. The 24 year-old patient had no obvious cardiac or lung disease, but suffered from severe dyspnea, chronic dizziness and cyanosis shortly before death.

In 1901, Abel Ayerza, an Argentina physician, described a similar clinical condition referring to it as “cadiaco negros” or black cardiac disease, and it became to be known as “Ayerza’s disease.”

Over the next few years, Escudera and Warthin in 1919 felt that this was due to syphilis. Oscar Brenner refuted the syphilitic etiology in 1935 [3] after a study of 100 cases. The term PH was suggested with reluctance by Terence East after a report on 3 cases in 1940 [4]. Although De Navasquez et al. suggested the term “pulmonary arteriosclerosis” briefly in their article, after an autopsy report of 3 cases in 1940, in their concluding remarks, they recommended using the term “idiopathic right ventricular hypertrophy” for this condition [5]. The diagnosis, then, was mostly made postmortem, and the absence of any technique to measure the pulmonary artery (PA) pressure antemortem stood in the way of confidently making a diagnosis of PH.

2.1.2 RHC

The first ever cardiac catheterization by Werner Forsmann (in himself), a German medical resident in 1929, opened the gates to the subsequent development of a cardiac catheterization lab [6]. The contributions of Cournand and Richards in 1944 led to accurate hemodynamic studies by RHC [7].

2.1.3 Post-RHC era

Following the advent of objective hemodynamic studies, the term “primary” pulmonary hypertension was then used in 1951 by Dresdale et al. [8].

2.2 Historical aspects of LT

Hardy et al. described the first LT in humans in 1963 [9]. Cooley did the first combined heart-lung transplantation (HLT) in a patient who survived only 14 h.

The first successful HLT for pulmonary vascular disease was performed in 1981 and reported by Reitz et al. [10], and the first successful isolated LT was reported in 1983 by the Toronto Lung Transplant Group [11]. The same group reported the first successful bilateral LT in 1986 [12].

The Indian scenario, as regards LT, has been one of gradual progress [13]. Of note, due to conditions peculiar to the Indian subcontinent, HLT is more often performed when compared to the developed countries [14].

2.3 Historical aspects of therapy for PH

It is, indeed, noteworthy that the first ever definitive treatment for PH was HLT—which was successfully performed in 1981. It was only 14 years later, in 1995, that the first drug—epoprostenol—was approved by the Food and Drugs Administration, United States (FDA) as targeted therapy for PH. Subsequently, over the years, numerous drugs have been found to be beneficial and approved for use by the FDA.

3. Number of LT performed worldwide and current global burden of PH: a supply–demand imbalance

While exact figures for the prevalence of this disease are unknown, global estimates suggest a prevalence ranging from 20 million to 70 million people [15, 16]. The prevalence is more in developing than in developed countries [17]. It is estimated that 80% of patients with PH live in developing countries, and the likelihood of developing PH is twice that in developing countries as compared to in developed countries [18].

As per the International Society for Heart and Lung Transplantation (ISHLT) Registry data, 67,493 LTs were performed worldwide from Jan 1992 to June 2018. Of these, 62,446 (92.5%) were performed in developed countries (North America and Europe). The remaining 7.5% of the cases were performed in the rest of the world—including developing countries. It has been estimated by the ISHLT that the figures reported may represent 80% of the transplant activity globally [19].

Another data set looking at transplants done worldwide between Jan 1995 and June 2018 reported only 1863 (2.9%) LTs done for PAH out of a total number of 63,530 LTs done worldwide during that period [20].

Based on data from Global Observatory on Donation and Transplantation (GODT), for the year 2021, a total of 6470 LTs were done worldwide [21]. Of these 6470 LTs, the contributions from each of the World Health Organization (WHO) regions [22] are as under: Region of Americas (AMR) 3096, European Region (EUR) 1964, Western Pacific Region (WPR) 1233, South East Asian Region (SEAR) 134, Eastern Mediterranean Region (EMR) 43, and African Region (AFR) 0. The number of LT from the SEAR, EMR, and AFR is only 177 (2.7%) LT in the year 2021.

