Indicazioni e stratificazione diagnostica alla riabilitazione nel paziente post-

trapianto di cuoreDipartimento di Scienze Cardiotoraciche

Seconda Università di NapoliDipartimento di Chirurgia Cardiovascolare e Trapianti

Azienda Ospedaliera MonaldiNapoli

108

68 9

12

20

32

38

28 27

22

34

28

37

32

3639

30

5

10

15

20

25

30

35

40

'88 '90 '92 '94 '96 '98 2000 2002 2004 2006

Il Trapianto CardiacoCasistica Chirurgica 1988 - 2006

430 trapianti in 425 pazienti

Il Trapianto CardiacoCasistica Chirurgica 1988 - 2006

430 trapianti in 425 pazienti

Pz. % Primitiva 184 44 % Post-ischemica 149 35.7 % Da valvulopatia 33 7.9 % Miocarditica 32 7.6 % Congenita 4 0.96 % Restrittiva 2 0.6 % Re-tx 5 1.3 % Miscellanea 9 2.3 %

Pz. % Primitiva 184 44 % Post-ischemica 149 35.7 % Da valvulopatia 33 7.9 % Miocarditica 32 7.6 % Congenita 4 0.96 % Restrittiva 2 0.6 % Re-tx 5 1.3 % Miscellanea 9 2.3 %

Cardiopatia di base in 418 trapianti cardiaci Cardiopatia di base in 418 trapianti cardiaci

Il Trapianto CardiacoTrattamento terapeutico al momento del trapianto

Il Trapianto CardiacoTrattamento terapeutico al momento del trapianto

Pz. Mortalità osp.

Terapia orale 336 9.8 % Terapia inotropa ev 60 22.0 % Inotropi + supp. mecc. 22 31.8 %

IABP 14 IABP + RVAD 1

LVAD 7ECMO 2

Pz. Mortalità osp.

Terapia orale 336 9.8 % Terapia inotropa ev 60 22.0 % Inotropi + supp. mecc. 22 31.8 %

IABP 14 IABP + RVAD 1

LVAD 7ECMO 2

Età del riceventeEtà del ricevente

Range 5 – 68 anni

42,9%

53%

36,6%

42,9%

24,8%

40,9%

8,6%

9,4%6,1% 5,7%

12,8%16,5%

0

10

20

30

40

50

60

Primitiva Ischemica Valvolare Altro

Etiologia della cardiomiopatia

1988-1995 1996-2000 2001-2005

0

11,4 10,59,5

10,5

6,7

22,8

12,814,8

17,4

9,8

22 2221,3

29,9

0

10

20

30

40

1988-1995 1996-2000 2001-2005

Mismatch di peso Status I Diabete Pregressa CCH PVR>5 UW

Trend caratteristiche cliniche del riceventeTrend caratteristiche cliniche del ricevente

Trend età del donatoreTrend età del donatore

Uso di donatori ≥ 50 anni: -1988-1995 4/105 (3.8%) P = 0.013-1996-2000 16/149 (10.7%)-2001-2005 25/164 (15.2%)

64,7

35,3

0 0 0

62,9

30,3

3,4 3,40

55,5

36,6

5,5

1,2 1,20

10

20

30

40

50

60

70

1988-1995 1996-2000 2001-2005

Trauma cranico Emorragia cerebraleIschemia cerebrale Arma da fuocoNeoplasia cerebrale

Cause di morte del donatoreCause di morte del donatore

Sopravvivenza dopo trapianto cardiacoDecessi totali: 136 / 418 procedure (32.5%) mortalità ospedaliera inclusa

Sopravvivenza dopo trapianto cardiacoDecessi totali: 136 / 418 procedure (32.5%) mortalità ospedaliera inclusa

100,0%

87,8%82,4% 80,8%

75,9%70,0%

55,1%

46,5%

89,6%

83,0%80,0%

72,7%

58,8%

47,1%

28,9%24,0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1m 6m 1a 3a 5a 10a 15a 17a

Sopravvivenza attuariale ISHLT Survival curve 1982-2001

100,0%

87,8%82,4% 80,8%

75,9%70,0%

55,1%

46,5%

89,6%

83,0%80,0%

72,7%

58,8%

47,1%

28,9%24,0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1m 6m 1a 3a 5a 10a 15a 17a

Sopravvivenza attuariale ISHLT Survival curve 1982-2001

Sopravvivenza dopo trapianto cardiacoDecessi totali: 136 / 418 procedure (32.5%)

