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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part II: Cardiac, surgical, perioperative, operative, and post-operative challenges and management statements

      Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

      Keywords

      Glossary

      AKI
      acute kidney injury
      BLTx
      bilateral lung transplant
      CAD
      coronary artery disease
      CKD
      chronic kidney disease
      CLAD
      chronic lung allograft dysfunction
      CPB
      cardiopulmonary bypass
      CNI
      calcineurin inhibitors
      CMRI
      cardiac magnetic resonance imaging
      CO
      cardiac output
      CT
      computed tomography
      CTEPH
      chronic thromboembolic PH
      CTD
      connective tissue disease
      CV
      cardiovascular
      D/C
      discharge
      DLCO
      diffusing capacity of the lungs for carbon monoxide
      ECLS
      extracorporeal life support
      ECMO
      extracorporeal oxygenation
      EF
      ejection fraction
      EP
      electrophysiology
      ERS
      European respiratory society
      ESC
      European society of cardiology
      GFR
      glomerular filtration rate
      GJ
      gastro-jejunal
      HD
      hemodynamic
      HFpEF
      heart failure with preserved ejection fraction
      HF
      heart failure
      HLTx
      heart-lung transplant
      HTN
      hypertension
      IBW
      ideal body weight
      ICU
      intensive care unit
      iPAH
      idiopathic pulmonary hypertension
      iNO
      inhaled nitric oxide
      ILD
      interstitial lung disease
      ISHLT
      international society for heart and lung transplantation
      LHD
      left heart disease
      LIJ
      left internal jugular
      lSSc
      limited cutaneous scleroderma
      LHC
      left heart catheterization
      LTx
      lung transplant
      LV
      left ventricle
      LVEDP
      left ventricular end-diastolic pressure
      MCS
      mechanical circulatory support
      MCTD
      mixed connective tissue disease
      PGD
      primary graft dysfunction
      MAP
      mean arterial pressure
      mPAP
      mean pulmonary arterial pressure
      RHC
      right heart catheterization
      OP
      operative
      OR
      operating room
      PA
      pulmonary artery
      PAC
      pulmonary arterial cannulation
      PA's
      pulmonary arteries
      PAH
      pulmonary arterial hypertension
      PAWP
      pulmonary artery wedge pressure
      PCH
      pulmonary capillary hemangiomatosis
      PFT
      pulmonary function test
      PGD
      primary graft dysfunction
      PH
      pulmonary hypertension
      PVOD
      pulmonary veno-occlusive disease
      PVR
      pulmonary vascular resistant
      RA
      rheumatoid arthritis
      RIJ
      right internal jugular
      RP
      raynaud's phenomenon
      RSBI
      rapid-shallow breathing index
      RV
      right ventricle
      SLE
      systemic lupus erythematosus
      SL
      single lumen
      SLTx
      single lung transplant
      SPO2
      oxygen saturation
      SSc
      systemic sclerosis
      SVO2
      central venous oxygen saturation
      TEE
      transesophageal echocardiogram
      TTE
      transthoracic echocardiogram
      VADs
      ventricular assist devices
      VA-ECMO
      veno-arterial extracorporeal oxygenation
      VV-ECMO
      veno-venous extracorporeal oxygenation
      VQ
      ventilation-perfusion
      VTE
      venous thromboembolism
      WHO
      world health organization
      WSPH
      world symposium on pulmonary hypertension
      This manuscript (Part II) presents the recommendations, agreed upon by consensus of the members of the workforce and supported by the International Society for Lung and Heart Transplantation, on cardiac, surgical, perioperative, operative, and post-operative challenges and management in patients with connective tissue disease (CTD).
      Patients with CTD present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The goals of this consensus paper are to address the surgical challenges, and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

      Methodology

      As detailed in Part I of this consensus document, the strength of the agreement was based on Delphi method voting
      • Holey E.A.
      • Feeley J.L.
      • Dixon J.
      • et al.
      An exploration of the use of simple statistics to measure consensus and stability in Delphi studies.
      sent to the workforce members. The voting range for each participant was from 0 to 9, with 0 as no agreement with the statement and 8 to 9 as high agreement. A consensus agreement was considered to be present when ≥ 80% of workforce members voted 8 or higher. The final statement was done based on the results of the team's survey voting and recommendations. A comprehensive literature search and review was performed to answer the identified questions based on the published evidence, and to provide guidance based on prevailing expert knowledge and experience.

      Relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with connective tissue diseases