The above data demonstrates the big divide between developed and developing nations. While the prevalence of PH is very high, the number of LT is disproportionately low, demonstrating an acute supply–demand condition.

In India, the data from Indian Transplant Registry (INTRAN) shows that a total of 473 LTs have been done until Feb 2023 [23]. A recent review article [24] has summarized the evolution of LT in India with available data stratified by the number and types of operations in various states from inception until the time of publication.

We have previously reported a 3-year survival in LT performed for ESLD due to all lung disease categories (including IPAH) of 76.2% [25].

In our unit in Chennai, India, 18 patients with ESLD due to IPAH have been wait-listed for transplantation.

Of these 18 patients, 14 patients underwent HLT. Given the late presentation, which is a common problem in India, all the patients had significant right ventricular (RV) dysfunction. Our unit’s policy has been to consider HLT for patients with severe RV dysfunction. Three patients died on the waiting list due to disease progression, and one patient currently awaits transplantation.

Among the 14 patients who were transplanted, there were 3 early deaths—1 due to bleeding and 2 patients succumbed to sepsis. There were 5 patients (36%) who developed primary graft dysfunction (PGD), out of which 4 patients required veno-venous (VV) extracorporeal membrane oxygenation (ECMO) for Grade 3 PGD. Three out of the 4 patients (75%) with post-op ECMO recovered fully, while 1 patient developed septic shock and died. The 1-year survival after HLT for IPAH in our unit is 79%.

4. Registries and risk stratification models in PH

4.1 PH registries

Numerous registries exist for PH [26], which help in the understanding of the disease and help in the development of risk stratification of models, which include the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL); Swedish Pulmonary Arterial Hypertension Registry (SPAHR); Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA); and French Pulmonary Hypertension Network Registry (FPHR). Others include registries in developing countries [27] and the Spanish Registry survival of PH [28].

4.2 Risk scoring systems

Notable risk stratification scores for PH include REVEAL Score 2.0; FPHR, SPHAR, and COMPERA risk assessment strategies; and the 2015 ERS/ESC PH risk table, which have been analyzed and reported.

REVEAL 2.0 scoring system [29] has 14 variables and categorizes patients into 3 groups: low risk (REVEAL Score </= 6), intermediate risk (REVEAL Score 7 & 8), and high risk (REVEAL Score >/= 9). The 2015 ERS/ESC PH guidelines [30] have also categorized patients based on predicted 1-year mortality into 3 groups: low risk (<5%), intermediate risk (5–10%), and high risk (> 10%).

4.3 Need for serial risk stratification

Risk stratification using objective scoring systems is a very important aspect of treatment for IPAH because treatment recommendations and algorithms are recommended based on risk stratification. At the same time, the first risk assessments allow the physician to decide on appropriate targeted therapy. Serial assessments by objective scoring help in assessing response to therapy and prognosis. Any deterioration is picked up early, and either therapy is escalated, or referral to an LT center is done—before it is too late [31].

4.4 Other assessments for risk stratification

Since both the above models have some limitations, in addition to the above scores, further clinical assessments like 6MWT (6-minute walk test) and investigations echocardiogram, cardiac MRI (magnetic resonance imaging), and serial biomarkers like NT-pro-BNP should be considered for serial risk assessment.

5. Clinical trials in PH

PH has been the subject of numerous clinical trials, which have changed the landscape of this dreadful disease over the decades, thereby improving the outlook of numerous patients. A review article has elegantly discussed the evolving landscape of clinical trials in PH [32]. There has been a sea change in IPAH from the rather dismal “the kingdom of near dead” [33] to “multiple clinical trial meta-analysis” [34]. As many as 41 RCTs in PH have been described until recently [35].

6. Indications, contraindications, and candidacy assessment for LT

6.1 Indications and candidate selection for LT

The general indications (apart from specific indications) for LT in end stage lung disease who are very symptomatic despite maximal optimal medical therapy include the following:

• 50% chance of dying in the next 2 years without a transplant

• 80% chance of surviving 90 days posttransplant

• 80% chance of surviving the next 5 years from a medical perspective, provided the graft function is adequate.

