Lung and heart-lung transplantation

Overview of the pathophysiology

Since the first human lung transplant was attempted in june 1963 by Hardy and colleagues. Over 8.000 lung and heart-lung transplant procedures have been performed. One-year actuarial

survival now approaches 75 to 80% after lung transplantation , which compares favorably with the sobering 18 days as witnessed for the initially reported case. Since the introduction during the

early 1980s of cyclosporine , a calcineurin inhibitor-type of immunosuppressive medication , lung and heart-lung transplantation have became clinically successful endeavors for myriad end-stage

cardiopulmonary diseases.

The physiologic responses observed posttransplant , however reflect not the attributes of the allograft lung but rather an admixture of responses as determined by the nature of each patients

native lung disease, state of conditioning , and type of transplant procedure ( e.g., single or bilateral lung , heart-lung transplant).furthermore ,potential adverse effects of

immunosuppressive drugs may affect the physiologic responses to exercise after transplantation . a thorough discussion regarding the clinical management of these complicated patients is beyond

the scope of this text ; however ,familiarity with their complex exercise physiology should aid exercise prescription and successful rehabilitation.

The type of surgical procedure is determined in light of several key factors:the native cardiopulmonary disease, recipient age,and scarcity of donor organs.in the united states ,

approximately 74.000 patients currently await solid organ transplantion , while nearly 4.000 specifically require either lung or heart –lung organ donation.therefore , single lung transplant

(SLT) procedures are frequently pursued for older recipients who suffer from either the spectrum of diseases associated with interstitial pulmonary fibrosis or emphysema.conditions associated

with significant pulmonary vascular disease (e.g., primary pulmonary hypertension , eisenmengers complex , sarcoidosis ) may be approached with either single or bilateral lung

transplantation but generally do not require an en bloc heart-lung transplant except in situations involving complex congenital heart disease. Pulmonary diseases characterized by chronic airway suppuration ( e.g., cystic fibrosis, bronchiectasis)require bilateral lung transplantation to thereby

eliminate both native lungs that pose a serious risk for posttransplant infection during immunosuppression.

The conventional surgical approach to either single or bilateral lung transplantation entails anastomosis of proximal mainstem bronchus (or bronchi,for bilateral),pulmonary artery , and reestablishing pulmonary venous effluent by means of anastomosis of a left atrial “cuff”.SLT is

accomplished via a traditional posterolateral thoracotomy incision , while an extensive transverse bilateral anterior thoracosternotomy ( clam shell incision ) is utilized for bilateral grafts. Heart-lung

transplantion involves the en bloc implantantion of bilateral lungs and heart via a median sternotomy incision. During these surgical procedures, most centers do not perform

revascularization of the bronchial arterial circulation while patients are similarly rendered “

extrinsically denervated” from autonomic influences and are devoid of normal pulmonary lymphatic drainage. The physiologic responses observed after transplant, therefore, may be

significantly affected by these fundamental physiologic differences.

Effects on the exercise response

Clinical investigations have suggested the following alterations in function that may impact the exercice response observed posttransplantation:

Bronchial hyperresponsiveness to either inhaled methacholine, hypertonic saline aerosol, or exercise has been demonstrated in a significant number of lung transplant recipients . hyperresponsiveness may relate to either extrinsic cholinergic pulmonary denervation or airway inflammation such as during allograft rejection or infection .

Abnormal mucociliary clearance may relate to a physical impediment imposed by the bronchial anastomosis. Additionally,studies have suggested bronchial mucosal abnormalities characterized by altered epithelium, decreased ciliary beat frequency , and alteration in mucous theology.

Cardiac sympathetic denervation after combined heart-lung transplantation, similar to isolated orthotopic heart transplantation ,can reduce the archieved maximum exercise heart rate, peak oxygen consumption (VO2peak), peak oxygen pulse, and lactate threshold.cardiac reinnervation later occurs in a proportion of such patients and is associated with improved chronotropic and inotropic cardiac responses and enhanced oxygen delivery to exercising skeletal muscles.