      Epidemiology and pathogenesis

      Estimating the prevalence of cardiac involvement in CTD across subgroups is challenging, given a discordance between clinically evident disease and autopsy reports.
      • Roldan CA.
      Chapter 35. connective tissue diseases & the heart.
      ,
      • Ansari A
      • Larson PH
      • Bates HD.
      Cardiovascular manifestations of systemic lupus erythematosus: current perspective.
      The most notable association is for Group 1 pulmonary arterial hypertension (PAH), especially in those with limited cutaneous scleroderma (lSSc),
      • Hachulla E
      • Gressin V
      • Guillevin L
      • et al.
      Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study.
      • Coghlan JG
      • Denton CP
      • Grunig E
      • et al.
      Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study.
      • Ruiz-Irastorza G
      • Garmendia M
      • Villar I
      • Egurbide MV
      • Aguirre C.
      Pulmonary hypertension in systemic lupus erythematosus: prevalence, predictors and diagnostic strategy.
      • Simonneau G
      • Montani D
      • Celermajer DS
      • et al.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      which is well described in the guidelines of the world health organization/World Symposium on Pulmonary Hypertension (WSPH). Beyond this, patients with CTD are at risk for developing other types of pulmonary hypertension (PH), including left heart disease, interstitial lung disease, or chronic thromboembolic PH (CTEPH).
      • Launay D
      • Sobanski V
      • Hachulla E
      • Humbert M.
      Pulmonary hypertension in systemic sclerosis: different phenotypes.
      • Kim NH
      • Delcroix M
      • Jais X
      • et al.
      Chronic thromboembolic pulmonary hypertension.
      • Nathan SD
      • Barbera JA
      • Gaine SP
      • et al.
      Pulmonary hypertension in chronic lung disease and hypoxia.
      • Vachiery JL
      • Tedford RJ
      • Rosenkranz S
      • et al.
      Pulmonary hypertension due to left heart disease.
      Regarding PAH, CTD associated-PAH (CTD-PAH) accounts for over half of the cases of nonidiopathic PAH and has a worse survival, with the highest risk subtype being CTD-PAH from systemic sclerosis (SSc).
      • Badesch DB
      • Raskob GE
      • Elliott CG
      • et al.
      Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry.
      ,
      • Tselios K
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      • Urowitz MB.
      Systemic lupus erythematosus and pulmonary arterial hypertension: links, risks, and management strategies.
      The best estimate of PAH prevalence in SSc comes from the Detection of PAH in SSc (DETECT) study, where the prevalence of PAH was estimated at 19%.
      • Coghlan JG
      • Denton CP
      • Grunig E
      • et al.
      Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study.
      PH in the setting of systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) is less common than SSc-PH but is often responsive to immunosuppressive therapy in conjunction with PAH specific therapy.
      • Tselios K
      • Gladman DD
      • Urowitz MB.
      Systemic lupus erythematosus and pulmonary arterial hypertension: links, risks, and management strategies.
      ,
      • Kommireddy S
      • Bhyravavajhala S
      • Kurimeti K
      • et al.
      Pulmonary arterial hypertension in systemic lupus erythematosus may benefit by addition of immunosuppression to vasodilator therapy: an observational study.
      Other cardiac manifestations include valvular dysfunction, conduction abnormalities, myocardial infiltration, pericardial involvement, and accelerated atherosclerosis from inflammation leading to ischemic heart disease.
      • Desai CS
      • Lee DC
      • Shah SJ.
      Systemic sclerosis and the heart: current diagnosis and management.
      • Meune C
      • Vignaux O
      • Kahan A
      • Allanore Y.
      Heart involvement in systemic sclerosis: evolving concept and diagnostic methodologies.
      • Kahan A
      • Coghlan G
      • McLaughlin V.
      Cardiac complications of systemic sclerosis.
      • Champion HC.
      The heart in scleroderma.
      • Comens SM
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      • Sharp GC
      • et al.
      Frequency of mitral valve prolapse in systemic lupus erythematosus, progressive systemic sclerosis and mixed connective tissue disease.
      • Rebollar-Gonzalez V
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      Cardiac conduction disturbances in mixed connective tissue disease.
      • Ungprasert P
      • Wannarong T
      • Panichsillapakit T
      • et al.
      Cardiac involvement in mixed connective tissue disease: a systematic review.
      • Tincani A
      • Rebaioli CB
      • Taglietti M
      • Shoenfeld Y.
      Heart involvement in systemic lupus erythematosus, anti-phospholipid syndrome and neonatal lupus.
      • Sattar N
      • McCarey DW
      • Capell H
      • McInnes IB.
      Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis.
      • Bissell LA
      • Md Yusof MY
      • Buch MH
      Primary myocardial disease in scleroderma-a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group.
      • Asanuma Y
      • Oeser A
      • Shintani AK
      • et al.
      Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
      While cardiac involvement in patients with CTD contributes significantly to their morbidity and mortality, limited data exist about routine screening for these entities.
      • Arnett DK
      • Blumenthal RS
      • Albert MA
      • et al.
      ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      ,
      • Peters MJ
      • Symmons DP
      • McCarey D
      • et al.
      EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.

      Diagnosis

      As noted above, PH is often a driver or a significant comorbid condition in a patient with CTD who is being considered for a lung transplant (LTx) or heart-lung transplant (HLTx). According to the most recent European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines, annual screening transthoracic echocardiography (TTE), along with pulmonary function testing (PFT) with diffusing capacity of the lungs for carbon monoxide (DLCO) and serum biomarkers (i.e., NT-proBNP) is recommended for asymptomatic SSc-spectrum disease patients.
      • Galie N
      • Humbert M
      • Vachiery JL
      • et al.
      2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
      In conjunction with the above, the adoption of the DETECT algorithm has also been suggested, whereby a score of weighted variables is generated to aid in the triage of patients for right heart catheterization.
      • Coghlan JG
      • Denton CP
      • Grunig E
      • et al.
      Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study.
      TTE serves as an important diagnostic modality across the broad spectrum of cardiopulmonary disease in patients with CTD. TTE is the initial diagnostic test of choice to assess myocardial systolic and heart failure with preserved ejection fraction (HFpEF) as well as valvular and pericardial dysfunction. HFpEF is prevalent in approximately 20% of patients and is associated with high mortality.
      • de Groote P
      • Gressin V
      • Hachulla E
      • et al.
      Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis.
      ,
      • Tennoe AH
      • Murbraech K
      • Andreassen JC
      • et al.
      Left ventricular diastolic dysfunction predicts mortality in patients with systemic sclerosis.
      Cardiovascular magnetic resonance imaging (CMRI) enables assessment of both biventricular function and evidence of pulmonary vascular disease and identification of myocardial fibrosis and inflammation.
      • Swift AJ
      • Capener D
      • Johns C
      • et al.
      Magnetic resonance imaging in the prognostic evaluation of patients with pulmonary arterial hypertension.
      ,
      • Mavrogeni S
      • Markousis-Mavrogenis G
      • Koutsogeorgopoulou L
      • Kolovou G.
      Cardiovascular magnetic resonance imaging: clinical implications in the evaluation of connective tissue diseases.
      The majority of SSc patients have such abnormalities as detected by CMRI, with a recent cross-sectional study reporting an abnormal CMRI in 43% of patients with SLE,
      • Hachulla AL
      • Launay D
      • Gaxotte V
      • et al.
      Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients.
      ,
      • Burkard T
      • Trendelenburg M
      • Daikeler T
      • et al.
      The heart in systemic lupus erythematosus- A comprehensive approach by cardiovascular magnetic resonance tomography.
      including the presence of stress perfusion deficits, pericardial effusion, and late gadolinium enhancement. These findings didn't correlate with the patient's degree of clinical symptoms.
      • Burkard T
      • Trendelenburg M
      • Daikeler T
      • et al.
      The heart in systemic lupus erythematosus- A comprehensive approach by cardiovascular magnetic resonance tomography.
      Several studies in the SSc population have shown that while resting hemodynamics may be consistent with PAH, that is, low pulmonary artery wedge pressure or left ventricular end-diastolic pressure, performing a saline challenge or exercise can unmask occult left heart disease.
      • Launay D
      • Sobanski V
      • Hachulla E
      • Humbert M.
      Pulmonary hypertension in systemic sclerosis: different phenotypes.
      ,
      • Robbins IM
      • Hemnes AR
      • Pugh ME
      • et al.
      High prevalence of occult pulmonary venous hypertension revealed by fluid challenge in pulmonary hypertension.
      ,
      • Fox BD
      • Shimony A
      • Langlebem D
      • et al.
      High prevalence of occult left heart disease in scleroderma-pulmonary hypertension.
      In addition to the hemodynamic considerations, chest imaging including computed tomography (CT) scan of the chest, ventilation-perfusion scan, PFTs with DLCO are essential to clarifying the clinical classification of underlying PH (i.e., WSPH group 3 or lung disease-associated PH, and WSPH Group 4, or CTEPH, respectively).
      • Coghlan JG
      • Denton CP
      • Grunig E
      • et al.
      Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study.
      ,
      • Launay D
      • Sobanski V
      • Hachulla E
      • Humbert M.
      Pulmonary hypertension in systemic sclerosis: different phenotypes.
      ,
      • Humbert M
      • Guignabert C
      • Bonnet S
      • et al.
      Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives.
      ,
      • Schreiber BE
      • Valerio CJ
      • Keir GJ
      • et al.
      Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function test.
      Additionally, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis are increasingly appreciated in the SSc population and may explain worse prognosis and response to PH therapy.
      • Launay D
      • Sobanski V
      • Hachulla E
      • Humbert M.
      Pulmonary hypertension in systemic sclerosis: different phenotypes.
      ,
      • Montani D
      • Lau EM
      • Dorfmuller P
      • et al.
      Pulmonary veno-occlussive disease.
      ,
      • Gupta S
      • Gupta A
      • Rehman S
      • et al.
      Pulmonary veno-occlusive disease is highly prevalent in scleroderma patients undergoing lung transplantation.
      PVOD can be difficult to distinguish from PAH. The typical histological diagnosis shows diffuse involvement of venules and septal veins by intimal sclerosis, resulting in luminal narrowing or obliteration. The hallmark findings on high-resolution CT chest include mediastinal lymph node enlargement, interlobular septal thickening, enlarged pulmonary arteries (PA's), normal caliber pulmonary veins, bilateral pleural effusions, and centrilobular ground-glass opacities.
      • Gunther S
      • Jais X
      • Maitre S
      • et al.
      Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension.
      Lastly, not all PH in CTD is PAH, and thus the etiology of PH needs to be well-elucidated as the treatment differs.
      • Launay D
      • Sobanski V
      • Hachulla E
      • Humbert M.
      Pulmonary hypertension in systemic sclerosis: different phenotypes.