For LT, disease-specific indications have also been described [36].

The available risk stratification models allow serial risk assessments and pick up patients who are deteriorating early on, thereby permitting earlier and timely referral for LT.

The indications and selection of candidates for LT were well-documented in 2015 [37] and the updated 2022 ERS/ESC PH guidelines [38] as well as the ISHLT 2014 consensus document [39] and updated ISHLT 2021 consensus document [40].

LT appears to be the only definitive therapy in patients who deteriorate despite full medical therapy. It is not a therapeutic option that can be provided at short notice. LT requires assessment for candidacy and wait-listing, which can be time-consuming. Moreover, the waiting times are unpredictable, and if HLT is needed, waiting times could be longer.

Given the nature of IPAH and its propensity for sudden deterioration despite therapy and the uncertainties involved in LT, it is suggested that patients are referred to a transplant center at an earlier stage prior to major clinical deterioration—so that valuable time is not lost.

6.1.1 Types of timing

In view of the uncertain disease progression in PH and uncertainties in LT, guidelines and consensus documents emphasize the importance of “timing,” which is of 2 types.

6.1.1.1 Timing for referral to a transplant center

Referral for transplantation is ideally done well in advance before the patient deteriorates and becomes urgently in need of transplantation.

Patients on targeted therapy for IPAH should be risk stratified, and this has to be serially done. The goal of therapy is to maintain a “low risk” status by either REVEAL or ERS 2015 risk assessment tools. In case of failure of therapy to prevent progression to “high risk” status after 3–6 months, the guidelines recommend referral to a transplant center. Consideration of referral to a transplant center does not necessarily mean that the patient will be wait-listed immediately. It is just to get assessments for candidacy and discuss future options.

The ISHLT 2021 consensus document [40] suggests the following “timing for referral when

• ESC/ERS intermediate or high risk or REVEAL risk score 8 despite appropriate PAH therapy.

• Significant RV dysfunction despite appropriate PAH therapy

• Need for IV or SC prostacyclin therapy.

• Progressive disease despite appropriate therapy or recent hospitalization for worsening PAH

• Known or suspected high-risk variants such as PVOD/PCH, scleroderma, and large and progressive pulmonary artery aneurysms

• Signs of secondary liver or kidney dysfunction due to PAH

• Potentially life-threatening complications such as recurrent hemoptysis.”

6.1.1.2 Timing for listing in a transplant center

Timing for listing as opposed to “referral” is when the patient has deteriorated further, and decisions for LT have been made.

The ISHLT 2021 consensus document [40] suggests the following “timing for listing when

• ESC/ERS high risk or REVEAL risk score > 10 on appropriate PAH therapy, including IV or SC prostacyclin analogue

• Progressive hypoxemia, especially in patients with PVOD or PCH Progressive, but not end-stage, liver or kidney dysfunction due to PAH

• Life-threatening hemoptysis”

The 2022 ERS/ESC PH Guidelines [38] offer similar recommendations regarding timing for referral and listing for LT.

• “It is recommended that potentially eligible candidates are referred for LTx evaluation when they have an inadequate response to oral combination therapy, indicated by an intermediate–high or high risk or by a REVEAL risk score > 7

• It is recommended to list patients for LTx who present with a high risk of death or with a REVEAL risk score ⩾10 despite receiving optimized medical therapy, including s.c. or i.v. prostacyclin analogues.”

The level of evidence for both the above recommendations is C [38].

6.1.2 Contraindications for LT:

Due to advances in all disciplines—surgical, pharmacological, immunology, basic sciences, care in the intensive care unit (ICU), and mechanical circulatory support—patients are now being considered for LT, whose clinical profiles a few decades ago might be considered prohibitively risky. The current contraindications for LT are listed in a recent consensus document by INSHLT [40].

6.1.3 Pretransplant workup, candidacy assessment, and decision-making process

This requires a comprehensive work of all systems of the body and has already been described previously [13, 40, 41].