Altered pulmonary vascular permeability may occur soon after lung transplantation and relate to “ischemia reperfusion” graft injury or, later in their clinical course.during episodes of rejection and associated perivascular inflamamation . physiologic consequences of an increased pulmonary vascular permeability and interstitial edema may include a decline in spirometric indices, increased wasted ventilation, and increased ventilation –perfusion inequality and gas exchange .

Altered respiratory pattern(i.e.,disproportionate increase in tidal volume at a reduced respiratory rate).consistent with the absence of vagal –mediated inflation inhibition (hering-breuer reflex),has been detected after combined heart-lung and bilateral lung transplantation .stable heart-lung recipients with normal graft function.however.manifiest an appropriate response of ventilation to exercise or progressive hypercapnia.furthermore. pulmonary denervation does not impede the normal tachypneic response to either an increased elastic impedance or intrinsic pulmonary restriction . by contrast, the hypercapnic ventilation response may appear blunted relatively soon after lung transplantation when specifically performed for end-stage hypercapnic chronic obstructive `pulmonary disease. But

subsequently returns toward normal.further. the detection of inspiratory resistive loads appears normal after combined heart-lung transplantation .despite the absence of pulmonary afferent innervations.

Abnormal pulmonary function tests are frequently observed after both hear-lung and isolated pulmonary transplantation . heart- lung transplant recipients often have a mild restrictive ventilator defect that may relate to volumetric constraints of the recipient chest cavity and thoracic musculature. The elastic behavior or pressurevolume relationships after uncomplicated lung transplantation appear relatively normal.values for vital capacity and maximum expiratory flow rates are expectedlyless after single(approximately 60% of predicted normal value) versus bilateral or heart-lung transplantation.

Effects of exercise training

Despite attaining higher spirometric values after single or bilateral lung or combined heart-lung transplantation,cardiopulmonary exercise studies have

demonstrated the following:

Values forVO2peak (approximately 45-55% of predicted)and maximum work rate in these recipients arre reduced.

An abnormally reduced “threshold”for lactate,ventilation ,and standard bicarbonate are observed in association with reduction in maximal tolerable exercise capacity, although this cannot be ascribed to factors such as cardiac dysfunction,anemia,or limitations imposed by pulmonary vasculature or lung mechanics.

Quadriceps muscle biopsies and 31P-magnetic resonance spectroscopy after clinical lung transplantation have suggested a decrease in proportion of type I fibers and reduced skeletal muscle oxidative capacity and reduced intracellular pH. No difference has been detected in the activities of glycolytic enzymes, while transplant recipients demonstrate a higher reliance on glycolyticnon-oxidative metabolism . therefore,alteration in fiber proportion and reduced mitochondrial activity may indeed contributed to the exercise limitation witnessed after lung transplantation.

Immunosuppressant medications may potentially contribute to an alteration in exercise physiology.systemic glucocorticoids have well-described adverse effects on peripheral skeletal muscle and are commonly administered to patients suffering from a spectrum of pulmonary diseases prior to transplant.as well as in combination therapies posttransplantation.

Glucocorticoids can induce a selective atrophy of type II fibers: however,because these are the major source for lactate production in exercising skeletal muscle, one would not expect corticosteroids to cause inordinate intracellular acidosis.calcineurin inhibitor-type immunosuppressive medications (e.g.,cyclosporine or tacrolimus) have been shown to inhibit skeletal muscle mitochondrial respiration in vitro and diminish endurance exercise time in rats.the mechanism involved is not entirely clear but may relate to diminished mitochondrial calcium efflux with subsequent mitochondrial dysfunction.no impact on fiber size has yet been attributed to cyclosporine.although reduction in capillarity of limb musculature may further contribute to the reduction in aerobic capacity.

Lung and heart-lung transplantation: exercise testing

methods measures Endpoints commentsaerobiccycle(ramp protocol 10-15 watts/min; staged protocol 25 watts/3min stage)Treadmill( 1 MET/3min stage)

12 lead ECG,HR

BP

Respired gas analysis

Blood lactate

RPE,dyspnea scales

(0-10) Pulse oximetry

or arterial PO2.

serious dysrhytmias

>2mm ST segment Depression T-wve inversión

with Significant ST

change

SBP>250mmHg or DBP>115mmHg

Máximum ventilation

VO2peak

Lactate / ventiltory

Threshold

•Atrial rrhythmiascommon earlyposttransplant .

