Lung Transplantation – Past and Present

C V Mangukia, Dept of CTVS, GBPH 1

Lung Transplantation Past and Present

Chirantan Mangukia Senior Resident

Department of CTVS G B Pant Hospital, New Delhi

Overview


History Disease specific indications Patient selection criteria Donor selection criteria Deceased Donor Lung Procurement Recipient Surgery Post operative care Complications Results

History


Vladimir Demikhov - 1947 The first lung transplantation in a dog

First attempt of human lung transplant 1963- University of Alabama - James D. Hardy and colleagues

First combined heart-lung transplant Denton Cooley in Texas on September 15, 1969

First successful heart-lung transplant 1981- Stanford University


First successful single lung transplant: use of omentum and withhold of steroids in a case of pulmonary fibrosis 1983-University of Toronto

First successful double lung transplant 1985-University of Toronto

First successful Domino procedure 1986-Newcastle Magdi Yacoub

First successful living donor lung transplant 1993-Stanford University

NUMBER OF LUNG TRANSPLANTS REPORTED BY YEAR AND PROCEDURE TYPE


5 7 38 89 204

450

758 970

1160 1289

1412 1389 1510 1547 1559

1700 1784 1975 2012

2218

2571 2795

2922 2981

3279 3519

3747

0

500

1000

1500

2000

2500

3000

3500

4000

1

9

8

5

1

9

8

6

1

9

8

7

1

9

8

8

1

9

8

9

1

9

9

0

1

9

9

1

1

9

9

2

1

9

9

3

1

9

9

4

1

9

9

5

1

9

9

6

1

9

9

7

1

9

9

8

1

9

9

9

2

0

0

0

2

0

0

1

2

0

0

2

2

0

0

3

2

0

0

4

2

0

0

5

2

0

0

6

2

0

0

7

2

0

0

8

2

0

0

9

2

0

1

0

2

0

1

1

Single Lung Bilateral/Double Lung

Source - The International Society for Heart and Lung Transplantation Registry

High volume centers


0

5

10

15

20

25

30

1-4 5-9 10-19 20-29 30-39 40-49 50+

EuropeNorth AmericaOther

N

u

m

b

e

r

o

f

C

e

n

t

e

r

s

Average number of lung transplants per year

Adult and Pediatric Lung Transplants Recipient Age by Year (Jan 1987 June 2012)


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%1

9

8

7

1

9

8

8

1

9

8

9

1

9

9

0

1

9

9

1

1

9

9

2

1

9

9

3

1

9

9

4

1

9

9

5

1

9

9

6

1

9

9

7

1

9

9

8

1

9

9

9

2

0

0

0

2

0

0

1

2

0

0

2

2

0

0

3

2

0

0

4

2

0

0

5

2

0

0

6

2

0

0

7

2

0

0

8

2

0

0

9

2

0

1

0

2

0

1

1

2

0

1

2

>6560-6550-5935-4918-3412-170-11

Mean age of Recipient


0

10

20

30

40

50

601

9

8

7

1

9

8

8

1

9

8

9

1

9

9

0

1

9

9

1

1

9

9

2

1

9

9

3

1

9

9

4

1

9

9

5

1

9

9

6

1

9

9

7

1

9

9

8

1

9

9

9

2

0

0

0

2

0

0

1

2

0

0

2

2

0

0

3

2

0

0

4

2

0

0

5

2

0

0

6

2

0

0

7

2

0

0

8

2

0

0

9

2

0

1

0

2

0

1

1

2

0

1

2

Median Age

Donor Age Distribution (Jan 1985 June 2012)


2.34

10.59

29.14

16.80

21.02

15.53

3.52 1.07 0

5

10

15

20

25

30

0-11 12-17 18-29 30-39 40-49 50-59 60-65 >65% of transplants

Diagnosis of lung transplant patients University of Alabama 1986 to 2009


40

13 13

14

2 4 1 4

1 8

COPDAT DeficiencyIPFCFPPHTalcosisBOEisenmenger'sBronchiectasisOthers

Diagnosis of lung transplant patients Barnes-Jewish Hospital, St. Louis, UOW


42

18

14 12 6

COPD orEmphysemaCF

AT deficiency

4th QtrIPF

PPH

Percentage of patients (n = 800)

COPD


Maximization of medical therapy (oxygen and bronchodilators)

LVRS Hyperinflation, Heterogeneous distribution of disease FEV1 of more than 20% Normal pCO2