Following the workup, we follow a 3-question decision-making process [13]:

1. Have we confirmed the disease is end stage, and no non-transplant options are available?

2. Are the other body systems adequately functioning to cope with a transplant operation?

3. Have we ruled out major absolute contraindications?

If the answers to all three questions are in the affirmative, a decision to proceed with wait-listing is considered after fully informed consent by the patient and family.

The risk assessment process takes the following into account.

Risk versus benefit of the proposed transplant.

Risks with transplant versus risks without transplant.

If the above risk profile is acceptable and patients provide fully informed consent, the patient is wait-listed for the appropriate transplant operation.

7. Pretransplant management of wait-listed patients

7.1 Care of stable patients at home

Maintenance of the status quo by taking care, whenever possible, to prevent deterioration until an organ is available would be the central aim. The cornerstone would be adherence to maximal and optimal medical therapy, ensuring compliance with salt and fluid restrictions and nutritional [42] and physical rehabilitation. Ensuring adequate intake of vitamins and trace elements while adhering to prescribed salt and fluid restriction is mandatory.

Physical therapy has plenty of beneficial effects [43, 44, 45, 46, 47] and is best performed under the guidance of the physiotherapist. Graded exercise regimens are to be undertaken to avoid heart rates of over 110/minute during exercise. Point-of-care testing could be done at home, such as pulse oximetry and blood pressure recordings. 6MWD can be easily measured at home. Any deviation from the accepted range of values can be brought to the attention of the transplant team for immediate action.

Avoidance of infection and oxygen supplementation, as advised, should be followed religiously.

7.2 Care of patients with clinical deterioration in ICU

7.2.1 Evaluation and monitoring

In addition to basic monitoring like continuous ECG, pulse oximetry, and respiratory rate on a cardiac monitor, these patients will also require invasive hemodynamic monitoring such as conitnuous arterail pressure and central venous pressure (CVP) monitoring. Insertion of Swan Ganz catheter may be needed in sick patients for monitoring pulmonary artery pressures (PAP), pulmonary capillary wedge pressures (PCWP), cardiac index (CI), pulmonary vascular resistance (PVR), and systemic vascular resistance (SVR). In these sick patients accurate fluid balance records must be maintained. Insertion of urinary catheter helps by monitoring hourly urine output. Almost always, these patients are volume overloaded, and boluses of volume infusion during hypotension must be avoided [48, 49].

7.2.2 Optimizing RV function

Optimizing RV function is the most important after treatment of the precipitating cause of exacerbation. Echocardiographic assessment of the RV indices, including RA, RV chamber size, and septal position, guides therapy and monitoring response. CVP measurements are monitored, and negative fluid balance with a view to reducing RA pressure is done. Bolus doses and infusion of intravenous diuretics often help. If adequate diuresis is not achievable, ultrafiltration needs to be considered.

Atrial arrhythmias are to be controlled by the correction of electrolyte imbalance and antiarrhythmic drugs, and if not controlled by the above, DC cardioversion is considered.

IV ionodilators such as milrinone and dobutamine help in optimising RV function, but frequently require concomitant vasopressors such as noradrenaline and vasopressin. Of the 2 vasopressors, vasopressin is preferable due to its pulmonary vasodilatory effects [50, 51].

Intravenous or inhaled pulmonary vasodilators are to be used when available. IV prostacyclin or inhaled prostaglandin, or IV sildenafil—given that the oral absorption of orally available pulmonary vasodilators may be suboptimal—is to be considered and used appropriately.

7.2.3 Mechanical ventilation

When other methods of oxygen delivery fail, and MV is mandatory, the deleterious effects on RV function need to be borne in mind, being ready to commence suitable inotropes and being ready for further escalation with mechanical circulatory support (MCS), if required.

7.2.4 Escalation to bridging therapies

Bridging therapies are only considered in

• Patients where recovery from the current deterioration is likely—Bridge to recovery (BTR)

• Suitable patients awaiting LT or are LT candidates—Bridge to Transplant (BTT)

7.2.4.1 Bridging by percutaneous intervention

7.2.4.1.1 Balloon atrial septostomy (BAS):

Done percutaneously, this helps to off-load the RA into the left side, but at the expense of oxygen saturation [52], and improves cardiac output by augmenting preload of the LV. Resting oxygen saturations below 90%, RA pressure greater than 20 mmHg, and LVEDP greater than 18 mmHg are contraindications [53].