      Pulmonary hypertension and right ventricle dysfunction

      While severe PAH refractory to medical therapy is an indication for LTx, an elevated mean pulmonary arterial pressure has been associated with a higher risk of primary graft dysfunction (PGD) postlung transplantation, as well as right ventricle (RV) dysfunction.
      • Van Raemdonck D
      • Hartwig MG
      • Hertz MI
      • et al.
      Report of the ISHLT Working Group on primary lung graft dysfunction Part IV: Prevention and treatment: a 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.
      ,
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      Patients with a diagnosis of PVOD require a prompt transplant evaluation, given the rapid progression of the disease and the absence of effective medical therapy.
      • Montani D
      • Lau EM
      • Dorfmuller P
      • et al.
      Pulmonary veno-occlussive disease.
      ,
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      In SSc-PAH, RV dysfunction occurs due to chronic pressure overload and SSc-related intrinsic RV cardiomyopathy.
      • Galie N
      • Channick RN
      • Frantz RP
      • et al.
      Risk stratification and medical therapy of pulmonary arterial hypertension.
      • Sanz J
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      • Bossone E
      • Bogaard HJ
      • Naeije R.
      Anatomy, function, and dysfunction of the right ventricle: JACC state-of-the-art review.
      • Tedford RJ
      • Mudd JO
      • Girgis RE
      • et al.
      Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.
      When compared to idiopathic pulmonary arterial hypertension (iPAH), RV contractile reserve is depressed in SSc-PAH at rest.
      • Hsu S
      • Houston BA
      • Tampakakis E
      • et al.
      Right ventricular functional reserve in pulmonary arterial hypertension.
      ,
      • Hsu S
      • Kokkonen-Simon KM
      • Kirk JA
      • et al.
      Right ventricular myofilament functional differences in humans with systemic sclerosis-associated versus idiopathic pulmonary arterial hypertension.
      Intrinsic RV dysfunction historically has been underappreciated in SSc patients without PH; however, with the recent advances of newer echocardiographic and CMRI techniques, it has gained recognition as a cause for worse outcomes and potential target of intervention in SSc-PAH.
      • Mavrogeni S
      • Markousis-Mavrogenis G
      • Koutsogeorgopoulou L
      • Kolovou G.
      Cardiovascular magnetic resonance imaging: clinical implications in the evaluation of connective tissue diseases.
      • Hachulla AL
      • Launay D
      • Gaxotte V
      • et al.
      Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients.
      • Burkard T
      • Trendelenburg M
      • Daikeler T
      • et al.
      The heart in systemic lupus erythematosus- A comprehensive approach by cardiovascular magnetic resonance tomography.
      ,
      • Mukherjee M
      • Mercurio V
      • Tedford RJ
      • et al.
      Right ventricular longitudinal strain is diminished in systemic sclerosis compared with idiopathic pulmonary arterial hypertension.
      ,
      • Pigatto E
      • Peluso D
      • Zanatta E
      • et al.
      Evaluation of right ventricular function performed by 3D-echocardiography in scleroderma patients.
      Most of the literature on CTD-PAH comes from studies performed on patients with SSc-PAH.
      • Durmus E
      • Sunbul M
      • Tigen K
      • et al.
      Right ventricular and atrial functions in systemic sclerosis patients without pulmonary hypertension. Speckle-tracking echocardiographic study.
      SSc-PAH has worse survival than iPAH, even with less severely compromised right heart hemodynamics.
      • Chung L
      • Liu J
      • Parsons L
      • et al.
      Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype.
      In the US REVEAL registry, 5-year survival in newly diagnosed SSc-PAH was 39.6% compared to 68% in IPAH.
      • Ramjug S
      • Hussain N
      • Hurdman J
      • et al.
      Long-term outcomes of domiciliary intravenous iloprost in idiopathic and connective tissue disease-associated pulmonary arterial hypertension.
      SSc-PAH has worse survival compared to other CTDs such as SLE and MCTD associated-PAH, which have similar survival to iPAH.
      • Durmus E
      • Sunbul M
      • Tigen K
      • et al.
      Right ventricular and atrial functions in systemic sclerosis patients without pulmonary hypertension. Speckle-tracking echocardiographic study.
      ,
      • Ramjug S
      • Hussain N
      • Hurdman J
      • et al.
      Long-term outcomes of domiciliary intravenous iloprost in idiopathic and connective tissue disease-associated pulmonary arterial hypertension.
      ,
      • Farber HW
      • Miller DP
      • Poms AD
      • et al.
      Five-Year outcomes of patients enrolled in the REVEAL Registry.