Preliminary LVRS does not jeopardize subsequent successful lung transplantation

SLT in short stature and old age patients

1- antitrypsin deficiency


1% of all the emphysema patients 0.012% of overall population Protease inhibitor Protects the lung from toxic substances released by

macrophages Smoking early onset of COPD DLT preferred, first preference in waiting list

Septic Lung Disease


Cystic fibrosis (mycobacterial, fungal colonies; pseudomonas aeruginosa MDR amikacin renal compromise)

Fungal infections Bronchiectasis Frequent sputum cultures Pan-resistant Burkholderia cepacia a contraindication at

several institutes DLT preferred

RLD and Pulmonary Fibrosis


IPF (3rd most common after COPD and ATD) Mean forced vital capacity of 1.35 L FEV1 of 1.14 L Moderate PAH

Sarcoidosis with elevated pulmonary artery pressures Obliterative bronchiolitis (not re-transplant cases) SLT can be good option well tolerated

PPH


Optimization of medical therapy Prostacyclin Endothelin receptor antagonists Phosphodiesterase inhibitors

Indications New york heart association [NYHA] class III or IV Mean pulmonary artery pressure >50 Right atrial pressure >10 mm hg Cardiac index


PPH B/L Lung Transplant preferred transplanted lung will receive a bulk of cardiac output stormy post-operative course

Patients with Eisenmengers syndrome and secondary pulmonary hypertension have not shown an improvement in survival after lung transplantation


Recipient Selection Criteria

Eligible candidates


Clinically and physiologically severe disease Medical therapy ineffective or unavailable Substantial limitations in activities of daily living Limited life expectancy Adequate cardiac function without significant coronary

disease Ambulatory, with rehabilitation potential Acceptable nutritional status Satisfactory psychosocial profile and emotional support

system

Exclusion


Age > 65 years Malignancy diagnosed in last 5 years (exception is B/L

BA Carcinoma) High dose of corticosteroids (Prednisolone > 20 mg/day or

equivalent)


Ventilatory dependency is not a contra-indication for lung transplant

It adds to the morbidity of the peri-operative procedure

Lung Allocation Score


LAS score

Waitlist Emergency Expected Survival after Transplant

Waitlist Emergency


Forced vital capacity Pulmonary artery systolic pressure Oxygen required at rest Age Body mass index Diabetes Functional status Six-minute walk distance Continuous mechanical ventilation Diagnosis

Expected Survival after Transplant


Forced vital capacity Pulmonary capillary wedge pressure 20 mm Hg Continuous mechanical ventilation Age Serum creatinine Functional status Diagnosis


Donor Selection Criteria

Shortage


Extreme shortage Among other organ donors only 20% have suitable lungs A majority of conditions resulting in brain death (e.g.,

trauma, spontaneous intracerebral hemorrhage) also lead to significant pulmonary parenchymal pathologic change because of lung contusion, infection, aspiration, or neurogenic pulmonary edema

Criteria


Age < 55 years (adverse outcome) No history of pulmonary disease Normal serial chest radiograph Adequate gas exchangePao2 > 300 mm Hg; Fio2, 100%;

positive end-expiratory pressure, 5 cm H2O Normal bronchoscopic examination Negative serologic screening for hepatitis B and human

immunodeficiency virus (HIV) Recipient matching for ABO blood group Size matching

Exclusion


Bronchoscopic aspiration of frank pus (fine mucopurulent secretions are not c/i)

Smoking (> 30 pack-years) Active malignancy Active HIV, Active Hepatitis B HLA mismatch

Size Match


Depends on nature of recipient's lung disease and type of transplant

Standard Normogram based on age, sex and height (PFT labs)

COPD patients undergoing SLT 10-15% larger size implanted (possible owing to large pleural space)

IPF reduced spaces possibility of oversizing cannot be denied while following Normogram

Oversizing hemodynamic instability while closing the chest


Split-lung technique bi-partitioning of left lung of large sized donor use for bilateral lung transplant in small sized donor considerable surgical expertise

Exercise Tolerance Program


All patients except those having primary pulmonary hypertension (PPH) or Eisenmengers syndrome

Improvement in strength and exercise tolerance without any measurable change in pulmonary function

Improved endurance


Donor Lung Procurement

Brain dead Donor


Flexible bronchoscopy Fine mucus or mucopurulent secretions Copious purulent secretions - reject

Communication regarding Anatomic variations Cannulation sites

Median sternotomy Lung compliance check by deflation palpation for gross

pathology SVC encircled and looped AP window dissected Pericardium incised above right PA Trachea dissected