7.2.4.1.2 Potts Shunt

This procedure can be done both percutaneously and surgically. Given that the right-to-left shunt is distal to the LSCA, the heart, brain, and upper limbs receive oxygenated blood, and this helps in preserving myocardial function while decompressing the right heart at the same time.

7.2.5 Bridging by MCS

7.2.5.1 ECMO

The most commonly used MCS for RVF [48, 54] due to PH is ECMO, which can be safely instituted at the bedside. ECMO is used most often as a BTT and occasionally as a BTR.

Most often, it is a peripherally inserted veno-arterial (VA) ECMO with distal arterial perfusion to avoid ischemic complications of the lower limb. On rare occasions, central-paced ECMO may be needed. ECMO helps off-load the right ventricle and helps oxygenation.

In peripheral VA ECMO, if gas exchange in the lungs is poor, there is a risk of differential oxygenation (Harlequin syndrome), with the heart and blood getting deoxygenated blood from native circulation and the lower limb getting oxygenated blood from the retrograde blood from the ECMO machine [55]. This will affect cardiac function and may need conversion to a veno-arterial-venous (VAV) configuration with an additional cannula to the superior vena cava (SVC) or RA from the arterial end of the ECMO machine to improve upper body oxygenation.

7.2.5.2 PA-LA shunt

This shunt requires surgical insertion of 2 cannulae in the PA and LA and connected to a pumpless oxygenator. The high pressure in the RV generates the flow. The main advantage is that of the oxygenated blood reaching the left side and, importantly, increasing the input to the LV, thereby preparing it for an eventual luxuriant flow from the transplanted lungs [56].

7.2.5.3 RVAD

While isolated RAVD as a support in PH has been reported [57], in comparison to ECMO, there are heightened risks of pulmonary edema and bleeding, as a result of which, it has not found widespread usage.

7.2.5.4 Outcomes after MCS for RVF in PH

The outcomes are very acceptable, given that these patients would not have survived without MCS support. A report in 2019 [48] elegantly summarizes the data from 11 studies on the outcomes after MCS in PH. Out of a group of 81 patients, 77 patients had MCS as a BTT. Of these, 72 patients out of 77 (94%) had LT. Among the 72 patients who had LT, 56 patients (78%) were discharged home.

8. Surgical considerations of LT for IPAH

8.1 The choice of type of LT

Currently, whenever feasible and in appropriate patients, DLT is the operation of choice for patients with ESLD due to IPAH and is the most commonly performed operation worldwide for this indication [20].

8.1.1 Single lung transplantation (SLT)

In view of the scarcity of organs, SLT is an alternative to HLT, which was initially done for patients with IPAH [58, 59]. It is now given up in most centers largely due to better outcomes with DLT in terms of survival, degree of recovery of right heart function, and symptomatic relief [60].

8.1.2 DLT

It is the most commonly performed type of LT for IPAH. This is borne out of the fact that 95% of all LTs for IPAH were DLTs [20]. DLT has even been recommended to be the preferred operation of choice over HLT, irrespective of the degree of right ventricular dysfunction, provided the left ventricular function is normal [61].

Furthermore, in patients with surgically correctable cardiac lesions such as septal defects, valve diseases, and coronary artery diseases, with normal left ventricular function, concomitant corrective cardiac surgery with DLT is the preferred option [62]. In patients with pulmonary artery (PA) aneurysms due to IPAH, PA plasty with DLT [63] has been reported.

8.1.3 Combined heart-lung transplantation

HLT has traditionally been the transplant operation of choice, being the first ever definitive therapy, in 1981, for ESLD due to IPAH [61, 64, 65]. By 1986, 28 cases of HLT were reported; however, at that point in time, caution was expressed in recommending it as a routine clinical intervention in view of the lack of long-term data [66]. As of now, HLT is usually considered for a subset of patients with IPAH, while the remaining great majority are offered DLT.