Sopravvivenza dopo trapianto cardiacoDecessi totali: 136 / 418 procedure (32.5%)

63,8%59,0%

75,8%

69,1%

100,0%90,8% 89,5% 88,5%

84,6% 84,6%

71,4%

64,7% 60%

83,5%

79,7% 77,4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 mese 6 mesi 1a 3a 5a

1988-1995 1996-2000 2001-2005

63,8%59,0%

75,8%

69,1%

100,0%90,8% 89,5% 88,5%

84,6% 84,6%

71,4%

64,7% 60%

83,5%

79,7% 77,4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 mese 6 mesi 1a 3a 5a

1988-1995 1996-2000 2001-2005

p = 0.001 A vs C

p = 0.042 B vs C

p = 0.001 A vs C

p = 0.042 B vs C

Classe funzionale NYHA

di 284 pazienti sopravvissuti Classe funzionale NYHA

di 284 pazienti sopravvissuti

I classe 255 II classe 19 III classe 8 IV classe 2

I classe 255 II classe 19 III classe 8 IV classe 2

ADULT HEART RECIPIENTS Functional Status of Surviving Recipients

(Follow-ups: April 1994 - June 2004)

0%

20%

40%

60%

80%

100%

1 Year (N = 15,901) 3 Years (N = 13,954) 5 Years (N = 11,872) 7 Years (N = 9,144)

No Activity Limitations Performs with Some Assistance Requires Total Assistance

ISHLT 2005J Heart Lung Transplant 2005;24: 945-982

ADULT HEART RECIPIENTSEmployment Status of Surviving Recipients

(Follow-ups: April 1994 - June 2004)

ISHLT 2005J Heart Lung Transplant 2005;24: 945-982

0%

20%

40%

60%

80%

100%

1 Year (N = 14,888) 3 Year (N = 12,842) 5 Year (N = 10,848) 7 Year (N = 8,371)

Retired

Not Working

Working Part Time

Working Full Time

Exercise intolerance in heart transplant

• I pazienti trapiantati che non effettuano un ciclo di riabilitazione cardiorespiratoria presentano una VO2 max ridotta rispetto ai controlli di pari età.

Causes of Exercise Intolerance in Heart Transplant Patients

Altered Anatomy and Physiology

Functional denervation Chronotropic incompetence

Decreased chronotropic reserve Slower kinetics of the chronotropic response

Heart rate increased at rest Heart rate decreased at peak exercise

Abnormal circulatory response to exercise Lowered cardiac output

Diastolic dysfunction

Effects of Previous Cardiac IllnessDeconditioning

Diminished pulmonary diffusion Skeletal muscle metabolism

Skeletal muscle strength Peripheral circulation

Effects of Immunosuppressive AgentsCyclosporine induced diastolic dysfunction

Osteopenia Osteoporosis

Myopathy Infections

Attivazione adreno-midollare e ANP

VO2 max

Efficacia sull’incremento della VO2 max

Efficacia sull’incremento della VO2 max

Efficacia sull’incremento della VO2 max

POST-HEART TRANSPLANT MORBIDITY FOR ADULTS Cumulative Prevalence in Survivors within 1 Year Post-Transplant (Follow-ups: April 1994 - June 2003)

Outcome Within 1

Year Total number with known response

Hypertension 73.2% (N = 15,305)

Renal Dysfunction 26.2% (N = 15,249) Abnormal Creatinine < 2.5 mg/dl 16.2% Creatinine > 2.5 mg/dl 8.6% Chronic Dialysis 1.3% Renal Transplant 0.2%

Hyperlipidemia 52.0% (N = 16,178)

Diabetes 25.0% (N = 15,300)

CAV 7.9% (N = 13,812)

POST-HEART TRANSPLANT MORBIDITY FOR ADULTS Cumulative Prevalence in Survivors within 5 Years Post-Transplant (Follow-ups: April 1994 - June 2003)

Outcome Within 5

Years Total number with known response

Hypertension 94.2% (N = 5,172)

Renal Dysfunction 31.8% (N = 5,571)

Abnormal Creatinine < 2.5 mg/dl 19.6% Creatinine > 2.5 mg/dl 9.4% Chronic Dialysis 2.4% Renal Transplant 0.4%

Hyperlipidemia 84.0% (N = 5,753)

Diabetes 32.8% (N = 5,128)

CAV 32.9% (N = 3,644)