Systemic heparinization A U-stitch proximal to the

bifurcation of MPA - Sarns (Sarns, Ann Arbor, MI) 6.5-mm curved metal cannula

500-g bolus dose of prostaglandin-E1

SVC ligated IVC divided Right vent


Aortic cross clamp Cardioplegia infusion LAA excised Left vent 50 to 75 mL/kg of cold (4 C) pulmonary preservation

solution (Perfadex) Ice slush heart and pleura Gentle ventilation is continued to prevent atelectasis and

homogeneously distribute the perfusate Clear perfusate exiting the left atriotomy confirms

adequate lung flushing Cannulae removed


Dissection beneath IVC preventing injury to RIPV

Time to separate posterior LA wall from rest of the heart Communication with heart team

The heart retracted to the right, and an incision is made with a #11 blade scalpel in the left atrium midway between the coronary sinus and the left inferior pulmonary vein


SVC transected heart freed Retrograde pulmonary flush (250 ml) using Foley

Better oxygenation Higher compliance Lower extravascular lung water index in transplanted lungs

En-bloc removal of mediastinal tissues Prevents devascularization to trachea and bronchus

ET is opened to the atmosphere and the lungs are allowed to deflate to approximate end-tidal volume

The trachea is divided between staple lines at least two rings above the carina. The esophagus is also divided using a stapler.


Superior dissection - The lungs are retracted inferiorly, and the superior mediastinal tissue is divided down to the spine. Staying directly on the spine, the posterior mediastinal tissue is divided in a superior-to-inferior direction until the level of the mid-thoracic spine.

Inferior dissection - The pericardium just superior to the diaphragm is divided, the inferior pulmonary ligaments are divided

Now both the dissections are connected with each other and the lungs are removed en bloc along with the thoracic esophagus and aorta.

Non-heart-beating Donor


D.G. de Antonio and colleagues (PMID 17449425) published excellent mid-term results

Lung ischemia time as long as 11 hours is tolerated Systemic heparinization - arteriovenous extracorporeal

membrane oxygenation (ECMO) via a femoral approach Fogarty catheter in the supra-diaphragmatic aorta for

better abdominal organ perfusion Bilateral chest tubes for topical lung cooling with cold

Perfadex Bronchoscopy Chest open


Ventilation resumed to allow adequate distribution of perfusate

3 to 5 liters of Perfadex + 300 ml of blood infused in PA ABG from the return in LA If found satisfactory retrograde perfusion and lung

procurement is followed

Atrial cuff and other injuries


Pulmonary artery injury RPA injury more common while dissecting SVC

Pulmonary Vein Injuries Commonest - right inferior pulmonary vein Due to excessive dissection of inferior pulmonary ligament

Inadequate left atrial cuff Requires reconstructive salvage procedure

Atrial Cuff Salvage (Neo-atrial cuff)


Atrial Cuff Reconstruction



Recipient Surgery

Preparation


Epidural catheter if CPB is not planned Double lumen tube Monitoring lines including Swan-Ganz Indications of CPB

Children Lobar transplants Non-feasibility of double lumen tube (small sized adults) PPH Along with intra-cardiac procedure

Bilateral Antero-lateral Thoracotomy


Sternum not divided Better healing than

Clamshell Infra-mammary skin

crease incision IMA ligated bilateraly

Trans-sternal Bilateral Thoracotomy incision


Excellent exposure of both the hilum

Full Clamshell may be required if Concomitant heart

transplant PPH with cardiomegaly RLD with small pleural

cavities

Posterolateral and Anterolateral Thoracotomy


Patients with RLD/ small chest cavities and patients with secondary PAH and cardiomegaly may present with their heart filling much of the left anterior hemithorax, making access to the left hilum via the anterior approach quite difficult

Left lung transplant first through a left posterolateral thoracotomy without CPB

The patient then is turned supine, and the right lung transplant is performed via a right anterolateral approach

Anterior axillary muscle sparing thoracotomy


For SLD in COPD Better mechanics of arm and thorax movements May be difficult while CPB is planned

Pneumonectomy


Bilateral hilar dissection and adhesiolysis completed -speedy removal of the second lung - minimizing the amount of time that the freshly implanted contralateral lung is exposed to the entire cardiac output

Lung with poorer function transplanted first more likely to support single lung ventilation

Principles Hemostasis, nerve preservation Dissection beyond 1st branch of PA and PV Stapler on central side, tie on peripheral side helps in

downsizing of recipient PA provides better size match


Pulmonary veins ligated beyond second branch point Bronchus divided proximal to upper lobe origin Meticulous hemostasis with cautery and ligation