In IPAH patients with intrinsic LV dysfunction and objective evidence of fibrosis and scarring of RV on Cardiac MRI, HLT can be considered [62]. Anatomical aspects such as severe cardiac enlargement, which may encroach on the pleural space [62], or the presence of giant aneurysms of the PA [67] may also lead to the consideration of HLT.

HLT is being considered in some centers, given the challenges of immediate postoperative balancing of LV and RV function after DLT patients [68]. The immediate postoperative ICU management of hemodynamics is much easier in HLT, provided there is no bleeding. Furthermore, the incidence of PGD is less compared to the patients who underwent DLT [69].

8.1.4 DLT vs. HLT in patients with IPAH

The debate continues as to the most appropriate transplant surgery for IPAH.

Given the scarcity of donor organs, DLT appears to have logical appeal, and the growing literature supports its use [69, 70]. However, in a subset of IPAH patients, outcomes after DLT may fall short, and its use may result in the loss of precious organs—again, in the background of scarce resources.

While there are reports suggesting that patients with severe RV dysfunction do better with HLT [64], some authors argue that RV dysfunction, no matter how severe, should not be a contraindication for DLT [48]. Objective evidence of RV recovery after DLT for IPAH has been confirmed by CMRI [71], further supporting the choice of DLT. Despite the reduced incidence of PGD following HLT, DLT is preferred by some centers [69], given that the overall survival and freedom from chronic lung allograft dysfunction (CLAD) are similar.

Some authors [70] have defined a subset of patients for whom HLT is more appropriate. There is an increased 3-month mortality following DLT for IPAH—mostly due to severe RVF or PGD. Furthermore, there are some patients whose RV does not recover. These authors believe identifying such a subset for HLT will be beneficial. They suggest that patients below 65 years with a high risk of RV failure, PGD, and low likelihood of RV recovery should be offered HLT.

Following their institutional policy of considering HLT for patients with severe RV dysfunction, in a center in France, the reported long-term outcomes between DLT and HLT for IPAH in 291 patients showed no significant difference [68], lending credence to the view that identifying subsets of patient for HLT results in overall better outcomes.

8.1.5 Giant PA aneurysms complicating IPAH

Giant PA aneurysms rarely occur in patients with severe IPAH. While HLT can be considered [67], given the higher risk of bleeding, the scarce resource, and the increased waiting time for HLT, consideration of DLT with surgical repair of PA aneurysm is appropriate and has been reported [72, 73, 74]. Two case series [75, 76] of patients with giant PA aneurysm who have been successfully managed with DLT without recourse to HLT suggest that the option of DLT with surgical repair of PA aneurysm must be considered whenever possible.

8.2 Incisions and access to the chest cavity

8.2.1 For DLT

We routinely use clamshell incision (bilateral anterior thoracotomy with transverse sternotomy) for access [25, 77] though many centers prefer median sternotomy [78]. The clamshell incision offers excellent exposure but can be painful and affect chest wall mechanics. Sternotomy, on the other hand, is less painful, but the exposure is not as good as in a clamshell incision, especially for the pulmonary vein (PV) anastomosis on the left side [79]. While some authors report better outcomes and results with sternotomy [80, 81], there are reports showing no statistically significant differences between either approach [82]. Some centers recommend bilateral anterior thoracotomy without sternal split [83, 84]. A minimally invasive video-assisted approach has also been described for DLT [85].

8.2.2 For HLT

The most common access for HLT is via median sternotomy, though at times, clamshell may be used in case of multiple previous surgeries or anatomical situations wherein sternotomy may be a challenge.

8.3 The technique of LT

The operative techniques of LT have been well described [77, 25, 86, 87]. Only those aspects of operative technique with more than one way of performing and that significantly impact outcomes are elaborated here in greater detail.

8.3.1 Avoidance (“Off-pump”) or use of circulatory support (“On pump”) during LT

Large volume centers have routinely performed the LT “Off-pump” in about 70% of their patients [88] without the use of circulatory support, resorting to their use only in cases of intraoperative hypoxemia, hypercarbia, hypotension, or cardiac instability [89]. The newly implanted lung oxygenates the body when the second lung implantation is in progress. This requires special protective ventilatory strategies to “protect” the newly implanted lung during bilateral sequential LT.