•Heart-lung transplant may be associated withcardiac denervation.

•Lung transplant may be associated with absent hering-breuer reflex.

Very reduced transitional thresholds for lactate and HCO3.

Endurance6min walk

distance Note vitals,dyspnea

Index,SaO2 at rest stops

•Useful measure in assessing pretransplant severity of illness and posttransplant progress.

Strength • Peak torque • Decreased

Isokinetic/isotonic

• Maximun number of reps

muscle mass/ force related to corticosteroids.

FlexibilitySit and stretch

•Hip,hamstring,lowerBack flexibility

• Post-thoracotomy pain may restrict flexibility.

NeuromuscularGait analysis Balance

Tremors and possible myopathy with calcineurin inhibitors.

• Decreased visual acuity due to cataracts or diabetes.

FunctionalSit to standStair climbinglifting

• Perform tests ifClinically indicated

MEDICATIONS

Many of the following medications are used for either immunosuppression or as prophylaxis to thereby prevent potential posttransplant complications:

Calcineurin-inhibitor immunosuppressive medications (e.g.,cyclosporine,tacrolimus),TOR inhibitor (e.g., rapamycin ), Antimetabolities (e.g., azathioprine, methotrexate, mycophenolate mofetil.

Loop and thiazide diuretics: may contribute to electrolyte abnormalities and muscle weakness.

Antihypertensive medications(e.g., beta blockers, ACE inhibitors,calcium-channel blockers).

Antibiotics( e.g., quinolone-type(e.g., ciprofloxacin), trimethoprim sulfamethoxazole,antiviral(e.g.,ganciclovir sodium, acyclovir).

MEDICATIONS (CONTINUED)

HMG CoA reductase inhibitor medications(e.g.,”statins”) for hyperlipidemia posttransplant: may cause muscle pain or severe muscle injury with potential kidney failure.

Calcineurin inhibitors: may cause tremor , neuropathy or myopathy, electrolyte abnormalities ( decreased magnesium and increased potassium), renal tubular metabolic acidosis,or kidney failure.

TOR inhibitors:may cause bleeding tendency (decreased patelets) and hyperlipidemia.

Beta blockers: may reduce heart rate response to exercise. Calcium-channel blockers: may cause leg swelling or hypotension. Quinoloneantibiotics:may cause tendinitis and tendon rupture . Antiviral medications: may have associated neurotoxicity. Many medications may cause anemia or leucopenia. The spectrum of adverse

medication effects may impact exercise capacity or muscle function.

The physiologic different in exercise physiology and aerobic capacity notwithstanding.one preliminary study after lung transplantation has demonstrated significant benefitsfrom formal exercise conditioning.after a six-week program whereupon training intensity ranged from 30 to 60& of maximum heart rate reserve.improvements were observed in minute ventilation,cardiac reserve, and VO2peak.congruent with these findings,recent studies of similarly immunosuppressed heart transplant recipients have also highlighted the benefits of structured exercise training.therefore to mitigate the potential adverse effects of immunosuppressive medications and the frequent preexistent state of deconditioning. Structured exercise rehabilitation program may offer significant clinical advantages.

Management and medications

Pulmonary transplantation offers a renewed sense of hope and quality of life for enumerable patients with end-stage cardiopulmonary diseases. Nevertheless,the required chronic

immunosuppressive medications represent a double-edged sword after transplant. Although decreasing the incidence of acute graft rejection.such medications may heighten the risk of

developing opportunistic infection, malignancy ,osteoporosis,hypertension,diabetes mellitus , and associated toxicity. The exercise physiologist should be cognizant of these potential complications

and maintain vigilance accordingly.notable complications for the posttransplant patient may include the following:

Acute allograft rejection and dysfunction are often heralded by increseaded subjective sensation of dyspnea, reduction in spirometric sunction, and gas exchange. Expeditious evaluation of the patient for possible transbronchoscopic biopsy and therapy is imperative.