Implantation


Wrapped in cold sponge lung is placed in pleural cavity

1st step - Bronchial anastomosis End-to-end anastomosis

using two strands of 4-0 polydioxanone (PDS) in a running stitch

Size mismatch anterior layer interrupted

Peri-bronchial tissue coverage

Pulmonary Artery Anastomosis


The donor and recipient PAs are trimmed to prevent excessive length and possible kinking, and an end-to-end anastomosis is fashioned using a continuous 5-0 polypropylene stitch, using precise small bites to prevent anastomotic stricture

Pulmonary Vein Anastomosis


The recipient pulmonary venous stumps are amputated and the two openings connected to create the atrial cuff.

The anastomosis with continuous 4-0 polypropylene suture

Mattress technique - achieves intima-to-intima apposition and excludes potentially thrombogenic atrial muscle

Bilateral Sequential Lung Transplant


The contralateral transplant is conducted in the same fashion.

Single Lung Transplant


Choice of Side Poorest function CPB required right side is preferred (right anterior approach) For Eisenmenger's right side is preferred simultaneous

closure of septal defects Exposure and pneumonectomy remains same

Technical strategies to overcome donor shortage


Size mismatch Accept oversized donor Downsize the lungs on back table Bilateral wedge resection targeting right middle lobe and the

lingula Living donor and split lung transplant

Two healthy donors lower lobe from each donor for either of sides

Pulmonary bi-partitioning and lobar implant Non-beating-heart donors Ex-vivo conditioning of unacceptable lungs


Post operative Management

Ventilation after DLT


Fio2 adjusted to maintain the Pao2 > 70 mm Hg Tidal volumes of 7 to 10 mL/kg PEEP of 5 to 7.5 cm H2O Frequent arterial blood gas analyses If the patients are hemodynamically stable, have no

significant bleeding and gas exchange appears satisfactory, weaning is initiated

Extubation is performed in accordance with standard requirements of gas exchange and respiratory mechanics

Ventilation after SLT


Preventing hyperinflation of the native lung and compression of the freshly implanted lung are the main concerns in patients with emphysema

Avoid the use of PEEP and use lower tidal volumes Air trapping (owing to lower tidal volumes reflecting in to

higher airway pressure and hypercarbia) might require to perform volume reduction of native lung

Position to keep the native lung dependent Helps in inflating and draining the opposite lung

SLT for PPH prolonged ventilation may be required

Fluid management and general care


Intake-output charts, daily weighting, swan-ganz catheter aids in fluid management

Vigorous chest physiotherapy Postural drainage Inhalation of bronchodilators Frequent clearance of pulmonary secretions


Complications

Technical Problems


Perioperative hemorrhage Large raw surface after explant in septic lung disease Coagulopathy and CPB May require delayed chest closure

Bronchial anastomosis constriction identified in post-operative bronchoscopy

PA anastomosis best assessed by contrast angiography gradient of 15-20 mmHg in SLT are common

Clot at PV anastomosis

Primary Graft Dysfunction


Incidence 25% Mortality 30% Deranged Pao2-to-Fio2 ratio in first 48 hours Pan-alveolar infiltrates in X-ray chest Grading based upon X-ray


Ischemia-reperfusion injury

Infection, aspiration or contusion

Cold storage accumulation of intracellular calcium, endothelial damage

Increased level of IL-8


PEEP, Inhaled Nitric Oxide, Aerosolized Prostacyclin Most of patient recover after several days of intensive

treatment satisfactory long term allograft function If conservative management fails ECMO Last resort re-transplantation

Bacterial Infection


Cause Preexisting colonization of recipient or donor Complication of surgery Nosocomial exposure Community-acquired infection

Culture and sensitivity antibiotics Wound infection similar to non-transplant surgeries

Staph. Aureus Atypical mycobacteria infections are common CF micro-abscess

Viral Infection


CMV commonest 13-75% Lungs can harbor high latent CMV loads Can predispose to chronic graft rejection PCR in blood tests and Cytomegalic cells with inclusion

bodies in tissue biopsy How to reduce transmission

Match sero-negative donors with sero-negative recipients Prophylaxis with Ganciclovir (iv or oral) in positive cases

Other are herpesvirus, respiratory syncytial virus, parainfluenza virus, influenza virus, adenovirus Antiviral therapy and supportive care

Fungal Infections


Candida ablicans colonizing or invasive Diagnosed on bronchoscopy earliest Combination of systemic and inhaled Amphotericin B and