POST-HEART TRANSPLANT MORBIDITY FOR ADULTS Cumulative Prevalence in Survivors within 7 Years Post-Transplant (Follow-ups: April 1994 - June 2003)

Outcome Within 7

Years Total number with known response

Hypertension 97.0% (N = 2,366)

Renal Dysfunction 35.5% (N = 2,657)

Abnormal Creatinine < 2.5 mg/dl 20.2% Creatinine > 2.5 mg/dl 10.4% Chronic Dialysis 4.0% Renal Transplant 0.9%

Hyperlipidemia 89.1% (N = 2,701)

Diabetes 35.0% (N = 2,362)

CAV 43.0% (N = 1,510)

Variabile 1 anno 5 anni

Ipertensione 36.8% (92/250) 57.6% (136/236)

Iperlipidemia 54.4% (136/250) 62.5% (148/236)

Diabete 19.6% (49/250) 26.7% (63/236)

100,00%

94,80% 94,80%93,20% 93,20%

96,30%

92,10%

87,00%

80,0%

93,20%

92,10%

70%

80%

90%

100%

0

1a

2a

3a

4a

5a

Creatinina < 1,5 Creatinina > 1,5

100,00%

94,80% 94,80%93,20% 93,20%

96,30%

92,10%

87,00%

80,0%

93,20%

92,10%

70%

80%

90%

100%

0

1a

2a

3a

4a

5a

Creatinina < 1,5 Creatinina > 1,5

Incidenza cumulativa di complicanze post-trapiantoIncidenza cumulativa di complicanze post-trapianto

p = 0.11

Clearance

4,03,02,01,00,0

Pre-op. Cr-ClF

requ

ence

80

60

40

20

0

Dev. Stand = ,79

Media = ,9

N = 160,00

Clearance

4,03,02,01,00,0

6 months Cr-ClF

requ

ence

80

60

40

20

0

Dev. Stand = ,78

Media = 1,0

N = 150,00

Clearance

4,03,02,01,00,0

1 Year Cr-ClF

requ

ence

70

60

50

40

30

20

10

0

Dev. Stand = ,79

Media = 1,3

N = 132,00

Clearance

4,03,02,01,00,0

3 Years Cr-Cl

Fre

quen

ce40

30

20

10

0

Dev. Stand = ,80

Media = 1,4

N = 88,00

Clearance

4,03,02,01,00,0

5 Years Cr-Cl

Fre

quen

ce

30

20

10

0

Dev. Stand = ,86

Media = 1,5

N = 55,00

Hyperlipidemia. 1. An elevation in blood lipids is documented in almost 50% of cardiac

recipients by 5 years posttransplantation.

2. Both steroids and CsA are thought to contribute to this problem.

3. Hyperlipidemia is also associated with posttransplant obesity.[38] During the first months posttransplantation, patients gain weight rapidly. Along with the gain in body weight, both serum cholesterol and triglycerides rise.

4. Management of hyperlipidemia begins with attention to diet and exercise. Lipid-lowering agents, especially the HMG-CoA inhibitors or "statins," are used routinely. It is reported that recipients started on these drugs within the first 6 weeks posttransplantation have a lower incidence of CAD, fewer serious acute rejection episodes, and improved survival.

Osteoporosis.1. Osteoporosis is a common problem, with the incidence of fractures

reported to be 35% within the first year after heart transplantation. Immunosuppressive drug therapy contributes to osteoporosis. Corticosteroids are the most problematic, as they reduce calcium absorption, increase excretion, and interfere with skeletal growth factors. CsA and TAC further inhibit calcineurin phosphate, amplifying the problem.

2. Periodic bone mineral density evaluations are recommended along with assessment of estrogen and testosterone levels. Prevention begins with administration of calcium, vitamin D, and sex hormone replacementTreatment with bisphosphonates and calcitonin may be added. An endocrinology consultation may benefit patients at risk and prevent the devastating effects of pathologic fractures.

3. The pain and physical disability that result from osteoporosis have a negative impact on quality of life posttransplantation.

Effect of training on Osteoporosis

Effect of training on obesity

RecommendationsSuggested Safety Precautions for Heart Transplant RehabilitationAllow 6 to 8 weeks for healing of the sternum and taper of steroids. Discontinue resistance training during acute episodes of rejection.