      Left heart failure

      LV diastolic dysfunction or HFpEF is particularly common in SSc, with a reported prevalence of 20% to 35% and is associated with increased mortality.
      • Meune C
      • Vignaux O
      • Kahan A
      • Allanore Y.
      Heart involvement in systemic sclerosis: evolving concept and diagnostic methodologies.
      ,
      • de Groote P
      • Gressin V
      • Hachulla E
      • et al.
      Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis.
      Evaluation and treatment for HFpEF is challenging, as LV ejection fraction (EF) is normal and dyspnea is masked by symptoms of the underlying lung disease. Patients with CTD, particularly those with SLE, SSc, and rheumatoid arthritis, have a higher incidence of valvular disease, myocardial ischemia, and microvascular endothelial disease, increasing the risk for HFpEF.
      • Chung L
      • Farber HW
      • Benza R
      • et al.
      Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry.
      ,
      • Jawad H
      • McWilliams SR
      • Bhalla S.
      Cardiopulmonary manifestations of collagen vascular diseases.
      The presence of HFrEF with an EF < 40% is usually an absolute contraindication for LTx alone, and those patients may benefit from combined HLTx, particularly when associated with severe or fixed PH.
      • Weill D
      • Benden C
      • Corris PA
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Herat and Lung Transplantation.
      ,
      • Mehra MR
      • Canter CE
      • Hannan MM
      • et al.
      The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update.
      Patients with CTD, particularly those with SLE or inflammatory myopathies (Polymyositis/Dermatomyositis), are at a higher risk of pericarditis and myocarditis, which can lead to HFrEF.
      • Chung L
      • Farber HW
      • Benza R
      • et al.
      Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry.
      ,
      • Jawad H
      • McWilliams SR
      • Bhalla S.
      Cardiopulmonary manifestations of collagen vascular diseases.
      CMRI is a very helpful tool to identify cardiac involvement, myocardial enhancement, and fibrosis. Patients with fulminant myocarditis should be treated for cardiogenic shock with inotropes while advanced HF therapies, like heart transplantation and ventricular assist devices (VADs) are reserved for patients that fail maximal medical therapy. VADs are typically contraindicated in those patients who are being evaluated for LTx alone.
      • Weill D
      • Benden C
      • Corris PA
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Herat and Lung Transplantation.
      • Mehra MR
      • Canter CE
      • Hannan MM
      • et al.
      The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update.
      • Sander GE
      • Giles TD.
      Cardiovascular complications of collagen vascular disease.

      Surgical, anesthesia, and ICU management in lung and heart-lung transplantation in patients with CTD

      Selection of transplant procedure, support strategies as a bridge for transplant, surgical planning and conduct, and intraoperative management: discussions, recommendations, and agreement strength

      Patients with CTD present unique surgical challenges to LTx and HLTx and outcomes rely heavily on disease and patient-specific factors. Surgical planning and conduct, and postoperative management (Figure 1) are key components for a successful operation and adequate long-term outcomes. This section cover these aspects to clarify common practices in successful high-volume surgical programs. The consensus group acknowledges that the paucity of evidence precludes any strong conclusions regarding the best surgical transplant selection, extracorporeal life support (ECLS) strategies, anesthesia, and ICU management in the perioperative and post-transplant period in patients with CTD. The willingness to accept any risk may vary between centers, depending on local expertise.
      Figure 1
      Figure 1Surgical Planning and Conduct and Post-Operative Management
      Legend Abbreviations: D/C, discharge; GJ, gastro-jejunal; HD, hemodynamic; HD, hemodynamic; LIJ, left internal jugular; MCS, mechanical circulatory support; OP, operative; OR, operative room; PA, pulmonary artery; PAC, pulmonary arterial cannulation; PH, pulmonary hypertension; Postop, postoperative; RIJ, right internal jugular; RV, right ventricle; SL, single lumen; TEE, transesophageal echocardiogram; VA ECMO, venous-arterial extracorporeal membrane oxygenation.

      Discussion: Selection of transplant procedure

      Bilateral lung transplant (BLTx) is most frequently utilized (up to 85% of the patients), with the theoretical benefit of improved survival, postoperative RV function and better reserve to compensate for any decline in lung function due to chronic lung allograft dysfunction over time.
      • Chambers DC
      • Cherikh WS
      • Goldfarb SB
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: Multiorgan Transplantation.
      ,
      • Fadel E
      • Mercier O
      • Mussot S
      • et al.
      Long-term outcome of double-lung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients.
      Due to the lack of definite evidence to support BLTx exclusively, single lung transplantation continues to be offered successfully in some patients with CTD in the absence of secondary pulmonary hypertension when the clinical condition requires a shorter waiting time on the list.
      Patients with severe structural or cardiac functional abnormalities or dysfunction, not likely to improve with normalization of pulmonary pressures, in conjunction with intrinsic lung disease or severe PAH, are considered for HLTx. This decision must be balanced with the likelihood of RV recovery after BLTx in the absence of objective assessment of infarcts or fibrotic changes of the RV.
      • Weill D
      • Benden C
      • Corris PA
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Herat and Lung Transplantation.
      ,
      • Mehra MR
      • Canter CE
      • Hannan MM
      • et al.
      The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update.
      ,
      • Chambers DC
      • Cherikh WS
      • Goldfarb SB
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: Multiorgan Transplantation.
      Importantly, the presence of moderate or severe LV dysfunction and/or profound RV dilation and dysfunction on high doses of inotropic support should be considered high-risk conditions for lung transplantation alone.

      Discussion: Support strategies as a bridge to lung and heart-lung transplant

      Patients with CTD can present with rapid clinical deterioration while awaiting transplantation resulting in progressive lung failure, and non-invasive means of supplemental oxygen delivery alone may be ineffective. Veno-arterial extracorporeal oxygenation (VA-ECMO) provides both preoperative cardiovascular support and is a useful adjunct for continued intraoperative
      • Fadel E
      • Mercier O
      • Mussot S
      • et al.
      Long-term outcome of double-lung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients.
      ,
      • Bermudez CA
      • Shiose A
      • Esper SA
      • et al.
      Outcomes of intraoperative venoarterial extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation.
      and postoperative support.
      • Van Raemdonck D
      • Hartwig MG
      • Hertz MI
      • et al.
      Report of the ISHLT Working Group on primary lung graft dysfunction Part IV: Prevention and treatment: a 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.
      ,
      • Machuca TN
      • Collaud S
      • Mercier O
      • et al.
      Outcomes of intraoperative extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation.
      Although ECLS has been used as a bridge to LTx in patients with CTD,
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      ,
      • Bermudez CA
      • McMullan DM.
      Extracorporeal life support in preoperative and postoperative heart transplant management.
      • Chicotka S
      • Pedroso FE
      • Agerstrand CL
      • et al.
      Increasing opportunity for lung transplant in interstitial lung disease with pulmonary hypertension.
      • Tudorache I
      • Sommer W
      • Kuhn C
      • et al.
      Lung transplantation for severe pulmonary hypertension–awake extracorporeal membrane oxygenation for postoperative left ventricular remodeling.
      • Salman J
      • Ius F
      • Sommer W
      • et al.
      Mid-term results of bilateral lung transplant with postoperatively extended intraoperative extracorporeal membrane oxygenation for severe pulmonary hypertension.
      the experience is limited, and a detailed analysis of outcomes in this setting is lacking. Even though ECLS bridge to transplant is becoming increasingly common practice, transplant center volume and ECLS expertise improve success rates pre-and post-operatively.
      • Hayes Jr., D
      • Tobias JD
      • Tumin D.
      Center volume and extracorporeal membrane oxygenation support at lung transplantation in the lung allocation score Era.
      Recommendations: Early consideration should be entertained for placement if feasible of an awake veno-venous extracorporeal oxygenation (VV-ECMO) system, via either an open or percutaneous technique. This may avoid the need for invasive mechanical ventilation or even tracheostomy. If prolonged invasive mechanical ventilation cannot be avoided, then there should be consideration for early tracheostomy. VV-ECMO may be less effective or inadequate support in patients with severe pulmonary hypertension and right heart dysfunction. In some patients this necessitates conversion of VV- to VA-ECMO or placement of VA-ECMO as the initial therapy.
      The team consensus statement agreement strength on these recommendations was 83.33%.