Fluconazole Aspergillus

High mortality, fatal Diagnosed in BAL Colonization risks invasive disease Wear mask, avoid gardening

Acute Rejection


Commoner than other organ transplants Although it may not be life threatening, increases chances

of chronic rejection Rare after 3 months post-transplant Dyspnea, hypoxemia, low-grade fever, and moderate

leukocytosis The chest radiograph often shows diffuse-perihilar

interstitial infiltrates 10% or greater decline in baseline FEV1 or forced vital

capacity Differentiation from early infection is difficult


Diagnosis by non-invasive method Nuclear scan high uptake in infections

Invasive methods BAL fluid IL-15 and Granzyme levels Transbronchial biopsy

Treatment Methyl-prednisolone Change in immunosuppression regimen

Chronic Rejection


Incidence is 50% at 5 years of follow-up Classical picture Bronchiolitis Obliterans Scarring and fibrosis of small airways with or without

inflammation


Diagnosis Airway neutrophilia

detected on BAL Elevated exhaled nitric

oxide fraction Air trapping on an

expiratory CT Not reversible Mostly conservative

management


Treatment - Augmenting immunosuppression High-dose corticosteroids Cytolytic therapy Substitution of MMF for azathioprine, Conversion of cyclosporine to tacrolimus

Commonest cause for pulmonary re-transplantation

Bronchial Anastomotic Complications


Incidence 7-14% Infection, dehiscence, stenosis, and malacia Necrosis growth of saprophytic fungus leads to

anastomotic dehiscence Membranous dehiscence generally heals without

significant stricture formation Anterior cartilaginous dehiscence results in more frequent

stricture formation Complete dehiscence can result in mediastinal sepsis or

uncontrolled air leaks requiring surgical intervention


Subacute ischemia - surgical stenosis, granulation tissue, infection, broncho-malacia

Surgical stenosis bronchoscopic balloon dilation or stent placement

Granulation tissue combination laser debridement, dilation and stenting

Post-transplant Lympho-proliferative Disease (PTLD)


Incidence 4-10% After first year of the transplant Common in thorax ranges from atypical lympho-

proliferative disease to Hodgkins lymphoma Treatment

Step-down the immunosuppression Anti-viral treatment CHOP regimen Rituximab anti CD20 monoclonal antibodies

GI complications


Esophagitis, pancreatitis, gastric atony, adynamic colonic ileus, gastroesophageal reflux, peptic ulcer disease, gastritis, GI bleeding, CMV hepatitis, CMV colitis, diverticulitis, cholecystitis, and Clostridium difficile colitis/diarrhea

Very rarely PTLD induced intussusception presents Most of infections are managed conservatively and rarely

require surgical treatment


Results

University of St. Louis (1988 to 2000)


The overall hospital mortality rate during this 13-year period was 6.2%, but from 1995 to 2000, it was only 3.9%

Significant improvement in FEV1 FVC 6 minute walk test

Overall 5-year survival was 58.6% 3.5% Emphysema DLT group survived significantly better

than SLT Similar experience in Washington University


From Trulock EP, Christie JD, Edwards LB, et al. Registry of the International Society of Heart and Lung Transplantation:

Twenty-fourth Official Adult Lung and Heart-Lung Transplantation Report2007. J Heart Lung Transplant 2007;26:782-95

Jan 1994 to June 2004

Post-crossover risk of death after lung transplant, relative to pre-transplant risk


American Journal of Transplantation Volume 9, Issue 7, pages 1640-1649, 29 JUN 2009 DOI: 10.1111/j.1600-6143.2009.02613.x

http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2009.02613.x/full#f4

Percentage survival at crossover point


91 87

68

82 83 84

0

10

20

30

40

50

60

70

80

90

100

CF Bronchiectesis PPH ILD COPD Other

Median post-transplant survival in days Disease specific


2436

3001

1534 1474 1795

1321

0

500

1000

1500

2000

2500

3000

3500

CF Bronchiectesis PPH ILD COPD Other

Domino procedure


BHF Professor Magdi Yacoub

National Heart and Lung Institute, Imperial College London and Founder

Domino procedure


Two patients one needed lungs, another needed heart One donor First patient receives heart-lung transplant The second patient receives Conditioned heart from the

first patient (chronic hypoxia conditions heart) Advantages

Technically easy to perform heart-lung transplant Preservation of aorto-bronchial collaterals Better tracheal healing Good adaptation of the conditioned heart for elevated

pulmonary pressures


Thank you

Lung Transplantation – Past and Present

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