Pneumonia,although often related to typical community-acquired viral or bacterial infections, may be attributed to opportunistic or atypical atypical pathogens caused by chronic immunosuppressive medications.routine patient vaccination with polyvalent pneumococcal and annual influenza vaccines are recommended.

Systemic hypertension is often related to adverse effects of glucocorticoids and calcineurin inhibitor-type medications.patients often will require antihypertensive medications with frequent dosage adjustments. However significant elevation in blood pressure may indicate a toxic blood level range for either cyclosporine or tacrolimus versus potential worsening renal function related to these medications.

Osteoporosis , related to both systemic glucocorticoids and calcineurin inhibitor-type immunosuppressants, poses a significant risk for vertebral and hip fracture after transplantation, newer prophylactic strategies for osteoporosis include calcium supplementation,hormonal replacement therapy,bisphosphonates,as well as exercise,strength,and balance training.

Chronic anemia is usually related to suppression of the bone marrow by immunosuppressive medications. However, various viral infections (e.g.,parvovirus B19, herpesvirus)may sometimes be responsible.severe reductions in hemoglobin concentration may affect the patients peak exercise tolerance and ventilator threshold.

Bronchiolitis obliterans syndrome(BOS)or chronic graft rejection represents the achillesheel of lung transplantation and may affect two –thirds of recipients by five years.progressive small airway fibrosis and obliteration result in an inexorable decay in lung function over time that frequently is refractory to augmented immunosuppressive therapies.recurrent respiratory tract infections and abnormalities of larger airways (i.e.,bronchiectasis ) frequently ensue.

Abnormalities of glucose tolerance and metabolism.related to immunosuppressive medications,may complicated the clinical course of these patients.excessive weight gain and potential diabetic complications may be favorably impacted by regular exercise and nutritional counseling.

Lung and heart-lung transplantation: exercise programming

Modes goals Intensity/frequency/duration

Time to goal

Aerobic Large muscle

activities (walking, cycling, swimming)

Increase VO2peak and endurance

Increase lactate and ventilatory thresholds

Decreased sensitivity to dyspnea

Develop more efficient breathing patterns

Restore ADLs

THR 60-80% of peak HR RPE 11-

13/20(comfortable pace) Monitor dyspnea 1-2 sessions /day 3-7 days/wk 20-30 min/session

(shorter intermittent exercise sessions may be necessary initially)

Emphasize duration over intensity

Variable,3-12 mo (depending on posttransplant medical/surgical complications)

Strength Free weights Isokinetic

/Isotonicmachines

Increase maximal number of reps

Increase isokinetic torque/work

Increased lean body mass

Low resistance, high reps 2-3 days/wk

Variable,3-12mo

Flexibility Stretching Tai chi

Increase ROM Daily

Neuromuscular Walking and

balance exercises

Breathing exercises

Improve gait and balance

Decrease muscle weakness and myopathy

Daily

Functional Activity-

specific exercises

Restore ADLs Return to work Improve quality of life Restore sexuality

Daily

medications Special considerations See exercise

testing table RPEand dyspnea are the preferred methods of

monitoring intensity. Many clients are unable to achieve a training HR yet demosntrate physiologic improvement.

Musculoskeletal complaints, postsurgical chest wall pain, and osteoporosis are common posttransplant complications

Myopathy involving respiratory and peripheral muscles may be related to calcineurin inhibitors and corticosteroid medications.severe muscle pain may indicate a serious complication of “statin” type lipid-lowering medications.

“bronchial hyperresponsiveness”posttransplant may

contribute to exercise-related bronchospasms and dyspnea

Clients usually respond to exercise optimally in mid to late morning, due to adverse effects(e.g.,nausea,fatigue)of morning medication schedules

Avoid extremes in ambient temperature and humidity caused by frequent use of antihypertensive and diuretic medications

Supplemental O2 may be required either early posttransplant or subsequent to graft complications

New or worsening SaO2 responses to exercise may indicate organ rejection or infection and should be communicated to the transplant team

Anxiety,depression,and/or fear are commom effects of dyspnea or medications such as corticosteroids