      Discussion: Surgical planning and conduct

      There are several considerations in developing an optimized surgical plan (Figure 1).
      Understanding the degree of RV dysfunction, pulmonary hypertension, and donor and recipient relative chest sizes are critical. This information determines optimum anesthesia techniques, type of intra- and post-operative and the likelihood of other required supportive measures.
      The induction of anesthesia is an important step in these patients. The failing right ventricle is extremely sensitive to fluctuations in pre-load or increases in afterload.
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      ,
      • Hoeper MM
      • Granton J
      Intensive care unit management of patients with severe pulmonary hypertension and right heart failure.
      Principles of anesthetic management in the presence of pulmonary hypertension are essential to prevent hemodynamic collapse. In this case VA-ECMO provides both preoperative cardiovascular support and is a useful adjunct for continued intraoperative
      • Fadel E
      • Mercier O
      • Mussot S
      • et al.
      Long-term outcome of double-lung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients.
      ,
      • Bermudez CA
      • Shiose A
      • Esper SA
      • et al.
      Outcomes of intraoperative venoarterial extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation.
      and postoperative support
      • Hoeper MM
      • Benza RL
      • Corris P
      • et al.
      Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.
      ,
      • Machuca TN
      • Collaud S
      • Mercier O
      • et al.
      Outcomes of intraoperative extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation.
      ,
      • Chicotka S
      • Pedroso FE
      • Agerstrand CL
      • et al.
      Increasing opportunity for lung transplant in interstitial lung disease with pulmonary hypertension.
      includes avoiding increasing pulmonary vascular resistance (PVR), maintaining pre-load while avoiding fluid overload, reducing RV afterload, and reducing tachycardia.
      • Hoeper MM
      • Granton J
      Intensive care unit management of patients with severe pulmonary hypertension and right heart failure.
      ,
      • Machuca TN
      • Collaud S
      • Mercier O
      • et al.
      Outcomes of intraoperative extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation.
      ,
      • Hayes Jr., D
      • Tobias JD
      • Tumin D.
      Center volume and extracorporeal membrane oxygenation support at lung transplantation in the lung allocation score Era.
      The goal is to maintain forward flow and avoiding precipitating rapid hemodynamic decompensation.
      • Hayes Jr., D
      • Tobias JD
      • Tumin D.
      Center volume and extracorporeal membrane oxygenation support at lung transplantation in the lung allocation score Era.
      Recommendations: The important considerations during the surgical LTx planning in patients with CTD includes understanding of the degree of RV dysfunction, PH, and donor and recipient relative chest sizes to determine the optimum anesthesia techniques, type of intra- and postoperative and the likelihood of other required supportive measures. The induction and management of anesthesia is also an important step and includes avoiding increasing PVR and maintaining pre-load while avoiding fluid overload, reducing RV afterload, with the goal is to maintain forward flow and avoiding precipitating rapid hemodynamic decompensation. The presence of a pulmonary artery catheter is essential to monitor pulmonary pressures, and CO throughout the procedure, and an extra right internal jugular venous access should be obtained in case postoperative VV-ECMO support is considered. Femoral access (arterial and venous) may be necessary soon after or even prior to induction in case a rapid deterioration is expected to initiate extracorporeal circulation or ECMO.
      The team consensus statement agreement strength on these recommendations was 90.38%.

      Intraoperative care and anesthesia challenges: Decisions, recommendations, and agreement strength

      Discussion: Vascular access: Challenges and concerns

      Patients with CTD may be at increased risk of vascular complications including, pseudoaneurysms, hematomas, arteriovenous fistulas, and limb ischemia. Pre-existing vasculopathy related to Raynaud's phenomenon creates a higher risk of complications related to arterial line placement such as digital embolization or hand ischemia.
      • Launay D
      • Savale L
      • Berezne A
      • et al.
      Lung and heart-lung transplantation for systemic sclerosis patients. A monocentric experience of 13 patients, review of the literature and position paper of a multidisciplinary working group.
      ,
      • Paik JJ
      • Hirpara R
      • Heller JA
      • Hummers LK
      • Wigley FM
      • Shah AA.
      Thrombotic complications after radial arterial line placement in systemic sclerosis: a case series.
      Given this, it has been recommended to avoid radial artery cannulation in this population. However, there are no consistent data regarding the optimal arterial line site. Modification of the usual intraoperative monitoring techniques should also be considered given the associated Raynaud's phenomenon using topical nitroglycerin as tolerated, warm gloves, warm blankets, and limiting the duration of use of radial arterial lines or consideration of femoral or brachial arterial lines based on institutional protocols may be preferred.
      The working group recommends close monitoring for signs of digital ischemia and prompt removal of the arterial line if there is suspicion of early ischemia to prevent digital necrosis and the need for amputation.
      Alterations of the skin and neck stiffness in patient with SSc increases the difficulty of skin nicking and dilation for central venous cannulation. Experienced proceduralists and ultrasound guidance results in fewer mechanical complications. Randomized controlled trials report fewer insertion attempts with the use of ultrasound for both internal jugular and subclavian vein central lines.
      • Karakitsos D
      • Labropoulos N
      • De Groot E
      • et al.
      Real-time ultrasound-guided catheterisation of the internal jugular vein: a prospective comparison with the landmark technique in critical care patients.
      ,
      • Fragou M
      • Gravvanis A
      • Dimitriou V
      • et al.
      Real-time ultrasound-guided subclavian vein cannulation versus the landmark method in critical care patients: a prospective randomized study.
      The group recommends avoiding the subclavian site for large bore central cannulation to prevent venous stenosis, a factor that may limit successful arteriovenous fistulas in cases of prolonged renal failure.
      • Schillinger F
      • Schillinger D
      • Montagnac R
      • et al.
      Post catheterization vein stenosis in haemodialysis: comparative angiographic study of 50 subclavian and 50 internal jugular accesses.

      Discussion: Intubation: Challenges and strategies

      The combination of microstomia with advanced lung disease poses a unique challenge for airway management. Also, patients with connective tissue disorders may have decreased salivary gland flow and tongue fibrosis. Having extra time to maneuver and secure the airway is unlikely as these patients also have parenchymal lung disease and will suffer rapid oxygen desaturation. Early evaluation of microstomia by the anesthesiology team is essential, and a difficult airway cart should be located near the patient. We recommend the treatment team to have both a detailed primary plan and a backup plan for securing the airway. We also recommend an awake technique, if possible. The combination of high-flow nasal oxygen therapy (e.g., Vapotherm, Exeter, NH) with fiberoptic bronchoscopic intubation is often utilized. A final consideration is the maintenance of appropriate minute ventilation. Patients with interstitial lung disease commonly have high pulmonary artery pressures and impaired right ventricular function. Any increase in CO2 retention may precipitate and subsequent cardiopulmonary collapse.