The proponents [90] for the use of cardiopulmonary bypass (CPB) argue that not all lung injury is due to the deleterious effects of CPB and that there is 35% alveolar damage in LT performed off-pump. Furthermore, a lot of lung injury results from increased hydrostatic pressure when the clamps are released. Also, when significant hypoxia develops because of severe mismatch due to perfusion in the native lung, the native PA must be clamped urgently to improve oxygenation. This results in the entire cardiac output being diverted to the newly grafted lung. Although gradual unclamping of PA can be done, controlled reperfusion to mitigate the effects of free radical injury during reperfusion as possible with CPB is seldom possible. The planned use of CPB is always preferable to “crashing” onto CPB with uncontrolled situations leading to suboptimal outcomes.

Those arguing for the avoidance of CPB [91] often cite the deleterious effects of CPB, such as complement activation, cytokine release, exposure of blood to the air-fluid interface in the reservoir, and the ensuing intense pro-inflammatory states that occur with CPB. Furthermore, they point out the need for systemic anticoagulation and increased incidence of bleeding—requiring transfusion of blood products that could cause lung injury.

8.3.2 CPB vs ECMO

The type of circulatory support could be either conventional CPB or ECMO, which has become more prevalent in the last 2 decades. With the premise that avoiding blood products is beneficial to LT patients, the advantages of intraoperative ECMO over intraoperative CPB include lesser anticoagulation with reduced likelihood of bleeding and requirements of blood products. Studies comparing intraoperative use of ECMO and CPB have been reviewed recently [92].

While some authors report worse outcomes with the use of ECMO during LT [93], most of the studies recommend ECMO over CPB for circulatory support during LT when needed [94, 95, 96]. A meta-analysis in 2017, looking at 6 studies comparing the use of ECMO and CPB during LT [97], reported that ECMO was beneficial in terms of shorter periods of ventilation and ICU stay and reduced incidence of PGD with reduced mortality rates at 3 months and 1 year in the ECMO group.

8.3.3 “Planned” extension of intraoperative ECMO onto postoperative period

Patients with long-standing and severe IPAH have an increased PVR, which limits the return to the left ventricle leading to an underfilled LV. These patients, after DLT, are unable to tolerate the copious return to the LV through the new lungs, which have a low PVR.

To mitigate this unfavorable effect on the “unprepared” LV, it was hypothesized that a period of the planned extension of VA-ECMO onto the postoperative period would be beneficial and would gradually help the LV adapt, remodel, and handle the extra inflow. This technique resulted in survival benefits at 3 months and 1 year [98]. Other reports further confirmed this finding along with excellent cardiac function [96, 99, 100]. A reduction in the incidence of PGD was also reported following this technique [101]. A review of these studies on the prolongation of intraoperative ECMO has been reported [92].

9. Postoperative aspects and complications after LT for PH

Only postoperative aspects and complications specific to LT for PH are discussed here.

9.1 PGD

PGD is the condition most often happens within 72 h after LT and is associated with hypoxemia and opacities on chest X-ray (CXR). Based on severity, PGD can be graded from grade 0 to grade 3 [102, 103, 104]. Grade 3 PGD is often treated with ECMO, and the sooner ECMO is instituted, the better are the outcomes.

PGD occurs more often when LT is done for PH and is an important cause for heightened early mortality seen after LT for these patients [102].

9.2 Maintenance of tenuous balance between LV and RV function

The real challenge of balancing the RV and LV function after DLT for PH is one of the reasons HLT is preferred in a few units.

In severe IPAH, because of the very high PVR, a relatively reduced amount of blood gets past the pulmonary circulation onto the left atrium and LV. Thus, the native LV is chronically underfilled, resulting in a small cavity, “stiff LV” with diastolic dysfunction. After a DLT, the new lung with low resistance allows a luxuriant flow across it to the left side. This sudden “flooding” of an unprepared LV results in pulmonary edema.