Utilize “perceived exertion” to adjust exercise intensity. Utilize conservative initial resistances to avoid compression

fractures. Ensure adequate systemic blood pressure (transient hypotension is

common). Alternate upper body exercise with lower body exercises

Symptomatic patients should walk for 2 minutes between exercise or perform standing calf raises

Include a cool-down walk at the end of each exercise session

70,1% 68,5%

73,7% 73,7%

100,0% 98,0%91,5% 90,7% 89,7% 89,7%

71,4%

64,7% 60%

83,5%

79,7%77,4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 mese 6 mesi 1a 3a 5a

1988-1995 1996-2000 2001-2005

70,1% 68,5%

73,7% 73,7%

100,0% 98,0%91,5% 90,7% 89,7% 89,7%

71,4%

64,7% 60%

83,5%

79,7%77,4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 mese 6 mesi 1a 3a 5a

1988-1995 1996-2000 2001-2005

Libertà attuariale da rigetto acuto (>1B)Libertà attuariale da rigetto acuto (>1B)

p = 0.001 C vs A & Bp = 0.001 C vs A & B

Protocollo di immunosoppressione 1Gennaio 1988 - Dicembre2000

Protocollo di immunosoppressione 1Gennaio 1988 - Dicembre2000

• Induzione: Thymoglobuline 2.5mg/Kg/24h per 5 giorni ATG 2.5mg/Kg/24h per 7 giorni

- sospensione in caso di : anafilassi/ leucopenia (<2000/µl)/ trombocitopenia (<50000/µl)

• Metilprednisolone 500 mg e.v. in S.O. → 125 mg/12h per 2 gg

• Prednisone: 1 mg/kg os → décalage → 0.1 mg/kg/24h (12°mese)

• Azatioprina: 2 mg/kg/24h → WBC 4000–6000/µl• Ciclosporina:

- 3 mg/kg/24h (dopo stabilizzazione emodinamica e con funzione renale soddisfacente)

- ciclosporinemia 300 ng/dl 1° anno- ciclosporinemia 150-200 ng/dl dopo 1° anno

• Induzione: Thymoglobuline 2.5mg/Kg/24h per 5 giorni ATG 2.5mg/Kg/24h per 7 giorni

- sospensione in caso di : anafilassi/ leucopenia (<2000/µl)/ trombocitopenia (<50000/µl)

• Metilprednisolone 500 mg e.v. in S.O. → 125 mg/12h per 2 gg

• Prednisone: 1 mg/kg os → décalage → 0.1 mg/kg/24h (12°mese)

• Azatioprina: 2 mg/kg/24h → WBC 4000–6000/µl• Ciclosporina:

- 3 mg/kg/24h (dopo stabilizzazione emodinamica e con funzione renale soddisfacente)

- ciclosporinemia 300 ng/dl 1° anno- ciclosporinemia 150-200 ng/dl dopo 1° anno

De Santo LS et al. Transpl Proc 2005, in press

Protocollo di immunosoppressione 2

da Gennaio 2001

Protocollo di immunosoppressione 2

da Gennaio 2001 • Induzione Thymoglobuline 1.5mg/Kg/24h per 5 giorni- sospensione in caso di : anafilassi/ leucopenia

(<2000/µl)/ trombocitopenia (<50000/µl)• Metilprednisolone 500 mg e.v. in S.O. → 125 mg/12h per 2 gg• Prednisone: 1 mg/kg os → décalage → 0.1 mg/kg/24h

(12°mese)• Mycophenolate mofetil: 1500mg x 2/24h• Ciclosporina:

- 3 mg/kg/24h (dopo stabilizzazione emodinamica e con funzione renale soddisfacente)

- ciclosporinemia 300 ng/dl 1° anno- ciclosporinemia 150-200 ng/dl dopo 1° anno

• Induzione Thymoglobuline 1.5mg/Kg/24h per 5 giorni- sospensione in caso di : anafilassi/ leucopenia

(<2000/µl)/ trombocitopenia (<50000/µl)• Metilprednisolone 500 mg e.v. in S.O. → 125 mg/12h per 2 gg• Prednisone: 1 mg/kg os → décalage → 0.1 mg/kg/24h

(12°mese)• Mycophenolate mofetil: 1500mg x 2/24h• Ciclosporina:

- 3 mg/kg/24h (dopo stabilizzazione emodinamica e con funzione renale soddisfacente)

- ciclosporinemia 300 ng/dl 1° anno- ciclosporinemia 150-200 ng/dl dopo 1° anno

De Santo LS et al. Transpl Proc 2005, in press

Protocollo di immunosoppressione 3

dal Maggio 2005

Protocollo di immunosoppressione 3

dal Maggio 2005 • Induzione ATG 1.5mg/Kg/24h per 5 giorni- sospensione in caso di : anafilassi/ leucopenia