      Discussion: Ventilation management intraoperative

      In general, CTD patients undergoing transplantation for fibrotic lung disease have restrictive pulmonary physiology. If transplantation is performed without ECLS support, the ventilator strategy will need to account for the poor lung compliance. Optimal ventilator settings include relatively low tidal volumes and a high respiratory rate. Following perfusion of the first allograft, efforts should be made to revert to a lung-protective strategy to avoid ventilator-induced allograft lung injury. Intra-operative FiO2 should be minimized to maintain peripheral arterial oxygen saturation (SPO2) > 90% and arterial oxygen tension (PaO2) > 60 mm Hg to avoid potential detrimental effects of hyperoxemia and oxidative stress.
      • Verbeek GL
      • Myles PS
      • Westall GP
      • et al.
      Intra-operative protective mechanical ventilation in lung transplantation: a randomised, controlled trial.
      The decision of the first lung to be transplanted is made based on the degree of ventilation and perfusion contribution of each lung (transplanting the lung contributing less) or on anatomical consideration where the left lung is frequently transplanted first since it will be the most difficult to implant and require heart retraction to expose the retracted left hilum. After implantation, if ECLS or cardiopulmonary bypass (CPB) are used, we encourage some pulsatility in the pulmonary artery (PA) waveform to ensure adequate lung perfusion. Following implantation, surgical sizing and staged closure or post-operative mechanical circulatory support (MCS), is considered based on hemodynamics and domain issues. A small-bore enteral tube is also placed to ensure early postoperative enteral feeding.

      Considerations during lung transplantation: Decisions, recommendations, and agreement strength

      Discussion: Surgical approach and cardio-pulmonary support

      The ideal surgical approach has not been determined in patients with CTD. Bilateral thoraco-sternotomy (Clamshell) or bilateral sequential thoracotomies are appropriate approaches based on the centers’ experience.
      In a recent study in patients undergoing LTx for SSc, 56% of the patients underwent LTx with the use of extracorporeal circulatory support vs 32% in the control group with pulmonary fibrosis.
      • Crespo MM
      • Bermudez CA
      • Dew MA
      • et al.
      Lung transplant in patients with scleroderma compared with pulmonary fibrosis. short- and long-term outcomes.
      Recent studies favor ECLS over standard CPB, although these benefits have not been specifically studied in the CTD population. The advantages of intra-operative VA- ECMO include reduced bleeding complications, less primary graft dysfunction, and diminished renal dysfunction compared to CPB.
      • Fadel E
      • Mercier O
      • Mussot S
      • et al.
      Long-term outcome of double-lung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients.
      ,
      • Bermudez CA
      • Shiose A
      • Esper SA
      • et al.
      Outcomes of intraoperative venoarterial extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation.
      Specifically, in patients with SSc, central aortic cannulation (aorta to the right atrium or aorta to right femoral vein) is the preferred approach to prevent ischemic limb complications.
      • Glorion M
      • Mercier O
      • Mitilian D
      • et al.
      Central versus peripheral cannulation of extracorporeal membrane oxygenation support during double lung transplant for pulmonary hypertension.
      Since many of these patients have some degree of right ventricular dysfunction, intraoperative use of TEE is useful.
      • Hahn RT
      • Abraham T
      • Adams MS
      • et al.
      Guidelines for performing a comprehensive transesophageal echocardiographic examination: recommendations from the American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists.
      Complications associated with TEE probe insertion in the general population include mortality (<0.01%-0.02%), major bleeding (<0.01%), and esophageal perforation (<0.01%).
      • Khandheria BK
      • Seward JB
      Tajik AJ Transesophageal echocardiography.
      ,
      • Seward JB
      • Khandheria BK
      • Oh JK
      • et al.
      Critical appraisal of transesophageal echocardiography: limitations, pitfalls, and complications.
      Patients should be screened for any absolute or relative contraindications to TEE placement listed in Table 1. TEE in patients with a known relative contraindication such as esophagitis or esophageal varices can be successfully performed.
      • Hilberath JN
      • Oakes DA
      • Shernan SK
      • et al.
      Safety of transesophageal echocardiography.
      ,
      • Poelaert JI
      • Trouerbach J
      • De Buyzere M
      • et al.
      Evaluation of transesophageal echocardiography as a diagnostic and therapeutic aid in a critical care setting.
      Table 1Absolute and Relative Contraindications to Transesophageal Echocardiogram
      AbsoluteRelative
      Perforated viscusHistory of head, neck or mediastinal radiation
      Esophageal stricture or tumorHistory of upper gastrointestinal surgery
      Esophageal diverticulum or lacerationRecent upper gastrointestinal bleed
      Active upper gastrointestinal bleedBarret's esophagus or dysphagia
      Restricted neck mobility
      Symptomatic hiatal hernia
      Esophageal varices
      Coagulopathy
      Active esophagitis or peptic ulcer disease
      Recommendations: It is important to keep in mind that small chest cavities, a common finding in patients with CTD, may lead to limited surgical exposure, and incisions providing the optimal surgical field are preferred. During the transplant procedure, cardio-pulmonary support is frequently required due to high pulmonary artery pressures and small chest cavities requiring significant cardiac retraction. In patients with SSc, central aortic cannulation (aorta to the right atrium or aorta to right femoral vein) is the preferred approach to prevent ischemic limb complications. If ECMO is needed into the postoperative period due to severe primary graft dysfunction, converting to peripheral VV- ECMO or maintaining the patient on central VA-ECMO configuration depending on the physiological needs are the best support choices in this population.
      The team consensus agreement strength on these recommendations was 90.5%.
      Recommendations: Special attention should be considered while using TEE in patients with CTD and underlying esophageal disease to avoid any esophageal injury. The use of smaller caliber probes is recommended whenever available. It is unclear what the degree of additional risk is in patients with CTD.
      The team consensus agreement strength on these recommendations was 88.46%.