Hence, the fluid balance must be judiciously managed, aiming for negative balance by reducing IV fluids and forcing diuresis. This method of treating the “flooded” LV is poorly tolerated by the dilated RV, which needs more filling. The scenario is exacerbated when there is concentric hypertrophy of RV in response to severe PH—creating a “right-sided-HOCM-like-picture” resulting in a type of dynamic RVOTO. Again, this scenario, quite paradoxically, needs volume infusion “to open” up the RV and avoidance of inotropes that can worsen RVOTO (very similar to how inotropes aggravate LVOTO in HOCM by systolic thickening of the hypertrophied ventricle).

Thus, diametrically opposing therapies must be cautiously balanced in the immediate postoperative period. For this reason, some authors electively “plan” to prolong the VA ECMO onto the postoperative period—to “prime” the LV, and excellent reports have been reported with this technique.

10. Outcomes

The outcome following LT depends on the preoperative clinical characteristics and the lung disease for which LT was performed. This is because, unlike other solid organ transplantation, the outcomes following LT depend on the disease for which LT was performed [105].

Among other classes of lung diseases requiring LT, in IPAH, the risk of developing PGD and early mortality after LT is higher than with other diseases [41].

Despite this early hump, more encouragingly, among the LT patients for IPAH who survive 3 months, the survival improves, with even further survival benefits conditional on surviving 1 year [20].

Table 1 summarises the data in a report from the ISHLT in 2019 [20] and depicts the median survival for LT all classes of lung disease. It can be seen from Table 1 that if the patients survive more than 1 year after LT, the IPAH patients enjoy an excellent median survival of 12 years, which is second only to patients with cystic fibrosis.

Disease category	Overall	3 month conditional survival	1 year conditional survival
CF	9.9	11.2	12.4
IPAH	7	10.6	12
AIATD	7.1	8.4	9.3
COPD	6	6.7	7.4
ILD – not IPF	6.7	7.6	8.5
IPF	5.2	6.3	7.3

Table 1.

Median survival in years after LT – all classes of disease.

11. Road ahead

11.1 Global perspective

Clearly, the outcome following LT has improved due to technological advances in all fields, leading to a better understanding of immunology, translating into better care postoperatively—in terms of diagnosis and treatment of rejection. While donor-derived cell-free deoxyribonucleic acid (dd-cfDNA) has been available [106, 107], methods using donor-derived cell-free ribonucleic acid (dd-cfRNA) as a liquid biopsy to give us early warning signs prior to the development of clinical rejection is very promising. Developments and advancements in the equipment for MCS further improve outcomes. The use of drones helps increase the donor pool. Ex vivo lung perfusion (EVLP) has been known to increase the donor pool. Various methods in order to “repair” donor lungs prior to transplantation have been reported [108], along with superior immunosuppression, surgical techniques, and better donor organ preservation. Donor preservation systems, while being available for decades, have improved further in recent times with regard to maintaining uniform cold temperatures with good clinical outcomes [109]. Most recently, the introduction of the Lung Composite Allocation System (CAS) in early 2023 has been expected to reduce waitlist mortality, improve posttransplant outcomes, and improve overall measures of equity [110]. A well-written editorial has been published recently, which discusses the future directions for LT makes interesting reading [111].

11.2 Indian perspective

While considerable strides have already been made in the field of heart and LT [25], it is worth keeping in mind that cutting-edge healthcare delivery across the spectrum can be labor- and resource-intensive with attendant high financial costs. Furthermore, in India, penetration by health insurance companies is very small, and most people may have to self-fund their healthcare expenses.

To minimize costs and to make this therapy available to all, several research teams involving the collaboration of clinicians and, basic science experts, mechanical engineers are in the process of developing indigenous models for drones, circulatory support needed for the care of these patients at a fraction of the current costs and thereby benefit more patients—who currently cannot afford the same.

12. Conclusion

The outlook of patients with IPAH is promising. Once an orphan disease with a bleak prognosis, the landscape of IPAH has undergone a paradigm shift. Among those patients undergoing LT, the current survival rate is excellent, with good quality of life.