(<2000/µl)/ trombocitopenia (<50000/µl)• Metilprednisolone 500 mg e.v. in S.O. → 125 mg/12h per 2

gg• Prednisone: 1 mg/kg os → décalage → 0.1 mg/kg/24h

(6°mese)• Everolimus: 1,5 mg/die• Ciclosporina:

- 3 mg/kg/24h (dopo stabilizzazione emodinamica e con funzione renale soddisfacente)

- ciclosporinemia 300 ng/dl 1° anno- ciclosporinemia 150-200 ng/dl dopo 1° anno

• Induzione ATG 1.5mg/Kg/24h per 5 giorni- sospensione in caso di : anafilassi/ leucopenia

(<2000/µl)/ trombocitopenia (<50000/µl)• Metilprednisolone 500 mg e.v. in S.O. → 125 mg/12h per 2

gg• Prednisone: 1 mg/kg os → décalage → 0.1 mg/kg/24h

(6°mese)• Everolimus: 1,5 mg/die• Ciclosporina:

- 3 mg/kg/24h (dopo stabilizzazione emodinamica e con funzione renale soddisfacente)

- ciclosporinemia 300 ng/dl 1° anno- ciclosporinemia 150-200 ng/dl dopo 1° anno

POST-HEART TRANSPLANTATION REHABILITATION AND PHYSICAL CONDITIONING HANDBOOK

Class I – Conditions in which there are evidences and/or agreement that some procedure is effective or useful:

1) early physical rehabilitation;2) aerobic physical activity;

3) resistance-exercise physical activity;4) supervised physical activity program;

5) exercise test, preferably cardiopulmonary exercise test.

Class II – Condition in which there are conflicting evidences and/or divergence of opinion with regard to the usefulness and effectiveness of

some procedure or treatment: a) Evidence or opinion that favors the utilization of the treatment:

1) non-supervised physical activity program;2) physical activity in heated swimming pool;

3) recreative activities. b) Evidence of less established opinion:

1) participation in competitive games without supervision;2) high-intensity sporadic physical activity.

Class III – Condition in which there are evidences and/or agreement that the procedure/treatment is not useful and in some

cases, it may even be harmful: 1) hemodynamic instability;

2) light or severe rejection episodes;3) infection process;

4) clinical, orthopedic or neurological limitation that disables physical activity.

Program Format Phase I Cardiac Rehabilitation

Phase I of Cardiac Rehabilitation begins during hospitalization. A cardiac nurse visits each patient to provide education and nutrition

counseling in preparation for discharge. Patients may also receive physical therapy during the hospital stay.

Phase II Cardiac Rehabilitation

Phase II is a 4 to 12 week exercise program, with three sessions per week.

Exercise sessions include several components: warm up walking or biking; aerobic exercise on treadmills, exercise bikes, stair-steps, and rowing machines to help the heart use oxygen more efficiently and

improve blood flow; resistance training to increase strength and stamina; and cool down stretching for flexibility. Small group sessions

provide heart monitoring during exercise, individualized care, and frequent blood pressure checks by the Cardiac Rehabilitation Staff.

Phase III Cardiac RehabilitationPhase III is designed to maintain cardiovascular fitness through

prescribed exercise. Candidates or Phase III include individuals who have a prior history of heart disease, those who are at high risk of

developing heart disease, and graduates of Phase II Cardiac Rehabilitation.

Efficacia sulla vasculopatia del graft?

Profilo lipidico

Ipertensione arteriosa

Aumento ponderale

ConclusioniConclusioni

♦ Il trapianto ortotopico di cuore è allo stato attuale l’unica terapia valida dello scompenso terminale in grado di restituire una buona qualità di vita al 70% dei pazienti per cinque anni, al 55% per 10 anni ed al 46,5% per 17 anni.

♦ La prevenzione e la cura del rigetto acuto hanno raggiunto soddisfacenti livelli di efficacia. Lo stesso puo’ dirsi per le complicanze infettive ivi comprese quelle virali.

♦ Il miglioramento del trattamento delle comorbidità raggiunto mediante l’inserimento di un medico internista nella gestione del programma trapianti ha offerto un miglioramento della qualità di vità del paziente trapiantato.

ConclusioniConclusioni

♦Tutti i pazienti sottoposti a trapianto di cuore necessiterebbero di una valutazione delle indicazioni ad un ciclo di riabilitazione prima della dimissione ospedaliera.