      Discussion: Hemodynamic monitoring and support

      At the end of the procedure, the use of vasoconstrictors should be minimized to avoid peripheral and coronary spasm, and optimal evaluation of fluid status and CO using a TEE and a Swan-Ganz catheter can aid in the immediate postoperative management. Awareness should be taken for those patients with a history of Raynaud's phenomenon who develop postoperative chest pain, as they are prone to coronary arterial spasm, which could be lethal if not promptly disrupted.
      • Desai CS
      • Lee DC
      • Shah SJ.
      Systemic sclerosis and the heart: current diagnosis and management.
      ,
      • Champion HC.
      The heart in scleroderma.
      Following LTx, SSc-specific cardiac complications can include: (1) LV diastolic dysfunction
      • Fidalgo P
      • Ahmed M
      • Meyer SR
      • et al.
      Incidence and outcomes of acute kidney injury following orthotopic lung transplantation: a population-based cohort study.
      and PH/SSc-related RV dysfunction, (2) PAH-related post- lung transplantation LV systolic dysfunction, (3) supraventricular and ventricular tachyarrhythmias, and less commonly (4) bradyarrhythmia or (5) unsuspected constrictive pericarditis.
      • Peters MJ
      • Symmons DP
      • McCarey D
      • et al.
      EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.
      Recommendations: Vasoconstrictors should be minimized in patients with CTD to avoid peripheral and coronary spasm, and optimizing evaluation of fluid status and CO is warranted. Hemodynamic monitoring together with blood products and fluid administration and avoidance of inotropes and vasoconstrictors at high doses are preferable post-operative resuscitative techniques that could have a deleterious effect on distal skin perfusion and renal function. Special attention should be taken for those patients with a history of Raynaud's phenomenon who develop postoperative chest pain. Limiting postoperative bleeding with early re-operations and liberal use of “open chest strategy” in patients with a small chest, or a significant coagulopathy or in patients with significant RV or LV dysfunction are critical to minimize peripheral and systemic effects of perfusion insufficiencies frequently compromised in patient with CTD. The liberal use of early postoperative VA-ECMO in cases of severe post-operative RV dysfunction or VV-ECMO in patients with early signs of PGD should be considered.
      The team consensus statement agreement strength on these recommendations was 90.56%.

      Management of primary graft dysfunction, ventilation and weaning, hemodynamics, and renal failure prevention: Discussions, recommendations and agreement strength

      Discussion: Primary graft dysfunction management

      The reported incidence of Grade 3 PGD varies in the medical literature but is estimated at approximately 30% early after transplant and 15-20% at 48 to 72 hours post-transplant.
      • Van Raemdonck D
      • Hartwig MG
      • Hertz MI
      • et al.
      Report of the ISHLT Working Group on primary lung graft dysfunction Part IV: Prevention and treatment: a 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.
      ,
      • Snell GI
      • Yusen RD
      • Weill D
      • et al.
      Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.
      The incidence of PGD in LTx recipients with CTD has not been specifically studied. However, given the high prevalence of PAH in CTD and the association between PAH and PGD, it is likely that CTD patients are at higher risk for PGD.
      • Gupta S
      • Torres F
      • Bollineni S
      • Mohanka M
      • Kaza V.
      Left Ventricular dysfunction after lung transplantation for pulmonary arterial hypertension.
      The impact of PGD on both short and long-term outcomes is well established, and has been associated with increased duration of mechanical ventilation, ICU and hospital length of stay, increased resource utilization and hospital costs.
      • Snell GI
      • Yusen RD
      • Weill D
      • et al.
      Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.
      ,
      • King CS
      • Valentine V
      • Cattamanchi A
      • et al.
      Early postoperative management after lung transplantation: Results of an international survey.

      Discussion: Postoperative ventilator management and ventilator weaning

      Consensus regarding the optimal ventilator strategy following lung transplant is lacking. A single randomized controlled trial of thirty patients comparing “open-lung protective ventilation” to a control arm is the only prospective study performed to date.
      • King CS
      • Valentine V
      • Cattamanchi A
      • et al.
      Early postoperative management after lung transplantation: Results of an international survey.
      Given this, no consensus regarding the optimal ventilator strategy following lung transplant exists. As mentioned above, the use of lung-protective ventilator strategies has been extrapolated from our knowledge of acute respiratory distress syndrome (ARDS) to the care of lung transplant recipients. An international survey of early postoperative management found that a lung-protective strategy is commonly employed by lung transplant centers, with 65% of respondents using tidal volumes ≤ 6 ml/kg of ideal body weight (IBW) and all respondents using ≤ 8 ml/kg of IBW.
      • King CS
      • Valentine V
      • Cattamanchi A
      • et al.
      Early postoperative management after lung transplantation: Results of an international survey.
      In these patients, the traditional parameter of rapid-shallow breathing index (RSBI) utilized by many clinicians as a tool to assess readiness for extubation may suggest patients are not ready to liberate from mechanical ventilation.
      • Karthika M
      • Al Enezi FA
      • Pillai LV
      • et al.
      Rapid shallow breathing index.
      Further studies on the predictors of extubation failure in transplant recipients are warranted.
      Recommendations: A lung-protective strategy using tidal volumes ≤ 6 ml/kg of ideal body weight (IBW) is recommended. IBW should be calculated using the donor rather than the recipient's height. A spontaneous breathing trial can be performed in patients with adequate oxygenation and ventilation in lung-protective settings. Anecdotally, many patients with restrictive lung disease before transplant seem to maintain a pattern of rapid shallow breathing in the early post-transplant period. Patients who maintain adequate oxygenation and ventilation without signs of distress when undergoing a spontaneous breathing trial should be considered for a trial of extubation regardless of RSBI.
      The team consensus agreement strength on these recommendations was 84.90%