Bronchial anastomosis complications may significantly affect clinical outcomes after lung transplantation. Fortunately,neither dehiscence nor bronchovascular fistula complications are presebtly commom.however development of bronchial anastomotic stricture or stenosis usually caused by exuberant scar tissue formation may both impair spirometric function and the normal”mucociliary escalator”.posttransplant inflammation involving airway cartilage rings may contribute to bronchomalacia, whereupon dynamic airway collapse may limit expiratory flow rates. Potential remedies may include endobronchial laser photoresection of granulation tissue and/ or deployment of a bronchial stent to thereby maintain the bronchial lumen.furthermore, localized infections of the anastomosis(e.g.,fungal) may require therapy with systemic or inhaled aerosol antibiotics.bronchoscopic assessment is generally required to establish a definitive diagnosis and ,thus, direct the appropriate therapies.

Recommendations for exercise testing

The primary objectives for exercise testing are two-fold(1) to assess the severity of exercise impairment prior to organ transplant or determine progression of disease and

urgency for transplantation and (2)to characterized exercise limitations posttransplantation .pretransplant assessment of VO2max or 6 min walk distance

correlate with severity of illness for cystic fibrosis .for example,and the associated risk of death while awaiting transplantation.posttransplant testing may be valuable in

determining whether exercise limitation is related to graft dysfunction,occult cardiac disease , peripheral muscle weakness. Or a persistent state of deconditioning .

During either era,pre-or posttransplantation,the principal objectives for exercise testing are similar (also see the lung and heart-lung transplantation: exercise testing table on page

119):

Assess severity of disease or progression Assess maximal physical work capacity and state of aerobic fitness Observed cardiorespiratory and metabolic responses to exercise Observe oxyhemoglobin saturation during exercise Provide a basis for prescribing exercise within safe limits and Assess changes in fitness and cardiorespiratory responses to exercise that occur

with disease progression or medical /surgical interventions.

Recommendations for exercise programming

The principal goals of exercise training, both pre-and posttransplantation,are to improve aerobic fitness and alleviate the sense of dyspnea.exercise prescriptions should be tailored to the type of native kung disease, level of patient fitness , and posttransplant allograft spirometric function(see

the lung and heart-lung transplantation: exercise programming table on page 12).pretransplant patients with pulmonary arterial hypertension,for example, may be predisposed to development of right ventricular ischemia , arterial oxygen desaturation,and syncope during exertion.exercise

of moderate intensity ( 60-80% of peak heart rate) should be targeted for approximately 20 to 30 min. beta blockers received posttransplant may limit exercise heart rate response; therefore. Assessment of perceived exertion may be preferable.patients should be encouraged to adopt

healhy lifestyle modifications that incorporate aerobic activities.balanced diet, and maintenance of appropriate body weight.

Special consideration

All patients after organ transplantion and certain patients prior to transplant require chronic immunosuppression , which poses and increased risk for serious infection. Isolation of such patients from the general population in rehabilitation programs is generally not warranted.

Although one should be cognizant of the potential risks for transmission of respiratory pathogens from other clients. Maintaining cleanliness of all exercise equipment and patient avoidance of potential ill contacts during these sessions should be emphasized. Potential for impaired glucose

tolerance or systemic hypertension as an adverse effect of immunosuppressive medications should be monitored during exercise and related to the referring physician. significant

deterioration in exercise tolerance or arterial oxygen saturation from prior baseline values may represent a harbinger of allograft rejection, cytomegalovirus, or other posttransplant opportunistic

infections. such data may be of crucial importance to the organ transplant team in determining the need for expeditious clinical evaluation and bronchoscopic lung biopsy. The clinical value in

maintaining excellent lines of communication with the transplant team is of paramount importance.

LUNG TRANSPLANTATION

CASE STUDY

A 45-year old woman underwent bilateral sequential lung transplantation three years ago for interstitial pulmonary fibrosis complicated by severe secondary pulmonary hypertension with

right-sided heart failure. She initially improved quite dramatically with respect to both spirometric lung function and exercise tolerance, and went home (to Kuwait) approximately three months posttransplant on standard triple-drug immunosuppression ( i.e.,cyclosporine, mycophenolate

mofetil, and prednisone). She returned for reevaluation complaining of progressive shortness of breath and recurrent respiratory tract infections with methicillin-resistant staphylococcus aureus

and pseudomonas aeruginosa. She also complained of severe low back pain after sustaining a “slip and fall” injury.

S: “ i cant breathe again, and my back hurts”

O: middle-aged woman, on oxygen,breathless and extremely fatigable with minimal exertion

Breath sounds: bilateral basilar crackles and musical inspiratory and expiratory rhoncho

Thoracolumbar spine: midly tender to palpation,with decreased ROM for flexion and extension

Neurologic examination: normal

Pulse oximetry: 95% arterial oxygen saturation on 3l/min O2 via nasal prongs

Chest Xrays: bibasilar scarring and probable dilated and thickened larger airways or bronchiectasis

Spirometry: significant decreases in FVC and FEV; severe obstructive ventilator defect

Spine X rays: multiple compression fractures of T7,T9 and L1

Spine MRI scan: no evidence of malignancy

A:

1. BOS, or chronic graft rejection2. Recurrent respiratory tract infection caused by bronchiectasis and recent exacerbation3. Osteoporosis with multiple vertebral compression fractures4. Severe exercise intolerance

P:

1. Intravenous antibiotic treatment of current respiratory infection is needed

mode frequency duration intensity progressionaerobic 3days/wk 20-30min/session THR(110

contractions/min)RPE 12/20

Progress as tolerated over 6-wk program

Strength ( all major muscle

groups)

2days/wk 2 sets of<_ 12 reps

To fatigue Add resistance until 12 reps achieves

fatigue

Flexibility Daily 20-60s/stretch Hold below discomfort threshold

Maintain

Neuromuscular (walk drills,

breathing exercises)

Daily Individualized as needed

As tolerated Maintain

Functional ( activity-specific

exercises)

Daily Individualized as needed

As tolerated Gradual over 3-12 mo

Warm-up/ cool-down

Before and after each session

10 min RPE<10/20

2. Prescribe aerosolized antibiotic prophylaxis for chronic bronchiectasis

3. Treat osteoporosis pharmacologically

4. Additional immunosuppression to prevent further loss of lung function from chronic rejection(e.g, tacrolimus and methotrexate) is necessary

5. Prescribe outpatient pulmonary rehabilitation

Exercise program

Goals:1. Improve functional capacity to increase and maintain ADLs2. Alleviate dyspnea;improve strength and balance/coordination3. Pulse oximetry during exercise to determine supplemental oxygen requirements

Suggested readings

Brings,MS M Fournier D.J ross and M.I. lewis 1998. Cellular adaptations of skeletal muscles to cyclosporine. Journal of applied physiology 84:1967-75.

Garone S and D.J ross 1999 bronchiolitis obliterans syndrome: rewiev of our know ledge and treatment strategies.current opinion in organ transplantation 4:254-63

Grossman.R.F and J.R maurer 1990 pulmonary considerations in transplantation.clinics in chest medicine 11:2

Hokanson, J.F . J.G mercier and G.A brooks.1995 cyclosporine a decreases rat skeletal muscle mitochondrial respiration in vitro.american journal of respiratory and critical care medicine 151:1848-51

Iber.C.P simon J.B skatrud et al 1995 the breuer-hering reflex in humans: effects of pulmonary denervation and hypocapnia.american journal of respiratory and critical care medicine 152:217-24

Joint statement of the American society for transplant physicians( ASTP)/American thoracic society (ATS)/European respiratory society (ERS)/international society for heart and lung transplantation (ISHLT).1998 international guidelines for the selection of lung transplant candidates.american journal of respiratory and critical care medicine 158:339-39

Miyoshi S. E.P trulock H-J schaefers et al 1990 cardiopulmonary exercise testing after single and double lung transplantation .chest 97:1130-36

Ross D.J P.F waters. A . mohsenifar et al 1993. Hemodynamic responses to exercise after lung transplantation .chest 103:46-53

Schwaiblmair M. W von scheidt. P uberfuhr et al 1999. Functional significance of cardiac reinnervation in heart transplant recipients.journal of heart and lung transplantation 18(9):838-45

Stiebellehner L. M quittan A end et al. 1998. Aerobic endurance training program improves exercise performance in lung transplant recipients.chest 113(4):906-12.