      Discussion: Post-transplant inotrope and vasopressor management

      LTX recipients are at risk for several physiologic derangements, which can complicate post-operative hemodynamic management. Patients may experience hypovolemia from blood loss, distributive shock from CPB and sedative effects, and cardiogenic shock from RV compromise. This can be assessed by careful physical examination, standard vital signs (blood pressure, SPO2), urine output, lactate, and central venous oxygen saturation (SVO2). Intraoperative TEE and TTE can also be useful in monitoring the size and function of both the RV and LV.
      High fluid volumes such as intra-operative volume resuscitation are associated with an increased risk of Grade 3 PGD in a retrospective study of 494 patients, with each additional liter of fluid increasing the odds of Grade 3 PGD by 22%.
      • Geube MA
      • Perez-Protto SE
      • McGrath TL
      • et al.
      Increased intraoperative fluid administration is associated with severe primary graft dysfunction after lung transplantation.
      Another retrospective study found that a central venous pressure > 7 mm Hg was associated with prolonged mechanical ventilation and short-term mortality even after controlling for cardiac dysfunction.
      • Pilcher DV
      • Scheinkestel CD
      • Snell GI
      • et al.
      High central venous pressure is associated with prolonged mechanical ventilation and increased mortality after lung transplantation.
      Low dose vasopressors can be used to facilitate diuresis by decreasing venous capacitance, and in turn, augmenting preload.
      • Foulon P
      • De Backer D.
      The hemodynamic effects of norepinephrine: far more than an increase in blood pressure!.
      Low dose vasopressors should be used to maintain a sufficient mean arterial pressure (MAP) with close observation to the development of signs of digital ischemia where a more liberal approach with volume resuscitation maybe be needed. In most patients, a MAP > 65 mm Hg is adequate; however, the MAP goal should take into account the patient's typical baseline blood pressure. Norepinephrine and vasopressin are the most commonly selected vasopressors. RV dysfunction deserves special attention as PH is common in CTD patients. The presence of PH prior to transplantation does not predict the need for significant RV support post-operatively, as the pulmonary vascular resistance is substantially reduced following the procedure. Conversely, overly aggressive support of the RV may lead to the development of PGD or pulmonary edema by unmasking LV dysfunction or increasing RV output.
      • Snell GI
      • Yusen RD
      • Weill D
      • et al.
      Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.
      Inhaled nitric oxide (iNO) or inhaled epoprostenol are effective vasodilators in the setting of persistent PH associated with reduced CO. Hypoxemia and hypercapnia should be corrected together with diuresis to reduce right atrial pressure and correct RV distention. Inotropes, such as dobutamine or milrinone, can also be used to reduce RV afterload and improve RV contractility. If significant RV dysfunction persists despite these measures, extracorporeal support can be considered.
      Recommendations: Clinicians should consider the patient's pre-transplantation hemodynamics, particularly the presence of pulmonary hypertension when developing a post-operative management plan. The primary goal of hemodynamic management is to ensure adequate end-organ perfusion while avoiding overly aggressive support that may be detrimental to the allograft. A conservative fluid strategy is typically recommended following LTx. However, volume or appropriate resuscitation with blood products should not be withheld at the expense of end-organ hypoperfusion in the setting of hypovolemic or hemorrhagic shock. Inotropes can be utilized if patients have an inadequate cardiac output despite adequate preload due to LV or RV dysfunction. RV dysfunction deserves special attention as PH is common in CTD patients. Inhaled epoprostenol or iNO are effective vasodilators in the setting of persistent PH associated with reduced CO. If significant RV dysfunction persists despite these measures, extracorporeal support can be considered.
      The team consensus agreement strength on these recommendations was 87.75%.

      Discussion: Renal failure prevention strategies and management

      Renal failure is a relatively common complication after LTx and HLTx that has both short and long-term consequences. The risk of transient or persistent acute kidney injury (AKI) early after transplantation can be as high as 68%.
      • Fidalgo P
      • Ahmed M
      • Meyer SR
      • et al.
      Incidence and outcomes of acute kidney injury following orthotopic lung transplantation: a population-based cohort study.
      Calcineurin inhibitors toxicity is associated with both a risk for AKI early after transplantation and the development of chronic kidney disease and the need for dialysis in longer-term survivors.
      • Fidalgo P
      • Ahmed M
      • Meyer SR
      • et al.
      Incidence and outcomes of acute kidney injury following orthotopic lung transplantation: a population-based cohort study.
      ,
      • Sole A
      • Zurbano F
      • Borro JM
      • Monforte V
      • Ussetti P
      • Santos F
      Prevalence and diagnsosis of chronic kidney disease in maintenance lung transplant patients: ICEBERG study.
      Patients requiring hemodialysis after transplant have a high mortality rate.
      • Hennessy SA
      • Gillen JR
      • Hranjec T
      • et al.
      Influence of hemodialysis on clinical outcomes after lung transplantation.
      Other potential risk factors for AKI post-transplant are severe pretransplant PH and cardio-renal syndrome or low glomerular filtration rate and pre- or post-transplant ECMO requirement.
      • Fidalgo P
      • Ahmed M
      • Meyer SR
      • et al.
      Incidence and outcomes of acute kidney injury following orthotopic lung transplantation: a population-based cohort study.
      ,
      • Sole A
      • Zurbano F
      • Borro JM
      • Monforte V
      • Ussetti P
      • Santos F
      Prevalence and diagnsosis of chronic kidney disease in maintenance lung transplant patients: ICEBERG study.
      Scleroderma renal crisis (SRC) can occur in up to 5% to 10% of SSc patients.
      • Penn H
      • Denton CP
      Diagnosis, management and prevention of scleroderma renal disease.
      • Steen VD
      • Syzd A
      • Johnson JP
      • Greenberg A
      • Medsger Jr., TA
      Kidney disease other than renal crisis in patients with diffuse scleroderma.
      • Bose N
      • Chiesa-Vottero A
      • Chatterjee S
      Scleroderma renal crisis.
      Patients with CTD, particularly SSc, are more at risk for developing AKI post-transplant. Raynaud's phenomenon and systemic vasospasm in SSc outside of the peripheral circulation might be playing a role in the pathogenesis of SRC and AKI post-transplant.
      • Bose N
      • Chiesa-Vottero A
      • Chatterjee S
      Scleroderma renal crisis.
      The use of high- glucocorticoids, (> 15 mg/day of prednisone or equivalent) is an independent risk factor for developing SRC.
      • Hummers LK.
      Raynaud's phenomenon: a guide to pathogenesis and treatment.
      ,
      • Dore A
      • Lucas M
      • Ivanco D
      • Medsger Jr., TA
      • Domsic RT
      Significance of palpable tendon friction rubs in early diffuse cutaneous systemic sclerosis.
      There have also been reports of patients developing hypertensive AKI with the use of cyclosporine.
      • Denton CP
      • Sweny P
      • Abdulla A
      • Black CM
      Acute renal failure occurring in scleroderma treated with cyclosporin A: a report of three cases.
      Recommendations: The group recommendations for renal protection post-transplantation in patients with CTD are: optimize low calcineurin inhibitors goal levels, avoid dehydration, nonsteroidal anti-inflammatory medications, and hypotension. Although scleroderma renal crisis is rare after transplant, the corticosteroid maintenance dose should be reduced to the minimal amount possible.
      Team consensus agreement strength on these recommendations was 77.77 % indicating poor agreement on renal preservation strategies.

      Summary and future recommendations

      Cardiothoracic transplantation in CTD recipients requires a comprehensive knowledge of the extrapulmonary manifestations of the particular disease states. The evaluation and the management of the extrapulmonary manifestations are critical to the care of this patient population compared to other patients undergoing lung transplantation since these conditions require special management and interventions both early and later after transplantation.  In addition, CTD patients may be maintained on a complex biologic immunosuppressive regimen before transplantation. Although only a limited amount of data exists in the literature to support the use of many of these agents in this patient population before discontinuation of these agents should carefully take into account a risk-benefit analysis. Therefore, a multidisciplinary team must be involved early in the management of these patients during the evaluation phase and throughout the subsequent phases of transplantation.
      In the future, with gained knowledge through clinical experience, a more refined approach to the management of the biologic regimen and the extrapulmonary manifestations including management of the gastrointestinal complications will be more standardized.

      Disclosure statement

      No specific funding was available for this project. Each workforce member disclosure their conflict of interest. The funding sources for each workforce member had no role in study design, data collection, data analysis, or writing of the report.
      We thank Mrs Megan Barrett for providing administrative support and for helping with the preparation and distribution of the surveys used for this project.
      We also thank the expert reviewers Dr. Jason Christie, Dr. Joseph Pilewski, and Dr. Paul Corris for their input.

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